@article {pmid41922603,
year = {2026},
author = {Meng, Q and Liu, J and Gao, Y and Liu, A and Liu, Y and Xia, Y and Xie, Z and He, S and Chen, L and Sulaman, U and Liu, M and Tang, C and Wang, M and Li, H and Zhang, R and Yang, Y and Li, J and Cheng, Z},
title = {Downregulation of NOX2 Expression Alleviates Severe Acute Pancreatitis by Restoring Autophagy and Inhibiting mtDNA-mediated Activation of the cGAS-STING Signalling Pathway.},
journal = {Inflammation},
volume = {49},
number = {1},
pages = {},
pmid = {41922603},
issn = {1573-2576},
abstract = {UNLABELLED: Severe acute pancreatitis (SAP) is characterized by intense inflammation and pancreatic tissue injury. However, the specific mechanism underlying the progression of the disease remains unclear. Here, the role of the cGAS-STING pathway in driving SAP was investigated in both in vivo and in vitro models. Robust activation of the cGAS-STING pathway in SAP was observed, as evidenced by increased expression of pathway markers and inflammatory cytokines. We reported that the excessive production of reactive oxygen species (ROS) exacerbates mitochondrial stress. Mitochondrial stress in acinar cells led to decreased mitochondrial membrane potential and increased mitochondrial morphological changes, thus resulting in the cytosolic leakage of mitochondrial DNA (mtDNA). Moreover, after mtDNA was released, the cGAS-STING pathway was activated. However, inhibition of ROS with N-acetylcysteine (NAC) attenuated mtDNA leakage, reduced inflammatory responses, and increased cell viability. Moreover, the restoration of autophagic flux with rapamycin alleviated mitochondrial stress, reduced mtDNA leakage, and protected against pancreatic injury. These findings demonstrated that NOX2-derived ROS exacerbated mitochondrial stress and inflammation in SAP. Collectively, by reducing NOX2-derived excessive ROS levels, autophagy is restored, and cGAS-STING activation driven by mtDNA leakage is alleviated, which correspondingly restrains the progression of SAP. Therefore, NOX2 may become a potential therapeutic target for treating SAP.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10753-026-02504-8.},
}
@article {pmid42136265,
year = {2026},
author = {Alborghetti, M and Caridi, M and Mascio, G and Bruno, V and Battaglia, G},
title = {N-acetylcysteine, Acetyl-L-carnitine, and Citicoline: A Potential Synergism in Neurological and Psychiatric Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X403105251105014447},
pmid = {42136265},
issn = {1875-6190},
abstract = {The cellular oxidative balance is finely regulated by glutathione (GSH) levels and its reduced form. N-acetylcysteine (NAC) is an antioxidant agent that reduces disulphide bonds, scavenges reactive oxygen species (ROS), and serves as a precursor for GSH biosynthesis. Moreover, NAC can modulate glutamatergic transmission in the central nervous system (CNS), stimulating the system xc- activity and thus enhancing the endogenous activation of metabotropic glutamate receptors type 2 and 3 presinaptically, which restrains the excessive release of glutamate. Acetyl-Lcarnitine (ALC) is an acetylated form of L-carnitine and plays a key role in cellular energy metabolism. NAC and ALC show great neuroprotective potential, owing to their ability to counteract oxidative stress, modulate the glutamatergic system and neurotransmission, and maintain mitochondrial bioenergy and membrane integrity, acting synergistically. Several preclinical and clinical studies suggest that NAC and ALC may have effects in different psychiatric and neurological disorders, including mood disorders, schizophrenia, substance use disorder, chronic pain, and neurodegenerative diseases. The combination of the two products together with citicoline could also be beneficial when cognitive fatigue or cognitive impairment are clinical manifestations. These agents act on complementary pathways-redox regulation, mitochondrial support, and membrane integrity-potentially enhancing each other's neuroprotective effects. The purpose of this review is to explore the fields (psychiatric, neurological, and also rheumatological), in which the combination of these compounds may benefit patient management, starting with preclinical evidence and focusing on clinical trials conducted over the years.},
}
@article {pmid42140447,
year = {2026},
author = {Cheng, X and Wu, H and Zhuang, X and Yang, B and Ding, M and Gao, H and Li, S and Li, Q and Wang, X},
title = {Unraveling the pyroptosis pathway: Key insights into methotrexate-induced liver injury.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118065},
doi = {10.1016/j.bcp.2026.118065},
pmid = {42140447},
issn = {1873-2968},
abstract = {Methotrexate (MTX)-induced liver injury (MTX-ILI) involves complex mechanisms that remain incompletely understood. This study investigated the role of NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in MTX-ILI and explored the regulatory involvement of reactive oxygen species (ROS) and mitochondrial permeability transition pore (mPTP) opening. Wistar rats administered MTX and L02 cells exposed to MTX exhibited significant hepatocellular injury and pyroptotic features, as evidenced by elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and Caspase-1 activities; increased interleukin-1β (IL-1β) and interleukin-18 (IL-18) levels; and upregulation of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), gasdermin D (GSDMD), and its N-terminal fragment (GSDMD-N). These effects were attenuated by the NLRP3 inhibitor MCC950. In vitro, scavenging ROS with N-acetylcysteine (NAC) and inhibiting mPTP opening with ciclosporin A (CsA) markedly suppressed pyroptosis by alleviating mitochondrial dysfunction, reducing ROS accumulation, restoring mitochondrial membrane potential, and preserving mitochondrial ultrastructure. Label-free quantitative proteomics and protein-protein interaction analysis identified KNG1 and PARP12 as key proteins associated with ROS/mPTP-mediated pyroptosis, which were validated by Western blotting. Furthermore, Connectivity Map analysis predicted four potential therapeutic agents, including RS-127445, SB-218795, proadifen, and balicatib. Collectively, these findings demonstrate that MTX induces NLRP3-dependent pyroptosis through ROS accumulation and sustained mPTP opening.},
}
@article {pmid42132226,
year = {2026},
author = {Chen, X and Liu, S and Jiang, M and Wei, M and Xu, S and Lin, JY and Huang, ZB and Xie, P and Cao, J and Yang, H and Bai, Y and Lu, G and Cui, M},
title = {PRKN-IMMT/MIC60 axis promotes myocardial ischemia-reperfusion injury via lysosomal degradation of GPX4.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2674713},
pmid = {42132226},
issn = {1554-8635},
abstract = {Mitochondrial damage is a pivotal driver of myocardial ischemia-reperfusion (MIR) injury. While PRKN (parkin RBR E3 ubiquitin protein ligase), a key E3 ubiquitin ligase in the PINK1 (PTEN induced kinase 1)-PRKN mitophagy pathway, has been extensively studied, its role and mechanisms in acute MIR injury remain incompletely understood. Here, we demonstrated that PRKN exacerbates MIR injury by promoting cardiomyocyte ferroptosis under hypoxia-reoxygenation (H/R) conditions. Mechanistically, PRKN interacts with and mediates the ubiquitination and proteasomal degradation of IMMT/MIC60 (inner membrane mitochondrial protein), a core mitochondrial inner membrane protein essential for cristae architecture and mitochondrial integrity. This disruption of IMMT facilitates lysosomal degradation of GPX4 (glutathione peroxidase 4), a major ferroptosis suppressor, thereby triggering ferroptosis. Consistent with these findings, cardiac-specific immt knockout mice displayed increased susceptibility to MIR injury in vivo. Our findings establish PRKN-driven IMMT degradation as a key pathological mechanism in MIR injury and identify the PRKN-IMMT axis as a potential therapeutic target for cardioprotection. Abbreviations: ATG5, autophagy related 5; ATP, adenosine triphosphate; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CHX, cycloheximide; cKO, cardiomyocyte-specific knockout; CQ, chloroquine; CRISPR, clustered regularly interspaced short palindromic repeats; EF, ejection fraction; Fer-1, ferrostatin-1; FS, fractional shortening; GO, Gene Ontology; GPX4, glutathione peroxidase 4; GST, glutathione S-transferase; gRNA, guide RNA; hiPSC-CMs, human induced pluripotent stem cell-derived cardiomyocytes; H/R, hypoxia-reoxygenation; IF, immunofluorescence; IHC, immunohistochemistry; IMMT/MIC60, inner membrane mitochondrial protein; IP, immunoprecipitation; LoxP, locus of X-overP1; KO, knockout; KR, lysine residues mutated to arginine; MDA, malondialdehyde; MFN2, mitofusin 2; MIR, myocardial ischemia reperfusion; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mtROS, mitochondrial reactive oxygen species; NAC, N-acetylcysteine; OMM, outer mitochondrial membrane; PRKN, parkin RBR E3 ubiquitin protein ligase; RAB7, RAB7, member RAS oncogene family; RNA-seq, RNA sequencing; UB, ubiquitin; WB, western blot; WT, wild-type.},
}
@article {pmid42134671,
year = {2026},
author = {Yu, T and Su, Y and Zou, P and Jian, Y and Wang, Y},
title = {The CRIP1/NFATC2/SREBF1 axis drives melanoma progression by promoting reactive oxygen species-mediated endoplasmic reticulum stress activation.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118055},
doi = {10.1016/j.bcp.2026.118055},
pmid = {42134671},
issn = {1873-2968},
abstract = {Malignant melanoma remains a formidable clinical challenge due to its propensity for metastasis and therapeutic resistance. Identifying molecular targets that regulate malignant melanoma progression is critical for developing effective therapies. In this study, we investigated the role of cysteine-rich intestinal protein 1 (CRIP1), a novel oncogene, in melanoma progression. CRIP1 expression was analyzed using public datasets, and functional roles of CRIP1 in proliferation, colony formation, migration, and invasion were assessed via overexpression cell models. Mechanistic insights were gained through RNA sequencing, bioinformatics, 4-phenylbutyric acid (4-PBA) or N-acetylcysteine (NAC) treatment, Western blot, dual-luciferase reporter, and chromatin immunoprecipitation (ChIP). Xenograft models were used to confirm in vivo effects. CRIP1 was significantly upregulated in melanoma tissues, particularly in metastases, and correlated with an endoplasmic reticulum (ER) stress gene signature. CRIP1 overexpression promoted malignant phenotypes in vitro and tumor growth in vivo, which was dependent on the activation of ER stress. Integrative analysis identified SREBF1 (Sterol Regulatory Element Binding Transcription Factor 1) as a downstream target. CRIP1 increased intracellular ROS levels by promoting SREBF1 expression, thereby activating ER stress and promoting malignant phenotypes in melanoma cells. Mechanistically, CRIP1 promoted NFATC2 (nuclear factor of activated T cells 2) binding to the SREBF1 promoter to drive transcription of SREBF1. These findings indicate that CRIP1 serves as a critical driver of melanoma progression through ER stress activation and identify a novel CRIP1/NFATC2/SREBF1 axis, providing insights into the role of CRIP1 in melanoma biology and presenting new potential therapeutic targets for this aggressive malignancy.},
}
@article {pmid42122086,
year = {2026},
author = {Pudineh Moarref, M and Black, W and Chen, Y},
title = {Performance of New Roche Cobas Pulse Glucose Meter Against Potential Interfering Substances and Hematocrit Variations.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/diagnostics16091383},
pmid = {42122086},
issn = {2075-4418},
abstract = {Background: Point-of-care (POC) glucometers are essential for rapid blood glucose monitoring but are subject to interference and hematocrit variations. This study evaluated the analytical performance of the new Cobas Pulse glucometer against the Accu-Chek Inform II meter in the presence of N-acetylcysteine (NAC, 0.32-2.5 mmol/L), ascorbic acid (0.28-2.84 mmol/L), D-galactose (5.5-27 mmol/L), hemolysis (0.5-5 g/L hemoglobin), icterus (200-1600 μmol/L bilirubin), lipemia (2.5-15 g/L Intralipid), and hematocrit variations (20-60%). Methods: Interference testing followed CLSI EP07 guidelines using three whole blood pools with low (2.0-2.7 mmol/L), medium (4.5-7.4 mmol/L), and high (16.3-23 mmol/L) glucose levels. Interferents were spiked into these whole blood pools. Duplicate glucose levels were measured by 2 Pulse meters and 2 Inform II meters. The results were then assessed using the international standards, e.g., ISO 15197:2017 criteria (±15% or ±0.83 mmol/L). Results: Accu-Chek Inform II showed severe positive interference from galactose (up to 446.3%, p < 0.001), ascorbic acid (up to 98.8%, p = 0.002), and NAC (up to 61.4%, p = 0.001), exceeding ISO limits. Cobas Pulse demonstrated minimal interference (maximum biases: -3.7% for galactose, -4.4% for ascorbic acid, 7.7% for NAC, all p > 0.05). Both meters showed similar hematocrit-dependent bias (positive at 20-30%, negative at 50-60%) and acceptable performance for hemolysis, icterus (≤800 μmol/L), and lipemia. Conclusions: Compared to the Accu-Chek Inform II, the Cobas Pulse demonstrated greater resilience to interferences. Cobas Pulse meets strict accuracy standards (±10% for hospital use) with low interference, which makes it suitable for care of critically ill patients. The Cobas Pulse is more dependable for POCT across various clinical situations, supporting its role in critical care.},
}
@article {pmid42123707,
year = {2026},
author = {Coelho, JA and Gomes, KS and Cerchiaro, G},
title = {Differential Antioxidant Capacities of Human Endometriotic and Endometrial Cell Models Under H2O2 Exposure.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27094131},
pmid = {42123707},
issn = {1422-0067},
support = {2024119438//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; },
mesh = {Humans ; Female ; *Hydrogen Peroxide/pharmacology ; *Antioxidants/pharmacology/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; *Endometriosis/metabolism/pathology ; Glutathione/metabolism ; *Endometrium/metabolism/drug effects/cytology/pathology ; Acetylcysteine/pharmacology ; Cell Survival/drug effects ; Lipid Peroxidation/drug effects ; DNA Damage/drug effects ; Oxidation-Reduction/drug effects ; Cell Line ; Protein Carbonylation/drug effects ; },
abstract = {Endometriosis is associated with oxidative stress and debilitating symptoms, yet its pathophysiology remains incompletely understood, and current treatments are still limited. In this study, oxidative stress responses were compared in 2D and 3D cultures of 12Z and Ishikawa cells using hydrogen peroxide (H2O2) as a pro-oxidant and N-acetylcysteine (NAC) as an antioxidant. We evaluated H2O2 sensitivity, Reactive Oxygen Species (ROS) production, glutathione redox homeostasis, and biomolecular damage. The results showed that 12Z cells display greater vulnerability to oxidative stress than Ishikawa cells, with higher basal ROS levels (p < 0.01) and increased sensitivity to H2O2. In 3D culture, 12Z cells exhibited a 72% depletion of total glutathione under oxidative stress, a response not observed in 2D cultures, which instead showed a compensatory pattern. This vulnerability was further supported by increased lipid peroxidation and protein carbonylation. Although NAC restored cell viability and protected lipids and proteins, it did not prevent DNA damage. Together, these findings demonstrate marked differences in antioxidant responses between the two cell models and reinforce the value of 3D systems for investigating oxidative stress-related mechanisms. These results provide mechanistic insights relevant to endometriosis-associated redox imbalance and support further investigation of glutathione dysregulation and ROS-mediated damage in disease-related contexts.},
}
@article {pmid42124519,
year = {2026},
author = {Cheng, X and Li, Q and Zu, H and Liu, S and Li, J and Wen, Y and Yang, C and Sun, S and Lu, H and Zhang, Y and Zhao, Y and Shi, G and Qin, M and Lu, X},
title = {N-Acetylcysteine-Mediated Surface Remodeling of Inhaled mRNA Lipid Nanoparticles Enables Coordinated Mucosal and Systemic Antitumor Immunity.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e73362},
doi = {10.1002/adma.73362},
pmid = {42124519},
issn = {1521-4095},
support = {2024YFA1212200//National Key Research and Development Program of China/ ; XDB0960100//Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 22175188//National Natural Science Foundation of China/ ; NSFC52473137//National Natural Science Foundation of China/ ; 027GJHZ2023179GC//International Partnership Program of the Chinese Academy of Sciences/ ; },
abstract = {Inhaled messenger RNA (mRNA) delivery is constrained by aerosolization-induced stress and airway barriers that limit post-deposition transport and immune activation. Here, we report an N-acetylcysteine (NAC)-enabled strategy that dynamically remodels inhaled mRNA lipid nanoparticles (LNP) after airway deposition. The LNPs are stabilized through electrostatic repulsions during nebulization by a negatively charged, disulfide-linked peptide-lipid conjugate on the LNP surface. Following deposition, NAC mediates thiol-disulfide exchange to cleave the peptide-lipid linkage, removing the anionic peptide and restoring cellular uptake while preserving aerosol stability. Concurrently, NAC reduces mucus density as a mucolytic, enhancing LNP penetration and trans-epithelial transport. As a result, inhaled mRNA-LNP yields robust pulmonary mRNA expression and enables mRNA expression in extrapulmonary tissues. Immunologically, inhaled mRNA-LNPs elicit strong mucosal immune responses, while NAC-enabled delivery additionally activates systemic immune activation. In mouse tumor models, this strategy achieves complete eradication of distant tumors and confers durable protection against tumor rechallenge. These findings highlight the potential of dynamic nanoparticle surface remodeling to overcome barriers in inhaled mRNA delivery.},
}
@article {pmid42126744,
year = {2026},
author = {Peng, J and Wang, J and Feng, H and Zhou, B and Zhou, H and Li, F},
title = {KLF9 Aggravates Doxorubicin-Induced Cardiotoxicity by Regulating the ROS/p53 Signalling Pathway.},
journal = {Cardiovascular toxicology},
volume = {26},
number = {5},
pages = {},
pmid = {42126744},
issn = {1559-0259},
support = {KC21067//Xuzhou Municipal Science and Technology Bureau/ ; },
mesh = {Animals ; Signal Transduction ; *Kruppel-Like Transcription Factors/genetics/metabolism ; Cardiotoxicity ; *Doxorubicin ; Mice, Inbred C57BL ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Myocytes, Cardiac/pathology/metabolism/drug effects ; Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Cell Line ; Male ; Rats ; *Heart Diseases/metabolism/chemically induced/pathology/genetics/physiopathology/prevention &amp; control ; Ventricular Function, Left/drug effects ; Mice ; Antibiotics, Antineoplastic ; Oxidative Stress ; },
abstract = {Doxorubicin (DOX) is a cytotoxic chemotherapeutic drug, the clinical value of which is limited by its cardiotoxicity. Krüppel-like factor 9 (KLF9) is known to modulate cell proliferation, differentiation, and apoptosis and plays critical roles in cardiovascular diseases. Here, we aimed to explore the potential effect of KLF9 on DOX-induced cardiotoxicity. C57BL/6J mice with cardiac-specific overexpression or silencing of KLF9 received single intraperitoneal injections of DOX to establish a DOX-induced cardiotoxicity model. The cardiac function of the mice was monitored by echocardiography, cardiac morphology was evaluated by histopathological staining, biomarkers of myocardial injury were detected using ELISA, and TUNEL staining and Western blotting were performed to evaluate apoptosis. In addition, H9c2 cells were used to validate the function of KLF9 in vitro. To test the involvement of thioredoxin reductase 2 (Txnrd2), ROS and p53 in the observed effects, siRNAs directed against p53 and Txnrd2 and the ROS inhibitor N-acetyl cysteine (NAC) were used. KLF9 expression was upregulated in the hearts of DOX-treated mice and H9c2 cells. Cardiac-specific KLF9 overexpression exacerbated, while cardiac-specific KLF9 silencing alleviated, DOX-induced apoptosis, acute myocardial injury and dysfunction. Mechanistically, KLF9 deficiency resulted in upregulation of Txnrd2 expression and subsequent suppression of apoptosis through modulation by ROS/p53 signalling. KLF9 exerts a pro-apoptotic effect on DOX-induced cardiotoxicity by inhibiting Txnrd2 and regulating the ROS/p53 signalling pathway. KLF9 deficiency may be a promising target for mitigating DOX-induced cardiotoxicity.},
}
@article {pmid42115982,
year = {2026},
author = {Ahmed, MAE and Amin, M and Abdalla, YE and Abdelghani, A and Eid, N and Samy, A and Kassar, O and Alsaadany, KR and Mansour, MEM},
title = {N-acetylcysteine for patients with alcohol use disorder, post-traumatic stress disorder, and their co-occurrence: a systematic review of placebo-controlled randomized trials.},
journal = {BMC psychiatry},
volume = {26},
number = {1},
pages = {},
pmid = {42115982},
issn = {1471-244X},
mesh = {Humans ; *Stress Disorders, Post-Traumatic/drug therapy/complications/epidemiology ; *Alcoholism/drug therapy/complications/epidemiology ; *Acetylcysteine/therapeutic use ; Randomized Controlled Trials as Topic ; Craving/drug effects ; Comorbidity ; },
abstract = {INTRODUCTION: Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are thought to be significant global contributors to the burden of mental illness. According to recent WHO epidemiological estimates, 3.9% of people worldwide have experienced PTSD at some point in their lives; this number rises to roughly 5.6% among those who have experienced trauma. NAC has shown promise in reducing PTSD symptoms and cravings in veterans, according to recent trials. Our analysis aims to resolve the conflict between results and determine whether NAC is an effective add-on therapy for PTSD, AUD, and co-occurring PTSD/AUD.<br><br>METHODS: We conducted this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, following our protocol (CRD420251170956). We searched PubMed, Scopus, Cochrane CENTRAL, Embase, EBSCO, and the Web of Science for relevant studies. Only randomized placebo-controlled trials were included. The primary outcomes were severity of PTSD and alcohol craving, while secondary outcomes were anxiety, depression, and alcohol use patterns and biomarkers.<br><br>RESULTS: Seven randomized, double-blind, placebo-controlled trials were included in this meta-analysis, enrolling a total of 566 participants. There were no significant differences between NAC and placebo in craving (SMD= -0.40, 95% CI [-1.05, 0.25], P&#x2009;=&#x2009;0.22, I&#xb2; = 56.1%). Regarding PTSD severity, the PCL scale pooled analysis demonstrated no significant difference between NAC and placebo (SMD&#x2009;=&#x2009;0.04, 95% CI [-0.40, 0.48], P&#x2009;=&#x2009;0.8) (I&#xb2; = 65.9%, P&#x2009;=&#x2009;0.05), while the CAPS scale pooled analysis demonstrated no significant difference between NAC and placebo (SMD = -0.13, 95% CI [-0.50, 0.24], P&#x2009;=&#x2009;0.49) (I&#xb2; = 54.8%, P&#x2009;=&#x2009;0.109). Leave-one-out sensitivity analysis showed that exclusion of the Back et al. (2025) study resulted in a significant effect favoring NAC (SMD = -0.35, 95% CI [-0.70, -0.01], P&#x2009;=&#x2009;0.04), with no observed heterogeneity (I&#xb2; = 0%).<br><br>CONCLUSION: Our meta-analysis indicates that N-acetylcysteine, when compared to placebo, does not demonstrate consistent efficacy in reducing the primary symptoms of AUD or PTSD in broad patient populations. However, the treatment is relatively safe. A noteworthy signal of potential efficacy for PTSD symptoms emerged in a sensitivity analysis, suggesting that the therapeutic promise of NAC should not be entirely dismissed.<br><br>CLINICAL TRIAL NUMBER: Not applicable.},
}
@article {pmid42119824,
year = {2026},
author = {Li, W and Su, SA and Zhu, Y and Zhu, S and Yu, Y and Yu, S and Zheng, ZA and Wang, Y and Ma, H and Xiang, M},
title = {TREM2[+] macrophages confers post-infarction cardioprotection by restraining ROS via NLRP3 inflammasome.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118051},
doi = {10.1016/j.bcp.2026.118051},
pmid = {42119824},
issn = {1873-2968},
abstract = {Maladaptive ventricular remodeling following myocardial infarction (MI) is governed by a dysregulated inflammatory-reparative sequence. Macrophages are central driver in cardiomyocyte death and cardiac fibrosis through mediating inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane glycoprotein selectively expressed by tissue-resident macrophages, has merged as a critical immune checkpoint. However, its cell-autonomous role in post-MI cardiac remodeling remains unclear. By applying permanent left-anterior-descending coronary ligation in WT mice and TREM2-knockout (TREM2 KO) mice, we found that TREM2 expression was rapidly upregulated in cardiac macrophages at day 7 post-MI, coinciding with the transition from inflammatory to reparative phase. TREM2 KO mice exhibited preserved baseline cardiac function but developed larger infarcts, lower ejection fraction, and higher mortality after MI. Mechanistically, TREM2 deficiency promoted macrophages towards a pro-inflammatory M1 phenotype, amplified the generation of reactive oxygen species (ROS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome in vitro. Additionally, a transwell co-culture model of bone marrow-derived macrophages (BMDMs) and primary mouse cardiomyocytes revealed that TREM2 suppressed cardiomyocyte apoptosis via ROS-NLRP3 signaling. The ROS scavenger N-acetylcysteine (NAC) markedly inhibited inflammatory factor production in TREM2 deficient macrophages and attenuate cardiomyocyte apoptosis. TREM2 functions as a macrophage-intrinsic checkpoint that coordinates the initiation, escalation, and resolution of post-MI inflammation by restraining ROS-NLRP3 signaling. Augmenting TREM2 activity or supplementing soluble TREM2 may represent a novel immunomodulatory strategy to limit adverse remodeling and improve outcomes after MI.},
}
@article {pmid42110819,
year = {2026},
author = {Reabroi, S and Sutjarit, N and Chairoungdua, A},
title = {Proteotoxic Stress Triggers Autophagy-Mediated AS160 Degradation and Metabolic Reprogramming in Colorectal Cancer.},
journal = {ACS omega},
volume = {11},
number = {17},
pages = {25701-25711},
pmid = {42110819},
issn = {2470-1343},
abstract = {AS160 (TBC1D4) is a key regulator of glucose transporter trafficking and is frequently overexpressed in several malignancies. However, the mechanisms regulating its protein stability and its contribution to colon tumor metabolism remain poorly understood. Here, we identify a proteotoxic stress-responsive mechanism regulating AS160 abundance that involves crosstalk between the ubiquitin-proteasome system (UPS), ER stress-related signaling, and autophagy. Paradoxically, proteasome inhibition with MG132 resulted in a dose-dependent reduction of AS160 protein levels in both HCT116 and HT29 colon cancer cells, accompanied by the induction of ER stress markers and autophagy activation, including p62 accumulation and increased LC3-II/LC3-I ratios. In contrast, blockade of lysosomal degradation with chloroquine (CHQ) led to marked AS160 accumulation, suggesting that autophagy drives AS160 turnover under proteotoxic stress. Alleviating ER stress with 4-phenylbutyric acid (4-PBA) or scavenging reactive oxygen species with N-acetylcysteine (NAC) did not prevent AS160 loss following MG132 treatment. Functionally, shRNA-mediated knockdown of AS160 did not significantly alter glucose uptake or total GLUT1 protein levels; however, it increased lactate secretion accompanied by reciprocal changes in lactate transporters including upregulation of the lactate transporter MCT4 and downregulation of MCT1. Overall, our results suggest that the stability of AS160 protein is regulated through autophagy-associated pathways and that reduced AS160 expression is associated with altered lactate handling. Targeting pathways that regulate AS160 stability may therefore represent a strategy to modulate tumor metabolic adaptation.},
}
@article {pmid42108273,
year = {2026},
author = {Birney, S and Cheng, A and Babuscio, T and Dwy, S and Orazietti, S and Worhunsky, PD and Shi, J and Sofuoglu, M and Constable, T and Potenza, MN and Carroll, K and Yip, SW},
title = {Neuroimaging as the 'missing link' for preclinical to clinical translation: an example using N-acetylcysteine among individuals with cocaine- and opioid-use disorders receiving methadone treatment.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42108273},
issn = {1432-2072},
support = {K01DA039299/DA/NIDA NIH HHS/United States ; },
abstract = {RATIONALE: Cocaine use disorder (CUD) remains a major public health problem, particularly among individuals receiving medications for opioid use disorder (mOUD), where ongoing cocaine use is associated with poorer treatment outcomes and elevated overdose risk. N-acetylcysteine (NAC) is a promising adjunctive candidate that reduces cocaine-seeking in preclinical models and shows mixed efficacy in humans, but its functional neural mechanisms in individuals with CUD-especially within mOUD settings-remain poorly understood.<br><br>OBJECTIVES: The present study uses functional magnetic resonance imaging (fMRI) to determine whether short-term NAC administration modulates brain activity in regions associated with inhibitory control and affective processing in people with CUD receiving medications for opioid use disorder (mOUD).<br><br>METHODS: In this double-blind, placebo-controlled, crossover study, 21 individuals with CUD enrolled in an mOUD program were randomized to receive NAC or placebo for 7&#xa0;days and participated in fMRI scanning on the 7th day of this period. Following a fourteen-day washout period, participants were crossed over to receive the other condition for another 7-day period. Participants received a second fMRI scan on the 7th day of this period. Participants completed a go/no-go (GNG) and emotion-regulation task (ERT) during each scan.<br><br>RESULTS: Compared to placebo, active NAC did not significantly affect brain activity during either the GNG task or the ERT.<br><br>CONCLUSIONS: Overall, short-term NAC did not robustly modulate neural circuits supporting inhibitory control or emotion regulation in individuals with comorbid CUD and OUD receiving mOUD, consistent with prior trials reporting limited efficacy of NAC for CUD. These findings underscore the value of incorporating neuroimaging into early-phase treatment trials to evaluate target engagement in humans.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier:&#xa0;NCT02994875, registered 2016-12-16.},
}
@article {pmid42100214,
year = {2026},
author = {Mahmood, M and Weide, T and Kerns, K},
title = {Ferroptosis contributes to boar sperm deterioration during liquid semen storage.},
journal = {Frontiers in veterinary science},
volume = {13},
number = {},
pages = {1816003},
pmid = {42100214},
issn = {2297-1769},
abstract = {Ferroptosis is an iron-dependent form of regulated cell death characterized by labile iron accumulation, glutathione depletion, mitochondrial dysfunction, and lipid peroxidation. Although ferroptosis has been linked to impaired spermatogenesis and male infertility in vivo, its occurrence and functional relevance in ejaculated spermatozoa during liquid semen storage at 17 °C has not been established. This study evaluated how ferroptosis inducers and inhibitors modulate boar sperm function during liquid semen storage at 17 °C and determined whether ferroptosis contributes to spontaneous sperm deterioration over time. Semen samples from five Duroc boars were treated with ferroptosis inducers: Erastin (system Xc[-] antagonist) and RSL-3 (GPX4 inhibitor), inhibitors: Ferrostatin-1 and N-acetylcysteine (NAC), and vehicle/untreated controls. Sperm motility was assessed by computer-aided sperm analysis, and comprehensive ferroptosis-associated biomarkers were quantified using spectral flow cytometry with a 7-fluorophore panel including sperm identification (Hoechst 33342), labile ferrous iron (FerroOrange), glutathione (monochlorobimane), reactive oxygen species (DCFDA), lipid peroxidation (BODIPY 581/591 C11), mitochondrial membrane potential (MitoTracker Deep Red), and plasma membrane integrity (propidium iodide). RSL-3 induced declines in total and progressive motility accompanied by elevated Fe[2+] accumulation, glutathione depletion, mitochondrial depolarization, and membrane disruption by day 3 (p < 0.05). Erastin produced similar but delayed effects, reaching maximum ferroptotic markers by day 7. Both Ferrostatin-1 and NAC mitigated oxidative injury and preserved motility and cellular integrity relative to inducers. Critically, untreated controls exhibited time-dependent increases in all ferroptosis-associated biomarkers over 7 days of liquid storage, indicating spontaneous ferroptotic activity independent of chemical induction. These findings establish ferroptosis as a mechanistically relevant contributor to sperm.},
}
@article {pmid42100868,
year = {2026},
author = {Lei, K and Yin, Q and Li, Q and Wang, Q and Zhang, Z and Xue, F and Xu, R and Zhou, X and Peng, L and Kokabu, S and Lin, S and Yuan, Q},
title = {METTL5 deficiency impairs osteogenesis through OSER1-dependent antioxidant regulation.},
journal = {JCI insight},
volume = {11},
number = {9},
pages = {},
doi = {10.1172/jci.insight.194068},
pmid = {42100868},
issn = {2379-3708},
mesh = {Animals ; *Methyltransferases/genetics/deficiency/metabolism ; Mice ; *Osteogenesis/genetics/drug effects ; *Antioxidants/metabolism/pharmacology ; Mice, Knockout ; Acetylcysteine/pharmacology ; Oxidative Stress ; Cell Differentiation/genetics ; Mesenchymal Stem Cells/metabolism ; Male ; Mice, Inbred C57BL ; },
abstract = {Methyltransferase-like 5 (METTL5) is a methyltransferase responsible for rRNA N6-methyladenosine (m6A) modification, mutations in which are associated with skeletal abnormalities and cognitive deficits. Despite METTL5's clinical relevance, the molecular mechanisms underlying METTL5-related genetic disorders remain poorly understood. In this study, we demonstrated that Mettl5 KO led to reduced bone mass and smaller body size in mice and impaired the osteogenic differentiation of mesenchymal stem cells. Mechanistically, Mettl5 deficiency decreased the translation efficiency of oxidative stress-responsive serine-rich protein 1 mRNA, downregulated the expression of key antioxidant genes, and diminished antioxidant capacity. Importantly, administration of the antioxidant N-acetylcysteine (NAC) partially rescued skeletal defects in Mettl5-KO mice. These findings reveal a critical role for METTL5 in antioxidant defense and suggest that NAC supplementation may represent a promising therapeutic strategy for METTL5-related disorders.},
}
@article {pmid42101951,
year = {2026},
author = {Pathak, A and K M, GM and Nandave, M and Jain, K},
title = {Development and Characterization of N-Acetylcysteine-Conjugated PAMAM Dendrimers: Biophysical Evaluation of Their Interactions with Proteins and Drug Delivery Applications.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c00166},
pmid = {42101951},
issn = {2576-6422},
abstract = {Poly(amidoamine) dendrimers (PAMAM) have been explored extensively for targeted drug delivery. Functionalization of the PAMAM dendrimer with N-acetyl cysteine (NAC) may reduce the toxicity associated with positively charged dendrimers and enable targeted delivery of cargo to the brain. In this research work, NAC-functionalized PAMAM G3.0 (NG3.0) and G4.0 (NG4.0) dendrimers were fabricated and characterized via [1]H NMR, FTIR spectroscopy, dynamic light scattering, and atomic force microscopy, where the results confirmed the successful functionalization of NAC over the PAMAM surface. Further, interaction studies of NG3.0 and NG4.0 with proteins, i.e., bovine serum albumin and β-lactoglobulin, were performed using spectroscopic studies (fluorescence, UV-Visible, and circular dichroism spectroscopy). The study suggested that dendrimeric conjugates were adsorbed over the biomolecules through H-bonds and hydrophobic interactions, inducing partial conformational changes in the native protein structure while preserving the overall structural integrity of the proteins. The dendrimeric conjugates were further loaded with paclitaxel, and in vitro drug release studies were performed at pH 5.5 and pH 7.4, where the results showed 36.39 ± 3.20% and 28.73 ± 0.83% release for paclitaxel-loaded NG3.0 and NG4.0, respectively, at pH 7.4 after 6 h, while at acidic pH (5.5), 49.31 ± 1.69% and 46.62± 0.97% release were reported for paclitaxel-loaded NG3.0 and NG4.0 after 6 h, respectively. Cell line studies in a rat C6 glioma cell line suggested superior cellular uptake via energy-dependent endocytosis and clathrin-mediated pathway for the NAC-functionalized dendrimeric conjugates. The in vivo pharmacokinetic profile of paclitaxel-loaded NG4.0 demonstrated the sustained and elevated levels of drugs for an extended period following NAC conjugation. Our findings clearly show the efficacy of the NAC-functionalized PAMAM dendrimer, which is biocompatible and could efficiently carry and internalize payloads to glioma cells. Therefore, the paclitaxel-loaded dendrimeric conjugates may serve as a promising chemotherapeutic formulation, exhibiting better efficacy and lower toxicity.},
}
@article {pmid42102103,
year = {2026},
author = {Su, W and Bai, W and Song, S and Suo, Y and Hu, Q and Wang, W and Zhang, P and Dong, C and Xiao, Y and Cheng, Z and Zeng, X and Hong, X},
title = {Pathology-Responsive Nanoprobes for NIR-II Imaging of Acute Kidney Injury.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c00589},
pmid = {42102103},
issn = {1520-6882},
abstract = {Acute kidney injury (AKI), a prevalent life-threatening syndrome triggered by drug-induced nephrotoxicity, ischemia-reperfusion injury (IRI), and surgical complications, rapidly progresses to chronic kidney disease without early intervention, escalating morbidity, and mortality. In this study, we synthesized a fluorescent probe CH-4T and leveraged disease-induced remodeling of the renal nano-bio interface during AKI to engineer a series of pathology-responsive nanoprobes (CH-4T@NP1-4). Systematic screening identified CH-4T@NP3 as optimal, exhibiting superior optical performance, stability, biocompatibility, and pathology-responsive renal accumulation. In cisplatin-AKI and IRI models, CH-4T@NP3 enabled high-sensitivity, real-time NIR-II imaging, with fluorescence signals quantitatively correlating to serum creatinine (Scr), blood urea nitrogen, kidney injury molecule-1 (KIM-1), histopathology (H&amp;E, TUNEL), and injury severity. It dynamically monitored N-acetylcysteine (NAC) therapy, aligning with renal recovery and reducing apoptosis with enhanced penetration and signal-to-noise ratio, offering a noninvasive platform for early AKI diagnosis, severity assessment, and therapeutic evaluation.},
}
@article {pmid42094480,
year = {2026},
author = {Zhang, Z and Moura-Assis, A and Liu, S and Millet, A and Shaked, J and Rajan, D and Alwaseem, H and Viscio, MI and Molina, H and Birsoy, K and Friedman, J},
title = {Macronutrient Composition and Genetic Background Determine the Response to a Ketogenic Diet.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.23.720368},
pmid = {42094480},
issn = {2692-8205},
abstract = {While standard high fat diets cause hyperphagia and obesity in mice, high fat-low carbohydrate ketogenic diets (KDs) reduce food intake and body weight. Because the basis for this difference is still unclear, we systematically altered the macronutrient content of a standard KD and found that feeding C57BL/6J (B6J) mice a KD with 5% protein resulted in hypophagia, weight loss, and hypoglycemia, whereas the same diet with 10% protein led to increased adiposity and glucose intolerance. However, these effects were strain-dependent as C57BL/6NJ (B6NJ) weighed similar amounts on the two diets leading us to investigate the molecular mechanisms. When fed the KD-5% diet, B6J but not B6NJ mice showed increased levels of two anorexigenic factors, GDF15 and LCN2, and loss of function of either blunted the weight loss of B6J mice fed the diet. B6J mice harbor mutations in Nnt (Nicotinamide nucleotide transhydrogenase) and Nlrp12 (NLR family pyrin domain containing 12), both of which are wildtype in B6NJ mice. B6J mice fed the KD-5% diet showed the RNA signature of oxidative and integrated stress responses (ISR) and restoring NNT function in liver reduced the levels of GDF15. RNA-seq also revealed that B6J but not B6NJ mice had the RNA signature for hepatic inflammation and a knockout of Nlrp12 led B6NJ mice to lose weight on the KD-5% diet with increased levels of LCN2. Suppression of oxidative stress with N-acetylcysteine (NAC) reduced expression of both GDF15 and LCN2 and prevented the weight loss associated with the KD-5% protein diet in B6J mice, whereas inhibition of the integrated stress response with ISRIB only attenuated the GDF15 axis. Collectively, these findings explain why B6J mice lose weight on a ketogenic diet and reveal a critical interplay between macronutrient composition and genetic background leading to increased levels of GDF15 and LCN2 to induce hypophagia. Finally, these data suggest that the response to different diets among humans might be similarly variable based on genetic variation and macronutrient composition, suggesting the possible need for personalized dietary interventions.},
}
@article {pmid42094595,
year = {2026},
author = {Lee, S and Han, JH},
title = {CIAPIN1 functions as a redox-sensitive transcriptional repressor of Tp53 during vascular remodeling.},
journal = {Theranostics},
volume = {16},
number = {11},
pages = {6350-6365},
pmid = {42094595},
issn = {1838-7640},
mesh = {*Tumor Suppressor Protein p53/metabolism/genetics ; Animals ; *Vascular Remodeling/genetics/physiology ; Humans ; Rats ; Muscle, Smooth, Vascular/metabolism/cytology ; Oxidation-Reduction ; Myocytes, Smooth Muscle/metabolism ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Male ; Cells, Cultured ; Signal Transduction ; Carotid Artery Injuries ; Rats, Sprague-Dawley ; Cell Proliferation ; Atherosclerosis/metabolism/pathology/genetics ; Promoter Regions, Genetic ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; },
abstract = {BACKGROUND: Phenotypic switching in vascular smooth muscle cells (VSMCs) is a major driver of pathological vascular remodeling, including atherosclerosis and restenosis. Although p53 is a key regulator of VSMC homeostasis, the precise molecular mechanisms responsible for suppressing p53 expression during growth factor-induced phenotypic transitions remain incompletely understood. The present study identifies cytokine-induced apoptosis inhibitor 1 (CIAPIN1) as a novel redox-sensitive regulator of the p53 signaling axis.<br><br>METHODS: Primary cultured VSMCs and a rat carotid balloon injury model were used to investigate the role of CIAPIN1 in VSMC dynamics. CIAPIN1 expression was modulated using both gain- and loss-of-function approaches. The interaction between CIAPIN1 and the Tp53 promoter was examined by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Redox-dependent subcellular trafficking of CIAPIN1 was assessed using N-acetylcysteine (NAC), Ivermectin (IVM) and site-directed mutagenesis of the nuclear localization signal (NLS).<br><br>RESULTS: In human atherosclerotic lesions, CIAPIN1 expression was markedly upregulated, whereas Tp53 mRNA levels were significantly lower compared with healthy controls. Stimulation with PDGF-BB increased CIAPIN1 expression and the induced CIAPIN1 protein directly bound to specific consensus sites in the Tp53 promoter, thereby repressing its transcription. This CIAPIN1-mediated suppression of p53 promoted a switch toward the synthetic phenotype in VSMCs, accelerating proliferation and migration. These effects were substantially attenuated by CIAPIN1 knockdown or by restoring p53 expression. Mechanistically, PDGF-BB triggered reactive oxygen species (ROS) production, which promoted the nuclear translocation of CIAPIN1 through a functional C-terminal NLS (residues 236-239) via the classical importin-&#x3b1;/&#x3b2; pathway. Blocking this trafficking axis with the ROS scavenger NAC, the importin inhibitor IVM or genetic deletion of the NLS (&#x2206;236-239) restored p53 expression and significantly reduced neointimal formation in vivo.<br><br>CONCLUSIONS: CIAPIN1 functions as a redox-sensitive transcriptional repressor of Tp53, driving VSMC phenotypic switching and neointimal hyperplasia. These findings highlight CIAPIN1 as a promising and specific therapeutic target for the treatment of proliferative vascular disorders.},
}
@article {pmid42095852,
year = {2026},
author = {Corley, C and McNealy, KR and White, AM and McManus, H and Khatri, SN and Stoops, WW and Gipson, CD},
title = {An evaluation of N-acetylcysteine in a sequential oxycodone and cocaine rat self-administration model.},
journal = {Experimental and clinical psychopharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1037/pha0000855},
pmid = {42095852},
issn = {1936-2293},
support = {/NH/NIH HHS/United States ; },
abstract = {Polysubstance use, particularly opioid-stimulant co-use, is a public health concern associated with higher overdose risk and poor treatment outcomes. Preclinical evidence suggests that oxycodone withdrawal increases cocaine consumption and disrupts nucleus accumbens glutamate homeostasis. N-acetylcysteine (NAC), a cysteine prodrug that restores glutamate homeostasis, has shown preclinical promise in reducing drug seeking in single substance seeking models. However, no studies have evaluated the efficacy of NAC in reducing behavioral outcomes, including self-administration, following opioid-stimulant polysubstance use. Here, we evaluated NAC as a pharmacotherapeutic for oxycodone-cocaine sequential use using our previously established rat intravenous self-administration model, which utilized an A-B-A-B design. We previously found that rats increase cocaine consumption during oxycodone withdrawal. Thus, here, we tested if NAC could reduce this effect and reduce oxycodone self-administration. Male and female rats first underwent oxycodone or food self-administration acquisition, followed by cocaine self-administration in Phase 2. Rats were subsequently treated with NAC (100 mg/kg) or vehicle during Phase 3, where the reinforcer switched back to the one presented in Phase 1. In Phase 4, we assessed cocaine self-administration and somatic signs during an oxycodone-free period. NAC treatment did not alter oxycodone or cocaine consumption, response discrimination, or somatic signs during drug onboard and drug-free periods. Cocaine consumption was inversely associated with somatic signs at early but not more protracted timepoints independent of NAC treatment. While NAC did not attenuate cocaine or oxycodone intake-related behaviors in our sequential use model, these results underscore the need for expanded polysubstance use pharmacotherapeutic and model development. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}
@article {pmid42098060,
year = {2026},
author = {Meng, Z and Liu, J and Zhang, Y and Yang, R and Zhang, J and Yang, H and Wang, Z and Wei, R and Li, Z and Guo, S and Hu, L and Sui, L},
title = {Collagen Type VI Alpha 1 as a Regulator of Redox Homeostasis in Antioxidant-Enhanced Osteogenesis of Dental Stem Cells.},
journal = {Cell proliferation},
volume = {},
number = {},
pages = {e70220},
doi = {10.1111/cpr.70220},
pmid = {42098060},
issn = {1365-2184},
support = {82471026//National Natural Science Foundation of China/ ; 82301030//National Natural Science Foundation of China/ ; 0203//Tianjin Medical University 123 clinical promotion project/ ; 2022YFC2405901//National Key Research and Development Program of China/ ; TJWJ2024MS009//Tianjin Health Research Project/ ; 24JCZDJC00920//Key Program of Tianjin Natural Science Foundation/ ; },
abstract = {Alveolar bone injury represents a prevalent clinical challenge in dentistry, for which stem cell-based therapy has emerged as a promising strategy to promote bone regeneration. N-acetylcysteine (NAC), a potent antioxidant, has been shown to modulate the PI3K-AKT signalling pathway and potentially enhance osteogenesis; however, the specific downstream effectors mediating this process remain unidentified. In this study, post-extraction serum metabolomic profiling revealed that alveolar bone injury is accompanied by systemic oxidative stress and metabolic remodelling. Transcriptomic analysis of antioxidant-treated dental stem cells further identified type VI collagen A1 (COL6A1) as a key functional mediator. We subsequently investigated the role of COL6A1 in antioxidant-mediated osteogenesis through immunofluorescence and protein assays, and performed knockdown and in vivo experiments to evaluate its function in oxidative stress regulation and osteogenic differentiation. Our results demonstrated that alveolar bone injury is associated with systemic oxidative stress and global metabolic alterations. In vitro, NAC markedly promoted the osteogenic differentiation of dental follicle stem cells (DFSCs) by activating the PI3K-AKT pathway and upregulating COL6A1. COL6A1 knockdown resulted in elevated reactive oxygen species (ROS) levels, impaired mitochondrial function, and attenuated NAC-mediated osteogenesis. In vivo, NAC-treated DFSCs exhibited enhanced bone healing and extracellular matrix (ECM) deposition in a rat model of alveolar bone injury, effects that were mediated through COL6A1 upregulation. Collectively, these findings demonstrate that NAC enhances osteogenesis in DFSCs via the PI3K-AKT-COL6A1 axis, offering a promising antioxidant-based strategy for stem cell therapies in bone regeneration. Moreover, COL6A1 is essential for maintaining redox homeostasis and represents a potential therapeutic target for improving regenerative outcomes.},
}
@article {pmid42098781,
year = {2026},
author = {Xia, L and Zhang, W and Liu, M and Shen, Y and Zhang, J and Wang, D and Wang, F and Zhang, Z and Zhong, Y and Huang, Y and Li, G and Wang, X and Wang, Z and Liu, S and Du, J},
title = {SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment.},
journal = {Reproductive biology and endocrinology : RB&amp;E},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12958-026-01547-8},
pmid = {42098781},
issn = {1477-7827},
support = {22ZR1456200//Natural Science Foundation of Shanghai/ ; },
abstract = {BACKGROUND: Premature ovarian insufficiency (POI) is a prevalent reproductive endocrine disorder, with genetic pathogenesis remaining largely elusive. SPATA22 is a known meiotic regulator in germ cells, while its function in ovarian somatic granulosa cells (GCs) and causal link to POI remain entirely uncharacterized.<br><br>METHODS: Whole-exome sequencing (WES) was performed in 608 idiopathic POI patients, with Sanger sequencing validating the identified SPATA22 variants in the affected pedigree. Pathogenicity and therapeutic potential were verified via in vivo phenotypic analysis of Spata22[+/-] mice, in vitro functional assays of primary mouse GCs, oocyte-GCs co-culture, and in vitro fertilization (IVF) embryo development assays, with N-acetylcysteine (NAC) intervention.<br><br>RESULTS: Two heterozygous pathogenic SPATA22 variants were identified in a POI pedigree with four affected infertile individuals. SPATA22 defects caused GCs dysfunction, accumulated DNA damage, oxidative stress, ovarian insufficiency, impaired fertility in mice. The antioxidant NAC effectively rescued GCs defects, and partially restored Spata22[+/-] mice fertility, ovarian function, co-cultured oocyte competence and embryo development potential.<br><br>CONCLUSIONS: The present study identifies SPATA22 as a causative gene for human POI, provides the first definitive demonstration of a non-canonical somatic function of SPATA22 in GCs, and offers a promising therapeutic strategy for SPATA22-related POI.},
}
@article {pmid41553940,
year = {2026},
author = {Al-Qadi, M and Jose, C and Gaudet, J and Thibeault, Y},
title = {Effects of &lt;sc&gt;n&lt;/sc&gt;-Acetyl-&lt;sc&gt;l&lt;/sc&gt;-Cysteine on the Progression of Kidney Dysfunction in Acadian Variant Fanconi Syndrome: A Case Series.},
journal = {Nephron},
volume = {150},
number = {5},
pages = {342-348},
pmid = {41553940},
issn = {2235-3186},
mesh = {Humans ; *Fanconi Syndrome/drug therapy/physiopathology/complications/genetics ; Disease Progression ; Male ; Female ; Glomerular Filtration Rate/drug effects ; Adult ; *Acetylcysteine/therapeutic use ; *Cysteine/therapeutic use ; Adolescent ; *Antioxidants/therapeutic use ; },
abstract = {<p>Introduction: Acadian variant Fanconi syndrome (AVFS) is an autosomal recessive disease caused by a mutation in the NDUFAF6 gene which results in mitochondrial dysfunction and oxidative damage to the kidneys. It presents as a slowly progressive chronic kidney disease and proximal tubular dysfunction that, in contrast to typical Fanconi syndrome, leads to end-stage renal disease. It is diagnosed clinically and is present only in Acadian people. The objective of this study was to evaluate the effect of <sc>n</sc>-acetyl-<sc>l</sc>-cysteine (NAC), an antioxidant, on the progression of loss of renal function in patients with AVFS. Case Presentation: Chart reviews were conducted on 4 active cases of AVFS not on kidney replacement therapy. Data on age, estimated glomerular filtration rate (eGFR), creatinine, medications, and blood pressure were collected. Progression of eGFR was evaluated in each patient before and after NAC prescription, and the projected time to kidney replacement therapy (eGFR = 10 mL/min/1.73 m2) with and without the use of NAC was calculated for each case. NAC had a positive effect on slowing the rate of eGFR loss in each patient. The projected need for kidney replacement therapy was delayed by an average of 14 years in the treated patients who otherwise would have required it by an estimated mean age of 28 years. Conclusion: This study suggests that NAC has a beneficial effect on slowing the progression of kidney disease in patients with AVFS. This may be due to the modulation of oxidative stress by NAC. Further studies are needed to evaluate the potential benefits of NAC in other chronic kidney conditions. </p>.},
}
@article {pmid42072089,
year = {2026},
author = {Kim, RJ and Park, HB},
title = {Cytoprotective Effects of Lipid Emulsion Against Bupivacaine-Induced Cytotoxicity in Human Rotator Cuff Fibroblasts.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/antiox15040447},
pmid = {42072089},
issn = {2076-3921},
support = {2019R1A6A3A01094496//National Research Foundation of Korea/ ; 2021R1I1A1A01051942//National Research Foundation of Korea/ ; },
abstract = {This study evaluated the protective effects of lipid emulsion (LE) against bupivacaine-induced cytotoxicity in human rotator cuff fibroblasts (hRCFs). hRCFs were divided into control, bupivacaine alone (Bupivacaine), LE alone (LE), LE-pretreated bupivacaine (LE + Bupivacaine), N-acetylcysteine alone (NAC), and NAC-pretreated bupivacaine (NAC + Bupivacaine). Cell viability was assessed by MTT and Live/Dead assays; ROS production by DCF-DA; apoptosis by Annexin V/PI staining and TUNEL assay; cleaved caspase-3 and PARP expression by Western blot; cell cycle by FACS; cell proliferation by Ki-67 staining; and wound healing. Cell viability decreased in a bupivacaine concentration-dependent manner (p < 0.001). Pretreatment with LE or NAC improved cell viability compared with bupivacaine alone (p < 0.001). ROS levels were elevated by bupivacaine, whereas LE and NAC pretreatments significantly reduced ROS (p < 0.001). Bupivacaine-induced apoptosis was significantly attenuated by LE and NAC, as evidenced by reductions in apoptosis rate, expression levels of cleaved caspase-3 and PARP-1, TUNEL-positive nuclei, and the subG1 population (p < 0.05). Cell proliferation and wound healing were suppressed by bupivacaine but restored by LE and NAC pretreatment. This study demonstrates bupivacaine-induced cytotoxicity in hRCFs and suggests that LE and NAC mitigate these effects by reducing oxidative stress and promoting cell survival and wound healing.},
}
@article {pmid42072102,
year = {2026},
author = {Zhang, Y and Wang, D and Wu, J and Sun, Z and Cao, G and Zhang, Y},
title = {Development of an AAPH-Induced Oxidative Stress Model in Bovine Mammary Epithelial Cells and Investigation of Its Molecular Mechanisms.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/antiox15040460},
pmid = {42072102},
issn = {2076-3921},
support = {No. 2023ZD04050//the Biological Breeding Major Project/ ; 32260866//the National Natural Science Foundation of China-Research on the In Vitro Maturation Effect and Mechanism of Ghrelin on Bovine Oocytes Obtained from Live Oocyte Retrieval/ ; 2023KYPT0013//the Laboratory Project on Veterinary Basics and Disease Control for Herbivorous Livestock in the Inner Mongolia Autonomous Region/ ; 2023-JSGG-2//National Dairy Technology Innovation Center Project/ ; },
abstract = {Bovine mastitis is a multifactorial inflammatory disease primarily characterized by inflammatory cell infiltration and the destruction of mammary alveoli. It is a major cause of reduced milk yield and quality. The imbalance between antioxidant defenses and the generation of reactive oxygen species (ROS), which occurs due to the high metabolic activity of the mammary gland during the periparturient period, increases the incidence of mastitis. During early lactation, especially in high-yielding dairy cows, the massive synthesis and secretion of milk increase the energy demand of mammary tissue, leading to excessive ROS accumulation. This results in cell membrane disruption and, ultimately, antioxidant dysfunction in the mammary tissue. This study established an in vitro oxidative stress model by treating bovine mammary epithelial cells (BMECs) with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). The optimal concentration of 1000 μmol/L AAPH was determined using the CCK-8 assay. Model validation showed that, compared to the control group, ROS levels were significantly elevated (p < 0.001) and mitochondrial membrane potential was significantly decreased (p < 0.001) in the AAPH-treated group. Transmission electron microscopy (TEM) analysis revealed that AAPH treatment caused ultrastructural damage, including reduced microvilli, mitochondrial swelling, disappearance of cristae, and vacuolization. Mechanistic studies demonstrated that AAPH treatment significantly upregulated the mRNA and protein expression of AMPK, HMOX-1, mTOR, NOS, and SOD (p < 0.001), while significantly downregulating CYP1A1 expression (p < 0.001). Pretreatment with N-acetylcysteine (NAC) effectively alleviated the oxidative stress damage caused by AAPH. This study successfully established an in vitro AAPH-induced oxidative stress model in BMECs and revealed its molecular mechanism of cellular damage. The damage occurs through modulation of the AMPK/mTOR signaling pathway and the regulation of antioxidant-related gene expression.},
}
@article {pmid42072415,
year = {2026},
author = {Wu, P and Yin, Y and Liu, J and Mo, Z and Ren, J and Ma, X and Liang, Z and Wang, M and Li, C and Chen, L},
title = {Prophylactic Nebulized hUC-MSC-EVs Attenuate Hypobaric Hypoxia-Induced Lung Injury via Alveolar-Capillary Barrier Stabilization and TEK/Tie2 Preservation.},
journal = {Biomedicines},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biomedicines14040874},
pmid = {42072415},
issn = {2227-9059},
support = {grant number 2022YFA1104704//the National Key Research and Development Program of China/ ; },
abstract = {Background/Objectives: High-altitude pulmonary edema (HAPE) remains a serious condition with limited preventive options. This study evaluated the prophylactic protective effects of nebulized human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) in a rat model of hypobaric hypoxia-induced lung injury and explored potential mechanistic clues, with a focus on oxidative stress and TEK/Tie2 signaling. Methods: Rats were exposed to hypobaric hypoxia (47 kPa; 9.7% O2) for 72 h and received prophylactic nebulized hUC-MSC-EVs (300 μg/rat). Lung injury was evaluated by histopathology, wet-to-dry ratio, and bronchoalveolar lavage fluid (BALF) protein concentration. Invasive pulmonary function indices were measured using a forced oscillation system. BALF cytokines (TNF-α, IL-6, and IL-10), reactive oxygen species (ROS), and TEK/Tie2 expression in lung tissue were assessed. In addition, transcriptome sequencing (RNA-seq) was performed to characterize global transcriptional changes. N-acetylcysteine (NAC), a classical antioxidant, was included as an auxiliary mechanistic intervention to assess the association of ROS with TEK/Tie2 changes. Results: Compared with hypoxia controls, prophylactic nebulized hUC-MSC-EVs reduced histopathological injury, pulmonary edema, and barrier leakage, and improved pulmonary function indices. hUC-MSC-EV intervention also attenuated inflammatory responses in BALF, with decreased TNF-α and IL-6 and increased IL-10. Hypobaric hypoxia increased ROS accumulation and decreased TEK/Tie2 expression, whereas nebulized hUC-MSC-EVs reduced ROS and partially preserved TEK/Tie2 expression. NAC pretreatment similarly reduced ROS and was accompanied by Tie2 preservation. Conclusions: Prophylactic nebulized hUC-MSC-EVs mitigated hypobaric hypoxia-induced lung injury, accompanied by reduced oxidative stress, improved vascular barrier integrity, and preservation of TEK/Tie2 expression. These findings support nebulized hUC-MSC-EVs as a potential lung-targeted prophylactic strategy for hypobaric hypoxia-induced lung injury and suggest that ROS imbalance may be associated with Tie2 preservation.},
}
@article {pmid42072718,
year = {2026},
author = {Maçin, A and Duman, E and Özdemir, &#x130; and Tuncer, MC},
title = {Quercetin Enhances Topotecan Cytotoxicity in Retinoblastoma Cells Through ROS-Associated Stress and Apoptotic Signaling.},
journal = {Biomolecules},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/biom16040597},
pmid = {42072718},
issn = {2218-273X},
mesh = {*Topotecan/pharmacology ; *Quercetin/pharmacology ; Humans ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; *Retinoblastoma/metabolism/drug therapy/pathology ; Cell Line, Tumor ; Signal Transduction/drug effects ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Cell Proliferation/drug effects ; Drug Synergism ; Acetylcysteine/pharmacology ; },
abstract = {Quercetin, a naturally occurring flavonoid, exhibits antiproliferative and pro-apoptotic effects across various cancer models. Topotecan, a topoisomerase I inhibitor, is used in the treatment of retinoblastoma; however, its clinical utility is limited by dose-dependent toxicity. This study aimed to investigate whether quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma and to explore the underlying mechanisms under both two-dimensional (2D) and three-dimensional (3D) conditions. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the combination index (CI) based on the Chou-Talalay method. Apoptosis was analyzed by Annexin V-FITC/PI staining and flow cytometry. Reactive oxygen species (ROS) levels and mitochondrial membrane potential were evaluated using fluorometric methods, and N-acetyl-L-cysteine (NAC) was used for functional modulation of oxidative stress. Three-dimensional tumor spheroid models were used to assess treatment effects under conditions that partially recapitulate tumor architecture. Gene expression levels of apoptosis-related markers and PI3K/Akt/mTOR pathway components were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The combination of quercetin and topotecan was associated with synergistic cytotoxic effects in Y79 cells (CI < 1), accompanied by increased ROS levels, mitochondrial membrane depolarization, and elevated apoptotic cell death. NAC co-treatment partially attenuated ROS levels and restored cell viability. In 3D spheroid models, combination treatment induced structural disruption, reduced viability, and increased cell death, effects that were partially reversed by NAC. Gene expression analysis revealed upregulation of pro-apoptotic genes and downregulation of survival-related genes, along with increased PTEN expression. Quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma cells under both 2D and 3D conditions. These effects were associated with ROS-associated cellular stress, mitochondrial dysfunction, and modulation of apoptotic and survival-related pathways. The partial rescue by NAC supports a contributory, but not exclusive, role of oxidative stress. These findings should be interpreted within a preclinical context and suggest that quercetin may represent a potential adjunct strategy warranting further validation in translational and in vivo models.},
}
@article {pmid42074117,
year = {2026},
author = {Maçin, A and Duman, E and Özdemir, &#x130; and Tuncer, MC},
title = {Synergistic Anticancer Effects of Resveratrol and Carboplatin in Y79 Retinoblastoma Cells: Mechanistic Insights into Apoptosis, G2/M Arrest, and ROS-Dependent Mitochondrial Dysfunction.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083473},
pmid = {42074117},
issn = {1422-0067},
mesh = {*Reactive Oxygen Species/metabolism ; Humans ; *Apoptosis/drug effects ; *Mitochondria/drug effects/metabolism ; *G2 Phase Cell Cycle Checkpoints/drug effects ; *Resveratrol/pharmacology ; Cell Line, Tumor ; *Carboplatin/pharmacology ; Drug Synergism ; *Retinoblastoma/metabolism/drug therapy/pathology ; Membrane Potential, Mitochondrial/drug effects ; Cell Survival/drug effects ; *Antineoplastic Agents/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {This study aimed to investigate the effects of resveratrol (RES) and carboplatin (CPT), alone and in combination, on cell viability, apoptosis, cell cycle progression, mitochondrial function, and oxidative stress in Y79 retinoblastoma (RB) cells. Particular emphasis was placed on evaluating the synergistic potential of the combination and elucidating the interconnected molecular mechanisms underlying its anticancer effects. Y79 cells were treated with RES, CPT, and their combinations. Cell viability and synergy were assessed using the MTT assay and combination index (CI) analysis. Apoptosis (annexin V/PI), cell cycle distribution (propidium iodide (PI) staining), intracellular ROS production (DCFH-DA), and mitochondrial membrane potential (JC-1) were evaluated by flow cytometry. ROS dependency was further examined using N-acetylcysteine (NAC) pretreatment. Expression levels of apoptosis- and cell cycle-related genes (BAX, BCL-2, CASP3, CASP9, CCNB1, and CDK1) were analyzed by RT-qPCR. Cytoskeletal alterations were assessed by immunocytochemistry. In addition, the antitumor effects of the combination were validated in a three-dimensional (3D) tumor spheroid model. RES and CPT reduced cell viability in a dose- and time-dependent manner and demonstrated synergistic effects (CI < 1) at selected concentrations. Combination treatment significantly increased apoptosis, induced G2/M phase arrest, enhanced ROS accumulation, and promoted mitochondrial depolarization compared with single-agent treatments. NAC pretreatment attenuated ROS generation and partially restored cell viability, supporting a contributory role of oxidative stress in combination-induced cytotoxicity. At the transcriptional level, the RES + CPT combination significantly increased the BAX/BCL-2 ratio and upregulated CASP3 and CASP9 expression, while downregulating CCNB1 and CDK1, consistent with mitochondrial apoptotic activation and G2/M arrest. Immunocytochemical analysis revealed pronounced cytoskeletal disruption and apoptotic morphology in the combination group. Importantly, in the 3D spheroid model, co-treatment markedly reduced spheroid size and viability and enhanced cell death compared with monotherapies. The combination of RES and CPT exerts a synergistic anticancer effect in Y79 RB cells through coordinated mechanisms involving ROS accumulation, mitochondrial dysfunction, caspase activation, and G2/M phase arrest. The attenuation of cytotoxicity by NAC and the validation of efficacy in a 3D tumor spheroid model strengthen the mechanistic relevance of these findings. These results support further preclinical investigation of this combination strategy in in vivo models and normal retinal cell systems.},
}
@article {pmid42075089,
year = {2026},
author = {Wójtowicz, M and Małek, P and Olszanecka-Glinianowicz, M},
title = {The Role of Dietary Supplements in the Treatment of Endometriosis: A Critical Review.},
journal = {Nutrients},
volume = {18},
number = {8},
pages = {},
doi = {10.3390/nu18081274},
pmid = {42075089},
issn = {2072-6643},
mesh = {Humans ; *Endometriosis/therapy/drug therapy ; *Dietary Supplements ; Female ; Animals ; Zinc ; Randomized Controlled Trials as Topic ; Curcumin ; Fatty Acids, Omega-3 ; },
abstract = {Background: There is a growing number of studies suggesting the effectiveness of dietary supplements in preventing and treating endometriosis. It has been suggested that deficiencies in vitamins D and E as well as zinc are associated with the increased risk of endometriosis development. Beneficial effects of magnesium, curcumin, resveratrol and epigallocatechin-3-gallate were found in experimental animal studies. A reduction in pain related to endometriosis was shown in women using omega-3 and alpha-lipoic acid. Meanwhile, decreasing endometriotic lesion size after the supplementation of omega-3, N-acetylcysteine, vitamin C and epigallocatechin-3-gallate was observed in animal and human studies. Thus, the aim of this critical review was to summarize the available data describing the effects of dietary supplements used in the treatment of endometriosis. Material and Methods: The PubMed, Embase, Cochrane, and Web of Science databases were searched for related studies until 15 December 2025. Finally, 34 studies were included in the synthesis. Results: Of these 34 studies, only 23 were randomized, placebo-controlled trials. There have been no RCTs evaluating the effectiveness of vitamin E, zinc, alpha-LA, EGCG and DIM in the treatment of endometriosis. Single studies evaluating the effectiveness of vitamin C, magnesium, resveratrol, NAC and PEA with PLD have not confirmed it. Meanwhile single studies evaluating the effectiveness of selenium, propolis and quercetin have confirmed it. Of the four studies assessing the effectiveness of vitamin D, two confirmed it and two did not; of the two studies assessing probiotics, one confirmed its effectiveness and one did not; of the two studies assessing curcumin, one confirmed its effectiveness and one did not; and of the three studies assessing omega-3, two confirmed its effectiveness and one did not. All four RCTs assessing the combination of vitamins C and E confirmed their effectiveness. Conclusions: Despite encouraging observations from experimental studies, the results of RCTs are less encouraging and do not allow for the formulation of recommendations concerning the use of supplements in the treatment of endometriosis symptoms according to EBM.},
}
@article {pmid42075956,
year = {2026},
author = {Choi, JY and Lee, WJ and Boo, YC},
title = {Therapeutic Potential of Cysteine and Its Derivatives in Dermatology.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {8},
pages = {},
doi = {10.3390/molecules31081277},
pmid = {42075956},
issn = {1420-3049},
mesh = {Humans ; *Cysteine/analogs &amp; derivatives/pharmacology/therapeutic use/chemistry ; Wound Healing/drug effects ; Animals ; Skin/drug effects/metabolism ; *Skin Diseases/drug therapy/metabolism ; Dermatology ; Antioxidants/pharmacology/chemistry/therapeutic use ; Oxidation-Reduction ; },
abstract = {Cysteine is a sulfur-containing amino acid that plays a central role in skin physiology through thiol-mediated redox regulation and glutathione (GSH) synthesis. It critically influences melanogenesis, collagen homeostasis, and wound healing. However, its clinical application is limited by poor stability and bioavailability. In this review, we provide a mechanistic and comparative analysis of cysteine and its derivatives, including N-acetylcysteine (NAC), cysteinamide (C-NH2), GSH, and related compounds. These derivatives regulate melanogenesis by modulating dopaquinone pathways and tyrosinase activity, maintain collagen balance by preserving redox-sensitive enzymatic processes, and enhance wound healing through antioxidant and anti-inflammatory mechanisms. Importantly, chemical modifications such as acetylation, amidation, and esterification improve pharmacokinetic properties, enabling more effective intracellular delivery. Furthermore, different derivatives exhibit distinct advantages depending on biological context, highlighting the importance of compound selection. Overall, cysteine derivatives emerge as promising therapeutic candidates for dermatological applications, particularly in pigmentation disorders and impaired wound healing. Future studies should focus on in vivo validation and clinical translation.},
}
@article {pmid42081992,
year = {2026},
author = {Ibrahim, HF and Thabet, EH and Assem, S and Abd El Mottelib, LMMA and Abd El-Kader, SB and Khan, MS and Rostom, D},
title = {Therapeutic Opportunities for Ferroptosis In Lipopolysaccharides- Induced Acute Kidney Injury; Liproxstatin-1 Versus N- Acetyl Cysteine.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178919},
doi = {10.1016/j.ejphar.2026.178919},
pmid = {42081992},
issn = {1879-0712},
abstract = {Acute kidney injury (AKI) is a fatal condition with high morbidity and mortality rates. Recent studies indicated that ferroptosis is implicated in the pathogenesis of AKI. This suggests that ferroptosis inhibitors deserve more attention as AKI therapeutic options. We explored the comparative effectiveness of liproxstatin-1 (Lip-1) and N- acetyl cysteine (NAC) in mitigating ferroptosis in lipopolysaccharides (LPS)- induced AKI. Herein, mice were exposed to a single intraperitoneal (IP) injection of 10 mg/kg LPS. They were treated either by 10 mg/kg Lip-1 or NAC (total 3 doses of each drug over 6 days). Serum urea, creatinine and malondialdehyde, along with tissue EGR-1, GPX-4 and iron, were assessed. Histological, immuno-fluorescence and ultrastructural studies were conducted as well. Our results elucidated that; Lip-1 possesses significant antiferroptotic effects that modulated the three cornerstones of ferroptosis; MDA, GPX-4 and iron. Additionally, it downregulated EGR-1 and PERK, and upregulated GB3P1, affecting the cellular pathways that relate ferroptosis to endoplasmic reticulum stress (ER stress), stress granules (SGs) formation and lysophagy. The antiferroptotic actions of NAC were less remarkable. In conclusion, our study presents a foundation for therapeutic options directed against ferroptosis in AKI, advocating application of Lip-1 or NAC, with a specific focus on Lip-1.},
}
@article {pmid42070336,
year = {2026},
author = {Tang, Z and Yang, X and Zhang, M and Yang, B and Li, H},
title = {Schisandrin B alleviates APAP-induced hepatocyte ferroptosis via the GPX4 axis: Insights from human iPSC-derived hepatic organoids and rat models.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {156},
number = {},
pages = {158241},
doi = {10.1016/j.phymed.2026.158241},
pmid = {42070336},
issn = {1618-095X},
abstract = {BACKGROUND: Acetaminophen (APAP) overdose is a major cause of liver injury, while N-acetylcysteine (NAC), the only approved antidote, has limitations. This study used human iPSC-derived hepatic organoids (iHep-Orgs) and a rat model to evaluate the hepatoprotective and anti-ferroptotic effects of Schisandrin B (Sch B), a bioactive lignan from Schisandra chinensis.<br><br>PURPOSE: To investigate whether Sch B protects against APAP-induced liver injury by modulating ferroptosis and related metabolic pathways.<br><br>STUDY DESIGN: A dual-model evaluation system integrating human hepatic organoids and an in vivo rat AILI model.<br><br>METHODS: Organoids and rats were exposed to APAP followed by Sch B treatment. Hepatic function, cytokines, MDA, GSH, GPX4/SLC7A11 expression, Fe[2+] levels, histology, metabolomics, docking, and molecular dynamics were assessed.<br><br>RESULTS: In iHep-Orgs, Sch B improved albumin secretion (p < 0.01), reduced TNF-&#x3b1;, IL-1&#x3b2;, and MDA (p < 0.01), and upregulated GPX4 and SLC7A11 mRNA (p < 0.01). Metabolomics revealed remodeling of GSH, amino acid, and lipid metabolism with ferroptosis-related enrichment. Docking and MD showed stable binding to GPX4 and SLC7A11, with stronger GPX4 affinity. In rats, Sch B lowered ALT/AST (p < 0.01), restored GSH (p < 0.05), reduced MDA (p < 0.01), alleviated histological injury, decreased iron deposition, normalized hepcidin (p < 0.01), and restored transferrin (p < 0.01). GPX4 protein increased significantly (p < 0.01), while SLC7A11 protein remained unchanged.<br><br>CONCLUSION: Sch B protects against APAP-induced liver injury by enhancing GPX4 activity, reducing lipid peroxidation, and improving iron homeostasis. The combined organoid-animal approach provides a practical framework for evaluating natural products in AILI.},
}
@article {pmid42070637,
year = {2026},
author = {Englund, A and Schillemans, T and Nordenskiöld, KY and Wallensten, J and Carlsson, AC and Wachtler, C},
title = {The association between N-acetyl-L-cysteine and development of depression: A longitudinal cohort study in all patients with chronic obstructive pulmonary disease in Region Stockholm.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {121905},
doi = {10.1016/j.jad.2026.121905},
pmid = {42070637},
issn = {1573-2517},
abstract = {BACKGROUND: Depression is a major cause of illness and sick leave and has a prevalence of 3,4% globally. Approximately 30-55% of patients suffering from depression do not respond to existing treatments. N-Acetyl-L-cysteine (NAC) is currently used as mucolytic agent and as antidote in paracetamol overdose. Lately, NAC has generated interest as neuroprotective agent. It is not known whether NAC can prevent depression.<br><br>RESEARCH QUESTION: This study investigated whether higher consumption of NAC is associated with a lower risk of developing depression in patients with Chronic Obstructive Pulmonary Disease (COPD).<br><br>STUDY DESIGN AND METHOD: The longitudinal cohort study included patients over 40&#x202f;years old in Stockholm with COPD and/or chronic bronchitis diagnosis 2014-2016 without depression 2014-2019 (n&#x202f;=&#x202f;16,875). Exposure consisted of defined daily doses (DDD) of NAC 2014-2019, and the outcome was occurrence of depression diagnosis 2020-2024.<br><br>RESULT: Cox regression adjusted for age and sex revealed a hazard ratio for depression of 1.37 (95% CI 1.25-1.52) with low NAC exposure (41-875 DDD) and of 1.29 (95% CI 1.09-1.52) with high exposure (>875 DDD). The associations were somewhat attenuated when adjusted for hospital admissions and other COPD medications.<br><br>CONCLUSION: Contrary to our hypothesis, our results show an increased hazard ratio of depression in patients treated with NAC. This most likely reflects the strong association, shown in other studies, between more severe COPD disease and an increased risk of depression. In this scenario, DDD of NAC acts as a proxy for disease severity.},
}
@article {pmid42070712,
year = {2026},
author = {Redeny, RMEL and Samaha, MM and El-Kashef, DH},
title = {Diacerein protects against thioacetamide-induced acute liver injury via modulating HMGB1/TLR4/MyD88/NF-κB signaling pathway.},
journal = {Toxicology and applied pharmacology},
volume = {},
number = {},
pages = {117848},
doi = {10.1016/j.taap.2026.117848},
pmid = {42070712},
issn = {1096-0333},
abstract = {Acute liver injury (ALI) is a serious disease which happens suddenly in people with or without previous liver disease. In this experiment, thioacetamide (TAA) was utilized to induce ALI. The experimental design was conducted using forty-eight adult male Sprague-Dawley rats, which were randomly divided into six groups (n = 8 per group). The control group received no treatment, TAA group received a single intraperitoneal injection of TAA at a dose of 500 mg/kg, Dia 100 group received diacerein (100 mg/kg, orally) only once daily for six consecutive days. For the treatment groups, rats were pretreated orally for six days prior to TAA administration; NAC + TAA group received N-acetylcysteine (50 mg/kg), followed by a single intraperitoneal injection of TAA (500 mg/kg) on day 6. Dia 50 + TAA group received diacerein (50 mg/kg) and Dia 100 + TAA group received diacerein (100 mg/kg) for six consecutive days, followed by TAA injection on day 6. Twenty-four hours after TAA administration, all rats were euthanized. Blood samples were collected for serum separation, and liver tissues were harvested for the assessment of biochemical parameters. Pretreatment with diacerein conferred hepatoprotective effects as evidenced by considerable (p ≤ 0.05) decrease in liver enzymes; ALT, AST, ALP, GGT concomitant with profound (p ≤ 0.05) elevation in serum level of albumin besides improvement in hepatic architecture when compared to TAA group. Diacerein also showed antioxidant properties as evidenced by the significant (p ≤ 0.05) decline in MDA content and substantial (p ≤ 0.05) increment in GSH level. Moreover, diacerein markedly (p ≤ 0.05) reduced inflammation by down-regulating HMGB1/TLR4/MYD88/NF-κB signaling pathway. Collectively, diacerein might be a potential therapeutic candidate for treatment of ALI pending further clinical studies to confirm this notion.},
}
@article {pmid42070744,
year = {2026},
author = {Hu, J and Chen, Y and Xu, L and Dai, A and Li, J and Liu, X},
title = {Polystyrene Nanoplastics Induce Hippocampal Damage and Cognitive Deficits through Oxidative Stress-Triggered Microglial Extracellular Traps and Neuronal Ferroptosis.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112120},
doi = {10.1016/j.cbi.2026.112120},
pmid = {42070744},
issn = {1872-7786},
abstract = {Exposure to polystyrene nanoplastics (PS-NPs) induces cognitive deficits and hippocampal damage in mice; however, the underlying mechanism remains unclear. The behavioral assessments performed in this study revealed significant impairments in learning and spatial memory in mice exposed to PS-NPs. Mechanistically, PS-NPs triggered oxidative stress in the hippocampus, which activated microglia and drove the excessive formation and release of microglial extracellular traps (MiETs). This sustained neuroinflammatory response, characterized by the release of MiETs and increased levels of proinflammatory cytokines (Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β)), was closely associated with neuronal ferroptosis. Ultimately, PS-NPs induced hippocampal ferroptosis, as evidenced by the loss of mitochondrial cristae, depletion of glutathione (GSH) and glutathione peroxidase 4 (GPX4), elevated lipid peroxidation, and disrupted iron homeostasis, characterized by reduced ferritin heavy chain 1 (FTH1) expression and increased levels of ferrous iron. Notably, the antioxidant N-acetylcysteine (NAC) effectively attenuated oxidative stress, suppressed microglial activation and MiET formation, and reduced neuroinflammation, thereby preventing neuronal ferroptosis and cognitive impairment. Coculture experiments confirmed that PS-NPs-induced MiETs mediate neuronal ferroptosis, and inhibition of ferroptosis ameliorates PS-NPs-driven neuroinflammation. These results demonstrate that PS-NPs induce cognitive impairment primarily through an oxidative stress-driven cascade involving microglial activation, MiET release, neuroinflammation, and hippocampal ferroptosis.},
}
@article {pmid42070819,
year = {2026},
author = {Ye, S and Luo, S and Tan, Y and Zhang, R and Ji, D and Xiao, F},
title = {Ambient NO2 induces premature pulmonary senescence in rats: The role of the ROS-DRG1/CDK5 axis.},
journal = {Journal of environmental sciences (China)},
volume = {164},
number = {},
pages = {271-282},
doi = {10.1016/j.jes.2025.08.058},
pmid = {42070819},
issn = {1001-0742},
mesh = {Animals ; Reactive Oxygen Species/metabolism ; Rats ; *Cellular Senescence/drug effects ; *Air Pollutants/toxicity ; *Nitrogen Dioxide/toxicity ; Humans ; Cyclin-Dependent Kinase 5/metabolism ; *Lung/drug effects ; Male ; Rats, Sprague-Dawley ; },
abstract = {Cellular senescence plays a crucial role in respiratory diseases. Nitrogen dioxide (NO2), a major air pollutant, causes multi-system toxicity, primarily affecting the respiratory system. However, the association between NO2 and pulmonary senescence remains unclear. This study systematically explored the association between NO2 exposure and premature pulmonary senescence using animal and cellular models. Rats were exposed for 45 days (4 h/day) to filtered air, 0.5 ppmV, or 5.0 ppmV NO2. Human bronchial epithelial (HBE) cells were treated with 0 or 120 μmol/L NaNO3, a stable metabolite of NO2, for 96 h. HBE cells exhibited hallmark senescence phenotypes, including elevated reactive oxygen species (ROS), increased expression of senescence-associated proteins (Fibronectin 1 (Fn1), Clusterin (CLU), senescence Marker Protein 30 (SMP30)), elevated β-galactosidase (β-gal) activity, increased developmentally regulated GTP-binding protein 1 (DRG1) and cyclin-dependent protein kinase 5 (CDK5) expression, and G1-phase cell cycle arrest. Treatment with the ROS inhibitor N-acetylcysteine (NAC), si-DRG1, or a CDK5 inhibitor alleviated these effects. Co-immunoprecipitation assays revealed that NaNO3 promoted the interaction between DRG1 and CDK5 during senescence. The study demonstrated that NO2/NaNO3 induces bronchial epithelial cellular senescence, contributing to pulmonary senescence via ROS-dependent upregulation of DRG1 and CDK5 expression and interaction. Targeting the ROS-DRG1/CDK5 axis may represent a therapeutic strategy for environmental pollutant-induced premature respiratory senescence and provide new insights for the management of related disorders.},
}
@article {pmid42063333,
year = {2026},
author = {Boboltz, A and Rathi, V and Kumar, S and Duncan, GA},
title = {Myeloperoxidase impairs mucociliary transport on human airway epithelium.},
journal = {Disease models &amp; mechanisms},
volume = {},
number = {},
pages = {},
doi = {10.1242/dmm.052764},
pmid = {42063333},
issn = {1754-8411},
support = {R01 HL160540/HL/NHLBI NIH HHS/United States ; F31HL176146/HL/NHLBI NIH HHS/United States ; DUNCAN24G0//Cystic Fibrosis Foundation/ ; },
abstract = {Dampening neutrophil-driven inflammation in the airways remains a challenge in treating cystic fibrosis (CF) lung disease. Myeloperoxidase (MPO) is a neutrophilic enzyme that produces reactive oxygen species and is highly concentrated in CF airways. Greater MPO concentrations have been previously correlated with increased mucus plugging in bronchiectasis, suggesting that MPO could impair mucociliary transport. As such, we evaluated the impact of MPO treatment on barrier integrity, mucin production, mucus viscoelasticity, and mucociliary transport in fully differentiated human airway epithelial cultures at ionic conditions reflective of the healthy and CF-affected airways. Using live cell imaging and particle velocimetry, we found that MPO inhibits mucociliary transport in vitro at CF-like and normal airway conditions. The impairment of mucus clearance by MPO was similar to neutrophil elastase (NE), another neutrophilic granular enzyme that damages the host tissues and impairs airway clearance. We also found subsequent treatment with the reducing agent, N-acetyl cysteine, could alleviate MPO-mediated mucociliary dysfunction through disulfide bond cleavage. These findings identify MPO as a therapeutic target to resolve deficits in airway clearance function in CF and related muco-obstructive lung diseases.},
}
@article {pmid42059474,
year = {2026},
author = {Zhang, T and Chen, X and Hao, S and Qin, Y and Luo, Q and Yan, R and Zhong, W and Xu, K},
title = {Silent-To-Bright CTCs-Hitchhiking Peptide Nanoprobe for Activatable NIR Imaging of Lung Metastasis in Mice.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c01149},
pmid = {42059474},
issn = {1520-6882},
abstract = {Metastasis remains the leading cause of cancer-related mortality, yet its early detection is hindered by the subtle and unpredictable nature of the metastatic niche. In this study, we developed a self-assembling peptide-based activatable nanoprobe, 1-CyBr(PBA)-NGR NPs, designed for the early detection of the metastatic niche through circulating tumor cells (CTCs)-mediated hitchhiking and hydrogen peroxide (H2O2)-induced fluorescence activation. The peptide probe spontaneously assembled into stable spherical nanoparticles in aqueous media and undergoes H2O2-triggered fluorescence recovery via oxidation of the phenylboronic acid masking group. Upon intravenous injection, 1-CyBr(PBA)-NGR NPs "hitchhike" CTCs through specific binding via the NGR moiety, utilizing the natural trafficking pathways of CTCs to reach the metastatic lesion. Upon reaching the metastatic site, the nanoparticles are selectively activated by the microenvironment, resulting in fluorescence activation and enabling precise optical imaging of the metastatic site. In vivo imaging in a lung metastatic mouse model revealed distinct fluorescence in the lungs following intravenous administration of 1-CyBr(PBA)-NGR NPs, whereas minimal fluorescence was observed in both the healthy control and antioxidant N-acetylcysteine (NAC)-treated metastatic mice, further confirming the probe's selective activation in response to the elevated H2O2 levels in the metastatic lesion. This study presents a "silent-to-bright" NIR imaging strategy for tumor metastasis monitoring, utilizing CTCs as "hitchhiking" carriers and the metastatic microenvironment as fluorescence activators, offering a promising approach for tumor metastasis diagnosis and intervention.},
}
@article {pmid42051726,
year = {2026},
author = {Kovacevic, S and Nenadovic, A and Jeremic, R and Ivanov, M and Brkic, P and Mihailovic-Stanojevic, N and Ostojic, JN},
title = {Hyperbaric oxygen therapy and N-acetylcysteine: a redox-dependent interaction.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1829074},
pmid = {42051726},
issn = {2296-858X},
abstract = {Hyperbaric oxygen therapy (HBOT) is widely used in clinical medicine and exerts its therapeutic effects primarily by modulating cellular redox signaling. Acute exposure to hyperbaric hyperoxia induces a transient increase in reactive oxygen species (ROS), which can initiate adaptive antioxidant responses and activate cytoprotective pathways. However, excessive ROS generation may also contribute to oxidative injury, depending on the treatment protocol and underlying pathological state. N-acetylcysteine (NAC), a precursor of glutathione and a widely used antioxidant, has therefore been investigated as a potential adjunct therapy to modulate HBOT-induced oxidative responses. This mini-review summarizes current evidence regarding the interaction between HBOT and NAC in experimental and clinical studies. The available studies indicate that the combined effects of HBOT and NAC are context-dependent. In conditions characterized by severe oxidative stress, NAC may enhance the therapeutic effects of HBOT by reducing pathological ROS accumulation and improving antioxidant capacity. In contrast, in models where ROS act as signaling molecules that trigger adaptive or regenerative pathways, antioxidant intervention may attenuate or abolish the beneficial effects of HBOT. Evidence also suggests that treatment timing, dosage, and baseline oxidative status may modify the outcomes of combined therapy. Overall, the interaction between HBOT and NAC reflects a delicate balance between pathological oxidative stress and redox-dependent signaling mechanisms. A better understanding of these dynamics may help optimize therapeutic strategies involving hyperbaric oxygen and antioxidant modulation in clinical practice.},
}
@article {pmid42056482,
year = {2026},
author = {Geldard, C and Browne, J and Bugarcic, A},
title = {Differential antimicrobial responses in polymicrobial triple-species biofilms associated with persistent urinary tract infections.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-50919-y},
pmid = {42056482},
issn = {2045-2322},
abstract = {Polymicrobial urinary tract infections (UTIs) pose significant treatment challenges due to interspecies interactions within biofilms. To address this, we developed a static, triple-species biofilm model comprising Escherichia coli, Enterococcus faecalis, and Candida albicans to simulate recurrent UTI communities. Biofilms were treated with ampicillin, ciprofloxacin, fluconazole, ethylenediaminetetraacetic acid (EDTA), and N-acetylcysteine (NAC), and evaluated for biomass (crystal violet assay) and viability (CFU/mL). Ampicillin and ciprofloxacin reduced bacterial viability by > 90%, but had limited impact on C. albicans, while EDTA disrupted biomass by ≈ 45% and variably reduced viability across species. Fluconazole elicited non-monotonic effects on biomass and viability, and NAC increased microbial viability despite structural disruption. These results reveal that biofilm disruption did not consistently correlate with reductions in microbial viability in this model, highlighting the importance of evaluating both biomass and viable cell counts when assessing antimicrobial effects on polymicrobial biofilms relevant to persistent UTIs.},
}
@article {pmid42038311,
year = {2026},
author = {Bu, Q and Liang, Y and Xu, Z and Pan, B and Wang, J and Liu, L and Ni, X and Wang, Q},
title = {Magnesium isoglycyrrhizinate ameliorates acetaminophen-induced acute liver injury with hyperglycaemia by modulating autophagy and oxidative stress in liver-resident macrophages.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1744099},
pmid = {42038311},
issn = {1663-9812},
abstract = {BACKGROUND: The prevalence of drug-induced acute liver injury, represented by acetaminophen (APAP), has seriously threatened human lives. Macrophages play an important role in acute liver injury; however, the treatment options remain limited. Therefore, exploring the pathogenesis of the disease and developing new treatment strategies targeted macrophages are particularly important.<br><br>METHODS: This study innovatively evaluates the hepatoprotective effects of magnesium isoglycyrrhizinate (MgIG) and elucidates its underlying mechanisms modulating Kupffer cell (KC) inflammation using an APAP-overdose mouse model. Hyperglycaemia was induced in C57BL/6J mice by streptozotocin treatment, and the mice were randomly divided into Saline, APAP, APAP + NAC, and APAP + MgIG groups.<br><br>RESULTS: The data demonstrated that APAP administration elicited pronounced histopathological injury and markedly upregulated serum transaminases (ALT and AST). Treatment with MgIG ameliorated these histological lesions and suppressed transaminase elevations, paralleling the effect of N-acetylcysteine (NAC). APAP induced oxidative stress in KCs, as evidenced by increased malondialdehyde (MDA) levels, decreased superoxide dismutase (SOD) activity, and a reduction in glutathione (GSH) content. Moreover, APAP exposure significantly impaired autophagy in KCs. MgIG mitigated oxidative damage and restored autophagic activity through the AMPK/AKT signalling cascade. Notably, combined treatment with MgIG and NAC produced even greater protection against APAP-induced hepatic injury.<br><br>CONCLUSION: This study demonstrates that MgIG provides both protective and therapeutic effects in APAP-challenged mice with hyperglycaemia by modulating autophagy and oxidative stress in liver-resident macrophages.},
}
@article {pmid42039211,
year = {2026},
author = {Wang, W and Liu, C and Li, Y and Zheng, Y and Dou, Q},
title = {Pathogenesis of MRSA-influenza co-infection: implications for ECMO therapeutic strategies - a mini-review.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1741603},
pmid = {42039211},
issn = {1664-3224},
mesh = {Humans ; *Methicillin-Resistant Staphylococcus aureus/pathogenicity/immunology ; *Extracorporeal Membrane Oxygenation/methods ; *Coinfection/therapy/microbiology ; *Influenza, Human/therapy/immunology/virology/complications/microbiology ; *Staphylococcal Infections/therapy/microbiology/immunology ; Animals ; *Influenza A virus ; },
abstract = {Influenza virus (Influenzavirus A) and Staphylococcus aureus (S. aureus) co-infection is a critical clinical challenge, often leading to severe complications such as necrotizing pneumonia. This review elucidates the mechanisms by which influenza virus facilitates S. aureus infections through epithelial damage and immune modulation, thereby exacerbating pulmonary injury. Specifically, influenza virus infection damages respiratory epithelial cells and disrupts the integrity of the lung barrier. This process facilitates the invasion of S. aureus, which produces various virulence factors, including Panton-Valentine leukocidin (PVL) and phenol-soluble modulins (PSMs), leading to enhanced inflammation and tissue destruction. Furthermore, methicillin-resistant S. aureus (MRSA) strains are associated with higher morbidity and mortality due to their resistance to beta-lactam antibiotics and increased toxin production. Understanding the interplay between influenza virus-induced epithelial damage and S. aureus toxin-mediated immune responses is crucial for developing effective therapeutic interventions to mitigate the severity of necrotizing pneumonia. This review also explores the potential roles of adjunctive therapies, such as extracorporeal membrane oxygenation (ECMO) and novel agents like intravenous immunoglobulin (IVIG) and N-acetylcysteine (NAC), in redefining treatment paradigms for these severe infections.},
}
@article {pmid42041773,
year = {2026},
author = {Altintop, I and Tatli, M and Sarica, ZS and Yay, AH and Karakukcu, &#xc7;},
title = {Investigation of Contrast-Induced Neurotoxicity and the Effects of Sildenafil and N-Acetylcysteine on HIF-1α Levels in Wistar Rats.},
journal = {Brain sciences},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/brainsci16040362},
pmid = {42041773},
issn = {2076-3425},
abstract = {BACKGROUND: Contrast-induced encephalopathy (CIE) is an uncommon yet clinically significant complication associated with iodinated contrast media, with its mechanisms remaining unclear.<br><br>OBJECTIVE: The aims of this study are to examine the neurotoxic effects of contrast media and assess the neuroprotective roles of N-Acetylcysteine (NAC) and sildenafil with regard to HIF-1&#x3b1; expression.<br><br>METHODS: Thirty-six female Wistar albino rats (n = 36) were allocated into four experimental groups (n = 9 each): control, contrast media + saline (CMA + Saline), contrast media + NAC (CMA + NAC), and contrast media + sildenafil (CMA + Sildenafil). NAC (150 mg/kg) and sildenafil (50 mg/kg/day) were administered intragastrically for 48 h before exposure to contrast media. Biochemical, histopathological, and immunohistochemical evaluations were conducted 48 h post-contrast administration.<br><br>RESULTS: Exposure to contrast media resulted in neuronal death, vascular obstruction, and increased hypoxia-inducible factor-1 alpha (HIF-1&#x3b1;) immunoreactivity. The primary outcome measure, tissue HIF-1&#x3b1; concentration by ELISA, did not differ significantly among groups (p = 0.119). Semi-quantitative immunohistochemical analysis revealed significant group differences in HIF-1&#x3b1; immunoreactivity (p < 0.001), with all injury/treatment groups differing significantly from control. The difference between the contrast media group and the sildenafil-treated group approached but did not reach statistical significance after correction for multiple comparisons (Dunn's test, p = 0.050).<br><br>CONCLUSIONS: The primary biochemical endpoint did not demonstrate significant group differences. Secondary IHC analysis suggests a potential attenuation of HIF-1&#x3b1; immunoreactivity by sildenafil, though this did not reach statistical significance and requires confirmation in adequately powered studies. HIF-1&#x3b1; immunoreactivity warrants further investigation as a potential biomarker for contrast-induced neural injury.},
}
@article {pmid42042073,
year = {2026},
author = {Cho, MD and Chou, SY and Hsu, YM and Li, CY and Tsai, YH and Chang, FR},
title = {Curcumin Attenuates LPS-Induced Migration/EMT and LPS/ATP-Associated IL-1β Release in Androgen-Independent Prostate Cancer Cells.},
journal = {Current issues in molecular biology},
volume = {48},
number = {4},
pages = {},
doi = {10.3390/cimb48040413},
pmid = {42042073},
issn = {1467-3045},
support = {KMSH-11303//Kaohsiung Municipal Min-Sheng Hospital/ ; },
abstract = {Inflammation can promote aggressive phenotypes in prostate cancer, including enhanced migration/EMT-like changes and inflammasome-associated cytokine release. Here, we examined whether curcumin modulates these inflammation-driven responses in androgen-independent prostate cancer cells. PC-3 and DU145 cells were treated with curcumin (10 or 25 μM) or N-acetylcysteine (NAC; 2 mM). Sub-cytotoxic dosing was defined by CCK-8 viability assays. LPS (0.5 μg/mL) was used to induce motility-, invasion-, and EMT-associated responses, assessed by wound-healing assay, Matrigel-coated Transwell invasion assay, and RT-qPCR of SNAI1, CDH1, and VIM. Intracellular ROS was quantified by CM-H2DCFDA flow cytometry. Inflammasome-associated and EMT-related protein changes were evaluated under LPS priming (24 h) followed by ATP triggering (5 mM, 1 h), with NLRP3, cleaved caspase-1, cleaved IL-1β, vimentin, and E-cadherin assessed by immunoblotting and IL-1β secretion measured by ELISA. Curcumin at 10-25 μM did not cause overt cytotoxicity and significantly reduced LPS-induced wound closure and invasive activity in both cell lines, accompanied by attenuation of EMT-associated transcriptional changes and a decrease in ROS-positive events. Under LPS priming/ATP triggering, inflammasome-associated protein signals and IL-1β secretion were robustly induced; curcumin suppressed IL-1β release and attenuated NLRP3, cleaved caspase-1, and cleaved IL-1β signals, while reversing vimentin/E-cadherin changes. NAC produced similar inhibitory patterns, supporting a redox-linked contribution to these responses. Collectively, curcumin dampens inflammation-driven motility/invasion, EMT-associated changes, and inflammasome-associated responses in androgen-independent prostate cancer cells.},
}
@article {pmid42033411,
year = {2026},
author = {Zolfaghari, M and Najafi, A and Aghajani, A and Bahrami-Samani, F},
title = {Idiopathic Intracranial Hypertension Associated With Therapeutic-Dose N-Acetylcysteine in a 6-Year-Old Boy: A Case Report.},
journal = {Journal of child neurology},
volume = {},
number = {},
pages = {8830738261427554},
doi = {10.1177/08830738261427554},
pmid = {42033411},
issn = {1708-8283},
abstract = {Pediatric pseudotumor cerebri syndrome (PTCS) is an uncommon cause of raised intracranial pressure in children. We report a case of PTCS temporally associated with standard-dose oral N-acetylcysteine (NAC). A 6-year-old boy (20 kg) presented with 1 week of worsening nocturnal headaches, vomiting, and photophobia. Examination revealed bilateral optic disc swelling. Brain magnetic resonance imaging and magnetic resonance venography were normal. Lumbar puncture showed an opening pressure of 80 cm H2O and normal cerebrospinal fluid composition. The patient had been treated with oral NAC 200 mg twice daily for 4 weeks before symptom onset. Acetazolamide and topiramate were started with no improvement; symptoms and papilledema improved rapidly within 24 hours of NAC discontinuation. The patient remained asymptomatic at 6 months of follow-up. This case suggests a possible association between therapeutic-dose NAC and intracranial hypertension. Clinicians should consider medication-induced PTCS in children who present with new-onset headaches and papilledema. Further pharmacovigilance and reporting are warranted.},
}
@article {pmid42035602,
year = {2026},
author = {Sun, YS and Chang, CJ and Chang, TM and Chen, P and Liu, JF},
title = {Ganoderma Microsporum immunomodulatory protein suppresses osteosarcoma growth through redox imbalance and ER stress-driven apoptosis.},
journal = {Bioorganic chemistry},
volume = {177},
number = {},
pages = {109909},
doi = {10.1016/j.bioorg.2026.109909},
pmid = {42035602},
issn = {1090-2120},
abstract = {Osteosarcoma (OS) is an aggressive bone malignancy with limited therapeutic advances and persistent chemoresistance, highlighting the need for safer and more effective treatments. Ganoderma microsporum immunomodulatory protein (GMI) is a fungal-derived bioactive molecule with reported antitumor activity, yet its effects in OS remain unknown. Here, we investigated the anticancer potential and mechanisms of GMI in osteosarcoma. GMI selectively reduced the viability of HOS and U2OS cells while exhibiting low toxicity toward normal osteoblasts. GMI induced morphological alterations, chromatin condensation, reduced colony formation, apoptosis, and G2/M arrest. RNA sequencing identified 292 upregulated and 158 downregulated genes, indicating suppression of DNA repair, proliferation, cell-cycle progression, and mitochondrial pathways, alongside activation of autophagy-related signatures. Mechanistically, GMI elevated intracellular reactive oxygen species (ROS), and N-acetylcysteine (NAC) attenuated GMI-induced apoptosis and restored viability. GMI-induced ER stress was associated with JNK activation, and sustained JNK activation disrupts the balance of BCL-2 family proteins by repressing anti-apoptotic BCL-2 and augmenting pro-apoptotic members, thereby driving mitochondria-dependent apoptosis in osteosarcoma cells. In addition, GMI treatment increases the formation of acidic vesicular organelles and autophagosome-like structures, accompanied by elevated LC3B-II and reduced p62 levels. Pharmacological blockade of autophagy using Baf A1, CQ, or 3-MA further augments GMI-induced apoptosis and exacerbates the reduction in cell viability. Finally, GMI significantly inhibited tumor growth in a xenograft model without affecting body weight. These findings identify GMI as a promising natural therapeutic candidate for osteosarcoma and warrants further preclinical and translational evaluation.},
}
@article {pmid42036056,
year = {2026},
author = {Wang, LQ and You, HN and Xu, QJ and Yu, WJ and Wu, XM and Pang, XQ and Chen, XX and Du, WB and Qiao, QF and Li, JA and Zhou, YM and Zhou, YJ},
title = {Pesticide beta-cypermethrin impairs endometrial decidualization and embryo implantation by suppressing autophagy through oxidative stress.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112107},
doi = {10.1016/j.cbi.2026.112107},
pmid = {42036056},
issn = {1872-7786},
abstract = {Beta-cypermethrin (β-CYP), a widely used synthetic pyrethroid and potential endocrine disruptor, is linked to adverse reproductive outcomes, yet the mechanisms by which it impairs early pregnancy remain unclear. Endometrial decidualization is often defective in pregnancy loss; however, how β-CYP disrupts this critical process is not fully defined. Here, we investigated the molecular basis of β-CYP-induced implantation failure in mice, focusing on the interplay between oxidative stress (OS) and autophagy in decidualization. Our results demonstrate that β-CYP significantly reduced implantation sites and suppressed decidualization markers both in vivo and in vitro. β-CYP triggered excessive OS in uterine decidua and endometrial stromal cells, as evidenced by elevated reactive oxygen species, malondialdehyde, and lactate dehydrogenase, alongside disruption of the glutathione antioxidant system. Concomitantly, autophagy was inhibited, indicated by a decreased LC3-II/LC3-I ratio, reduced Beclin1, ULK1, and ATG5 levels, and increased P62 accumulation. Mechanistically, OS acted upstream of autophagy suppression; quenching OS with N-Acetylcysteine (NAC) restored autophagic activity and partially rescued decidualization. Conversely, enhancing autophagy with trehalose (Tre), was sufficient to reverse β-CYP-impaired decidualization. The protective effect of NAC was abolished by co-treatment with the autophagy inhibitor 3-Methyladenine (3-MA), confirming that autophagy restoration is required for its rescue effect. Collectively, these findings identify a causal pathway wherein β-CYP-induced OS inhibits autophagy, thereby disrupting endometrial decidualization and compromising embryo implantation.},
}
@article {pmid42033169,
year = {2026},
author = {},
title = {RETRACTION: Ameliorative Effect of N-acetyl Cysteine on Alpha-Cypermethrin-Induced Pulmonary Toxicity in Male Rats.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.70112},
pmid = {42033169},
issn = {1522-7278},
}
@article {pmid42028010,
year = {2026},
author = {Zhang, Z and Yu, Z and Shi, H and Ding, T and Shi, Y and Zhao, J and Cai, K and Wang, F},
title = {High sucralose exposure in early pregnancy increases the susceptibility of heart defects in mice offspring.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115603},
pmid = {42028010},
issn = {2589-0042},
abstract = {Maternal sucralose exposure during pregnancy has been demonstrated to interfere embryonic development, yet limited studies have investigated its potential hazards on fetal cardiogenesis. In the present study, we employed a mice model to investigate the impact of sucralose exposure in early pregnancy on the risk of heart defects in offspring. Pregnant C57BL/6J mice received either control or sucralose water. The incidence of heart defects in the sucralose group was 13.86%, significantly higher than that in the control group. Transcriptional downregulation of cardiogenic genes involving Gata4, Nkx2.5, Tbx5, and Tbx20 were confirmed, potentially due to increased CREB phosphorylation. N-acetylcysteine (NAC) reduced CREB phosphorylation, partially reversed sucralose-induced suppression of cardiogenic genes, and reduced the incidence of heart defects from 16.67% to 4.81%. Our study demonstrates that sucralose exposure during early pregnancy increases the risk of heart defects via transcriptional suppression of cardiogenic genes, while NAC potentially functions as a protective factor.},
}
@article {pmid42030847,
year = {2026},
author = {Tang, Q and Wang, Y and Wang, Y and Qi, H and Hu, J and Xu, L and Li, J},
title = {Coexposure to heat stress and polystyrene nanoplastics induces neuroinflammation and cognitive impairment via oxidative stress-NLRP6-pyroptosis axis.},
journal = {Journal of hazardous materials},
volume = {511},
number = {},
pages = {142151},
doi = {10.1016/j.jhazmat.2026.142151},
pmid = {42030847},
issn = {1873-3336},
abstract = {Global warming and plastic pollution constitute interconnected environmental threats. However, their combined neurotoxic effects, particularly in the context of climate change-driven temperature rise, remain unexplored, posing a critical knowledge gap for environmental health risk assessment. To address this gap, we developed a mouse model subjected to coexposure to heat stress (36 °C, 4 h/day) and well-characterized polystyrene nanoplastics (PS-NPs, 60 nm, 10 mg/kg/day) for 30 consecutive days. Multidisciplinary approaches, including behavioral testing, histopathological analysis and molecular profiling, were employed to assess cognitive dysfunction and its underlying mechanisms. Compared with the single-exposure groups, coexposure induced pronounced cognitive deficits in mice, which were concomitant with hippocampal neurodegeneration, bloodbrain barrier (BBB) compromise, and exacerbated hippocampal oxidative stress. Transcriptomic profiling and subsequent validation revealed a novel role for oxidative stress-induced NLR family pyrin domain containing 6 (NLRP6) inflammasome activation in driving microglial pyroptosis, which exacerbates neuroinflammation through a feedforward loop. The administration of the antioxidant N-acetylcysteine (NAC) attenuated these pathological alterations by suppressing oxidative damage, thereby rescuing cognitive performance. This study elucidates a novel mechanism whereby heat stress and PS-NP coexposure synergistically disrupt neurological homeostasis via redox-sensitive inflammatory pathways, offering critical insights for the development of preventive strategies against combined environmental neurotoxicity.},
}
@article {pmid42031158,
year = {2026},
author = {Sabo, AN and Filaudeau, E and Lebert, A and Da Silva, S and Becker, G and Monassier, L and Kemmel, V},
title = {Nicotine alters alveolar-barrier integrity by blocking autophagy and occludin trafficking.},
journal = {Toxicology},
volume = {},
number = {},
pages = {154474},
doi = {10.1016/j.tox.2026.154474},
pmid = {42031158},
issn = {1879-3185},
abstract = {Tobacco smoke inhalation disrupts the integrity of the alveolar-capillary barrier (ACB) and contributes to the pathogenesis of multiple chronic pulmonary diseases as chronic obstructive pulmonary disease (COPD). Nicotine, a major component of both cigarette smoke and electronic cigarette (e-cigarette) aerosol, is predominantly deposited on the alveolar surface, where it is rapidly absorbed, yet its specific contribution to ACB dysfunction remains insufficiently characterized. Our objective was to decipher the effects of nicotine across a wide concentration range (2.5µM to 250mM) on the modulation of the ACB in vitro. To this end, the following endpoints were investigated: cell viability (MTS and BrdU assays), cytotoxicity (LDH assay), mitochondrial oxidative stress (MitoSOX assay) and barrier integrity using Trans-Epithelial/Endothelial Electric Resistance (TEER) following exposure to increasing nicotine concentrations. Autophagic flux (LC3B-II, p62 and LAMP2 protein expression and localization) and occludin modulation and trafficking were also examined and compared with the effects of bafilomycin A1. Nicotine exposure slowed cell proliferation and enhanced mitochondrial reactive oxygen species (ROS) production, effects that were partially reversed by N-acetyl-cysteine (NAC). Nicotine inhibited autophagic flux through a mechanism distinct from that of bafilomycin A1, and this inhibition was partially reversed by NAC. In parallel, nicotine compromised barrier integrity, inducing a TEER decrease associated with occludin internalization and defective lysosomal degradation and recycling. These findings identify nicotine as an independent disruptor of ACB integrity, acting through oxidative stress, impaired autophagy and junctional remodeling, mechanisms relevant to smoking-related pulmonary diseases beyond COPD, including those associated with e-cigarette use.},
}
@article {pmid42031227,
year = {2026},
author = {Kim, JE and Wang, SH and Kang, TC},
title = {Oxidative stress-induced mitochondrial fragmentation inhibits CREB-mediated PV regulation and facilitates caspase-3-mediated PV neuronal degeneration following status epilepticus.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110990},
doi = {10.1016/j.neuropharm.2026.110990},
pmid = {42031227},
issn = {1873-7064},
abstract = {Parvalbumin (PV)- expressing neurons (PV neurons) are a subpopulation of γ-aminobutyric acid (GABA)-ergic interneurons that are highly vulnerable to oxidative stress. Although mitochondrial homeostasis is an essential housekeeping function for maintaining PV expression level, the underlying mechanisms of PV downregulation caused by aberrant mitochondrial dynamics are largely unknown. In this study, using an in vivo male rat model, we found that oxidative stress induced by L-buthionine sulfoximine (BSO) reduced PV expression and cAMP-response-element-binding protein (CREB) serine (S) 133 phosphorylation through cyclin-dependent kinase 5 (CDK5)-dynamin-related protein 1 (DRP1)-mediated mitochondrial fission within hippocampal PV neurons under normal control conditions. These effects were ameliorated by roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission). Similar to BSO, WY14643-induced mitochondrial fission decreased PV expression and CREB S133 phosphorylation in PV neurons. Furthermore, CREB knockdown also led to PV downregulation without altering CDK5 activity or mitochondrial dynamics. Notably, these treatments did not lead to PV neuronal degeneration. In a pilocarpine-induced status epilepticus (SE) model, however, massive PV neuronal degeneration was observed accompanied by decreased CREB S133 phosphorylation and excessive mitochondrial fragmentation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 attenuated SE-induced PV neuronal degeneration by preserving CREB S133 phosphorylation and mitochondrial integrity. These findings indicate that the CDK5-DRP1-CREB pathway may evoke PV downregulation under sublethal oxidative stress and lead to irreversible PV neuronal degeneration under severe pathological conditions such as SE. Therefore, our findings suggest that this signaling pathway may be a therapeutic target to preserve PV neurons in neurological and psychiatric diseases.},
}
@article {pmid42021860,
year = {2026},
author = {Wi, GH and Oh, SH},
title = {The resveratrol-induced apoptosis and/or necroptosis of lung cancer cells is dependent on the activation status of PARP-1 and MLKL under oxidative stress.},
journal = {Toxicological research},
volume = {42},
number = {3},
pages = {383-393},
pmid = {42021860},
issn = {1976-8257},
abstract = {UNLABELLED: While numerous studies have described the anticancer effects of resveratrol (RES), some aspects of its underlying molecular mechanisms remain to be elucidated. In this study, we investigated the molecular mechanisms by which RES attenuates lung cancer progression. RES inhibited cell growth by blocking G1/S and G2/M transitions in a concentration-dependent manner. It also concentration-dependently increased the number of cells with apoptotic nuclei. This effect was associated with caspase-9-dependent apoptosis and with necroptosis induced by phospho-receptor interacting protein 1 (P-RIP1) and phospho-mixed lineage kinase domain-like protein (P-MLKL) downstream of apoptosis. Furthermore, RES treatment induced poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, which was enhanced by NAD[+] supplementation, leading to increased apoptosis and necroptosis. Conversely, PARP-1 inhibition decreased P-RIP1 and P-MLKL levels, thereby suppressing necroptosis while simultaneously increasing apoptosis. Therefore, the PARP-1 and MLKL activation status plays a crucial role in RES-induced cell death. RES induced the degradation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidants, including heme oxygenase-1 (HO-1) and disrupted the mitochondrial membrane potential. Hemin-induced HO-1 upregulation counteracted RES-induced Nrf2 degradation and increased PARP-1 activation-mediated necroptosis. Compared with RES, N-acetylcysteine (NAC) slightly reduced RES-induced Nrf2 and HO-1, but upregulated catalase and SOD2 and increased PARP-1 cleavage and P-γH2AX level. RES or NAC treatment alone reduced hemin-induced reactive oxygen species (ROS) levels but generated ROS when combined. This suggests that RES scavenges ROS, and their excessive removal by NAC may paradoxically generate more of them. In conclusion, RES exerts anticancer effects through cell cycle arrest, mitochondria-mediated apoptosis, and PARP-1 hyperactivation-mediated necroptosis.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43188-026-00351-1.},
}
@article {pmid42021924,
year = {2026},
author = {Nahm, WJ and Falanga, V and Chen, R and Sakunchotpanit, G and Kim, KJ and Lee, DA and Koo, J},
title = {Treatment of recurrent facial ulcerations and dysesthesias from trigeminal trophic syndrome with chronic transcutaneous vagus nerve stimulation.},
journal = {JAAD case reports},
volume = {71},
number = {},
pages = {137-141},
pmid = {42021924},
issn = {2352-5126},
}
@article {pmid42022959,
year = {2026},
author = {Gocen, ES and Demirtas, F and Akar, H and Erdemir, GY},
title = {TAPP-based fluorescent probes for selective cysteine detection: insights into structure-reactivity relationships.},
journal = {RSC advances},
volume = {16},
number = {23},
pages = {20747-20755},
pmid = {42022959},
issn = {2046-2069},
abstract = {Herein, a series of TAPP-based π-conjugated fluorescent probes functionalized with aldehyde, malononitrile, and cyanoacrylate groups were designed and synthesized to investigate structure-reactivity relationships in cysteine (Cys) sensing. The photophysical properties of the probes were systematically examined in THF, DCM, and DMSO. The results revealed that the absorption and emission features are primarily governed by π-π* transitions localized on the TAPP framework, while the terminal acceptor groups mainly modulate the electronic distribution without significantly altering the ground-state transitions. Among the investigated derivatives, only the aldehyde-functionalized probe exhibited a pronounced "turn-on" fluorescence response toward Cys. This behavior is attributed to a reaction-based sensing mechanism involving the formation of a thiazolidine ring between the aldehyde group and Cys. The proposed mechanism is supported by complementary spectroscopic analyses, including [1]H NMR and HRMS, which confirm the consumption of the aldehyde group and the formation of a new product species. The probe displayed rapid response kinetics, reaching a stable fluorescence signal within approximately 50 s, and exhibited high selectivity for glutathione (GSH) over N-acetylcysteine (NAC), other amino acids, inorganic sulfur species, and metal ions. Fluorescence titration experiments showed a linear response over 0-15 µM, with a low limit of detection (LOD) of 0.37 µM. Furthermore, pH-dependent studies demonstrated that the probe operates effectively under near-physiological conditions. Spiking experiments yielded satisfactory recovery values, confirming its practical applicability. Overall, this study not only presents a sensitive and selective fluorescent probe for cysteine detection but also provides mechanistic insight into how terminal group functionality governs reaction-based sensing behavior in TAPP-based systems.},
}
@article {pmid42015439,
year = {2026},
author = {Rafique, B and Arshad, AR and Sabir, S and Ijaz, U and Rahman, OU},
title = {N-acetylcysteine as Prophylaxis Against Contrast-Induced Nephropathy: A Meta-Analysis.},
journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP},
volume = {36},
number = {4},
pages = {508-519},
doi = {10.29271/jcpsp.2026.04.508},
pmid = {42015439},
issn = {1681-7168},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Contrast Media/adverse effects ; *Acute Kidney Injury/chemically induced/prevention &amp; control ; Renal Dialysis ; Administration, Oral ; Incidence ; },
abstract = {This study aimed to determine the effect of N-acetylcysteine (NAC) in preventing contrast-induced nephropathy. A literature search was carried out in PubMed and Cochrane CENTRAL, and 49 studies were finally included. With oral NAC, there was no difference in the incidence of acute kidney injury (AKI; OR: 1.00; 95% CI: 0.90- 1.11; p = 0.98), the need for haemodialysis (HD; OR: 0.94; 95% CI: 0.61- 1.46; p = 0.79), or mortality (OR: 1.08; 95% CI: 0.83- 1.41; p = 0.55). The results were not affected during subgroup analysis for low- or high-dose oral NAC. With intravenous (IV) NAC, there was no difference in the incidence of AKI (OR: 0.84; 95% CI: 0.67- 1.04; p = 0.19), the need for HD (OR: 0.74; 95% CI: 0.19- 2.86; p = 0.66), or mortality (OR: 1.11; 95% CI: 0.67- 1.85; p = 0.68). Neither oral nor IV NAC decreases the risk of contrast-induced nephropathy. Key Words: Acetylcysteine, Acute kidney injury, Mortality, Renal dialysis.},
}
@article {pmid42020841,
year = {2026},
author = {Kumar, A and Bhaskar, M and Rani, R},
title = {Synergistic mitigation of lead [Pb(II)] stress in Triticum aestivum L. by heavy metal-tolerant plant growth-promoting (HMT-PGP) microbes and N-acetylcysteine (NAC).},
journal = {Plant cell reports},
volume = {45},
number = {5},
pages = {},
pmid = {42020841},
issn = {1432-203X},
abstract = {Synergistic application of N-acetylcysteine (NAC) and heavy metal-tolerant plant growth promoting (HMT-PGP)microbial consortia enhances Pb(II) phytostabilization and stress tolerance in Triticum aestivum L. by improvinggrowth, redox balance, and limiting metal uptake. This study emphasizes a synergistic approach using N-acetylcysteine (NAC) and heavy metal-tolerant plant growth-promoting (HMT-PGP) microbes to enhance lead [Pb(II)] phytostabilization in Triticum aestivum L. under hydroponic conditions. Though microbial consortia (MC) and NAC individually improved seed germination and viability, along with physiological and biochemical parameters under Pb(II) stress, the effects were more pronounced in the combined treatment (MC and NAC). In the combined treatment, seed germination, viability, amylase, and protease activities were found to increase by 20.7, 27.7, 21.4, and 10.82%, respectively, compared to the Pb(II)-stressed control (T1). Furthermore, combined treatment (NAC + MC) enhanced plant root, shoot length, biomass, and total chlorophyll by 46.9, 34.1, 21.6, and 45.6%, respectively, while total carotenoids and chlorophyll-carotenoid ratio decreased by 14.1 and 43.8%, respectively. Treatment with MC and NAC protected the plants against Pb(II) toxicity, as evidenced by significant declines in oxidative stress markers (hydrogen peroxide, malondialdehyde, proline) and in antioxidant enzyme activity. MC and NAC, individually and synergistically, restricted the Pb(II) uptake and accumulation in plants, thus leading to a significant reduction in bioconcentration (BCF) and translocation factor (TF) values. The BCF values for Pb(II) in the plants were 0.74 (untreated), 0.61 (MC), 0.67(NAC), and 0.58 (MC + NAC); while those for TF were 0.16, 0.11, 0.12, and 0.095, respectively. The treatments also promoted colonization of root endophytes. The findings suggest that MC and NAC, independently and synergistically, not only maintain redox homeostasis but also restrict Pb(II) entry in the plant. Therefore, it offers a novel approach for enhancing T. aestivum tolerance to Pb(II)-induced stress, promising avenues for sustainable agricultural practices and environmental remediation.},
}
@article {pmid41814419,
year = {2026},
author = {Chen, Y and Zhang, X and Pang, X and Yang, Y and Lu, D and Zhao, J and Zhu, J and Du, W and Gu, C and Li, J and Gu, L and Huang, JA and Liu, Z and Zeng, Y},
title = {SHMT2 inhibition triggers mitochondrial apoptosis to suppress lung adenocarcinoma progression.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {},
pmid = {41814419},
issn = {1479-5876},
support = {82272648//the National Natural Science Foundation of China/ ; 82202886//the National Natural Science Foundation of China/ ; SKY2022133//the Science and Technology Plan Project of Suzhou/ ; SKY2023160//the Science and Technology Plan Project of Suzhou/ ; GSWS2021001//Suzhou Gusu Medical Youth Talent/ ; ZDXK202201//Jiangsu Provincial Medical Key Discipline/ ; },
abstract = {BACKGROUND: Mitochondrial dysfunction has been implicated in various cancers, including non-small cell lung cancer (NSCLC). This study aimed to elucidate the role of mitochondrial dysfunction in NSCLC prognosis and the molecular mechanisms involved, particularly focusing on the Serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in mitochondrial metabolism.<br><br>METHODS: We analyzed the expression of SHMT2 in NSCLC tissue and its prognostic correlation by using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus Series (GSE81809) databases. Further, the CRISPR-Cas9 system was employed to establish SHMT2-knockout lung adenocarcinoma (LUAD) cell lines, assessing its impact on cell proliferation and apoptosis through various in vitro assays and in vivo nude mouse xenograft models. Mitochondrial homeostasis was evaluated by assessing the ROS levels, mitochondrial morphology, and membrane potential. Meanwhile, the SHMT2 inhibitor SHIN1 and the ROS scavenger N-Acetylcysteine (NAC) were employed to validate the underlying mechanism.<br><br>RESULTS: The results revealed that SHMT2 was significantly overexpressed in LUAD tissues and was associated with poor patient prognosis. SHMT2-knockout as well as SHIN1-treatment significantly inhibited the proliferation of LUAD cells and induced ROS-dependent mitochondrial apoptosis. Mechanistically, SHMT2 deficiency could increase the recruitment of BAX to mitochondria, reducing &#x394;&#x3a8;m, and release of Cytochrome C (Cyto C) from mitochondria, thereby activating the caspase cascade and initiating intrinsic mitochondrial apoptosis. NAC treatment can reverse the apoptosis and mitochondrial dysfunction induced by SHMT2 knockout. In vivo experiments further confirmed that SHMT2 knockout significantly inhibited tumor growth, whereas ROS scavenging attenuated its antitumor effects.<br><br>CONCLUSIONS: Our findings suggest that SHMT2 is vital for regulating LUAD apoptosis by maintaining mitochondrial ROS homeostasis, and its deficiency triggers apoptosis through the ROS-BAX-Cyto C-Caspase signaling. Targeting SHMT2 could thus offer new clinical insights and be a promising strategy for LUAD treatment.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07975-9.},
}
@article {pmid42011586,
year = {2026},
author = {Chen, J and Zhang, H and Guo, YJ and Li, JR and Liu, BB and Ji, ES and Li, DL},
title = {[Danggui Buxue Decoction delays vascular endothelial cell senescence induced by intermittent hypoxia through regulating Nrf2].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {5},
pages = {1390-1400},
doi = {10.19540/j.cnki.cjcmm.20251114.801},
pmid = {42011586},
issn = {1001-5302},
mesh = {Animals ; *NF-E2-Related Factor 2/metabolism/genetics ; *Drugs, Chinese Herbal/pharmacology/administration &amp; dosage ; *Cellular Senescence/drug effects ; *Endothelial Cells/drug effects/metabolism/cytology ; Mice ; Mice, Inbred C57BL ; Male ; Oxidative Stress/drug effects ; Sirtuin 1/metabolism/genetics ; *Hypoxia/metabolism/drug therapy/physiopathology/genetics ; },
abstract = {This study aims to explore the antioxidant molecular mechanism of Danggui Buxue Decoction(DBD) in delaying the vascular endothelial cell senescence induced by intermittent hypoxia(IH). The C57BL/6N mouse model of chronic intermittent hypoxia(CIH) was established under 5%-21% O_2, 20 cycles·h~(-1), 8 h·d~(-1) and administrated with DBD(4.68 g·kg~(-1)·d~(-1)) by gavage. The IH model of mouse thoracic aortic endothelial cells was established(0.1% O_2 3 min-21% O_2 7 min, 6 cycles·h~(-1)). The cells were then treated with the antioxidant N-acetylcysteine(NAC), DBD-containing serum, or DBD-containing serum plus nuclear factor-erythroid 2-related factor 2(Nrf2) siRNA. The vascular function, pathological changes, and the aging condition of the aorta tissue in mice were detected. The senescence status of cells, the level of oxidative stress, mitochondrial membrane potential, and the apoptosis level were measured via commercial kits. The expression levels of silent information regulator 1(SIRT1), tumor protein p53, superoxide dismutase 2(SOD2), nicotinamide adenine dinucleotide phosphate oxidase 2(NOX2), Kelch-like ECH-associated protein 1(Keap1), Nrf2, heme oxygenase-1(HO-1), B cell-lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), and cysteinyl aspartate-specific proteinase-3(Caspase-3) were determined by Western blot or Real-time fluorescence quantitative PCR. The results showed that DBD significantly improved the vascular function and attenuated the vascular endothelial damage and senescence in mice. Compared with the IH group, 5% DBD-containing serum or 1 mmol·L~(-1) NAC significantly increased the proliferation level of endothelial cells, promoted the expression of SIRT1, Nrf2, and HO-1 at protein and mRNA levels in endothelial cells, raised the expression level of SOD2, the mitochondrial membrane potential, and the mRNA level of Bcl-2, while significantly reducing the number of senescent cells, the expression of p53 and Keap1 at protein and mRNA levels, the content of reactive oxygen species in endothelial cells, the protein level of NOX2, and the mRNA levels of Bax and Caspase-3. The above-mentioned therapeutic effects were inhibited after intervention with Nrf2 siRNA. These results suggest that DBD alleviates the oxidative stress and inhibits the apoptosis of endothelial cells by activating the Nrf2 signaling pathway, thereby slowing down endothelial cell senescence under IH exposure.},
}
@article {pmid42012260,
year = {2026},
author = {Strojny, Z and Sikora, W and Hoffmann-Aulich, J and Kanikowska, D and Bręborowicz, A},
title = {Antisenescent and antiinflammatory effect of N-acetylcysteine in peritoneal mesothelial cells.},
journal = {Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis},
volume = {},
number = {},
pages = {8968608261443578},
doi = {10.1177/08968608261443578},
pmid = {42012260},
issn = {1718-4304},
abstract = {BackgroundPeritoneal dialysis induces an intraperitoneal inflammatory reaction, which causes damage to the peritoneum. Inflammation also accelerates cellular senescence. We studied in vitro effect of the dialysates from peritoneal dialysis patients on the senescence of the peritoneal mesothelial cells (MCs). The effect of N-acetylcysteine (NAC) on that process was studied.MethodsReplicative senescence was induced in MC cells exposed to culture medium, medium mixed with the dialysate ± NAC 0.025 mmol/L. After 10 passages, markers of the cellular senescence and secretory activity of the cells were measured. Additionally, the effect of NAC on the senescent cells was studied.ResultsExposure of MC to the dialysate accelerated, more than in medium alone, their senescence as reflected by elongation of the population doubling time, increased expression of p21, p53 genes and β-galactosidase activity. Secretion of IL6 and transforming growth factor β (TGFβ) was increased, and fibrinolytic activity, as reflected by the tissue plasminogen activator/plasminogen activator inhibitor-1 ratio, was reduced. NAC slowed down the process of senescence in MC treated with the dialysate. NAC suppressed the proinflammatory properties of the senescent MC.ConclusionThe proinflammatory properties of the peritoneal dialysate accelerate the senescence of MC. Decreased fibrinolytic activity of MC, increased secretion of IL6 and TGFβ may accelerate fibrosis of the peritoneum. Supplementation of NAC in patients treated with peritoneal dialysis may help preserve the peritoneum as the dialysis membrane.},
}
@article {pmid42013074,
year = {2026},
author = {Xu, H and Cao, M and Wang, Q and Ju, Y and Wang, X and Liu, Q and Zeng, T and Chen, X},
title = {Effects of N-acetyl-L-cysteine on sperm quality during chilled storage of Maguan hornless goat semen.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0347756},
doi = {10.1371/journal.pone.0347756},
pmid = {42013074},
issn = {1932-6203},
mesh = {Animals ; Male ; *Acetylcysteine/pharmacology ; *Semen Preservation/methods/veterinary ; *Spermatozoa/drug effects/metabolism ; Goats ; *Semen Analysis/veterinary ; Reactive Oxygen Species/metabolism ; *Semen/drug effects/metabolism ; Apoptosis/drug effects ; Antioxidants/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Sperm Motility/drug effects ; },
abstract = {The Maguan hornless goat is a valuable indigenous goat breed in Yunnan Province, China. As a rare and endangered genetic resource, its population protection and breeding are challenged by numerous challenges, particularly during artificial insemination procedures. During chilled storage, sperm generate excessive levels of reactive oxygen species (ROS), which disrupt the integrity of the sperm plasma membrane, damage the celluar structures, and lead to a decline in semen quality. This study investigated the effects of different concentrations (0, 5, 7, 9 mM) of N-acetylcysteine (NAC) on the chilled storage of semen collected from Maguan hornless goats. Semen was collected from four healthy rams with normal reproductive performance. The different concentrations of NAC were added to the semen diluent, and the samples were diluted 10-fold prior to storage at 4 °C for up to 72 h. After defining storage intervals, sperm kinetics, antioxidant gene transcription, and oxidative stress-related enzymatic activity were analyzed. Results showed that sperm samples extended in diluent supplemented with 7 mM NAC and subjected to 72 h of chilled storage at 4 ℃ exhibited improved antioxidant levels. This approach also reduced sperm apoptosis, enhanced membrane integrity and mitochondrial membrane potential, and suppressed the expression of pro-apoptotic genes (BAX, Caspase 3) while upregulating that of antioxidant genes (GPX4, GPX1). The results suggest NAC supports semen chilled storage in endangered species by enhancing antioxidant capacity and inhibiting cell death-related pathways. This study provides insights into the application of reproductive biotechnology in small ruminants.},
}
@article {pmid42013574,
year = {2026},
author = {Hartmann, RJ and Pradhan, S and Bylyku, D and Markieta, K and Scozzafava, J and Lucyk, S and Yarema, M},
title = {Cerebral Edema and Brain Death Following Intravenous N-Acetylcysteine Overdose: A Case Report.},
journal = {Canadian journal of physiology and pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1139/cjpp-2025-0341},
pmid = {42013574},
issn = {1205-7541},
abstract = {N-acetylcysteine (NAC) infusions are rarely associated with cerebral edema. We present a patient that received 1242.2 mg/kg intravenous NAC over 8.3 hours who developed seizures, cerebral edema, and died. A 17-24 year-old female (48.3 kg) presented after an acute acetaminophen ingestion. Their initial presumed five-hour acetaminophen concentration was 591.7 umol/L. Initial ALT and AST were 16 and 21 IU/L, respectively. Due to inconsistencies in the time of ingestion, IV NAC was initiated as a two-step protocol of 150 mg/kg over one hour followed by 15 mg/kg/hr for 20 hours. During treatment, the patient developed vomiting, flushing, and a maculopapular rash. It was discovered that NAC had been administered continuously at 150 mg/kg/hr for 8.3 hours and was stopped. The patient became confused and agitated, and subsequently developed seizures. They were treated with lorazepam, phenytoin, intubation, and propofol. Neuroimaging demonstrated cerebral edema with cerebellar tonsillar herniation. Despite neurocritical care, the patient died 86 hours post-ingestion. The patient's ALT and AST remained normal. Investigations including lumbar puncture and post-mortem toxicology analysis was unremarkable. Clinicians must be aware of the clinical features of supratherapeutic IV NAC dosing errors and potential adverse effects.},
}
@article {pmid42014372,
year = {2026},
author = {Fu, YY and Zhou, YF and Hu, HJ and Liu, YR and Zhang, ZQ and Han, GZ},
title = {Silica Promotes Silicosis via the ROS/NF-κB p65 Signaling-Activated Hypoxia-Lactate Axis in Rats.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70209},
pmid = {42014372},
issn = {1099-1263},
support = {202512041350//Medical and Health Science and Technology Development Project of Shandong Province/ ; },
abstract = {Hypoxia occurs during silicosis progression; however, the mechanisms by which silica induces hypoxia and its precise role in the pathogenesis remain poorly understood. In this study, 50 male rats were assigned to five groups: a control group, a model group, and three intervention groups. The rats in the model and intervention groups were intratracheally administered a silica suspension only once, whereas the control rats were intratracheally administered phosphate buffer solution (PBS). Then the rats in intervention groups received daily intravenous injections of N-acetylcysteine (NAC) (at doses of 20, 40, and 80 mg/kg, respectively) while the rats in control and model groups received PBS injections. After 60 days, the lung samples were harvested for histopathologic evaluation, and the hypoxia-related proteins (nuclear factor-κB p65 [NF-κB p65], hypoxia-inducible factor-1α [HIF-1α], and vascular endothelial growth factor A [VEGFA]), lactate-metabolism markers (glucose transporter type 1 [GLUT1] and lactate dehydrogenase A [LDHA]), and pulmonary-injury indicators (interleukin-1β [IL-1β] and transforming growth factor-β1 [TGF-β1]) were quantified using Western blot. The results showed that compared with the control group, the lung of the model group exhibited obvious damage and collagen deposition, accompanied by upregulation of the aforementioned cytokines. When NAC was employed to inhibit silica-induced ROS, all of the above phenomena were reversed in a dose-dependent manner. These findings indicated that silica induced pulmonary hypoxia via the ROS/NF-κB p65 pathway, which subsequently triggered inflammation and fibrosis through lactic acid fermentation, ultimately leading to silicosis.},
}
@article {pmid41999222,
year = {2026},
author = {Ou, C and Bai, ZP and Hu, GH and Chen, B and Wu, DH and Long, HJ},
title = {Rougan Tongluo Decoction Initiates Neuroprotection Against Cerebral Ischemia by Activating the Endogenous SLC6A8-Creatine-EARS2 Mitochondrial Pathway.},
journal = {Mediators of inflammation},
volume = {2026},
number = {1},
pages = {e4419137},
doi = {10.1155/mi/4419137},
pmid = {41999222},
issn = {1466-1861},
support = {[2022] 75//2022 National Famous Elderly Chinese Medicine Experts Inheritance Workshop Construction Project/ ; kq2208145//Natural Science Foundation of Changsha City/ ; C202303078160//Hunan Provincial Health and Wellness Commission Scientific Research Program Project/ ; 2026JJ81855//Natural Science Foundation of Hunan Province/ ; },
mesh = {Animals ; Rats ; *Brain Ischemia/drug therapy/metabolism ; Male ; *Mitochondria/metabolism/drug effects ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Rats, Sprague-Dawley ; PC12 Cells ; *Creatine/metabolism ; *Neuroprotective Agents/therapeutic use ; Membrane Potential, Mitochondrial/drug effects ; Hippocampus/metabolism ; *Nerve Tissue Proteins/metabolism ; Cell Survival/drug effects ; },
abstract = {OBJECTIVE: The traditional Chinese medicine formula Rougan Tongluo Decoction (RGTL) was widely used to treat neurological injury after cerebral ischemia, though its specific underlying mechanisms remain unknown. This study investigates the mechanisms via which RGTL helps alleviate cerebral ischemic injury to provide theoretical support for its application in cerebral ischemia treatment.<br><br>METHODS: A middle cerebral artery occlusion reperfusion (MCAO/R) rat model was established and treated with RGTL, N-acetylcysteine (NAC), creatine, or sh-EARS2. Network pharmacology and metabolomics were conducted to analyze the key efficacy-related metabolites in the hippocampal tissue. An OGD/R cell model was constructed using PC12 cells and treated with creatine, RGTL-containing serum, sh-SLC6A8, and sh-EARS2. Neuronal damage in the hippocampal tissues was assessed using HE and Nissl staining. Neuronal cell viability, mitochondrial membrane potential, and ROS levels were measured using CCK8, JC-1, and DCFH-DA assays. Mitochondrial damage was determined using transmission electron microscopy. The expression of SLC6A8/EARS2 axis and mitochondrial-related proteins (cytochrome c [Cyt c]) was examined using RT-qPCR and Western blot.<br><br>RESULTS: RGTL treatment reduced TNF-&#x3b1;, IL-6, and ROS levels while increasing ATP and JC-1 in brain tissues of MCAO/R rats, thereby alleviating mitochondrial damage. The neuroprotective effects of RGTL were more pronounced than those of NAC. Succinic acid and creatine were identified as active drug ingredients and differential metabolites that may mediate RGTL's therapeutic effects via MMP3, GAMT, SLC6A8, and CASP3. Silencing SLC6A8 abolished the protective effects of creatine against OGD/R-induced neuronal cell apoptosis and mitochondrial damage. Creatine could bind to the EARS2 protein. Cell and animal experiments demonstrated that silencing EARS2 blocked the therapeutic effects of creatine in OGD/R and MCAO/R models, reversing its inhibition of neuronal apoptosis and mitochondrial damage.<br><br>CONCLUSION: Creatine mediates the neuroprotective effects of RGTL by binding to EARS2, thus inhibiting mitochondrial damage and neuronal apoptosis to improve ischemic brain injury.},
}
@article {pmid42001928,
year = {2026},
author = {Lin, Z and Hu, M and Li, R and Gong, X and Zhao, M and Zhang, H and Xuan, J and Qiao, W and Li, A},
title = {TDCIPP induces placental dysfunction and fetal growth restriction via oxidative stress-mediated PINK1/Parkin mitophagy.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {116103},
doi = {10.1016/j.fct.2026.116103},
pmid = {42001928},
issn = {1873-6351},
abstract = {Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphate flame retardant increasingly linked to reproductive toxicity, yet its placental toxic mechanisms remain unclear. This study demonstrates that TDCIPP exposure disrupts placental homeostasis by inducing oxidative stress, which triggers excessive PINK1/Parkin-mediated mitophagy in both human trophoblasts (HTR-8/SVneo) and pregnant mice. Integrated network toxicology analysis predicted mitochondrial dysfunction and oxidative stress as central pathways, validated by upregulation of ATG5 and HMOX1, downregulation of SOD2, elevated ROS and mitochondrial superoxide, loss of mitochondrial membrane potential, and ultrastructural evidence of mitophagic vacuoles. TDCIPP activated the PINK1/Parkin pathway-evidenced by increased PINK1, Parkin, LC3-II/I, p62, reduced TOMM20, and enhanced Parkin-TOMM20 colocalization-while alternative mitophagy receptors FUNDC1 and BNIP3 remained unaffected. Mechanistically, oxidative stress acted upstream, as N-acetylcysteine (NAC) pretreatment suppressed ROS accumulation and PINK1/Parkin activation. Functionally, TDCIPP impaired trophoblast proliferation, induced apoptosis, and caused fetal growth restriction (FGR) in vivo. Notably, both genetic knockdown of Parkin in vitro and pharmacological inhibition of mitophagy with Mdivi-1 in vivo significantly alleviated trophoblast apoptosis and rescued placental and fetal weights. These findings establish that TDCIPP-induced placental injury is driven by an oxidative stress-PINK1/Parkin-mitophagy axis, revealing dysregulated mitophagy as a pivotal mechanism underlying TDCIPP-associated developmental toxicity and offering new insights into the reproductive risks of environmental flame retardant exposure.},
}
@article {pmid42002801,
year = {2026},
author = {Luo, J and Wang, X and Ju, Y and Ji, Q and Li, R and Ruan, Y and Zhao, J and Long, Q and Shang, Y and Li, P and Cao, M and Chen, X},
title = {Dietary N-acetylcysteine enhances sperm motility by remodeling the rumen microbiome and its metabolic axis in goats.},
journal = {Journal of animal science and biotechnology},
volume = {17},
number = {1},
pages = {},
pmid = {42002801},
issn = {1674-9782},
support = {2021YFD1200403//National Key Research and Development Program/ ; GZNYJGHX-2023006//Guizhou Province Mountainous Agriculture Key Research Program/ ; Qian Kehe Platform Talent-CXTD[2023]025//Guizhou Province Mutton Sheep Genetic Improvement and Innovative Utilization Science and Technology Innovation Talent Team Project/ ; GCC[2022]021-1//Guizhou Province High-level Innovative"Hundred" Level Talent Project/ ; },
abstract = {BACKGROUND: Enhancing sperm motility is crucial for improving male fertility in ruminants. The rumen microbiota, central to nutrient metabolism of ruminants, represents a promising yet underexplored target for dietary intervention. This study investigated whether N-acetylcysteine (NAC) improves sperm motility via modulating the rumen microbiota-metabolite axis.<br><br>RESULTS: Dietary NAC supplementation significantly enhanced sperm motility in goats (P&#x2009;<&#x2009;0.05), with the optimal effect observed at 0.3%, which coincided with improvements in sperm membrane integrity, antioxidant capacity, and mitochondrial function. Functional analysis revealed that NAC-induced microbial remodeling enriched KEGG pathways involved in antioxidant, energy, and lipid metabolism. Correspondingly, beneficial bacteria such as Pediococcus pentosaceus, Bacteroides acidifaciens, and Akkermansia, among others, were significantly enriched (P&#x2009;<&#x2009;0.05). Notably, metabolic alterations in these pathways were consistently reflected in both the rumen fluid and plasma metabolomes, as evidenced by 25 conserved pathways and 2 overlapping metabolites. Collectively, these metabolic alterations ultimately enhanced sperm motility by improving sperm antioxidant status, energy supply, and lipid homeostasis.<br><br>CONCLUSIONS: Our study thus reveals that NAC enhances sperm motility via a rumen microbiome-mediated "rumen-plasma-sperm" axis. This novel insight broadens the understanding of how NAC-and potentially other antioxidants-regulates sperm motility, highlighting the promise of NAC-based dietary interventions for improving reproductive performance.},
}
@article {pmid42004260,
year = {2026},
author = {Zhu, R and Li, DL and Zhang, BY and Zhang, FF and Zhou, K and Qin, GX and Wu, LF and Xie, FX},
title = {N-Acetylcysteine alleviates glycinin-induced intestinal damage in common carp: Multi-target regulation inhibiting apoptosis and restoring mucosal barrier integrity.},
journal = {Animal nutrition (Zhongguo xu mu shou yi xue hui)},
volume = {25},
number = {},
pages = {310-326},
pmid = {42004260},
issn = {2405-6383},
abstract = {Glycinin is a major anti-nutritional factor in soybeans and can induce growth inhibition and intestinal damage in aquatic animals. N-Acetylcysteine (NAC) possesses antioxidant and anti-inflammatory properties while promoting intestinal mucosal development. Therefore, this study aimed to elucidate the protective effects and underlying mechanisms of NAC against glycinin-induced intestinal damage in common carp (Cyprinus carpio). A total of 450 juvenile common carp (2.93 ± 0.03 g) were randomly assigned to five groups: a control group (CK), an 8.00% glycinin-damaged group (Gly), and three NAC-treated groups receiving 0.15%, 0.30% and 0.60% NAC supplementation (Gly-N1, Gly-N2, and Gly-N3). Each group contained three replicates for a 56-d feeding trial. Results showed that dietary 0.30%-0.60% NAC supplementation effectively alleviated the glycinin-induced impairments in growth performance and feed utilization, while concurrently restoring intestinal protease activity and muscle protein deposition (P < 0.05). The NAC mitigated the intestinal morphological damage induced by glycinin, including mucosal fold atrophy and microvilli shedding, and enhanced barrier integrity by upregulating the mRNA expression of tight junction proteins occludin, claudin-3, claudin-7 and zo-1, and reducing intestinal permeability (P < 0.05). Intestinal transcriptome analysis indicated NAC's ameliorative effects involving inflammation- and apoptosis-related pathways. Mechanistically, NAC exerted multi-target protection: it inhibited the MAPK/PI3K-AKT/NF-κB inflammatory network by downregulating the phosphorylation of p38, JNK, PI3K and AKT, and the expression of NF-κB p65, thereby inhibiting pro-inflammatory cytokines IL-1β and TNF-α release (P < 0.05). Concurrently, NAC activated the Nrf2 antioxidant pathway to counteract oxidative stress. Furthermore, NAC inhibited the mitochondrial apoptosis pathway by modulating Bcl-2/Bax expression and inhibiting Caspases activation, while restoring ATPase activity and membrane potential to improve intestinal mitochondrial function. In summary, dietary supplementation with 0.30%-0.60% NAC alleviated glycinin-induced intestinal damage through a multifaceted mechanism involving inhibition of inflammatory signaling, activation of antioxidant defense, and inhibition of mitochondrial apoptosis.},
}
@article {pmid42000504,
year = {2026},
author = {Wu, M and Li, L and Zhao, T and Mao, Y and Lin, J and Li, X and Bai, Y and Han, F and Chen, S and Peng, T and Liao, C and Ye, X and Ke, H and Huang, Z and Yue, M and Che, Y and Song, Y and Chen, Z and An, G},
title = {Polystyrene microplastics disrupt the blood-testis barrier via CEBPB-driven lysosomal autophagy and induce ferroptosis-like injury in human sperm, compromising embryo development.},
journal = {Journal of hazardous materials},
volume = {510},
number = {},
pages = {142073},
doi = {10.1016/j.jhazmat.2026.142073},
pmid = {42000504},
issn = {1873-3336},
abstract = {Environmental exposure to microplastics, especially polystyrene microplastics (PS-MPs), poses growing concerns for male reproductive health. In this study, we demonstrate that PS-MPs internalize into Sertoli cells, triggering CEBPB-mediated lysosomal hyperactivation and the degradation of tight junction proteins, thereby impairing the structural integrity of the blood-testis barrier (BTB). Concurrently, PS-MPs accumulate in mature human sperm, damaging mitochondrial ultrastructure and inducing ROS-driven lipid peroxidation and ferroptosis-like injury. These alterations result in reductions in motility, DNA integrity, and early embryonic development following intracytoplasmic sperm injection (ICSI). Crucially, the antioxidant N-acetylcysteine (NAC) rescued sperm functional metrics and restored embryo quality. These findings reveal dual cellular pathways, disruption of both the barrier and sperm mitochondrial integrity, by which environmental PS-MPs impair male fertility. The study highlights NAC as a promising intervention and identifies chloroquine as a potent modulator of lysosome-mediated BTB disruption. The environmental relevance of PS-MPs and their mechanistic impact on human reproductive health underscore the urgent need for strategies to reduce pre-fertilization microplastic exposure.},
}
@article {pmid41993622,
year = {2026},
author = {Tucker, EW and Kim, J and Erice, C and Sharma, A and Damiba, NNL and Ordonez, AA and Allende Labastida, J and Sah, N and Mota, F and de Jesus, P and Saini, R and Schiaffino, KF and Jain, SK and Kannan, RM and Kannan, S},
title = {Host-directed nanotherapy for the treatment and imaging of tuberculous meningitis.},
journal = {Theranostics},
volume = {16},
number = {10},
pages = {5105-5124},
pmid = {41993622},
issn = {1838-7640},
mesh = {Animals ; *Dendrimers/chemistry/administration &amp; dosage ; Positron-Emission Tomography/methods ; *Tuberculosis, Meningeal/diagnostic imaging/drug therapy/therapy ; Rabbits ; Blood-Brain Barrier/metabolism ; Disease Models, Animal ; *Theranostic Nanomedicine/methods ; Microglia/metabolism ; Tissue Distribution ; Brain/diagnostic imaging ; },
abstract = {RATIONALE: Tuberculous meningitis (TB meningitis) is a devastating infection where the host immune response drives brain injury. Standard adjunctive corticosteroids often fail to prevent neurological sequelae or improve survival in many populations. Host-directed therapies that can cross the blood-brain barrier (BBB) and reduce neuroinflammation are urgently needed. We evaluated a hydroxyl-terminated polyamidoamine (PAMAM) dendrimer as a theranostic nanoplatform to visualize and treat microglia-mediated neuroinflammation in a young rabbit model of TB meningitis.<br><br>METHODS: A novel radiolabeled dendrimer ([124]I-dendrimer) was synthesized for noninvasive positron emission tomography (PET) imaging, with post-mortem gamma counting and fluorescent-labeled dendrimer (D-Cy5) confirming biodistribution. For therapy, rabbits with TB meningitis (i.e., infected) received weekly intravenous dendrimer-N-acetyl cysteine (D-NAC) or phosphate buffered saline (PBS). After two weeks, treatment efficacy was evaluated with longitudinal neurobehavioral scores and multimodal PET ([18]F-FDG for glucose metabolism, [18]F-py-albumin for BBB integrity, and [124]I-DPA-713 for microglial/macrophage activation). Post-mortem analyses included bacterial burden (colony-forming units [CFU]), cerebrospinal fluid (CSF) protein and cytokine levels, and brain immunohistochemistry for glial and white matter markers.<br><br>RESULTS: [124]I-Dendrimer demonstrated selective accumulation within brain lesions, co-localizing primarily with activated microglia. D-NAC significantly improved neurological outcomes and attenuated neuroinflammation and brain injury, even without antimicrobial therapy. Longitudinal PET imaging confirmed D-NAC efficacy, showing decreased neuroinflammation ([124]I-DPA-713) and improved BBB integrity ([18]F-py-albumin). Post-mortem analyses corroborated these findings, demonstrating that D-NAC reduced microglial inflammation and IL-17a levels, while improving myelination and BBB integrity.<br><br>CONCLUSIONS: This study establishes D-NAC as a promising host-directed theranostic strategy for TB meningitis and supports the clinical potential of dendrimer nanoplatforms to diagnose and treat central nervous system infections.},
}
@article {pmid41994792,
year = {2026},
author = {Bhalla, AK and Kumar, S and Verma, H and Sheth, G and Kumar, B and Mondal, R and Jayaraman, GV and N, N and Mitra, M},
title = {The Efficacy and Safety of N-acetylcysteine and Taurine (Nefrosave®) in Chronic Kidney Disease: A Double-Blind, Multicenter, Placebo-Controlled Trial (DELAY-CKD).},
journal = {Cureus},
volume = {18},
number = {3},
pages = {e105078},
pmid = {41994792},
issn = {2168-8184},
abstract = {Background and objective Chronic kidney disease (CKD) is a progressive disorder with declining renal function and an elevated risk for end-stage renal disease (ESRD) and mortality. While oxidative stress is implicated in its pathogenesis, treatment using antioxidants remains uncertain. This study aimed to evaluate the effectiveness of the combination of N-acetylcysteine (NAC; 150 mg) and taurine (500 mg) in CKD. Methods A multicenter, double-blind, randomized, placebo-controlled trial was conducted across India between February 2021 and October 2023. Consenting adults aged 18-65 years with CKD stages 1-3 and serum creatinine <3.0 mg/dL were enrolled. Participants received NAC+taurine (Nefrosave[®]) or an identical placebo twice daily for 180 days, in addition to standard of care (SOC) and a low-protein diet. Primary endpoints included mean changes in urinary albumin-creatinine ratio (uACR), serum cystatin C, and estimated glomerular filtration rate (eGFR) from baseline to day 180. Secondary endpoints included time to event (hemodialysis, renal transplantation, treatment escalation). Safety was analyzed on the basis of adverse events (AEs). Results Efficacy analysis was conducted in 80 of the 100 randomized participants (NAC+taurine+SOC: 42; placebo+SOC: 38). Early-stage CKD (stages 1 and 2) was identified in 11 (26.19%) and 11 (28.95%) participants in the test and control arms, respectively. Microalbuminuria was observed in 10 (23.81%) participants in the NAC+taurine+SOC arm and 14 (36.84%) in the placebo+SOC arm. An overall 18.57% reduction in uACR at day 180 was observed with NAC+taurine supplementation compared with placebo, including a 34.09% reduction in microalbuminuria and a 19.34% reduction in macroalbuminuria; the between-group difference reached statistical significance for microalbuminuria (p=0.043). Overall, cystatin C decreased by 21.46% in the NAC+taurine+SOC arm, representing a 39.17% greater reduction than in the placebo+SOC arm (p=0.079). The increase in serum creatinine was lower in the NAC+taurine+SOC arm (0.03 mg/dL (1.78%)) compared with placebo+SOC (0.19 mg/dL (11.52%)), resulting in an overall relative reduction of 9.74% in the test arm. Comparable relative reductions were observed in CKD stages 1 and 2 (27.43%) and among participants with microalbuminuria (20.41%) in the NAC+taurine+SOC arm compared with placebo+SOC. Modest increases in mean eGFR were observed with NAC+taurine supplementation in CKD stage 3a, although overall changes were comparable to placebo+SOC. No clinically significant events were reported. Mild AEs were reported in five participants in the test arm. Conclusions Adjunctive NAC+taurine (Nefrosave[®]) therapy was well tolerated and was associated with favorable trends in albuminuria and other renal biomarkers as compared to SOC. The between-group difference in uACR reached statistical significance in participants with microalbuminuria and early CKD, supporting the need for further evaluation of this adjunctive strategy in larger trials.},
}
@article {pmid41994801,
year = {2026},
author = {Mercola, J},
title = {Optimizing Brain Biology Through Near-Infrared-Induced Mitochondrial Melatonin Synthesis: A Hypothesis Paper.},
journal = {Cureus},
volume = {18},
number = {3},
pages = {e105322},
pmid = {41994801},
issn = {2168-8184},
abstract = {The human brain consumes approximately 20% of total energy production despite comprising only 2% of body mass, rendering neurons particularly vulnerable to oxidative damage. Modern indoor lifestyles have dramatically reduced exposure to near-infrared (NIR) radiation, a component of sunlight that penetrates biological tissues. Concurrently, age-related declines in both pineal melatonin production and mitochondrial function have been implicated in the pathogenesis of neurodegenerative diseases. Additionally, aging is associated with declining availability of glutathione precursors, particularly glycine and cysteine, which may limit endogenous antioxidant responses even when enzymatic capacity is preserved. This hypothesis paper synthesizes evidence from photobiomodulation (PBM) research, mitochondrial biology, and melatonin biochemistry to propose a mechanistic framework whereby NIR radiation activates mitochondrial melatonin synthesis, potentially triggering an antioxidant cascade that may confer neuroprotection. The framework explicitly incorporates the requirement for adequate glutathione precursor substrate availability as a potential rate-limiting factor. A targeted narrative synthesis informed the development of the proposed mechanistic framework. Peer-reviewed publications were identified through searches of PubMed, Web of Science, and Google Scholar (1990-2025) using terms related to PBM, mitochondrial melatonin, glutathione metabolism, and neuroprotection. Studies were selected based on relevance to the proposed framework, with emphasis on mechanistic studies, randomized controlled trials, and systematic reviews. Priority was given to publications from 2020 to 2025, while seminal foundational studies were retained regardless of publication date. Evidence supporting each component of the proposed cascade was categorized by strength to maintain transparency regarding the distinction between established findings and untested hypotheses. The proposed NIR-mitochondrial melatonin-glutathione cascade represents a biologically plausible mechanism for endogenous neuroprotection, contingent upon adequate substrate availability. While substantial evidence supports individual components, the integrated hypothesis requires rigorous experimental validation. Concurrent attention to glutathione precursor status through glycine and N-acetylcysteine (NAC) supplementation may be necessary to realize the full therapeutic potential of this approach.},
}
@article {pmid41987738,
year = {2026},
author = {Wang, AQ and Jin, XY and Luo, YH and Wu, N and Tang, YJ and Liu, YZ and Li, TZ and Jin, CH},
title = {Isoguanosine exerts anticancer effects in Huh-7 cells by modulating ROS-dependent MAPK and AKT signaling.},
journal = {Neoplasma},
volume = {},
number = {},
pages = {},
doi = {10.4149/neo_2026_251204N508},
pmid = {41987738},
issn = {0028-2685},
abstract = {Isoguanosine (ISO) is a naturally occurring bioactive compound with multiple pharmacological properties. In this study, the inhibitory effects of ISO on hepatocellular carcinoma (HCC) cells and its underlying molecular mechanisms were investigated. The cell viability after ISO treatment was assessed using the CCK-8 assay, trypan blue staining, and Hoechst 33342/PI double staining. The relevant targets of ISO and their regulatory mechanisms were predicted using network pharmacology and molecular docking technology. The induction of apoptosis by ISO on Huh-7 cells was detected by Annexin V-FITC/PI double staining combined with flow cytometry and western blotting. The cell cycle arrest effect of ISO on Huh-7 cells was detected by Ki-67 staining, flow cytometry, and western blotting. The migration-inhibition effect of ISO on Huh-7 cells was detected by the wound healing, Transwell, and western blotting. In addition, the effects of reactive oxygen species (ROS) and protein kinase B (AKT) on Huh-7 cells were investigated by using N-acetyl cysteine (NAC) and AKT inhibitor HY10249, respectively. Cell viability assays demonstrated that ISO exerts a significant cytotoxic effect on HCC cell lines. Network pharmacology analysis revealed that the core targets of ISO are associated with ROS, AKT, and mitogen-activated protein kinase (MAPK) signaling pathways. Molecular docking results indicate that ISO has a strong binding affinity for AKT1, CASP3, and GSK3B. Apoptosis assays indicated that ISO induces apoptosis in Huh-7 cells via the mitochondria-dependent pathway. Furthermore, ISO modulates apoptosis through the MAPK and signal transducer and activator of transcription 3 (STAT3) signaling pathways. Cell cycle assays showed that ISO induces G2/M phase arrest by elevating intracellular ROS levels. Migration assays demonstrated that ISO inhibits cell migration by regulating the AKT signaling pathway. In addition, pretreatment with NAC reversed ISO-induced apoptosis, cell cycle arrest, and inhibition of migration. ISO promotes apoptosis, induces cell cycle arrest, and inhibits Huh-7 cell migration. These findings provide a theoretical basis for further pharmacological research and support the potential development and application of ISO as an anticancer agent.},
}
@article {pmid41988466,
year = {2026},
author = {Huang, T and Li, H and Huang, X and Li, B and Zhang, H and Bai, X and Oliver, BG and Tian, M and Yi, C and Li, D and Chen, H},
title = {Daily intake of antioxidants ameliorates PM2.5-induced neuronal injury in mice.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1806418},
pmid = {41988466},
issn = {2296-861X},
abstract = {OBJECTIVE: Fine particulate matter (PM2.5) within polluted air is a significant health risk and a strong oxidant. Even exposure to low-level PM2.5 (at or below the WHO standard) is linked to neuroinflammatory, oxidative stress and the development of neurological disorders in the long term. This study aimed to investigate the prophylactic effects of antioxidant supplementation on mitigating sub-chronic exposure to low-level PM2.5-induced brain pathology in mice.<br><br>MATERIALS AND METHODS: Mice were exposed to traffic-derived PM2.5 (5&#x202f;&#x3bc;g/day) collected from a highway in Sydney, Australia, once daily for 3&#x202f;weeks, while receiving antioxidant, vitamin C (10&#x202f;mM) or N-acetylcysteine (NAC, 40&#x202f;mM), via drinking water. Oxidative stress and neuronal loss were assessed across different brain regions. In vitro experiments were conducted to evaluate neuronal integrity and mitochondrial function by VC and NAC treatment in PM2.5-exposed primary neurons.<br><br>RESULTS: Sub-chronic PM2.5 exposure increased lipid peroxidation and reduced neurofilament density in the cortex, hippocampus, and thalamus, which were mitigated by VC and NAC supplementation. Although oxidative stress (ROS accumulation and increase in 4-HNE) was prevented in all brain regions by VC and NAC, neurofilament loss remained. In vitro, VC and NAC reduced mitochondrial ROS production, which in turn improved neuronal and synaptic survival, suggesting mitochondria-dependent oxidative stress plays a central role in PM2.5-induced neurotoxicity at least in the cortex and hippocampus.<br><br>CONCLUSION: Mitochondria-dependent oxidative stress is a key mechanism underlying PM2.5-induced neurotoxicity, which can be attenuated by VC and NAC supplementation. This highlights a potential prophylactic strategy to partially protect the brain from polluted air.},
}
@article {pmid41989985,
year = {2026},
author = {Sun, M and Lu, Z and Chen, WM and Lv, S and Fu, N and Yang, Y and Wang, Y and Miao, M and Wu, SY and Zhang, J},
title = {N-Acetylcysteine and Dementia Risk in Elderly Patients.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {4},
pages = {e70212},
doi = {10.1002/gps.70212},
pmid = {41989985},
issn = {1099-1166},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/therapeutic use ; Male ; Aged ; Female ; Taiwan/epidemiology ; *Dementia/epidemiology/prevention &amp; control ; Aged, 80 and over ; *Pulmonary Disease, Chronic Obstructive/drug therapy/epidemiology ; Proportional Hazards Models ; Risk Factors ; Dose-Response Relationship, Drug ; Propensity Score ; },
abstract = {OBJECTIVE: This study aimed to investigate the association between N-acetylcysteine (NAC) use and dementia risk in elderly individuals diagnosed with Chronic Obstructive Pulmonary Disease (COPD).<br><br>METHODS: Utilizing Taiwan's National Health Insurance Research Database (NHIRD), we conducted a population-based cohort study of 105,144 elderly COPD patients to investigate the association between NAC use and dementia risk. Propensity score matching (PSM) ensured balanced covariates between NAC users and nonusers. Cox regression analysis and Poisson Regression analysis were employed to assess dementia risk, considering NAC dosage, treatment duration, and comorbidities. Competing risk analysis and Kaplan-Meier method were used to account for mortality risk and estimate dementia incidence, respectively.<br><br>RESULTS: Elderly NAC users demonstrated a significant association with a lower dementia risk (adjusted hazard ratio [aHR]: 0.76, 95% confidence interval [CI]: 0.74-0.78). Higher daily NAC intake was associated with a dose-dependent decline in dementia risk, with optimal benefits observed at an average daily dose of 1.61 defined daily doses (DDD). Stratification by cumulative defined daily doses (cDDD) of NAC revealed a consistent dose-response relationship, with progressively diminished dementia risk across quartiles of cDDD. Notably, NAC use was associated with a lower risk of Alzheimer's dementia (aHR: 0.68, 95% CI: 0.66-0.70) compared to non-NAC antimucolytic users.<br><br>CONCLUSIONS: NAC use is associated with a dose-dependent reduction in dementia risk among elderly COPD patients, particularly for Alzheimer's dementia. Our findings underscore the potential of NAC as a potential protective factor against dementia in this vulnerable population, warranting further investigation and consideration in clinical practice.},
}
@article {pmid41857443,
year = {2026},
author = {Watson, CJ and Simpson, MD and Saraiya, N and Wilkosz, CA and Yu, MB and Burns, MM and Neavyn, MJ and Simone, KE and Strout, TD},
title = {N-Acetylcysteine Dose and Treatment Duration in High-Risk Acetaminophen Ingestions Treated Within Eight Hours: A Retrospective Cohort Study.},
journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology},
volume = {22},
number = {2},
pages = {253-262},
pmid = {41857443},
issn = {1937-6995},
support = {U54 GM115516/GM/NIGMS NIH HHS/United States ; T32HL155020/GF/NIH HHS/United States ; T32 HL155020/HL/NHLBI NIH HHS/United States ; U54GM115516/GF/NIH HHS/United States ; K12 TR004384/TR/NCATS NIH HHS/United States ; K12TR004384/GF/NIH HHS/United States ; },
abstract = {INTRODUCTION: Toxicologists may use high dose n-acetylcysteine (HD-NAC) for early-treated high-risk acetaminophen ingestions (EHRAI) given concerns over standard NAC (S-NAC) dosing’s efficacy. We utilize the novel, clinically relevant outcome of mean additional 16-hour NAC maintenance infusions (NMI) to evaluate differences in treatment duration for EHRAI patients treated with S-NAC versus HD-NAC.<br><br>METHODS: Retrospective multistate poison center study from 1/1/2019-7/4/2024 of patients &#x2265; 13-years-old who were treated with S-NAC or HD-NAC within eight hours of a high-risk acetaminophen ingestion. The primary outcome was mean additional NMI. Secondary outcomes were NAC infusion duration, hepatotoxicity, coagulopathy, transplant, and death. Sensitivity analyses evaluated for robustness of findings.<br><br>RESULTS: Of 127 included cases, 52.0% (66/127) received HD-NAC. 7.1% (9/127) had anti-peristaltic co-ingestions. HD-NAC cases received more fomepizole (23.1% versus 1.6%; difference 21.1%). Acetaminophen concentrations controlled for time since ingestion were similar (mean acetaminophen ratio for HD-NAC: 2.7, IQR: 2.3, 3.3 versus S-NAC: 2.4, IQR: 2.2, 2.7; difference &#x2013; 0.3). 26.0% (33/127) received NMI solely for residual detectable serum acetaminophen. There was no difference in mean additional NMI (HD-NAC: 0.53 versus S-NAC: 0.38; p = 0.240). Median NAC infusion durations were equal across groups (21.0; IQR: 21.0, 37.0; difference 0.0) (p = 0.137). One patient per group developed hepatotoxicity; there were no transplants or deaths. Sensitivity analyses yielded similar results.<br><br>CONCLUSIONS: We found no difference in mean NMI for EHRAI based on NAC dose. These findings support additional NMI as an objective, common, clinically relevant outcome for acetaminophen toxicity research.},
}
@article {pmid41977015,
year = {2026},
author = {Demirci, U and Bilgin, ZT and Baysal, M},
title = {N-Acetylcysteine Therapy in Thrombotic Thrombocytopenic Purpura: A Systematic Review and Critical Appraisal.},
journal = {Journal of clinical medicine},
volume = {15},
number = {7},
pages = {},
pmid = {41977015},
issn = {2077-0383},
abstract = {Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition resulting from a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, leading to the accumulation of ultra-large von Willebrand factor (vWF) multimers and widespread microvascular thrombosis. While therapeutic plasma exchange and immunosuppression have significantly improved response, refractory and relapsed disease are significant challenges. N-acetylcysteine (NAC) has emerged as a biologically plausible adjunctive therapy due to its potential to reduce disulfide bonds in vWF multimers. However, its clinical role is unclear. This systematic review aimed to evaluate the clinical evidence regarding the efficacy and safety of N-acetylcysteine in patients with immune-mediated TTP. Methods: We performed a systematic review in accordance with the PRISMA guidelines. PubMed/MEDLINE, Google Scholar, and ClinicalTrials.gov were searched until January 2026. Studies involving patients with immune-mediated TTP treated with NAC were included. Case reports, case series, and observational studies involving patients with immune-mediated TTP treated with NAC were included. Risk of bias was evaluated using adapted quality assessment tools. Results: Sixteen studies encompassing 69 patients met the inclusion criteria. Most reports were case reports or small case series; two were larger observational cohorts. NAC was predominantly used as adjunctive therapy in relapsed or refractory TTP. Dose regimens varied. Platelet recovery following NAC was reported within 1-15 days in responding cases. Predominantly positive haematological responses were observed in small series. Significant heterogeneity in patient populations, timing of initiation, concomitant therapies, and outcome reporting limited causal inference. Conclusions: The current evidence suggests that NAC has a biologically rational and potentially adjunctive value in TTP, particularly in refractory disease or resource-constrained settings. However, current data are largely heterogeneous and derived from low-level evidence. Well-designed prospective studies and randomized controlled trials are needed to determine whether NAC provides significant clinical benefit beyond standard therapy.},
}
@article {pmid41977262,
year = {2026},
author = {Mîndreanu, R and Chiș, IC and Sevastre-Berghian, A and Login, C and Stan, A and Stan, T and Clichici, S and Suciu, &#x218;},
title = {N-Acetylcysteine in Neurological Disorders: A Systematic Review of Clinical and Translational Evidence Across Seven Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073076},
pmid = {41977262},
issn = {1422-0067},
mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Nervous System Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy ; Translational Research, Biomedical ; Antioxidants/therapeutic use ; Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Multiple Sclerosis/drug therapy ; Brain Injuries, Traumatic/drug therapy ; },
abstract = {N-acetylcysteine (NAC) is a glutathione precursor with established antioxidant and anti-inflammatory properties that has been investigated as a neuroprotective agent across multiple neurological conditions. This systematic review systematically mapped the clinical evidence for NAC across seven neurological disorders. PubMed and Cochrane Library were searched for studies published between 1 January 1995 and 31 December 2025. Twenty-three studies were included: traumatic brain injury (TBI, n = 6), Alzheimer's disease (AD, n = 5), Parkinson's disease (PD, n = 5), multiple sclerosis (n = 4), amyotrophic lateral sclerosis (n = 2), and migraine (n = 1); no eligible epilepsy studies were identified. The strongest evidence emerged for acute mild TBI, where early NAC administration significantly improved symptom resolution, and for PD, where combined intravenous/oral NAC improved dopamine transporter binding. In AD, nutraceutical formulations including NAC and other active compounds showed trends toward cognitive stabilization. Most included studies had a high or serious risk of bias, and only eight of 23 assessed oxidative stress biomarkers. NAC demonstrated a favorable safety profile across all conditions. Despite fragmented and heterogeneous evidence, the encouraging signals identified warrant large-scale randomized controlled trials with a standardized biomarker assessment.},
}
@article {pmid41977442,
year = {2026},
author = {Gu, Q and Silva, CS and Twaddle, NC and Beland, FA and Kanungo, J},
title = {N-Acetylcysteine Prevents Arsenic-Induced Apoptosis but Not Supernumerary Motor Neuron Development in Zebrafish Embryos: Assessment of Protein Carbonylation and the p53 Pathway.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073263},
pmid = {41977442},
issn = {1422-0067},
mesh = {Animals ; *Zebrafish/embryology/metabolism ; *Acetylcysteine/pharmacology ; *Apoptosis/drug effects ; *Tumor Suppressor Protein p53/metabolism ; *Arsenic/toxicity ; Reactive Oxygen Species/metabolism ; Embryo, Nonmammalian/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; *Protein Carbonylation/drug effects ; Signal Transduction/drug effects ; Arsenites/toxicity ; *Zebrafish Proteins/metabolism ; Sodium Compounds/toxicity ; Antioxidants/pharmacology ; Embryonic Development/drug effects ; },
abstract = {Arsenic induces apoptosis in both cancerous and non-cancerous cells. The mechanism of arsenic-induced apoptosis is complex. We previously demonstrated that the antioxidant acetyl L-carnitine prevented sodium arsenite-induced apoptosis in zebrafish embryos. To gain more insight into the mechanism of arsenic-induced apoptosis, we explored the effect of another antioxidant, N-acetylcysteine (NAC). Co-treatment of sodium arsenite with 1 or 2 mM NAC had no effect on zebrafish development. There was a significant but partial reduction in apoptosis in the embryos co-treated with sodium arsenite and 1 mM NAC, while embryos treated with 1 mM NAC alone showed the loss of normal apoptosis that was observed in the control embryos. Complete abolition of apoptosis occurred in embryos co-treated with sodium arsenite and 2 mM NAC; however, 2 mM NAC alone resulted in 100% mortality, indicating antioxidant toxicity at high doses. NAC (1 mM) did not prevent sodium arsenite-induced increase in motor neurons, suggesting that arsenic-induced apoptosis and supernumerary motor neuron development are mediated via distinct pathways. To determine whether NAC prevented arsenic-induced apoptosis via reactive oxygen species (ROS) signaling, we assessed ROS levels and oxidative modification of proteins (carbonylation) using an OxyBlot assay. Neither sodium arsenite nor NAC altered protein oxidation, ROS levels, or p53, a pro-apoptotic protein, transcript levels. Additionally, dicoumarol, an inducer of p53 protein degradation, did not inhibit sodium arsenite-induced apoptosis. These results indicate that protein oxidation and p53 signaling are not involved in arsenic-induced apoptosis and that NAC prevents arsenic toxicity in zebrafish embryos through a hitherto unknown mechanism.},
}
@article {pmid41980058,
year = {2026},
author = {Daiya, A and Nayak, C and Chowdhury, R and Chowdhury, S and Mukherjee, S},
title = {Cisplatin-Induced Oxidative Stress Regulates YAP to Modulate Epigenome Promoting the Survival of Osteosarcoma Cells.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.5c00538},
pmid = {41980058},
issn = {1520-4995},
abstract = {The widely used chemotherapeutic drug cisplatin (CDDP) is an integral part of the preoperative chemotherapy protocol for high-grade osteosarcoma (OS). However, despite an aggressive treatment regimen, drug refractoriness is a major hindrance to successful therapy. We previously identified key transcriptomic alterations that support the survival of OS cells following CDDP exposure. In the present study, our in vitro analyses further demonstrate that CDDP treatment promotes an adaptive, ROS-dependent enrichment of the repressive histone mark H3K27me3 at the upstream promoter regions of growth-associated genes such as CCNA2, as well as at the promoter of LATS1, a negative regulator of Yes-Associated Protein (YAP). This enrichment contributes to the transcriptional repression of these genes and is associated with growth arrest; notably, quenching of reactive oxygen species with N-acetyl cysteine (NAC) reversed this effect. Furthermore, reduced LATS1 expression was associated with increased nuclear localization of YAP. Importantly, pharmacological inhibition or genetic ablation of YAP attenuated the CDDP-induced accumulation of repressive marks. Mechanistically, YAP was found to colocalize and coimmunoprecipitate with EZH2, the catalytic member of the Polycomb Repressive Complex 2 (PRC2), suggesting a potential role for YAP in facilitating EZH2-mediated transcriptional repression. Consistent with these observations, inhibition of YAP or pharmacological reversal of the repressive chromatin state using a histone deacetylase (HDAC) inhibitor enhanced the sensitivity of the OS cells to low-dose CDDP treatment. Overall, the present study demonstrates an interplay among oxidative stress, epigenetics, and YAP in modulating OS cell fate post-CDDP exposure.},
}
@article {pmid40803359,
year = {2026},
author = {Chen, F and Lu, SZ and Chohan, H and Lau, A},
title = {The role of fomepizole in acetaminophen-related poisoning: a narrative review.},
journal = {Clinical and experimental emergency medicine},
volume = {13},
number = {1},
pages = {13-27},
doi = {10.15441/ceem.25.059},
pmid = {40803359},
issn = {2383-4625},
abstract = {N-acetylcysteine (NAC) as the gold standard antidote in cases of acetaminophen (APAP)-related poisoning might not be sufficient with delayed presentation or massive ingestion. Human reports published up to July 2021 suggest that fomepizole could play a role in APAP overdoses by inhibiting cytochrome P450 2E1 (CYP2E1)-mediated N-acetyl-p-benzoquinone imine (NAPQI) production and JNK-mediated oxidative damage. This narrative review builds on previous systematic and scoping reviews by adding the latest evidence about the use of fomepizole in APAP poisoning to better understand the hepatoprotective role and safety profile of this medication, as well as its practical place in therapy. A systematic search of MEDLINE and Embase was completed through November 2024. Studies involving human patients with APAP toxicity who received fomepizole treatment were included. Each case was summarized in tables to identify clinical trends, particularly the risk of hepatotoxicity, quantity of ingestion, time of presentation since ingestion, therapeutic and dosing regimens, and clinical outcomes. This review covers 28 studies and 45 patients across 18 case reports and 6 case series. When used with NAC, fomepizole seemed to result in favorable laboratory and clinical outcomes in most patients at high risk of hepatotoxicity because of late presentation or massive APAP ingestion. The available data suggest that fomepizole might complement NAC in treating severe APAP toxicity. Though they lack detailed clinical outcome analyses, case studies suggest that fomepizole could improve hepatotoxicity, survival, and transplant-free days.},
}
@article {pmid41969569,
year = {2026},
author = {Zhao, J and Montenegro, D and Kim, HJ and Ueda, K and Sparrow, JR},
title = {Disease mechanisms revealed in the P23H opsin knock-in mouse model of retinitis pigmentosa.},
journal = {PNAS nexus},
volume = {5},
number = {4},
pages = {pgag088},
pmid = {41969569},
issn = {2752-6542},
abstract = {The molecular mechanisms driving disease progression in autosomal dominant retinitis pigmentosa (adRP) due to a proline-to-histidine substitution (P23H) in opsin are not completely understood. Thus, we undertook to unlock features of the P23H/+ knock-in mouse model. Bisretinoids, the source of short-wavelength fundus autofluorescence (SW-AF), were elevated in albino P23H rhodopsin transgenic rats and in black and albino P23H/+ mice relative to wild type. Conversely, bisretinoid levels were lower in albino P23H/+ relative to black P23H/+ mice. Fluorescence microscopy revealed an inherent and aberrant autofluorescence in photoreceptor inner segments of albino P23H/+ mice. Outer nuclear layer (ONL) thinning indicative of photoreceptor degeneration was more pronounced in albino versus black P23H/+ mice and was accentuated in inferior versus superior hemiretina. Dark-rearing alleviated ONL thinning in albino P23H/+. The greatly diminished levels of ocular retinoid were not fully accounted for by loss of photoreceptor cells. P23H/+ mice treated with the antioxidant N-acetylcysteine (NAC) exhibited higher intensities of SW-AF, improved photoreceptor viability, and diminished 4-hydroxynonenal (HNE) immunoreactivity; the latter included 4-HNE adducts deposited in association with photoreceptor cells. The lower levels of bisretinoid in association with higher retinal illuminance are indicative of toxic bisretinoid photooxidation/degradation while the higher bisretinoid levels conferred by NAC are consistent with inhibition of these photodegradative processes. Collectively, these findings reveal that anomalous bisretinoid production can account for fundus hyperautofluorescence, and the photoreactive properties of bisretinoids can explain the propensity for environmental light to exacerbate photoreceptor cell degeneration. The findings support the benefits of antioxidant intervention in human adRP.},
}
@article {pmid41967236,
year = {2026},
author = {Pyo, MK and Park, HS and Ko, JH and Lim, DS and Gwon, HJ and Abd El-Aty, AM and Yağan, R and Song, JH and Shin, YK and Jeong, JH and Jung, TW},
title = {Hepassocin drives EGFR-dependent endothelial atherogenic activation via NOX1/ROS amplification and p38 signaling.},
journal = {Archives of biochemistry and biophysics},
volume = {781},
number = {},
pages = {110820},
doi = {10.1016/j.abb.2026.110820},
pmid = {41967236},
issn = {1096-0384},
abstract = {Metabolic stress results in the production of circulating hepatokines that can be coupled to hepatic injury and vascular dysfunction, but the underlying biochemical signaling routes remain incompletely defined. Hepassocin (HPS; FGL1) is a hepatocyte-derived factor implicated in metabolic inflammation; however, whether it directly programs endothelial pro-atherogenic signaling is unclear. Here, we report that a high-fat diet (HFD) increases serum HPS and that palmitate induces oxidative stress-dependent HPS expression and release from hepatocytes, as these responses are reversed by N-acetylcysteine (NAC). Recombinant HPS directly drives endothelial injury and activation in human umbilical vein endothelial cells (HUVECs), increasing ROS levels and lipid peroxidation (MDA/H2O2), promoting apoptosis, and enhancing adhesion molecule expression and monocyte-endothelial adhesion. Mechanistically, HPS activates EGFR and engages a redox-amplifying EGFR-NOX1 module characterized by the induction of NOX1 and p22phox, leading to robust oxidative stress signaling. EGFR or NOX1 silencing abolishes HPS-induced redox stress and atherogenic endothelial phenotypes. In parallel, HPS activates p38 downstream of EGFR, and p38 suppression mitigates HPS-driven endothelial activation and monocyte adhesion independent of ROS amplification, revealing a second mechanism. Together, these data define dual, targetable pathways-HPS-EGFR-NOX1/ROS and HPS-EGFR-p38-that mechanistically connect a liver-derived circulating factor to endothelial dysfunction and immune cell recruitment, positioning HPS-EGFR signaling as a tractable axis for metabolic stress-associated vascular disease.},
}
@article {pmid41957945,
year = {2026},
author = {Das, A and Bhandari, S and Datta, N and Mishra, S and Mahapatra, SK and Rajasekaran, S},
title = {The Biocide Triclosan Drives the Inflammatory Responses in Epithelial Cells and Macrophages via ROS-Mediated Activation of ERK/NF-κB Signaling Pathways.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70202},
pmid = {41957945},
issn = {1099-1263},
support = {CRG/2023/000028//Anusandhan National Research Foundation (ANRF), Department of Science and Technology (DST), Government of India/ ; },
abstract = {Triclosan (TCS) is an antimicrobial agent that is commonly spread and detected in various environmental matrices and organisms, including human tissues and biological fluids. A sustained inflammatory response is an important initial event in various disease developments. TCS-induced inflammatory response and its fundamental molecular mechanisms remain largely unexplored. In this current study, the impact of TCS exposure on inflammatory activation was investigated in both noncancerous (BEAS-2B) and cancerous (A549) lung epithelial cells in addition to murine macrophages (J774). The results revealed that TCS treatment could significantly induce various pro-inflammatory mediators' expression that includes cytokines and chemokines, in all cell types compared to the corresponding vehicle-treated cells. Further, TCS-mediated inflammatory response is associated with reactive oxygen species (ROS)-mediated activation of extracellular-signal-regulated kinase (ERK)1/2 and nuclear factor-kappa B (NF-κB) p65 signaling pathways. Scavenging of TCS-induced ROS by N-acetylcysteine (NAC) could mitigate signaling pathways activation. As expected, inhibitors specific for ERK1/2 (PD98059) and NF-κB p65 (IMD0354) signaling pathways efficiently attenuated TCS-induced inflammatory response in BEAS-2B cells. Thus, ROS/ERK/NF-κB axis contributes to the TCS-induced inflammatory response. Further, animal studies are required for a better understanding of TCS-mediated inflammatory response in various organs, including the lungs.},
}
@article {pmid41960010,
year = {2026},
author = {Ahl, A and Abadir, S and Kalfayan, G and Desai, K},
title = {Epstein-Barr Virus (EBV) Hepatitis Treated With N-Acetylcysteine: Placebo Versus True Effect.},
journal = {Cureus},
volume = {18},
number = {3},
pages = {e104922},
pmid = {41960010},
issn = {2168-8184},
abstract = {Epstein-Barr virus (EBV) is a herpesvirus that is known to cause multiple conditions, ranging from malignancies like Hodgkin and non-Hodgkin lymphomas to infectious and autoimmune conditions like infectious mononucleosis and systemic lupus erythematosus. Infectious mononucleosis causes systemic symptoms including cervical lymphadenopathy, splenomegaly, malaise, myalgias, and fever. While the spleen and liver are involved in some cases, most cases result in mild elevation of transaminases, not exceeding two to three times the upper normal limit. The transaminitis is usually subclinical with a self-limiting course. On rare occasions, liver involvement is associated with significant transaminitis reaching up to 10 times the upper normal limit. These patients usually also present with jaundice. Such severe or fatal hepatitis is most commonly seen in immunocompromised individuals. Here, we present a 31-year-old man who came to us with progressive jaundice, upper quadrant abdominal pain, and greasy stools after what he thought was just the flu. The patient was found to have EBV-induced hepatitis, requiring N-acetylcysteine administration.},
}
@article {pmid41960652,
year = {2026},
author = {Nabi, Z and Dasireddy, PS and Sayyed, M and Reddy, P and Goud, R and Rughwani, H and Singh, AP and Inavolu, P and Reddy, PM and Basha, J and Gupta, R and Tandan, M and Reddy, DN},
title = {Impact of Timing of Premedication on Mucosal Visibility During Endoscopy: A Randomized Controlled Trial.},
journal = {Journal of gastroenterology and hepatology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgh.70392},
pmid = {41960652},
issn = {1440-1746},
abstract = {BACKGROUND: Adequate gastric mucosal visibility (GMV) is essential for high quality upper gastrointestinal (GI) endoscopy. Simethicone and N-acetylcysteine (NAC) are commonly used to improve mucosal visibility, but the optimal timing of administration remains uncertain.<br><br>OBJECTIVE: This double-blinded randomized controlled trial (RCT) evaluated the optimal interval between premedication (simethicone&#x2009;+&#x2009;NAC) and endoscopy for achieving adequate GMV.<br><br>DESIGN: In this RCT, adults undergoing elective upper GI endoscopy were randomized to four groups: placebo (Group 1), premedication to endoscopy interval of 10-20 (Group 2), 21-30 (Group 3), or >&#x2009;30&#x2009;min (Group 4). GMV was scored in four gastric regions (antrum, distal body, proximal body, fundus) on a 4-point scale (range 4-16). The primary outcome was adequate GMV (total score <&#x2009;7). Secondary outcomes included median total GMV score, region-wise mucosal visibility scores, lesion detection rate, and predictors of adequate GMV.<br><br>RESULTS: A total of 1200 adults were randomized to four groups. Adequate GMV was significantly more frequent in Groups 3 (64.7%) and 4 (66.7%) than in placebo (2.7%) or Group 2 (25.0%). Subgroup analysis within Group 4 demonstrated a declining trend after 50&#x2009;min. ROC analysis suggested an optimal cut-off of 25&#x2009;min in predicting adequate GMV with area under the curve of 0.80. In region-wise analysis, mean visibility scores were lowest in antrum and distal body. There was no significant difference in the detection of gastric lesions across study groups (p&#x2009;=&#x2009;0.913). No serious adverse events related to premedication were observed.<br><br>CONCLUSION: Premedication with simethicone and NAC significantly improves GMV. The improvement becomes optimal at 20-30&#x2009;min after ingestion and is consistently maintained up to 50&#x2009;min.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06581783.},
}
@article {pmid41953516,
year = {2026},
author = {Qu, HQ and Kao, C and Hakonarson, H},
title = {Redefining the role of the thiol-based agent N-acetylcysteine in human health and disease and elucidating potential advantages of its amide derivative.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41953516},
issn = {2632-8682},
abstract = {N-Acetylcysteine (NAC) is the established antidote for acetaminophen toxicity and an approved mucolytic agent. Beyond these traditional uses, increasing evidence highlights its broader role as a modulator of thiol-redox biology. Rather than functioning as a nonspecific antioxidant, NAC modulates glutathione metabolism, redox-sensitive signaling, immune checkpoints, thiol-based post-translational modifications, ferroptosis susceptibility, and glutamatergic neurotransmission. This review synthesizes mechanistic, preclinical, and clinical evidence across pulmonary, hepatic, neuropsychiatric, metabolic, cardiovascular, and oncologic disorders, emphasizing how variability in baseline redox state, pharmacogenetics, and delivery contributes to heterogeneous outcomes. Strategies to improve pharmacokinetics and tissue targeting include structural derivatives such as N-acetylcysteine amide (NACA), and combination regimens such as NAC with probenecid or GlyNAC. Emerging applications span long COVID, neurodegeneration, psychiatric disorders, microbiome-redox interactions, environmental toxicology, and cancer immunotherapy. NAC and NACA exemplify the evolution of redox-targeted therapeutics. NAC is well established for safety and clinical utility, but its pharmacokinetic and tissue distribution properties constrain broader efficacy. NACA, a lipophilic amide derivative, enhances membrane permeability and cellular uptake, suggesting it may achieve higher tissue exposure at lower doses. Future progress will rely on biomarker-guided, precision approaches that optimize dosing, formulation, and delivery while exploring rational combinations across disease contexts defined by redox biology.},
}
@article {pmid41947576,
year = {2026},
author = {Mero, C and Haan, R and Tamimi, SA and Gonzalez, VB and Penfil, S and Schultz, BRE},
title = {High Risk Acetaminophen Ingestion in a Nine-Month-Old Requiring Hemodialysis: A Case Report.},
journal = {Pediatric emergency care},
volume = {},
number = {},
pages = {},
doi = {10.1097/PEC.0000000000003598},
pmid = {41947576},
issn = {1535-1815},
abstract = {BACKGROUND: High-risk acetaminophen (APAP) overdose in infants is rare but may result in rapid metabolic deterioration due to early mitochondrial dysfunction. Prompt recognition and aggressive intervention are essential for survival, yet pediatric-specific management strategies remain limited in the literature.<br><br>CASE PRESENTATION: A previously healthy 9-month-old boy ingested an estimated 25 g of acetaminophen (&#x223c;2700&#xa0;mg/kg by history) following an exploratory ingestion. Within 4 hours, he developed an altered mental status, severe anion-gap metabolic acidosis with lactic acidosis, early coagulopathy, and respiratory failure. He was diagnosed with high-risk acetaminophen poisoning complicated by adenovirus-associated acute respiratory distress syndrome (ARDS).<br><br>MANAGEMENT AND OUTCOME: Treatment included high-dose N-acetylcysteine (NAC), adjunctive fomepizole, 2 sessions of intermittent hemodialysis (HD), followed by 16 hours of continuous renal replacement therapy (CRRT). Management also required aggressive phosphorus repletion and prolonged mechanical ventilation. The patient was extubated on day 17 and discharged on day 35 without progression to acute liver failure.<br><br>CONCLUSION: This case demonstrates successful multimodal management of high-risk acetaminophen poisoning in an infant using extracorporeal toxin removal and adjunctive therapies. It highlights practical considerations for NAC dose adjustment during HD and CRRT and underscores important public health concerns regarding the accessibility and formulation of potentially lethal medications. Regulatory strategies limiting acetaminophen quantities per container and discouraging formulations attractive to young children may reduce the risk of severe exploratory ingestions.},
}
@article {pmid41947699,
year = {2026},
author = {Babereh, R and Shayani-Jam, H and Yaftian, MR and Farajmand, B and Moeini, MH and Moeinifar, S},
title = {Electrochemical evaluation of plant extracts as potential antidotes for acetaminophen poisoning.},
journal = {The Analyst},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5an01322d},
pmid = {41947699},
issn = {1364-5528},
abstract = {Acetaminophen, a widely used analgesic, causes severe liver damage in overdose situations due to N-acetyl-p-benzoquinoneimine (NAPQI), a toxic metabolic intermediate. Current antidotes, like N-acetylcysteine (NAC), are effective but costly and not universally accessible. There is a critical need for novel, cost-effective antidotes to mitigate acetaminophen-induced hepatotoxicity. This study investigates the electrochemical oxidation of acetaminophen in the presence of plant extracts, including pomegranate peel, pomegranate, bell pepper, black radish, and turnip, to evaluate their potential as alternative antidotes. Cyclic voltammetry (CV) and controlled-potential coulometry were employed to study acetaminophen oxidation, confirming NAPQI formation. CV analysis revealed that pomegranate peel extract exhibited superior reactivity with NAPQI, with an anodic-to-cathodic peak current ratio (IpA/IpC) exceeding that of N-acetylcysteine (NAC), the standard antidote for acetaminophen poisoning, by 40-45%. Coulometric experiments corroborated this high reactivity, suggesting an EC' mechanism for pomegranate peel extract and an EC mechanism for other extracts. Other plant extracts showed moderate reactivity, with bell pepper and turnip achieving 30-50% of pomegranate peel's IpA/IpC, indicating their potential as NAPQI scavengers. These findings highlight the varying scavenging capacities of plant extracts. The high reactivity of pomegranate peel extract with NAPQI, driven by an EC' mechanism, suggests its potential as a cost-effective, natural antidote for acetaminophen poisoning. This study introduces a novel electroanalytical approach for antidote development, elucidating interaction mechanisms between plant extracts and NAPQI. Unlike traditional methods, this electrochemical strategy offers precise, rapid assessment of antidote efficacy, providing a scalable framework for evaluating natural compounds to mitigate acetaminophen-induced liver damage.},
}
@article {pmid41945235,
year = {2026},
author = {Kim, JS and Oh, JM and Choi, H and Choi, H and Kim, SW and Kim, SW and Kim, BG and Cho, JH and Lee, J and Lee, DC},
title = {Polystyrene Nanoplastics Induce Inflammasome Activation in Nasal Epithelial Cells via ROS-Mediated Mitochondrial Dysfunction.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.70093},
pmid = {41945235},
issn = {1522-7278},
support = {CMCDJ-P2024-019//Catholic University of Daejeon St. Mary's Hospital/ ; //Catholic Medical Center Research Foundation/ ; //Otorhinolaryngology Alumni Fund of the Catholic University of Korea/ ; },
abstract = {Nanoplastics are emerging airborne pollutants capable of reaching the nasal cavity. However, their effects on nasal epithelial health remain poorly understood. This study investigated how polystyrene (PS) nanoplastics affect nasal epithelial cells, focusing on NOD-like receptor protein 3 (NLRP3) inflammasome activation, oxidative stress, and mitochondrial injury. Human RPMI 2650 nasal epithelial cells were exposed to PS nanoplastics at various concentrations for 24 h. Cellular responses were evaluated by assessing viability, inflammasome protein expression, reactive oxygen species (ROS) generation, mitochondrial membrane potential, and adenosine triphosphate (ATP) levels using colorimetric assays, Western blotting, and flow cytometry. Mitochondrial ROS was analyzed with MitoSOX, and mitochondrial regulators sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) were examined to clarify underlying mechanisms. The antioxidant N-acetylcysteine (NAC) was used to assess the role of oxidative stress. PS exposure reduced cell viability and increased the expression of inflammasome-related proteins including NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and cleaved caspase-1. Protein levels peaked at moderate concentrations and declined at higher doses, suggesting a progression toward pyroptosis. These alterations were accompanied by increased intracellular and mitochondrial ROS, mitochondrial depolarization, decreased ATP levels, and downregulation of SIRT1 and AMPK. NAC pretreatment mitigated ROS accumulation, alleviated mitochondrial impairment, and attenuated inflammasome activation. PS induce oxidative stress, mitochondrial impairment, and dysregulation of SIRT1-AMPK signaling, collectively promoting inflammasome activation in nasal epithelial cells. These findings highlight potential health risks of inhaled nanoplastics and underscore the need for further investigation into antioxidant-based protective strategies.},
}
@article {pmid41937369,
year = {2026},
author = {Liu, M and Wang, S and Li, R and Qi, W and Xiong, T and Shi, X and Chen, W and Ding, F and Wei, C and Liu, J and Li, N and Huang, Q and Liu, Z and Ai, K},
title = {Halting Mitochondrial Domino Effect in Acute Liver Injury: Polyphenol-Sr Nanodrugs Attenuate Cell Death and Sterile Inflammation by Combating ROS Burst and Calcium Overload.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e71121},
doi = {10.1002/adhm.71121},
pmid = {41937369},
issn = {2192-2659},
support = {2023ZD0506904//National Science and Technology Major Project of China/ ; 82574405//National Natural Science Foundation of China/ ; 82373871//National Natural Science Foundation of China/ ; 2023QYJC017//Central South University Research Programme of Advanced Interdisciplinary Studies/ ; 2024JK2114//Key Research and Development Program of Hunan Province/ ; 2023LNJ12//Project Program of National Clinical Research Center for Geriatric Disorders/ ; 2024JJ1015//Nature Science Foundation of Hunan Province/ ; 2024JJ6691//Nature Science Foundation of Hunan Province/ ; 1053320242202//Fundamental Research Funds for the Central Universities of Central South University/ ; },
abstract = {Acute liver injury (ALI) is a significant clinical cause of liver failure, potentially occurring at any stage of liver disease and posing a considerable health burden. One prevalent model of ALI stems from acetaminophen (APAP) overdose, where a vicious cycle of "mitochondrial damage-inflammation amplification" and limited availability of small molecular drugs hinder current therapeutic approaches. Herein, a novel tannic acid (TA)-strontium (Sr) nanodrug (SrTA) is proposed. With liver-accumulating and mitochondria-targeting capabilities, SrTA effectively harnesses the broad-spectrum antioxidant properties of TA along with the calcium homeostasis-regulating function of Sr[2+]. And its therapeutic efficacy surpassed that of an equivalent dose of N-acetylcysteine (NAC). Mechanistically, SrTA directly scavenges mitochondrial reactive oxygen species (ROS), protects mitochondrial integrity, and alleviates endoplasmic reticulum (ER) stress and intracellular oxidative damage. Additionally, SrTA antagonizes calcium signaling, reduces the formation of mitochondria-ER contacts, and inhibits mitochondrial calcium overload. By safeguarding mitochondrial function and preventing the aberrant opening of the mitochondrial permeability transition pore (mPTP), SrTA significantly curtail hepatocyte death and mitigates mtDNA-induced sterile inflammation, effectively halting the injury cascade. In conclusion, this study presents a novel therapeutic strategy for ALI that targets mitochondria and synergistically regulates ROS bursts and calcium overload, achieving multifaceted therapeutic effects.},
}
@article {pmid41940506,
year = {2026},
author = {Kuttikrishnan, S and Suleman, M and Ahmad, F and Mariyam, Z and Patil, K and Anver, R and Khan, AQ and Prabhu, KS and Bhat, AA and Buddenkotte, J and Steinhoff, M and Uddin, S},
title = {Sanguinarine Induces ROS-Mediated Mitochondrial Dysfunction and Inhibits AKT/GSK3 Signaling to Potentiate Apoptotic Effects in Cutaneous T-Cell Lymphoma.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70318},
pmid = {41940506},
issn = {1099-1573},
support = {MRC-01-23-065//Hamad Medical Corporation/ ; //Qatar National Library/ ; },
abstract = {Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma with limited durable treatment options and poor overall survival, underscoring the need for new therapeutic approaches. Sanguinarine (SNG), a natural benzophenanthridine alkaloid, has demonstrated anticancer activity in several malignancies, but its potential role in CTCL remains unexplored. We hypothesized that SNG induces oxidative stress and mitochondrial dysfunction, leading to the inhibition of the PI3K/AKT/GSK3 pathway and apoptosis in CTCL cells. In vitro experiments were performed using HH and H9 CTCL cell lines. Cytotoxicity, apoptosis, and mitochondrial function were evaluated by cell viability assays, caspase activation, PARP cleavage, Bax/Bcl-2 ratio, mitochondrial membrane depolarization, and cytochrome c release. ROS generation and glutathione depletion were measured with and without N-acetyl cysteine (NAC) rescue. Western blotting assessed modulation of the AKT/GSK3α/β/mTOR pathway and expression of anti-apoptotic proteins (XIAP, cIAPs, Mcl-1). Synergistic effects with bortezomib (BTZ) were analyzed. Network pharmacology, molecular docking, molecular dynamics (MD) simulations, and binding free energy (BFE) calculations were used to identify SNG's molecular targets. SNG reduced CTCL cell viability (IC50 < 5 μM) and triggered mitochondrial-mediated apoptosis, accompanied by Bax/Bcl-2 modulation, ΔΨm loss, cytochrome c release, and caspase-9/3 activation. ROS accumulation and glutathione depletion contributed to cytotoxicity, effects that were reversed by NAC. SNG suppressed AKT/GSK3/mTOR signaling and downregulated anti-apoptotic proteins. Notably, SNG enhanced the anticancer activity of BTZ in combination studies. Computational analyses supported AKT and Bcl-2 as key binding targets. SNG exerts potent anticancer effects in CTCL by inducing ROS-dependent mitochondrial apoptosis and inhibiting the PI3K/AKT/GSK3 signaling pathway. Its synergy with BTZ and computational validation of AKT/Bcl-2 targeting underscore its potential as a novel therapeutic candidate for CTCL, warranting further preclinical investigation.},
}
@article {pmid41941390,
year = {2026},
author = {Cyndari, KI and Elkins, JM and Coleman, MC and Mulford, KE and Johnson, RM and Butler, KL and Parlet, CP and Huston, HC and Draayer, T and Naveen, P and Petersen, CA},
title = {A Pre-Clinical Model of Synovitis Using Ex vivo Human Synovial Tissue with Preserved Function and Architecture.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {229},
pages = {},
doi = {10.3791/69734},
pmid = {41941390},
issn = {1940-087X},
mesh = {Humans ; *Synovial Membrane/pathology ; *Synovitis/pathology/microbiology ; },
abstract = {Arthritis is an inflammatory state within joints resulting in cartilage damage, pain, and loss of mobility. Recent advances in arthritis research specifically demonstrate that the joint capsule (e.g., synovium) is an important source of this inflammation, but there are no human models that replicate essential synovial architecture. To address this, the Joint Space Analysis System, or JSAS, was created. Anterior synovium was obtained intra-operatively from patients undergoing Total Knee Arthroplasty (TKA). Synovium was dissected and sectioned into 3 mm biopsy cores. Cores were placed in the upper well of a 5 µm or 0.4 µm transwell with 300 µl of DMEM with10% FBS. In the bottom well, 600 µL of media was added, and exchanged every 2-3 days. Viability was assessed up to 7 days in hyperoxic (50%), atmospheric/standard (~21%), and physiologic (5%) incubation conditions. Stimuli in the bottom well included monocyte chemoattractant protein 1 (MCP-1/CCL2), lipopolysaccharide (LPS), N-acetyl cysteine, S. aureus, and B. burgdorferi. Media was stored for ELISA, and tissue was stored for formalin fixed paraffin embedded (FFPE) analysis. In standard conditions, synovium remained fully viable for 3 days. Stimulus modified the structure and function of intimal lining and sublining synovial cells, including loss of the resident macrophage border, sublining expansion, upregulation of pathogenic fibroblasts, and production of cytokines IL-1β and TNFα. Immune cells and fibroblasts migrated to the bottom chamber (5 µm pores) per flow cytometry analysis. Mobile B. burgdorferi migrated into tissue at the 0.4 µm pore size while non-motile S. aureus did not. Relevant cytokines were expressed in sufficient quantity for ELISA. JSAS is a modular system capable of studying acute alterations to human synovium, allowing for the complexity of 3D structures in a pre-clinical model while maintaining biologically relevant structure and function.},
}
@article {pmid41934902,
year = {2026},
author = {Zhang, P and Liu, C},
title = {SiO2 exposure triggers NOX1/ROS-dependent epithelial necroptosis and drives Th17 cell activation to initiate pneumonia in mice.},
journal = {International immunopharmacology},
volume = {179},
number = {},
pages = {116598},
doi = {10.1016/j.intimp.2026.116598},
pmid = {41934902},
issn = {1878-1705},
abstract = {SiO2 (silicon dioxide) particles have been classified as one of the most hazardous environmental pollutants for the respiratory system, yet their hazards are often overlooked. The abnormal activation of Th17 helper T cells that produce interleukin-17 (IL-17) is associated with the development of multiple inflammatory diseases. However, it is unclear whether SiO2 exposure-induced pneumonia is attributed to the recruitment and differentiation of pathogenic Th17 cells, and its specific mechanism. Thus, in this study, we exposed C57BL/6 J mice to 50 nm, 300 nm, and 1 μm SiO2 particles, and employed Transwell methods to establish co-culture models of lung epithelial cells with Th17 cells. Based on RNA-seq analysis, we demonstrated that the activation of pro-inflammatory Th17 cells relied on NOX1 (NADPH oxidase 1)-mediated reactive oxygen species (ROS) burst in damaged epithelial cells, in a size-dependent manner. NOX1/ROS stress evoked the sustained elevation of calcium ions (Ca[2+]) in epithelial cells, activated phosphorylated Ca[2+]/calmodulin-dependent protein kinase II (p-CaMKII)/phosphorylated AMP-activated protein kinase (p-AMPK) pathways, leading to necroptosis, as well as increased expression of damage-associated molecular patterns (DAMPs), chemokines and pro-inflammatory cytokines. The enrichment of these signaling factors promoted the activation of Th17 cells, which exacerbated epithelial cell death, contributing to a vicious cycle of inflammation. Treating MLE12 cells with siNOX1 (small interfering RNA targeting NOX1), NAC (N-acetylcysteine) or KN-93 (a CaMKII inhibitor) to alleviate NOX1/ROS stress suppressed the elevation of transcription factors retinoic acid receptor-related orphan receptor gamma t (RORγt) and signal transducer and activator of transcription 3 (STAT3) in Th17 cells, and their activation. Additionally, notably, SiO2 exposure-triggered NOX1/ROS stress was equally closely associated with Th17 cell activation. Collectively, this research reveals that under conditions of SiO2 exposure, NOX1-mediated oxidative stress acts as a hub inducing necroptosis of lung epithelial cells to enhance Th17 cell recruitment and differentiation, thereby initiating pneumonia. This research establishes a scientific basis for evaluating pneumonia caused by environmental pollutant SiO2 and provides reference for comparative medicine.},
}
@article {pmid41935446,
year = {2026},
author = {El-Barbary, AM and El-Sahn, AA and Manaa, EA and Khalifah, A and Aboelnour, A and Abdulkader, A and Taha, AE and Alagawany, M and Abdel-Latif, MA},
title = {Effect of N-acetyl cysteine on productive performance, biochemical indicators, mRNA expression of growth, antioxidant and heat shock protein related genes and hepatic morphology in broilers under heat stress.},
journal = {Poultry science},
volume = {105},
number = {6},
pages = {106801},
doi = {10.1016/j.psj.2026.106801},
pmid = {41935446},
issn = {1525-3171},
abstract = {Poultry farmers in tropical, subtropical, and temperate climates have challenges due to heat stress caused by heat waves. Egypt's already dry climate will become even more severe due to climate change. The aim of the experiment was to examine the impact of N-acetyl cysteine (NAC) as antioxidant on growth performance, biochemical indicators, heat shock protein related genes and hepatic morphology for broiler chicks under heat stress. Two hundred and forty one-week-old male broiler chicks (Cobb 500) with an average initial body weight of 158.81 ± 8.03 g were used in a completely randomized design with four treatments and ten replicates for 35 days. The basal diet was fed to the first group. The second (NAC1), third (NAC3), and fourth (NAC5) ones were dietary supplemented with 1, 3, and 5 g/kg NAC, respectively until 35 days old. Body weight (BW) and body weight gain (BWG) were improved (p ˂ 0.05) in N-acetyl cysteine supplemented groups with at 3 g/ kg while feed conversion ratio (FCR) was improved in NAC3 and NAC5 respectively. Biochemical indices were improved by NAC supplementation compared to control group without negative effects on hematological parameters. Upregulation (p < 0.001) of growth hormone related genes (growth hormone (GH), growth hormone receptors (GHR), and insulin-like growth factor 1 (IGF1)) was recorded in NAC3 group in comparison with other groups. Also, upregulation (p < 0.05) of antioxidant-related genes (catalase (CAT), glutathione peroxidase 1 (GPX1), and superoxide dismutase 1 (SOD1)) of NAC3 group was shown. Meanwhile, the genes associated with heat shock proteins (heat shock transcription factor 1 (HSF1), heat shock protein 70 (HSP70), and heat shock protein 90 (HSP90) showed downregulations (p < 0.05) in the NAC3 group compared to others. A notable reduction in congestion and erythrocytic extravasation was shown in the NAC3 group. Also, the morphology of the hepatocytes was more similar to normal. Collectively, dietary N-acetyl cysteine supplementation at a level of 3 g/kg ameliorates the adverse impacts of heat stress in broilers regarding growth performance, biochemical indicators, antioxidants and heat shock protein related genes and hepatic morphology.},
}
@article {pmid41935817,
year = {2026},
author = {Zhai, Y and Dong, L and Hao, X and Li, X and Li, W and Hu, Z and Peng, Y and Zheng, J},
title = {In vitro and in vivo metabolic activation of diaveridine mediated by CYP3A.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {116089},
doi = {10.1016/j.fct.2026.116089},
pmid = {41935817},
issn = {1873-6351},
abstract = {Diaveridine (DVD) is an anticoccidial drug and antibacterial synergist used in the livestock and poultry industries worldwide. DVD residues have been reportedly detected in pork and related meat products. Human exposure to DVD through the environment and the food chain has attracted wide attention, due to the abuse of DVD. Liver injury of animals administered with DVD has been observed and reported, but the potential mechanisms are unelucidated so far. This study aimed to reveal the metabolic activation pathway of DVD that may be related to its hepatotoxicity. DVD was found to be metabolized to an electrophilic species reactive to nucleophilic sulfhydryl groups of cysteine, glutathione (GSH), and N-acetylcysteine (NAC) to generate the cysteine, GSH, and NAC conjugates correspondingly. The GSH conjugates and NAC conjugate(s) were detected in the bile and urine of mice administered with DVD. Furthermore, cysteine conjugates were observed in proteolytic mixture of hepatic proteins obtained from DVD-administered mice in a dose-dependent pattern. CYP3A4 was found to mediate the metabolism of DVD, and an iminoquinone methide intermediate reactive to sulfhydryl of GSH was observed in vitro and in vivo. The GSH conjugates were also detected in primary mouse hepatocytes after exposure to DVD. Pretreatment with ketoconazole (an inhibitor of CYP3A) decreased the formation of the GSH conjugates, and the cytotoxicity associated with DVD was mitigated. This study suggests that DVD was metabolized to the corresponding iminoquinone methide intermediate possibly associated with the hepatotoxicity induced by DVD. This finding facilitates the risk assessment strategies for DVD in food safety supervision.},
}
@article {pmid41936986,
year = {2026},
author = {Kuttikrishnan, S and Anver, R and Ahmad, F and Mariyam, Z and Habeeba, U and Akhtar, S and Salameh, I and Siddiqui, S and Prabu, KS and Ansari, AW and Bhat, AA and Khan, AQ and Uddin, S},
title = {Pristimerin drives ROS-dependent apoptosis in cutaneous T-cell lymphoma via inhibition of the AKT-SKP2 axis.},
journal = {Toxicology and applied pharmacology},
volume = {},
number = {},
pages = {117816},
doi = {10.1016/j.taap.2026.117816},
pmid = {41936986},
issn = {1096-0333},
abstract = {Cutaneous T-cell lymphoma (CTCL) is a skin-predominant form of non-Hodgkin lymphoma for which improved therapeutic options are needed. Here, we investigated the anti-lymphoma effects of pristimerin (PS) and defined its underlying mechanism in H9 and HH CTCL cell lines. PS strongly reduced cell growth and induced apoptosis, with hallmarks of mitochondrial (intrinsic) pathway activation, including caspase processing. PS also decreased basal AKT activity and downregulated pro-survival factors such as XIAP. In addition, PS reduced the abundance of S-phase kinase-associated protein 2 (SKP2) and was accompanied by increased levels of the cyclin-dependent kinase inhibitors p21[Cip1] and p27[Kip1]. Genetic suppression of AKT intensified apoptosis-associated signaling, reflected by increased H2AX activation and PARP cleavage. Notably, PS elevated intracellular reactive oxygen species (ROS), and scavenging ROS with N-acetylcysteine (NAC) significantly attenuated PS-driven cytotoxicity, supporting a ROS-dependent mechanism. Finally, PS combined with the proteasome inhibitor bortezomib produced greater anti-CTCL activity than either agent alone, consistent with a synergistic interaction. Together, these findings show that PS promotes ROS-dependent, mitochondria-mediated apoptosis in CTCL and support further evaluation of PS-based strategies for this malignancy.},
}
@article {pmid41933561,
year = {2026},
author = {Yu, S and Bao, C and Liu, N and Yan, B and Qu, Z and Chen, S and Ni, J and Guo, X and Liu, X and Wang, H},
title = {The Mitigating Effects of N-Acetylcysteine on TiO2 Nanoparticles-Induced Toxicity: Efficacy in Cytotoxicity Reduction in Vitro and Complexity in Vivo.},
journal = {Environmental toxicology and pharmacology},
volume = {},
number = {},
pages = {105013},
doi = {10.1016/j.etap.2026.105013},
pmid = {41933561},
issn = {1872-7077},
abstract = {To investigate how the antioxidants N-Acetyl-L-cysteine (NAC) and Vitamin C (Vc) exert optimal antioxidant effects to mitigate the cytotoxicity induced by titanium dioxide nanoparticles (TiO2 Nanoparticles, TNPs), this study employed human normal colon epithelial cells (NCM460), human hepatocyte L-02 cells, C57BL/6 mice and Drosophila melanogaster. In NCM460 cells experiment (48h), results showed that TNPs+NAC co-exposure significantly inhibited malondialdehyde (MDA), enhancing total antioxidant capacity, and reducing chromosomal damage and cell death. This protective sequence was validated in L-02 cells experiment (144h). In C57BL/6 mice, TNPs+NAC co-exposure reduced the micronucleus frequency in bone marrow polychromatic erythrocytes (PCEs), yet had no significant effect on Morris water maze behavior. Conversely, it adversely affected climbing ability in Drosophila melanogaster. Our study concludes that TNPs + NAC co-exposure effectively mitigates cytotoxicity of TNPs in vitro by enhancing antioxidant effects. However, in vivo outcomes may differ due to factors such as exposure routes and individual variations.},
}
@article {pmid41924470,
year = {2026},
author = {Wali, S and Gutte, S and Nair, R and Gurjar, M},
title = {Acute Arsenic Poisoning: A Case Report and Literature Review.},
journal = {Journal of emergencies, trauma, and shock},
volume = {19},
number = {1},
pages = {46-50},
pmid = {41924470},
issn = {0974-2700},
abstract = {Acute arsenic poisoning, a life-threatening condition, results from exposure to inorganic arsenic compounds such as arsenic trioxide (As2O3). This case report describes a 27-year-old male who ingested 25 g of As2O3 and presented with severe gastrointestinal (GI) toxicity and acute kidney injury. Management involved airway protection, GI decontamination with activated charcoal, chelation therapy using D-penicillamine, and supportive care including N-acetylcysteine (NAC) and dialysis for renal failure. GI endoscopy revealed diffuse mucosal ulceration consistent with arsenic's corrosive effects. The patient recovered following three sessions of sustained low-efficiency dialysis and was discharged with improved renal function. This case highlights the critical role of prompt supportive management, chelation, and hemodialysis in arsenic poisoning. It also highlights novel use of NAC as an adjunctive therapy and the importance of monitoring multi-organ involvement for improved outcomes.},
}
@article {pmid41924719,
year = {2026},
author = {Hillebrand, J and Oltmanns, H and Meißner, J},
title = {In vitro efficacy of four potential antimicrobial substances against Klebsiella species and Streptococcus uberis isolated from bovine mastitis.},
journal = {Frontiers in veterinary science},
volume = {13},
number = {},
pages = {1782821},
pmid = {41924719},
issn = {2297-1769},
abstract = {Mastitis is an important disease in dairy cattle with huge influence on animal welfare and economic situation of farmers. With very limited choices in antibiotic therapy of bovine mastitis and the relevance of emerging antimicrobial resistances, discovery of new antimicrobials is one of the major challenges for veterinary pharmacological research. Thus, in vitro efficacy of four promising substances was investigated: polyvinylpyrrolidone iodine (PVP iodine), N-acetylcysteine (NAC), N-chlorotaurine (NCT), and methylglyoxal (MGO). PVP iodine is an antiseptic commonly used in all medical fields. The two amino acid derivates NAC and NCT are a potent antioxidant respective oxidant with antimicrobial properties in various indications. MGO is one of the active components in Manuka honey, causing bacterial death by repression of protein and nuclei acid synthesis. For experiments, Klebsiella species (spp.) and Streptococcus (S.) uberis were isolated from bovine milk samples. Subsequently, broth microdilutions with common antibiotic agents and the four potential antimicrobials for determination of minimal inhibitory concentrations (MICs) and examinations regarding minimal bactericidal concentrations (MBCs), also time-dependent, were performed according to CLSI standards. Regarding antimicrobial susceptibility, growth of Klebsiella spp. isolates was not restrained by examined concentrations of benzylpenicillins, aminopenicillins, isoxazolyl penicillins, macrolides, and lincosamides. However, studied concentrations of aminopenicillins combined with beta-lactamase inhibitors, cephalosporins (partly combined with aminoglycosides) as well as fluoroquinolones inhibited their growth. In contrast, all S. uberis isolates were susceptible to tested concentrations of penicillins, cephalosporins, macrolides, lincosamides, and fluoroquinolones. Broth microdilutions of the four substances revealed median MICs of PVP iodine with 5 mg/mL for Klebsiella spp. and 4 mg/mL for S. uberis and NAC with MICs of 5 mg/mL for Klebsiella spp. and 1.75 mg/mL for S. uberis. MICs of NCT were 1.5 mg/mL for Klebsiella spp. and 1 mg/mL for S. uberis. The lowest MICs were found for MGO with 0.4 mg/mL for Klebsiella spp. and 0.1375 mg/mL for S. uberis. Growth of every bacterial isolate was inhibited through all four substances, even when resistant to commonly used antibiotic agents. Therefore, with positive findings in further experiments regarding biocompatibility and efficacy, they could be considered as auspicious alternatives for mastitis treatment in dairy cattle.},
}
@article {pmid41918410,
year = {2026},
author = {Andrade, BF and Carmo, LRD and da Silva, VM and Filho, RAT and Fontes, PR and Ramos, ALS and Ramos, EM},
title = {Decomposition Kinetics of Solution and Lyophilized Powder of S-Nitroso-N-Cetylcysteine.},
journal = {Journal of food science},
volume = {91},
number = {4},
pages = {e71005},
doi = {10.1111/1750-3841.71005},
pmid = {41918410},
issn = {1750-3841},
support = {311305/2022-9//National Council for Scientific and Technological Development/ ; CVZAPQ02904-17//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de Minas Gerais/ ; },
mesh = {Kinetics ; Powders/chemistry ; Freeze Drying ; Solutions/chemistry ; *Acetylcysteine/chemistry/analogs &amp; derivatives ; Temperature ; Meat Products/analysis ; },
abstract = {Recently, S-nitrosothiols (RSNO) have received increased attention in the food industry as replacements for nitrite salts in meat products. However, their industrial applications are limited because of their high instability in concentrated aqueous solutions. In this study, S-nitroso-N-acetylcysteine solutions (NAC-SNOSol) of different concentrations (200, 300, and 400 mM) were stabilized, impregnated with salt, and freeze-dried (NAC-SNOPow). The decomposition kinetics of the solutions at 4°C and the resulting powders at different storage temperatures (-18 to 30°C) were evaluated using zero-, first-, and second-order ordinary differential equations. The NAC-SNO decomposition followed a first-order reaction in non-stabilized solutions and a zero-order reaction in stabilized solutions, with the half-life (t1/2) increasing from 1.1 to 9.9 days and decreasing in more concentrated solutions. The decomposition of NAC-SNOPow had a better fit for second-order decay, with an average activation energy (Ea) of 92 kJ/mol and a Q10 of 4.0. The stability of the powders increased with concentration, with t1/2 values reaching up to 100 days at the highest concentration and refrigeration temperature (2°C). Stabilizing and obtaining NAC-SNOPow at higher concentrations and refrigerated or frozen storage is an interesting optimization strategy for industrial use, as it presents good yield (approximately 79%), stability, and practical use. PRACTICAL APPLICATIONS: Previous studies demonstrated the potential use of RSNO solutions to replace the nitrite additive in meat products, maintaining the desired characteristics and reducing the risks of carcinogenic compound formation. However, the high instability of these compounds in solution limits their practical use. This research introduced an innovative approach by developing a more stable solid form of NAC-SNOSol and determining the best storage conditions for use as a food additive. This advancement is crucial for enabling the industrial application of RSNO, making them a more accessible and efficient alternative for nitrite replacement in meat products.},
}
@article {pmid41918448,
year = {2026},
author = {S, HH and Kishore, A and Sivanesan, S and Kasirajan, SP and Rajendiran, N and Pulidindi, IN and Meivelu Moovendhan, and Yuvaraj Maria Francis, },
title = {Neuroprotective Effects of Naringin Against Lead Acetate-Induced Oxidative Stress and Neurotoxicity in Wistar Rats.},
journal = {Chemistry &amp; biodiversity},
volume = {23},
number = {4},
pages = {e02291},
doi = {10.1002/cbdv.202502291},
pmid = {41918448},
issn = {1612-1880},
mesh = {Animals ; *Flavanones/pharmacology/chemistry ; *Oxidative Stress/drug effects ; Rats, Wistar ; *Neuroprotective Agents/pharmacology/chemistry ; Male ; Rats ; *Organometallic Compounds/antagonists &amp; inhibitors/toxicity ; Brain/drug effects/metabolism/pathology ; Dose-Response Relationship, Drug ; Antioxidants/pharmacology ; },
abstract = {Lead acetate (LA) exposure induces oxidative stress and neurotoxicity, leading to behavioral, biochemical, and histopathological alterations. Naringin, a natural flavonoid with potent antioxidant properties, has shown promise in ameliorating such damage. This study investigates the protective effects of naringin at different doses against LA-induced neurotoxicity in wistar rats. Thirty adult male wistar rats were randomly assigned to five groups (n = 6 each). Group I served as the control, receiving distilled water (2 mL/kg/day). Group II was administered LA (100 mg/kg/day) to induce neurotoxicity. Groups III, IV, and V were co-treated with LA and either N-acetylcysteine (NAC) (150 mg/kg/day), naringin low dose (50 mg/kg/day), or naringin high dose (100 mg/kg/day), respectively, for 28 days. At the end of the 28-day treatment period, blood and brain tissues were collected for biochemical assays. Apoptotic marker caspase-3 expression, oxidative stress markers such as malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) levels were measured in serum and brain homogenates. Behavioral assessments were conducted using the elevated plus maze (EPM). Histopathological studies of brain tissues were also performed with a special focus on the hippocampus. The study highlights the neuroprotective effects of NAC and naringin against LA-induced neurotoxicity in wistar rats. LA exposure caused increased caspase-3 expression, elevated MDA levels, reduced antioxidant enzyme activities (CAT and SOD), and heightened anxiety-like behavior. NAC and high-dose naringin effectively mitigated these effects, restoring oxidative balance, improving behavior, and reducing neuronal damage. Histopathology confirmed significant neuroprotection with NAC and high-dose naringin, highlighting naringin's dose-dependent efficacy as a potential therapeutic agent comparable to NAC for lead-induced neurotoxicity. Naringin demonstrated dose-dependent neuroprotective effects against LA-induced neurotoxicity by improving antioxidant defenses, reducing oxidative stress, and preserving neuronal integrity. These findings support the therapeutic potential of naringin in managing neurotoxic conditions.},
}
@article {pmid41919888,
year = {2026},
author = {Alvarenga, LM and Moraes, MA and Flausino, AR and Altoé-Adorno, BS and Miranda, CES and Pitondo-Silva, A},
title = {Antimicrobial effects of N-acetylcysteine against bacterial strains associated with odontogenic infections.},
journal = {Brazilian journal of biology = Revista brasleira de biologia},
volume = {86},
number = {},
pages = {e303157},
doi = {10.1590/1519-6984.303157},
pmid = {41919888},
issn = {1678-4375},
mesh = {*Acetylcysteine/pharmacology ; Microbial Sensitivity Tests ; *Anti-Bacterial Agents/pharmacology ; Humans ; *Gram-Positive Bacteria/drug effects/classification ; *Gram-Negative Bacteria/drug effects/classification ; Biofilms/drug effects ; },
abstract = {Bacterial infections of the oral cavity result from factors such as inadequate biofilm control and host immune status. Odontogenic infections involve a complex polymicrobial community, comprising aerobic and anaerobic species, and have become increasingly challenging to manage due to the global increase in antimicrobial resistance. In this context, alternatives to conventional antibiotics are needed. N-acetylcysteine (NAC), a compound with antioxidant and mucolytic properties, has also been shown to have antimicrobial and antibiofilm activity, representing a promising candidate for dental applications. This study evaluated the antimicrobial activity of NAC by determining the minimum inhibitory and bactericidal concentrations against bacterial species associated with odontogenic infections. NAC showed inhibitory activity against all tested bacteria, including clinically relevant and highly resistant isolates. Although higher concentrations were required for some species, this finding is consistent with the physicochemical mode of action of NAC and its proposed use as a topical agent in dentistry. Overall, the results support the potential of NAC as an alternative or adjuvant antimicrobial strategy in the management of odontogenic infections, especially in the face of the growing challenge posed by antimicrobial resistance.},
}
@article {pmid41921310,
year = {2026},
author = {Guo, C and Toyomoto, T and Tsutsuki, H and Fujiwara, Y and Komohara, Y and Zhang, T and Honda, H and Lindahl, S and Niidome, T and Fang, J and Xian, M and Sawa, T},
title = {Hepatic supersulfides attenuate acetaminophen-induced liver injury via enhanced detoxification and anti-inflammatory mechanisms.},
journal = {Redox biology},
volume = {92},
number = {},
pages = {104140},
doi = {10.1016/j.redox.2026.104140},
pmid = {41921310},
issn = {2213-2317},
abstract = {Acetaminophen (APAP) is a widely used antipyretic and analgesic agent; however, overdose can lead to hepatotoxicity and, in severe cases, acute liver failure. Development of therapeutics that mitigate APAP-induced liver injury is essential to prevent progression to hepatic failure. Upon overdose, APAP is metabolized in the liver to the highly reactive electrophile N-acetyl-p-benzoquinone imine (NAPQI), which induces hepatocellular damage. Glutathione (GSH), a key intracellular nucleophile, exists partially in a modified form as glutathione hydropersulfide (GSSH), which exhibits enhanced nucleophilicity and functions as a supersulfide. While detoxification of NAPQI via GSH conjugation is well established, the role of GSSH in NAPQI detoxification has remained unknown. In this study, we investigated the protective role of hepatic supersulfides against APAP-induced liver injury using a murine model. Utilizing a newly developed tandem mass spectrometry technique, we demonstrated that supersulfides form conjugates with NAPQI, which are subsequently excreted in the urine. Moreover, administration of supersulfide donors, such as N-acetylcysteine (NAC) tetrasulfide and thioglucose tetrasulfide, elevated hepatic supersulfide levels and significantly attenuated APAP-induced liver injury. Notably, the protective effects of these donors surpassed those of conventional NAC treatment. Our findings suggest that the hepatoprotective effects of supersulfide donors involve not only enhanced detoxification of NAPQI, thereby reducing hepatocellular damage, but also suppression of inflammation. These results highlight the therapeutic potential of targeting hepatic supersulfides in the treatment of APAP overdose.},
}
@article {pmid41922335,
year = {2026},
author = {Zhang, H and Valestil, K and Butcher, RM and Pierce, EA},
title = {Oxidative DNA damage drives apoptotic photoreceptor loss in NMNAT1-associated inherited retinal degeneration: a therapeutic opportunity.},
journal = {Cell death &amp; disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08680-7},
pmid = {41922335},
issn = {2041-4889},
support = {EY012910//U.S. Department of Health &amp; Human Services | NIH | National Eye Institute (NEI)/ ; 2024-40//Knights Templar Eye Foundation (Knights Templar Eye Foundation, Inc.)/ ; },
abstract = {Early-onset inherited retinal degenerations (IRDs), such as Leber congenital amaurosis (LCA) caused by pathogenic variants in the NMNAT1 gene, lead to severe vision loss in children. Despite its ubiquitous expression, reduced NMNAT1 function primarily affects photoreceptor cells (PRs) of the retina, yet the mechanisms underlying their vulnerability remain incompletely understood. Here, we demonstrate that reduced NMNAT1 enzyme function due to the p.V9M mutation leads to DNA damage in PRs, characterized by the progressive accumulation of the oxidative DNA adduct 8-oxo-dG in Nmnat1[V9M/V9M] mutant mice. Cells with oxidative DNA damage also demonstrate DNA double-strand breaks, as evidenced by co-staining with antibodies to phosphorylated H2AX (γH2A.X). This DNA damage correlates with apoptosis-driven PR degeneration, as evidenced by caspase-9 activation and TUNEL staining in the PRs of the Nmnat1[V9M/V9M] mutant mice, while alternative cell death pathways such as necroptosis and parthanatos were not significantly activated. Treatment with the antioxidant N-acetylcysteine (NAC) reduced oxidative DNA damage and retinal immune responses, mitigated apoptosis, and preserved cone PRs. Longitudinal assessment via optical coherence tomography (OCT) and electroretinography (ERG) revealed sustained structural and functional protection of the retina in NAC-treated mice. These findings establish oxidative DNA damage as a key driver of PR degeneration in the Nmnat1[V9M/V9M] model and highlight NAC's potential as a therapeutic strategy for NMNAT1-associated IRD and potentially other IRDs in which oxidative DNA damage contributes to disease pathogenesis.},
}
@article {pmid41916174,
year = {2026},
author = {Rizzo, M and Marussi, G and Castellani, G and Crosera, M and Baj, G and Magnano, GC and Montini, T and Fornasiero, P and Adami, G and Larese Filon, F},
title = {Size-dependent transdermal absorption of cadmium sulphide quantum dots: an ex-vivo study using Franz diffusion cells.},
journal = {Journal of hazardous materials},
volume = {508},
number = {},
pages = {141902},
doi = {10.1016/j.jhazmat.2026.141902},
pmid = {41916174},
issn = {1873-3336},
abstract = {Cadmium sulphide (CdS) quantum dots (QDs) are semiconductor nanomaterials extensively used in optoelectronic and biomedical applications, raising concerns regarding potential health hazards associated with dermal exposure. This study investigated the size-dependent transdermal absorption of N-acetylcysteine (NAC)-capped CdS QDs using an ex-vivo human skin model and Franz diffusion cells. Three QD sizes (3.4, 5.8 and 6.7 nm) were synthesised in aqueous solution, characterised by UV-Vis and fluorescence spectroscopy, and applied to intact and damaged human skin. Cadmium permeation into the receptor fluid and accumulation within skin layers were quantified by ICP-MS, while QD distribution was qualitatively assessed by fluorescence microscopy. Intact skin effectively limited CdS QD permeation, with cadmium levels comparable to blank controls and predominant retention within the epidermis. In contrast, damaged skin exhibited a marked and statistically significant increase in cadmium penetration, strongly dependent on particle size. The smallest QDs (3.4 nm) showed the highest permeation and tissue accumulation, reaching 303 ± 135 μg/cm[2] after 24 h, followed by 5.8 nm QDs, whereas 6.7 nm QDs displayed minimal penetration. Fluorescence imaging confirmed enhanced epidermal and trans-epidermal localisation of smaller QDs, particularly under compromised barrier conditions. Overall, these findings demonstrate that nanoparticle size and skin barrier integrity are key determinants of CdS QD dermal absorption. The results provide relevant evidence for hazard identification and risk assessment of cadmium-based nanomaterials, especially in occupational and environmental exposure scenarios involving impaired skin integrity.},
}
@article {pmid41910852,
year = {2026},
author = {Taki, F and Farhat, M and El-Atat, O and Al-Samman, S and Assaf, N and Abi-Habib, RJ},
title = {Arginine deprivation induces ROS dependent autophagic cell death in human acute myeloid leukemia cells.},
journal = {Human cell},
volume = {39},
number = {4},
pages = {},
pmid = {41910852},
issn = {1749-0774},
support = {PIRF Grant # I0026//Lebanese American University/ ; },
mesh = {Humans ; *Arginine/deficiency ; *Reactive Oxygen Species/metabolism ; *Leukemia, Myeloid, Acute/pathology/metabolism/genetics ; *Autophagic Cell Death/drug effects/genetics ; Cell Line, Tumor ; *Autophagy/drug effects ; Chloroquine/pharmacology ; },
abstract = {In this study, we assess the activation of autophagy and its impact on cytotoxicity following [HuArgI (Co)-PEG5000]-induced arginine deprivation in AML cells. We have previously shown that arginine deprivation is selectively cytotoxic to AML cells and that cell death is caspase independent and non-apoptotic, hence the mechanism of cell death remained elusive. We tested a panel of 7 AML cell lines, and we first demonstrated that the cytotoxicity of [HuArgI (Co)-PEG5000] to AML cells is long-term and sustained despite re-expression of overexpression of ASS1 in all cell lines. We also demonstrated that arginine deprivation leads to a prolonged and extensive activation of autophagy starting at 24 and lasting up to 120 h in all cells. Autophagy was shown to induce cell death since its inhibition using chloroquine (CQ) significantly decreased [HuArgI (Co)-PEG5000]-induced cytotoxicity, indicating autophagic cell death in AML cells following arginine deprivation. Moreover, we showed that arginine deprivation leads to ROS accumulation and that neutralizing ROS using N-acetylcysteine (NAC) does not affect the autophagic response but completely reverses the cytotoxicity of arginine deprivation, demonstrating that death by autophagy is dependent on ROS generation in AML cells.},
}
@article {pmid41911441,
year = {2026},
author = {Tseng, YE and Teng, MC and Huang, YS and Pan, CH and Chang, YP and Wang, CC and Fan, HF},
title = {Incense Aerosol-Induced Neurotoxicity Disrupts α-Synuclein Homeostasis in a Cellular Parkinson's Disease Model, Distinct from Cigarette Aerosols.},
journal = {Chemical research in toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.chemrestox.6c00091},
pmid = {41911441},
issn = {1520-5010},
abstract = {Incense burning is a widespread indoor combustion practice, yet its neurotoxic potential and impact on α-synuclein (α-Syn) proteostasis remain poorly defined. Using SH-SY5Y cells overexpressing α-Syn as a cellular Parkinson's disease model, we exposed cells to size-fractionated incense aerosol extracts (IAE) prepared as organic-phase (OP) or water-soluble phase (WP). α-Syn overexpression augmented vulnerability to IAE, producing greater losses in viability and pronounced increases in intracellular hydrogen peroxide (H2O2), mitochondrial membrane potential depolarization, and engagement of programmed cell-death pathways. Live-cell fluorescence cross-correlation spectroscopy (FCCS) revealed that both OP-IAE and WP-IAE shifted α-Syn from oligomeric to monomeric states in the cytosol, indicating disruption of oligomerization equilibrium. Antioxidant intervention revealed mechanistic differences compared with other indoor air pollutants, cigarette smoke. OP-IAE-induced cytotoxicity cannot be mitigated by N-acetylcysteine (NAC) or rutin, whereas WP-IAE-induced toxicity was partially attenuated, with NAC surpassing rutin. By contrast, for cigarette aerosol extracts (CAE), both OP- and WP-CAEs were robustly rescued by NAC and, to a lesser extent, rutin. Together, these results indicate that incense aerosols, particularly OP-IAE, engage reactive oxygen species (ROS)-linked mitochondrial injury and programmed cell-death pathways while uniquely driving α-Syn monomerization, while exhibiting relative resistance to classical antioxidant intervention compared with cigarette aerosols. This work points out incense smoke as a distinct indoor neurotoxicant with implications for α-Syn homeostasis and Parkinsonian risk in exposed populations.},
}
@article {pmid41897092,
year = {2026},
author = {Villani, C and Di Clemente, A and Invernizzi, RW and Rezzonico, R},
title = {N-Acetylcysteine Reduces Tissue Injury Induced by Oxygen-Glucose Deprivation in an Organotypic Culture of Mouse Cerebral Cortex Slices.},
journal = {Children (Basel, Switzerland)},
volume = {13},
number = {3},
pages = {},
doi = {10.3390/children13030379},
pmid = {41897092},
issn = {2227-9067},
support = {A009114//Zambon (Italy)/ ; },
abstract = {BACKGROUND/OBJECTIVES: Hypoxic-ischemic encephalopathy is the leading cause of infant mortality and disability. Hypothermic therapy is effective in hypoxic-ischemic encephalopathy, albeit in a limited number of cases. Hypothermia requires advanced technologies and significant financial resources, which are difficult to sustain in low-income countries, with devastating consequences. Valid alternatives to hypothermia therapy are therefore needed.<br><br>METHODS: In vitro organotypic cultures of mouse cerebral cortex slices were used to demonstrate the direct protective effect of N-acetylcysteine (NAC) against brain tissue damage induced by oxygen-glucose deprivation (OGD), and to identify the concentrations and time window that maximize the drug's effectiveness. NAC's effectiveness was measured by the incorporation of propidium iodide (PI), a marker of cell membrane integrity.<br><br>RESULTS: Adding 0.1 and 1 mM NAC to the incubation medium before OGD strongly reduced OGD-induced PI incorporation, by 80% (p < 0.0002) and 89% (p < 0.0001), respectively. Administration of 1 mM NAC 1 h after OGD maintained a high degree of protection against OGD-induced damage (80% reduction in PI incorporation; p < 0.0001), while at 0.1 mM, the efficacy of NAC dropped to 44% (p < 0.005). Administration of NAC 4 h after OGD reduced PI incorporation to 52% (p < 0.005) at 1 mM, while at 0.1 mM, the effect was not significant (17%; p > 0.05). Exposure of slices to 0.1 and 1 mM NAC reduced PI incorporation in female cerebral cortex slices (p < 0.006), while only the higher concentration was effective in male slices (p < 0.05). Exposure to 0.1 mM NAC increased tissue levels of total glutathione (p = 0.0185), while no significant effect was observed with 1 mM NAC.<br><br>CONCLUSIONS: This work highlights the direct effect of NAC in protecting cerebral cortex cells from OGD-induced damage and identifies the concentrations and time window that maximize the drug's effect. The results underscore the need for further studies to verify the in vivo efficacy of NAC at concentrations found to be active in vitro, and for clinical trials to evaluate whether NAC can reduce hypoxia-induced brain damage in newborns.},
}
@article {pmid41897452,
year = {2026},
author = {Stranieri, C and Di Leo, EG and Danese, E and Poffe, R and Barbieri, A and Pighi, L and Randon, A and Cominacini, L and Fratta Pasini, AM},
title = {Decreased Plasma Concentration of Hydrogen Sulfide in Hospitalized COVID-19 Patients: A Novel Determinant of Mortality?.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/antiox15030307},
pmid = {41897452},
issn = {2076-3921},
support = {NO GRANT NUMBER//University of Verona, Italy, School of Medicine and Zambon Italia SRL./ ; },
abstract = {In this study, we first focused on measuring H2S and oxidative stress as indicators of in-hospital mortality observed within 24 h from admission in hospitalized non-survivor and survivor patients affected by COVID-19. Then, we analyzed whether N-acetylcysteine (NAC) can increase H2S and GSH concentrations in different cell lines. H2S levels were significantly increased in all COVID-19 patients (both survivors and non-survivors) compared to non-COVID-19 subjects (p = 0.0016), but non-survivors showed significantly lower H2S plasma levels than survivors (p = 0.008). Oxidative stress measured as circulating malondialdehyde (MDA) resulted in lower levels in non-COVID-19 subjects than in the two COVID-19 patient groups (p = 0.03). However, non-survivors had significantly higher plasma MDA than survivors (p = 0.0001). A Kaplan-Meier curve for H2S indicates a markedly reduced survival probability in COVID-19 patients with lower H2S levels (log-rank p = 0.004). NAC activity significantly reduced reactive oxygen species and lipid peroxidation induced by tert-butyl hydroperoxide in cultured cells (p from <0.01 to <0.001). Furthermore, NAC increased the cellular production of H2S (p < 0.01) and GSH (p < 0.01). These findings indicate the important prognostic role of H2S in COVID-19 patients at hospital admission and that NAC might be helpful in all clinical situations characterized by low levels of H2S.},
}
@article {pmid41897494,
year = {2026},
author = {Babiloni-Chust, I and Donato, L and Sartori, S and Carl, M and Zerti, D and Rinaldi, C and Flati, V and Feligioni, M and D'Angelo, R and Maccarone, R and Poggi, L},
title = {Oxidative Stress Signaling and Regenerative Responses in a Larval Zebrafish Model of Retinal Light Damage.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/antiox15030348},
pmid = {41897494},
issn = {2076-3921},
abstract = {The zebrafish (Danio rerio) is a widely used model for studying retinal regeneration. In adults, light-induced retinal damage (LIRD) serves as an environmental phototoxic stressor that induces photoreceptor degeneration and regenerative responses, whereas larval models remain comparatively underexplored. In this study, we validate a larval LIRD paradigm as a versatile system for studying acute phototoxic injury and early regeneration-associated transcriptomic responses. Using high-throughput RNA sequencing, we profiled retinal transcriptional changes 48 h post-LIRD and complemented these findings with targeted pharmacological modulation of redox signaling. Larval LIRD induced robust activation of canonical apoptotic and regeneration-associated pathways, recapitulating key features of adult LIRD models while engaging previously underexplored gene-regulatory networks. Among these, pathways related to oxidative stress responses, antioxidant enzymes, and oxygen metabolism were prominently regulated. Functional attenuation of oxidative stress using the N-acetylcysteine reduced phototoxic injury-induced apoptosis and proliferation, while inflammatory markers remained largely unaffected. Conversely, subtoxic intra-retinal hydrogen peroxide exposure was sufficient to induce proliferative markers without eliciting apoptosis response. At the signaling level, modulation of oxidative stress influenced components of growth-associated signaling pathways activated during early injury response. Together, these findings support a role for oxidative stress as a key component of early injury-associated signaling in larval retinal regeneration. This study integrates histological, transcriptomic, and pharmacological analyses to interrogate early regenerative programs and provides a comprehensive transcriptomic resource for exploring redox-associated mechanisms in retinal injury and repair.},
}
@article {pmid41898249,
year = {2026},
author = {Duman, E and Maçin, A and Özdemir, &#x130; and Öztürk, &#x15e; and Tuncer, MC},
title = {Synergistic Antitumor Effects of Rosmarinic Acid and Cisplatin in Retinoblastoma: Evidence from 2D and 3D Tumor Models.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030602},
pmid = {41898249},
issn = {2227-9059},
abstract = {Background/Objectives: Retinoblastoma (RB) is the most common primary intraocular malignancy in children, with treatment limited by chemoresistance and therapy-related toxicity. Enhancing the efficacy of conventional chemotherapeutics while reducing dose-related adverse effects is crucial. This study investigates the chemosensitizing potential of rosmarinic acid (RA), a natural polyphenolic compound, in combination with cisplatin (Cis) in RB models. Methods: The antiproliferative and synergistic effects of RA and Cis were evaluated in Y79 and WERI-Rb1 RB cell lines using MTT assays and Combination Index (CI) analysis. Apoptosis and oxidative stress were assessed by Annexin V-FITC/PI flow cytometry and intracellular reactive oxygen species (ROS) measurements, respectively. Three-dimensional (3D) tumor spheroids were generated from Y79 cells for in vitro validation using spheroid size analysis, ATP-based viability assays, and live/dead fluorescence staining. The ROS dependency of cytotoxicity was further examined using N-acetylcysteine (NAC) pretreatment. Cytokine secretion was analyzed by ELISA, and apoptosis-related gene expression was assessed by qRT-PCR. Results: RA and Cis reduced cell viability in a dose- and time-dependent manner, while their combination induced significantly enhanced cytotoxicity, confirmed by CI values < 1. Combined treatment increased apoptotic populations, elevated intracellular ROS, and upregulated Caspase-3 and Caspase-9. These effects were maintained in 3D spheroids, with reduced spheroid size and impaired integrity. NAC pretreatment attenuated ROS generation and partially rescued cell viability, indicating a ROS-dependent, but not exclusive, contribution to cytotoxicity. Conclusions: RA synergistically enhances cisplatin-induced anticancer effects in RB through oxidative stress, engagement of intrinsic (mitochondria-associated) apoptotic signaling, and reduction of tumor cell-derived inflammatory and angiogenic mediators. These findings highlight the potential of RA and Cis combination as a chemosensitizing strategy for RB therapy, warranting further in vivo evaluation.},
}
@article {pmid41898408,
year = {2026},
author = {Muriel, P and Vargas-Pozada, EE and Márquez-Quiroga, LV and Ramos-Tovar, E},
title = {Potential Therapeutic Strategies for Steatosis, Oxidative Stress, Inflammation, and Fibrosis in Liver Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062546},
pmid = {41898408},
issn = {1422-0067},
mesh = {Humans ; *Oxidative Stress/drug effects ; *Liver Cirrhosis/drug therapy/metabolism ; *Inflammation/drug therapy/metabolism ; Ursodeoxycholic Acid/therapeutic use/pharmacology ; Animals ; *Fatty Liver/drug therapy/metabolism ; *Liver Diseases/drug therapy/metabolism ; Antioxidants/therapeutic use/pharmacology ; Pyridones/therapeutic use/pharmacology ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; },
abstract = {Liver disease encompasses a wide range of conditions, each requiring tailored therapeutic approaches. This review describes and critically discusses treatments with robust evidence for improving liver health. Ursodeoxycholic acid (UDCA) is a drug approved by the Food and Drug Administration of the USA to treat primary biliary cholangitis (PBC). In addition, UDCA has been demonstrated to protect against metabolic dysfunction-associated steatohepatitis, fibrosis, and drug-induced liver injury (DILI). The mechanism of action of UDCA has been attributed not only to decreasing the effects of toxic bile acids but also to protecting mitochondrial integrity and function, as well as to antioxidant, anti-inflammatory, and anti-apoptotic activities. UDCA can scavenge reactive oxygen species (ROS) and activate the nuclear factor-E2-related factor-2 (Nrf2) pathway, thereby exerting antioxidant activity. The anti-inflammatory activity of UDCA is associated with its ability to inhibit the nuclear factor-κB pathway. Pirfenidone is a well-recognized antifibrotic drug for the treatment of idiopathic pulmonary fibrosis; its effects on liver fibrosis have also been demonstrated. Pirfenidone exerts anti-inflammatory effects by attenuating the nucleotide-binding oligomerization domain-like receptor 3 inflammasome signaling pathway. The antioxidant actions of pirfenidone are associated with its ability to upregulate the Nrf2 pathway. Both the anti-inflammatory and antioxidant properties of pirfenidone act together to attenuate lung and liver fibrosis, decreasing transforming growth factor-β levels, inhibiting profibrogenic hepatic stellate cell activation, and increasing extracellular matrix degradation. Methyltransferases utilize S-adenosyl-L-methionine (SAM) as a methyl donor for most transmethylation reactions in the body. SAM increases reduced glutathione (GSH) levels, exerting important antioxidant effects. Evidence indicates that SAM prevents fibrosis and attenuates hepatocellular carcinoma development, improving patient survival. N-acetylcysteine (NAC) is a precursor to L-cysteine and GSH and is used in clinical settings to treat cancer, nephropathy, heart disease, pulmonary fibrosis, polycystic ovary syndrome, and influenza. Regarding the liver, NAC is the most accepted treatment for DILI, especially after paracetamol overdose. Owing to its antioxidant and anti-inflammatory actions, NAC has been successfully used to treat chronic liver injuries, including hepatosteatosis and fibrosis. Therefore, ursodeoxycholic acid, pirfenidone, S-adenosyl-L-methionine, and N-acetylcysteine could represent therapeutic strategies for the treatment of liver pathologies.},
}
@article {pmid41888118,
year = {2026},
author = {Angioli, C and Ferriero, A and Eleonora, P and Tesoriere, G and Agostini, B and Tramonti, A and Contestabile, R and Vernì, F},
title = {Tumor suppressor function of SHMT in a Drosophila Ras[V12]Dlg[RNAi] model: DNA damage and synergistic gene-nutrient interaction with PLP.},
journal = {Cell death &amp; disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08602-7},
pmid = {41888118},
issn = {2041-4889},
support = {AR1231889041EBDD//Sapienza Universit&#xe0; di Roma (Sapienza University of Rome)/ ; AR1241905DD95C63//Sapienza Universit&#xe0; di Roma (Sapienza University of Rome)/ ; },
abstract = {Serine hydroxymethyltransferase (SHMT) is a key enzyme in one-carbon (1 C) metabolism, essential for nucleotide synthesis and epigenetic maintenance. In mammals, there are two distinct SHMT isozymes: the cytosolic SHMT1 and the mitochondrial SHMT2. Several studies report that high SHMT levels in cancer contribute to metabolic reprogramming. Conversely, a limited number of studies have linked decreased SHMT1 expression to the progression and poor prognosis of hepatocellular carcinoma and renal cell carcinoma, suggesting that SHMT may play dual roles as an oncogene or tumor suppressor, depending on the cellular context. However, the molecular mechanisms underlying SHMT tumor suppressor role remain unknown. In this work, we used the Drosophila Ras[V12]Dlg[RNAi] cancer model to investigate the effects of SHMT depletion on cancer progression and the associated mechanisms. We found that RNAi-mediated SHMT silencing promotes the progression of Ras[V12]Dlg[RNAi] cancers by impairing thymidylate biosynthesis in the folate pathway. SHMT depletion in Ras[V12]Dlg[RNAi] cells causes DNA and chromosome damage and renders these cells sensitive to genotoxic stressors such as X-rays or hydroxyurea. Genome instability is correlated with cancer progression, and it is largely due to the generation of reactive oxygen species (ROS) and, to a lesser degree, to replicative stress and compromised DNA repair mechanisms, all arising from SHMT depletion. Antioxidant treatment with N-acetyl cysteine (NAC) significantly reduces both DNA damage and tumor progression. Intriguingly, the combined depletion of SHMT and its cofactor pyridoxal 5'-phosphate (PLP) further increases oxidative stress, leading to extensive DNA damage that induces apoptosis in Ras[V12]Dlg[RNAi] cells, thereby limiting the tumor growth. Taken together, our data suggest that a diminished SHMT activity may drive the progression of Ras[V12]Dlg[RNAi] cancers through ROS-induced genome instability. Additionally, our study points to a novel gene-nutrient interaction, SHMT-PLP, that impacts cancer growth with potential therapeutic implications.},
}
@article {pmid41889224,
year = {2026},
author = {Badroo, IA and Nandurkar, HP and Nagale, VK and Khan, SK and Khanday, AH and Wani, ZA and Lone, MA},
title = {Paraquat Dichloride Induced Cytotoxicity in Primary Hepatocytes via an Antioxidative and Mitochondrial-Dependent Pathway.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70162},
pmid = {41889224},
issn = {1099-1263},
abstract = {The liver serves as the primary detoxification organ, playing a crucial role in protecting against environmental toxicants. Paraquat (PQ), a widely used herbicide in agricultural and domestic applications, has been extensively documented to induce severe toxicity in various tissues and disrupt multiple cellular signaling pathways. This study investigates the cytotoxic and genotoxic effects of PQ on isolated primary rat hepatocytes, obtained via the collagenase perfusion method. A comprehensive toxicity assessment was conducted, including cell viability at different PQ concentrations, reactive oxygen species (ROS) generation, reduced (GSH) and oxidized glutathione (GSSG) levels, mitochondrial membrane potential (MMP) collapse, lysosomal integrity, and lipid peroxidation (MDA) content. A significant increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) leakage indicated hepatocellular membrane disruption. PQ exposure resulted in excessive ROS generation, mitochondrial dysfunction, oxidative stress, and apoptosis activation through the caspase-9/-3 signaling cascade. Notably, coincubation with the ROS scavenger N-acetylcysteine (NAC) significantly attenuated ROS generation, apoptosis, and hepatocyte damage, underscoring the role of oxidative stress in PQ-induced hepatotoxicity. These findings provide mechanistic insights into PQ-induced cytotoxicity, demonstrating that ROS overproduction and mitochondrial impairment are the primary drivers of hepatocyte injury. Given the extensive use of PQ and its potential environmental and human health risks, these findings are critical for understanding its toxicological impact and exploring antioxidant-based therapeutic strategies to mitigate liver damage.},
}
@article {pmid41887487,
year = {2026},
author = {Zhang, B and Liu, Z and Li, Q and Tian, M and Gao, Y and Kishi, H and Xu, D},
title = {Endoplasmic reticulum stress mediates oxidative stress-driven endothelial impairment and atherogenesis induced by sodium perfluorononenoxybenzene sulfonate exposure.},
journal = {Environmental research},
volume = {},
number = {},
pages = {124344},
doi = {10.1016/j.envres.2026.124344},
pmid = {41887487},
issn = {1096-0953},
abstract = {Sodium perfluorononenoxybenzene sulfonate (OBS), a substitute for perfluorooctane sulfonate (PFOS), has been frequently detected in the environment and human blood. Although OBS exposure has been identified as a novel risk factor for atherosclerosis associated with endothelial dysfunction, the underlying molecular mechanisms remain unclear. In this study, in vitro experiments using human umbilical vein endothelial cells (HUVECs) demonstrated that OBS exposure induced oxidative stress, activated the PERK-eIF2α-ATF4 axis of endoplasmic reticulum stress (ERS) and triggered NF-κB signaling. Pharmacological inhibition with N-acetylcysteine (NAC, an antioxidant), 4-phenylbutyric acid (4-PBA, an ERS inhibitor), and BAY 11-7082 (an inhibitor for NF-κB signaling pathway) revealed a sequential pathogenic cascade, in which oxidative stress acts upstream to initiate ERS and compromise endothelial barrier function, leading to NF-κB activation, which drives inflammatory responses, monocyte adhesion, and impaired endothelial migration. Consistent with these findings, in vivo experiments in ApoE[-]/[-] mice showed that OBS exposure caused endothelial impairment, collagen deposition, and oxidative stress in aortic tissues, accompanied by upregulating the expression of ERS and inflammation-related markers. These findings suggest that ERS serves as a key mediator linking oxidative stress to inflammation in OBS-induced endothelial dysfunction, highlighting the potential cardiovascular hazards of OBS as an emerging PFOS alternative.},
}
@article {pmid41878339,
year = {2026},
author = {Valenzuela-Valderrama, M and Varas, A and Rubilar, M and Lorca, M and Mella, J and Espinosa-Bustos, C and Mellado, M and Echeverría, J},
title = {3D-QSAR study for the development of chalcone-based inhibitors targeting ovarian cancer cells with experimental validation.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1746658},
pmid = {41878339},
issn = {1663-9812},
abstract = {BACKGROUND: Ovarian cancer remains one of the most lethal gynecological malignancies, mainly due to late-stage diagnosis and frequent chemoresistance.<br><br>PURPOSE: This study sought to develop 3D-QSAR models-Comparative Molecular Field and Similarity Index Analysis (CoMFA and CoMSIA)-to predict the antiproliferative activity of synthetic chalcone derivatives against A2780 ovarian cancer cells and to explore potential mechanisms of action through antioxidant response biomarkers.<br><br>MATERIALS AND METHODS: CoMFA and CoMSIA models were developed using a dataset of 64 chalcone derivatives and validated using q[2], r[2] ncv, and other statistical metrics. Twelve chalcones predicted as active were synthesized and characterized by FT-IR and NMR spectroscopy. Their antiproliferative effects were evaluated using MTT assays, complemented by clonogenic testing, intracellular glutathione quantification, and analysis of biomarkers, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO1). The most active compounds were further assessed in a cisplatin-resistant A2780 subline, with N-acetylcysteine (NAC) used to probe reactive oxygen species (ROS)-dependent mechanisms.<br><br>RESULTS AND DISCUSSION: The CoMFA and CoMSIA models demonstrated strong predictive performance (q[2] = 0.763/0.789; r[2] ncv = 0.963/0.920). Contour maps highlighted steric and electrostatic features linked to enhanced antiproliferative activity. The twelve synthesized chalcones exhibited experimental pIC50 values that strongly correlated with model predictions. Compounds 065, 066, and 072 showed the highest potency, with compound 072 also reducing clonogenic survival. Active derivatives increased intracellular glutathione and upregulated HO-1 without activating canonical Nrf2 signaling. In cisplatin-resistant A2780 cells, compounds 072 and 074 displayed markedly higher potency (IC50 = 6.50 and 10.22&#xa0;&#x3bc;M) than cisplatin (93.4&#xa0;&#x3bc;M). Their cytotoxicity was abrogated by NAC, indicating a ROS-dependent mode of action.<br><br>CONCLUSION: CoMFA and CoMSIA models accurately predicted the activity of synthetic chalcones, and the biological findings identify these derivatives as promising candidates for the treatment of ovarian cancer, including chemoresistant forms.},
}
@article {pmid41874704,
year = {2026},
author = {Mohammed, I and Nankya, Y and Hong, UT and Kan, A and Abdelhafid, AM and Latunde-Dada, GO},
title = {The role of N-acetylcysteine and glutathione in the management of Parkinson's disease: a systematic review of oxidative biomarkers and clinical outcomes.},
journal = {Amino acids},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00726-026-03513-5},
pmid = {41874704},
issn = {1438-2199},
abstract = {Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic neurons, leading to both motor and non-motor symptoms. Oxidative stress is a significant contributor to the pathophysiology of PD, and glutathione (GSH) depletion contributes to neuronal damage. N-acetylcysteine (NAC), a bioavailable cysteine donor, can support endogenous GSH synthesis and may also exert antioxidant effects independent of GSH replenishment. NAC and GSH are proposed neuroprotective interventions due to their antioxidant properties. This systematic review evaluated the effects of NAC and GSH on oxidative stress and PD symptoms, comparing them with healthy controls or a placebo. A systematic search was conducted in Cochrane Library, PubMed, Web of Science, Ovid (Embase and MEDLINE), Scopus, and ProQuest for studies published between January 2003 and December 2024, including randomised controlled trials (RCTs) and non-randomised studies. Two reviewers assessed the study quality and extracted data. The primary outcome was the change in motor and non-motor symptoms as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) and were interpreted using minimal clinically important difference (MCID) thresholds. Secondary outcomes included biochemical redox markers such as blood GSH, cerebrospinal fluid (CSF) GSH, GSSG, and GSH/GSSG ratio and imaging-based functional outcomes, particularly DAT binding assessed by DaTscan SPECT. The GSH/GSSG ratio reflects redox status (reduced vs. oxidised glutathione), CSF outcomes primarily reported NAC concentrations, and brain GSH was quantified using magnetic resonance spectroscopy (MRS). Exclusion criteria included studies on conditions other than PD, those that did not use NAC or GSH as the primary intervention, and those without a comparator group. Nine studies, conducted between 2009 and 2019, met the inclusion criteria and involved 196 participants. NAC improved both motor and non-motor symptoms and significantly increased GSH/GSSG ratios, GSH levels in the CSF, and DAT binding. In contrast, intranasal GSH showed only modest increases in brain levels without significant improvements in symptoms or oxidative stress markers. The studies had limitations, including small sample sizes, short intervention durations, and inconsistencies in dosage and administration routes. These factors constrain the strength of the conclusions, and evidence for both NAC and GSH remains preliminary. Furthermore, while NAC shows promise as a neuroprotective intervention, findings for GSH are inconclusive. More large-scale, long-term randomised controlled trials are needed to validate these results and explore NAC and GSH's long-term therapeutic potential in managing PD.},
}
@article {pmid41868894,
year = {2026},
author = {Zhang, Y and Han, X and Jiao, F and Huang, G and Liang, Y},
title = {Association of vitamin D and N-acetylcysteine supplementation with anxiety, cognition, and biomarkers in generalized anxiety disorder: a retrospective cohort study.},
journal = {American journal of translational research},
volume = {18},
number = {2},
pages = {1517-1527},
pmid = {41868894},
issn = {1943-8141},
abstract = {OBJECTIVE: To investigate the association between combined vitamin D and N-acetylcysteine (NAC) supplementation and clinical outcomes in patients with generalized anxiety disorder (GAD).<br><br>METHODS: This retrospective cohort study included 88 propensity-score-matched patients with GAD from Beidahuang Group Neuropsychiatric Hospital. Based on clinical records, patients were classified into an observation group (vitamin D3 + NAC + usual care) and a control group (usual care only). Anxiety symptoms and cognitive function were assessed using the Beck Anxiety Inventory (BAI), Automatic Thought Questionnaire (ATQ), and Dysfunctional Attitudes Scale (DAS). Serum levels of 25-hydroxyvitamin D [25(OH)D], inflammatory markers [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)], oxidative stress parameters [glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD)], and neurochemical markers [brain-derived neurotrophic factor (BDNF), dopamine (DA), Serotonin (5-HT), norepinephrine (NE)] were measured at baseline and week 8.<br><br>RESULTS: After 8 weeks, both groups showed significant improvements in BAI, ATQ, and DAS scores, with greater reductions in the observation group (all P < 0.05). The observation group also exhibited more favorable changes in biomarkers: greater increases in 25(OH)D, GSH, SOD, BDNF, DA, 5-HT, and NE, and greater decreases in MDA, IL-6, and hs-CRP compared to the control group (all P < 0.05). Adverse event incidence was low and similar between groups.<br><br>CONCLUSION: In this retrospective cohort, combined vitamin D and NAC supplementation was associated with significantly greater improvements in anxiety symptoms, cognitive patterns, and relevant metabolic biomarkers in patients with GAD compared to usual care alone, supporting its potential as an adjunctive therapy.},
}
@article {pmid41870350,
year = {2026},
author = {Cardoso, JMDF and Ferreira, RV and Rasslan, R and Otsuki, DA and Utiyama, EM and Montero, EFS and , },
title = {Combined N-acetylcysteine and tranexamic acid attenuate acidosis and fibrinolysis in a swine polytrauma model.},
journal = {The journal of trauma and acute care surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/TA.0000000000004965},
pmid = {41870350},
issn = {2163-0763},
abstract = {BACKGROUND: Traumatic coagulopathy is a major contributor to mortality after severe hemorrhage. Tranexamic acid (TXA) reduces fibrinolysis, and N-acetylcysteine (NAC) has antioxidant and anti-inflammatory properties. Both agents have shown benefit individually, but their combined effect has not been previously investigated in trauma. We hypothesized that early administration of NAC with TXA during resuscitation could attenuate acidosis and fibrinolysis in an experimental study with a hemorrhagic shock and polytrauma swine model.<br><br>METHODS: Thirty-six male Landrace pigs (28.3 &#xb1; 3.0&#xa0;kg) were randomized into five groups: Sham (n = 5), Ringer lactate (n = 5), NAC (n = 6), TXA (n = 6), and NAC+TXA (n = 6). Animals underwent experimental standardized polytrauma (femur fracture, controlled hemorrhage of 60% blood volume), followed by immediate resuscitation and a grade IV liver injury. Standard physiological parameters, blood gases, lactate, coagulation tests, fibrinogen, and thromboelastometry (ROTEM parameters) were assessed at baseline, post-shock, post-resuscitation, post-liver injury, and final.<br><br>RESULTS: All trauma groups developed profound shock physiology compared with Sham. The NAC+TXA group demonstrated the most complete correction of acid-base status, achieving the highest final pH (7.5 &#xb1; 0.03), significantly greater than Ringer lactate (7.3 &#xb1; 0.09), NAC (7.3 &#xb1; 0.06), and TXA (7.3&#xb1;0.11) (P = 0.001). Lactate and base deficit showed directionally similar improvements.Thromboelastometry showed attenuated fibrinolysis with combined therapy. The NAC+TXA group exhibited lower maximum lysis after liver injury compared with NAC (10 &#xb1; 3% vs 16 &#xb1; 4%, P = .008). Other ROTEM parameters displayed directionally similar trends toward improved clot formation.<br><br>CONCLUSIONS: In this swine polytrauma model, the combined administration of NAC and TXA was associated with improved in acid-base status and attenuation of fibrinolysis. While these physiological effects are preliminary, they support additional experimental investigations to clarify mechanisms, reproducibility, and potential translational relevance of NAC+TXA as an adjunct in damage control resuscitation. (J Trauma Acute Care Surg. 2026;00:00-00. Copyright &#xa9; 2026 Wolters Kluwer Health, Inc. All rights reserved.<br><br>LEVEL OF EVIDENCE: Experimental animal study.},
}
@article {pmid41862922,
year = {2026},
author = {Essam, A and Domiaty, SE and Attia, N and Helal, H and Meheissen, M},
title = {N-acetylcysteine nano-spray versus conventional treatment in the management of radiotherapy-induced oral mucositis in oral cancer patients: a randomized clinical trial.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-026-07959-7},
pmid = {41862922},
issn = {1472-6831},
abstract = {BACKGROUND: Radiation-induced oral mucositis (RIOM) is a common and debilitating complication of radiotherapy in oral cancer patients, significantly impairing quality of life and potentially interrupting treatment. This study evaluated the therapeutic efficacy of N-acetylcysteine (NAC) nano-spray in managing RIOM, with particular emphasis on mucositis severity, quality of life, and serum gastrin-17 levels.<br><br>MATERIALS AND METHODS: In this randomized clinical study, 40 oral cancer patients undergoing radiotherapy were allocated in a 1:1 ratio to receive either NAC nano-spray (n&#x2009;=&#x2009;20) or conventional therapy (n&#x2009;=&#x2009;20) for six weeks. Mucositis severity was assessed using the World Health Organization (WHO) Oral Mucositis Severity Scale, and quality of life was evaluated using the Oral Health Impact Profile (OHIP-14). Serum gastrin-17 levels were measured before and after treatment.<br><br>RESULTS: Patients treated with NAC nano-spray demonstrated a significant reduction in WHO mucositis grades and significantly improved OHIP-14 scores compared with the control group (p&#x2009;<&#x2009;0.05). Additionally, a significant increase in serum gastrin-17 levels was observed in the NAC group relative to conventional therapy (p&#x2009;<&#x2009;0.05). These effects were evident during radiotherapy and at the end of treatment.<br><br>CONCLUSIONS: N-acetylcysteine nano-spray appears to be an effective therapeutic option for the management of RIOM, reducing mucositis severity and improving quality of life in oral cancer patients.<br><br>TRIAL REGISTRATION: The trial was registered at Clinical Trials .gov on 24/7/2025, registration number: (NCT07082621).},
}
@article {pmid41863011,
year = {2026},
author = {Tola, HT and Kılıç, S},
title = {Experimental evaluation of N-acetylcysteine against doxorubicin cardiotoxicity in rats.},
journal = {BMC pharmacology &amp; toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40360-025-01073-0},
pmid = {41863011},
issn = {2050-6511},
abstract = {BACKGROUND: Doxorubicin (DOX) is a widely used anthracycline antibiotic in the treatment of pediatric malignancies. However, its clinical application is significantly limited by its well-documented cardiotoxic side effects. The hypothesis of this study is that N-acetylcysteine (NAC), as an antioxidant agent, may reverse DOX-induced cardiotoxicity. Therefore, we aimed to evaluate the potential protective role of NAC against DOX-induced cardiotoxicity in rat heart tissue in this experimental study.<br><br>METHODS: Thirty rats were randomly divided into three groups (n&#x2009;=&#x2009;10 each): control, DOX, and DOX&#x2009;+&#x2009;NAC. The control group received physiological saline via oral gavage at 0 and 24&#xa0;h, followed by intraperitoneal saline at 48&#xa0;h. The DOX group received saline at the same intervals, but received 20&#xa0;mg/kg DOX intraperitoneally at 48&#xa0;h. The treatment group received 140&#xa0;mg/kg NAC orally at 0 and 24&#xa0;h, followed by 20&#xa0;mg/kg DOX intraperitoneally at 48&#xa0;h.<br><br>RESULTS: Compared to controls, the DOX group showed significantly increased malondialdehyde levels and decreased levels of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase (p&#x2009;<&#x2009;0.05). In the NAC-treated group, these values were comparable to controls. Histologically, the DOX group exhibited edema, inflammation, vacuolization, hemorrhage, necrosis, and myofibrillar disorganization, while these alterations were largely absent in the NAC group (p&#x2009;<&#x2009;0.005).<br><br>CONCLUSION: In our study, NAC did not produce significant biochemical improvement in DOX-damaged heart tissue but provided substantial histological protection against DOX toxicity. These findings highlight NAC as a promising agent for reducing DOX-induced cardiac toxicity.},
}
@article {pmid41856984,
year = {2026},
author = {Huang, S and Song, Z and Shi, C and Tao, D and Wen, J and Chen, Y and Luo, Y},
title = {A single extinction-based treatment with N-Acetylcysteine produces long-term reduction in cocaine relapse.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03954-2},
pmid = {41856984},
issn = {2158-3188},
abstract = {Cocaine addiction is characterized by high relapse rates associated with glutamate dysregulation, presenting significant challenges for long-term treatment. N-acetylcysteine (NAC) has shown promise in preventing drug relapse by normalizing glutamate function, potentially mediated by glutamate 2/3 (mGlu2/3) receptor activation. This study investigated the therapeutic potential of NAC in reducing cocaine-seeking behavior using the self-administration model. After establishing stable cocaine self-administration and a 7-day abstinence period, rats received a single dose of NAC (100 mg/kg, i.p.) 30 min before the first extinction training session. NAC significantly reduced cocaine-seeking behavior on the first day of extinction but not in subsequent extinction sessions. Following extinction, tests for cue-induced reinstatement and spontaneous recovery were conducted. Results showed that NAC administration on the first day of extinction effectively reduced cocaine-seeking during the reinstatement test, with effects lasting at least 28 days. The mGlu2/3 antagonist LY341495 (1 mg/kg) fully blocked this enduring suppression of reinstatement without altering the immediate decrease in drug-seeking observed on the first day of extinction. Additionally, NAC administration on the initial extinction day also reduced context-induced reinstatement of cocaine-seeking behavior. These results indicate that NAC exerts its anti-relapse effects via mGlu2/3 receptors. A single NAC treatment combined with extinction training can produce lasting suppression of relapse, highlighting its therapeutic promise for addiction treatment.},
}
@article {pmid41861379,
year = {2026},
author = {Barthelemy, N and Lee, W and Gregori, NZ and Lam, BL and Sengillo, JD},
title = {Nutritional supplements: current evidence for retinitis pigmentosa and Stargardt disease.},
journal = {Current opinion in ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1097/ICU.0000000000001213},
pmid = {41861379},
issn = {1531-7021},
abstract = {PURPOSE OF REVIEW: Inherited retinal diseases (IRDs) are genetically and phenotypically heterogeneous disorders that cause progressive vision loss and lack broadly effective disease-modifying therapies. Increasing evidence implicates metabolic stress, oxidative injury, and photoreceptor-retinal pigment epithelium (RPE) dysfunction in IRD pathophysiology. This review evaluates the evidence and limitations surrounding nutritional and metabolic interventions for retinitis pigmentosa and Stargardt disease.A narrative review of preclinical studies, randomized controlled trials, and contemporary genetic re-analyses was performed. Nutritional interventions reviewed include vitamin A, vitamin E, N-acetylcysteine (NAC), omega-3 fatty acids (docosahexaenoic acid), carotenoids and apocarotenoids, and the deuterated vitamin A analog C20-D3-retinyl acetate (ALK-001).<br><br>RECENT FINDINGS: Initial studies suggesting a protective effect of vitamin A in retinitis pigmentosa were not confirmed in subsequent trials or genetic re-analyses, which identified baseline differences between groups as a possible contributor to the original findings. In contrast, supplemental vitamin E may accelerate disease progression. NAC demonstrated acceptable tolerability and modest short-term improvements in visual function in early-phase trials, with a phase 3 study ongoing. Omega-3 fatty acids, carotenoids, and apocarotenoids have not shown consistent clinically meaningful benefit in retinitis pigmentosa or Stargardt disease despite strong mechanistic rationale. In Stargardt disease, ALK-001 reduces lipofuscin accumulation in animal models and clinical trials are ongoing to assess efficacy in patients.<br><br>SUMMARY: Most nutritional supplements studied to date have not demonstrated durable or clinically meaningful benefit in IRDs. Vitamin A supplementation in retinitis pigmentosa is no longer supported by current evidence, while NAC remains a promising metabolic therapy under investigation. High-quality, genotype-informed clinical trials with clinically relevant endpoints are needed before nutritional interventions can be incorporated into IRD management guidelines.},
}
@article {pmid41862110,
year = {2026},
author = {Liu, Y and Xiao, Z and Zhang, Y and Chen, Q and Luo, S and Wang, Y and Miao, Z and Tao, Z and Gong, D},
title = {Polypyrrole nanozymes with cell-free DNA scavenging and ferroptosis inhibition capabilities for the treatment of acetaminophen-induced acute liver injury.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.03.030},
pmid = {41862110},
issn = {1878-7568},
abstract = {Acute liver failure (ALF) can result from the progressive development of acute liver injury triggered by acetaminophen (APAP) overdose. The core mechanisms involve an imbalance in the antioxidant system and upregulation of the inflammatory response, which collectively induce ferroptosis/apoptosis. Herein, nanozymes (PPy-Mg NPs) were synthesized through coordination reaction between polypyrrole nanoparticles (PPy NPs) and magnesium ions. The enriched PPy-Mg NPs were explored as active anti-inflammatory nanozymes for effective acute liver injury treatment. Enriched cationic PPy-Mg NPs in the liver effectively scavenged excess reactive oxygen and nitrogen species (RONS) and cell-free DNA. It is worth emphasizing that in the delayed AILI mouse models, bioactive PPy-Mg NPs not only reduced oxidative stress levels but also modulated multiple biological signaling pathways, such as NF-κB, Nrf2-Keap1, ferroptosis/apoptosis. The research indicates the possible medical application of PPy-Mg NPs nanozymes in efficient enrichment treatment for acute liver injury. STATEMENT OF SIGNIFICANCE: APAP-induced liver injury (AILI) can progress to acute liver failure (ALF), presenting a significant clinical challenge. Currently, N-acetylcysteine (NAC) is the only medication approved treatment; however, its efficacy in patients with advanced AILI remains unsatisfactory. Therefore, the development of new therapeutics for the treatment of AILI are crucial. This work developed a PPy-Mg NPs nanozyme for the efficient AILI treatment. PPy-Mg NPs provide constructive applications of polypyrrole-based nanozymes for AILI treatment, which covers upstream metabolic rescue (RONS scavenging), necrotic debris clearance (cfDNA removal), and residual cell protection (ferroptosis inhibition) across temporal and spatial dimensions, holds potential for extending therapeutic windows and enhancing protection rates in high-risk/complex cases.},
}
@article {pmid41862408,
year = {2026},
author = {Hareedy, MS and Abdelrahem, MH and Hassan, SS and Elkaliny, HH},
title = {Effects of Lithium and Verapamil on Thyroid and Kidney Function in Mice: A Preclinical Study.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70172},
pmid = {41862408},
issn = {1099-1263},
abstract = {Lithium (Li) salts are still one of the basic therapies for manic-depressive illness, which has a double-edged nature where the good efficacy is threatened by possible toxicity if Li levels are elevated. The effects of verapamil and N-acetylcysteine (NAC) on Li levels and Li-related toxicity in the thyroid gland and kidneys were studied. Five groups of mice (normal control, Li, verapamil, Li + verapamil, and Li + NAC) were evaluated for levels of urea, creatinine, thyroid hormones (T3 and T4), thyroid-stimulating hormone (TSH), sodium, and potassium after 6 weeks. Li levels were measured in all groups that received Li. Renal and thyroid tissues were assessed histologically. T4 and T3 were significantly elevated in the Li, Li + verapamil, and Li + NAC groups compared to the normal control (p < 0.0001), while TSH was significantly decreased (p < 0.001). Levels of Li, potassium, and urea were elevated by the co-administration of verapamil or NAC, while serum creatinine was significantly decreased compared to the Li-treated group. Verapamil and NAC elevated the serum levels of Li and augmented the effects of Li on the thyroid gland, urea, and potassium levels.},
}
@article {pmid41852760,
year = {2026},
author = {Elsheshtawy, NE and Risha, EF and Abdelhamid, FM and Rajab, BS and Bagadood, R and Bokhari, B and Sindi, G and Ateya, AI and Rezk, S and El-Boshy, ME},
title = {Protective effects of Lagerstroemia speciosa against paracetamol-induced renal and testicular toxicity in rats via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.},
journal = {Frontiers in toxicology},
volume = {8},
number = {},
pages = {1751678},
pmid = {41852760},
issn = {2673-3080},
abstract = {INTRODUCTION: Paracetamol (PCM) is widely used as an analgesic; however, at high doses, it is well recognized for its hepatotoxic effects and is increasingly associated with renal and reproductive damage.<br><br>METHODS: In the present study, the protective potential of ethanolic Lagerstroemia speciosa leaf extract (EELS; 500 mg/kg/day, orally for 24 days) was investigated against PCM-induced kidney and testicular injury in male rats, using N-acetyl cysteine (NAC) as a reference treatment.<br><br>RESULTS: PCM administration led to pronounced impairment in sperm quality and significant disturbances in serum biochemical parameters, reflected by elevated renal function markers, sodium, and phosphorus levels, together with reduced calcium, potassium, and testosterone. These changes were accompanied by clear evidence of oxidative stress, as indicated by increased malondialdehyde and decreased reduced glutathione. Moreover, inflammatory and apoptotic responses were markedly intensified, whereas antioxidant and steroidogenic regulators were suppressed. Histopathological findings further confirmed extensive structural damage in renal and testicular tissues. Notably, treatment with EELS or NAC substantially mitigated these alterations, restoring most parameters toward normal values.<br><br>CONCLUSION: Collectively, these findings demonstrate that EELS exerts notable nephroprotective and gonadoprotective effects comparable to NAC, largely through the attenuation of oxidative stress, inflammation, and apoptosis.},
}
@article {pmid41854407,
year = {2026},
author = {Qi, L and Kou, H and Chernatynskaya, A and Huang, D and Mani, VJ and Karacal, H and Ercal, N and Yang, H},
title = {Dendrimer Nanogels with Built-in Free Radical Scavenging Enable Efficient Topical Delivery of a Hydrophilic Antioxidant to Restore Lens Redox Balance for Cataract Treatment.},
journal = {ACS applied materials &amp; interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c24072},
pmid = {41854407},
issn = {1944-8252},
abstract = {Cataract is a leading cause of vision impairment worldwide and are primarily caused by oxidative stress that damages and aggregates lens proteins, leading to lens opacification. However, the eye's anatomical barriers limit the penetration and bioavailability of antioxidant therapies. To address this challenge, a dendrimer-based nanogel with a built-in reactive oxygen species (ROS)-scavenging capability developed by us was employed to deliver the antioxidant N-acetylcysteine (NAC) to the lens. NAC was loaded into a generation-5 PEGylated poly(amidoamine) dendrimer (G5-PEG-TK, termed the GPT) nanogel. The resulting NAC-GPT was characterized for its ROS-scavenging activity, bioavailability, and corneal permeability. The efficacy of NAC-GPT was evaluated ex vivo and in vivo using a sodium selenite (Na2SeO3)-induced cataract model. Both ex vivo and in vivo results demonstrated that NAC-GPT significantly increased the level of NAC accumulation in the lens. Furthermore, the in vivo study shows that NAC-GPT significantly increased the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), an indicator of redox balance restoration. In particular, the GSH/GSSG ratio in NAC-GPT-treated lenses was nearly 2-fold higher than that of the untreated cataract control. These findings indicate that the GPT nanogel platform can effectively deliver antioxidants to the eye and is a promising noninvasive antioxidant delivery strategy with the ability to restore redox balance in cataract.},
}
@article {pmid41845136,
year = {2026},
author = {Meadows, JW and Hendrickson, RG and Stolbach, AI},
title = {ACMT Practice Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose (2026 Update).},
journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology},
volume = {},
number = {},
pages = {},
pmid = {41845136},
issn = {1937-6995},
}
@article {pmid41847871,
year = {2026},
author = {Singh, LK and Singh, SP and Sharma, P},
title = {Oxidative-stress-responsive polymeric nanocarriers for Alzheimer's disease: emerging antioxidant strategies using NAC and curcumin.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-37},
doi = {10.1080/09205063.2026.2644503},
pmid = {41847871},
issn = {1568-5624},
abstract = {A complex combination of oxidative stress, mitochondrial dysfunction, neuroinflammation, and protein aggregation initiates Alzheimer disease (AD), and redox imbalance becomes an initial and lead pathological process. Traditional antioxidants like N-acetylcysteine (NAC) and curcumin demonstrate high mechanistic capacity but have poor stability, are rapidly metabolicized and have low blood-brain barrier (BBB) penetration. Polymeric nanocarriers can be a solution to these drawbacks, as they offer controlled delivery, better targeting to the brain, and dynamic delivery in response to microenvironmental changes. This review is a synthesis of recent developments in oxidative-stress-responsive polymeric systems (PLGA-, chitosan-, and hybrid polymer-based nanoparticles) designed to be used in precise redox modulation. We emphasize the therapeutic synergies of co-delivery of dual NAC-curcumin that is backed with in-vitro and in-vivo results of enhanced antioxidant activity, mitochondrial integrity, and cognitive improvements in AD models. The most important translational obstacles such as nanoparticle scalability, regulatory obstacles, and interpatient heterogeneity are acutely addressed, as well as new developments such as AI-driven formulation design and personalized oxidative biomarker profiling. All these innovations put redox-targeted nanomedicine as a prospective next-generation therapy of AD.},
}
@article {pmid41840883,
year = {2026},
author = {Tian, Y and Zhang, L and Zhao, P and Liu, X and Jin, F and Liu, Y and Li, J},
title = {Electroacupuncture mitigates lung injury, increases endogenous antioxidant levels and modulates Nrf2 signaling in a rat model of chronic obstructive pulmonary disease.},
journal = {Acupuncture in medicine : journal of the British Medical Acupuncture Society},
volume = {},
number = {},
pages = {9645284261424261},
doi = {10.1177/09645284261424261},
pmid = {41840883},
issn = {1759-9873},
abstract = {BACKGROUND: Electroacupuncture (EA) has shown efficacy in the treatment of chronic obstructive pulmonary disease (COPD), but the underlying mechanism of action remains unclear. Oxidative stress is a main pathological process in COPD. This aim of this study was to explore the anti-oxidant effect of EA in a COPD rat model.<br><br>METHODS: Rats were divided into control, model, EA, sham acupuncture (SA) and N-acetylcysteine (NAC) groups. All rats except those in the control group were exposed to cigarette smoke combined with repeated bacterial infection to induce a COPD rat model. Rats in the EA group received EA at GV14 and bilateral BL13/BL23 for a further 8&#x2009;weeks, while rats in SA group were given manual acupuncture at sites 5&#x2009;mm from the traditional acupuncture point locations (without electrical stimulation) as a negative control. NAC (54&#x2009;mg/kg/d) was used in the NAC group as a positive control. Lung function was assessed by whole body plethysmography, and tissue structure was assessed by histology. mRNA and protein levels of oxidative indicators and nuclear factor E2-related factor (Nrf2) signaling were measured by qPCR and immunohistochemistry or Western blotting, respectively.<br><br>RESULTS: After EA treatment, lung function and pathological features were improved. Total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) in serum, as well as SOD1 and heme oxygenase (HO)-1 in lung tissue, were increased, while markers of oxidative stress-lipid peroxidation (LPO) and malonaldehyde activity (MDA)-were decreased. Nrf2 protein in the nucleus of lung tissue, as well as HO-1 and &#x3b3;-glutamylcysteine synthetase (&#x3b3;-GCS) mRNA and protein, were improved. NAC, as an antioxidant, was better than EA at increasing the expression of HO-1 protein and &#x3b3;-GCS mRNA.<br><br>CONCLUSIONS: EA was beneficial for the treatment of COPD in this rat model and exerted antioxidant effects via mechanisms potentially related to Nrf2 signaling.},
}
@article {pmid41841373,
year = {2026},
author = {Walls, AC and Vaughan, AS and Balachandran, K},
title = {Development of a nasal airway-on-chip co-culture model to study particulate matter exposure.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5lc00978b},
pmid = {41841373},
issn = {1473-0189},
abstract = {Particulate matter (PM) is a major component of urban air pollution and is strongly associated with respiratory diseases. However, the mechanisms of PM-induced inflammation remain poorly understood due to a lack of physiologically-relevant airway models which can incorporate PM exposure. To address this, we used our nasal airway-on-chip platform to establish a co-culture model of human nasal epithelial cells and human pulmonary microvascular endothelial cells and used this model to investigate the effects of PM exposure on the nasal airway. In particular, we sought to understand the PM-induced reactive oxygen species (ROS)-mediated inflammatory response of the co-culture. Upon PM exposure, we observed a significant increase in ROS production consistent with oxidative stress-mediated injury. Additionally, treatment with the ROS scavenger N-acetyl-cysteine attenuated ROS levels and showed a trend toward reduced inflammation, suggesting a protective effect. These findings support the utility of our model for studying PM-induced airway inflammation in a more physiologically-relevant environment.},
}
@article {pmid41832950,
year = {2026},
author = {de Oliveira, AP and Pacheco, G and Lopes, ALF and da Silva Araujo, AK and de Sousa Chaves, L and de Araújo, S and de Sousa Lima, EB and Alves, EHP and Queiroz-Junior, CM and Teixeira, MM and Costa, VV and Souza, JMT and Barros, AB and de Araujo Sousa, PS and Rocha, JA and Araújo, AJ and Filho, JDBM and Véras, LMC and Vasconcelos, DFP and Medeiros, JVR},
title = {Imidazole Alkaloids Epiisopilosine and Epiisopiloturine Attenuate Acetaminophen-Induced Liver Toxicity in Mice via Autophagy Modulation and Anti-Inflammatory Effects.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {3},
pages = {e70782},
doi = {10.1002/jbt.70782},
pmid = {41832950},
issn = {1099-0461},
support = {308981/2023-5//Conselho Nacional de Desenvolvimento Cient&#xcd;fico e Tecnol&#xd3;gico/ ; //Coordena&#xc7;&#xc3;o de Aperfei&#xc7;oamento de Pessoal de N&#xcd;vel Superior/ ; 308981/2023-5//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; //Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; },
mesh = {Animals ; *Autophagy/drug effects ; Male ; Mice ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology/metabolism/prevention &amp; control ; *Acetaminophen/adverse effects/toxicity ; Mice, Inbred BALB C ; *Anti-Inflammatory Agents/pharmacology ; *Imidazoles/pharmacology/chemistry ; *Alkaloids/pharmacology/chemistry ; *Liver/drug effects/metabolism/pathology ; 4-Butyrolactone/analogs &amp; derivatives ; },
abstract = {There is increasing interest in natural metabolites, such as alkaloids, due to their potential in treating liver diseases, including acetaminophen (APAP)-induced hepatotoxicity. Alkaloids are known to modulate autophagy, a mechanism associated with liver protection. Epiisopilosine (EPIIS) and epiisopiloturine (EPI), imidazole alkaloids derived from Pilocarpus microphyllus (Jaborandi), exhibit anti-inflammatory and hepatic immunomodulatory effects. Therefore, this study aimed to compare the hepatoprotective and autophagy-modulating effects of EPI and EPIIS in a murine model of APAP-induced hepatotoxicity. In the experimental design, male BALB/c mice received APAP (750 mg/kg, i.p.) to induce hepatotoxicity, followed by phosphate-buffered saline (PBS), N-acetylcysteine (NAC-318 mg/kg, i.p.), or alkaloids (0.3, 1, or 3 mg/kg, i.p.) 30 min later. To assess the involvement of autophagy, hydroxychloroquine (HCQ; 80 mg/kg, i.p.), an autophagy inhibitor, was administered 2 h before APAP. Treatment with EPI, EPIIS, or NAC significantly reduced liver toxicity (p < 0.05). APAP-treated mice exhibited marked centrilobular necrosis, which was markedly reduced following the treatment with Jaborandi alkaloids. Furthermore, EPIIS and EPI significantly reduced the inflammatory and oxidative markers. Administration of HCQ 2 h before APAP abolished these effects. Western blotting analysis revealed increased LC3B expression, a marker of autophagy, in the hepatic tissues of the treated mice, indicating that EPIIS and EPI modulate autophagy. Molecular docking analysis suggested potential interactions between the alkaloids and CXCL10, a chemokine linked to inflammation and autophagy inhibition. These findings demonstrate that EPIIS and EPI protect against APAP-induced hepatotoxicity in mice, potentially by modulating autophagy and reducing inflammation.},
}
@article {pmid41812834,
year = {2026},
author = {Rathor, P and Tiwari, AK and Patel, RP and Verma, A and Singh, SP and Ch, R},
title = {Brain lipidomics identifies mitochondrial redox dysfunction and metabolic trade-offs associated with Parkinson's disease-like pathology induced by Nanoplastics exposure.},
journal = {Free radical biology &amp; medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.03.023},
pmid = {41812834},
issn = {1873-4596},
abstract = {Growing nanoplastics exposure raises concern for neurotoxicity, particularly given recent evidence of plastic accumulation within human brain tissue a highly lipid enriched organ, yet effects on brain lipid metabolism remain poorly understood. Here, we employed high-resolution untargeted lipidomics to map brain lipid perturbations in Drosophila melanogaster chronically exposed to environmentally relevant levels of polystyrene nanoplastics (PS- NPs). PS-NPs accumulated in fly brains and induced dose-dependent remodeling of mitochondrial membrane lipids, notably cardiolipins and phosphatidylethanolamines, accompanied by increased diacylglycerols/triacylglycerols and monounsaturated fatty acids and by lipid droplet expansion. Guided by these lipidomic signatures, targeted biochemical assays demonstrated depolarized mitochondrial membrane potential, elevated mitochondrial reactive-oxygen species, inhibition of respiratory-chain complexes I and IV, and a shift in NAD(H) and NADP(H) redox couples toward a reduced state and increasing lipid peroxidation. This redox imbalance was accompanied by decreased tyrosine-hydroxylase expression, dopamine depletion, and impaired locomotor behavior, hallmarks of Parkinson's disease (PD)-like neurodegeneration. Dopaminergic neurochemistry was impaired (tyrosine hydroxylase and dopamine decreased), with concomitant reduction of GABA, and locomotor and circadian deficits emerged. Remarkably, co-treatment with the antioxidant N-acetylcysteine (NAC) restored mitochondrial membrane potential, reduced mitochondrial ROS and lipid peroxidation, normalized neutral lipid and MUFA accumulation, and rescued neurotransmitter levels and behavior. Stable-isotope tracing confirmed disrupted TCA cycle flux after NPs exposure that was rescued by NAC. Collectively, these findings reveal lipidomic remodeling as a critical link between environmental NPs exposure and PD-like pathology, highlighting mitochondrial redox-lipid interactions as early determinants and support redox-directed interventions to mitigate risk.},
}
@article {pmid41809881,
year = {2026},
author = {Huang, NF and Ling, P and Xu, YJ and Feng, XF and Zheng, Y and Sun, T},
title = {Xing-Pi-Qing-Gan decoction alleviates alcoholic liver disease by down-regulating DDIT3 and restoring Nrf2/HO-1 antioxidant signaling: Multi-omics and experimental evidence.},
journal = {World journal of gastroenterology},
volume = {32},
number = {8},
pages = {115077},
pmid = {41809881},
issn = {2219-2840},
mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Liver Diseases, Alcoholic/drug therapy/pathology/metabolism ; NF-E2-Related Factor 2/metabolism ; Signal Transduction/drug effects ; Humans ; Mice ; Disease Models, Animal ; Ethanol/toxicity ; Oxidative Stress/drug effects ; Liver/pathology/drug effects ; Male ; Heme Oxygenase-1/metabolism ; Down-Regulation/drug effects ; Antioxidants/metabolism/pharmacology ; Mice, Inbred C57BL ; Hep G2 Cells ; Network Pharmacology ; Membrane Proteins/metabolism ; Multiomics ; },
abstract = {BACKGROUND: Alcoholic liver disease (ALD) is driven by oxidative stress, lipid metabolism, inflammation, and apoptosis. Current therapies lack efficacy in targeting multi-pathway mechanisms. Xing-Pi-Qing-Gan decoction (XPQG) is an improved traditional Chinese medicine designed to alleviate ALD, but its molecular mechanism remains unknown.<br><br>AIM: To illustrate the therapeutic targets and molecular pathways of XPQG for the treatment of ALD by integrating chemical profiling, network pharmacology, transcriptomics, and experimental verification in vivo and in vitro.<br><br>METHODS: The components of XPQG were analyzed using ultra-high performance liquid chromatography quadrupole-time-of-flight mass spectrometry. Then, the protective effect of XPQG on ethanol-induced liver injury, especially its regulatory effect on DDIT3 expression and associated Nrf2/HO-1 antioxidant signaling, was investigated through in vivo animal experiments and in vitro cell experiments. A mouse model of ALD was developed, and the mechanism of XPQG was validated through hematoxylin and eosin (H&amp;E) staining, Western blot, and quantitative RT-PCR. In addition, the key role of DDIT3 in XPQG-mediated protection was further verified by siDDIT3 cell transfection technology. Animal experiments with the reactive oxygen species inhibitor N-acetylcysteine (NAC) further validated the mechanism of XPQG to alleviate liver injury by regulating oxidative stress.<br><br>RESULTS: In ethanol-treated HepG2 cells, XPQG dose-dependently reduced the formation of lipid droplets, inhibited the expression of tumor necrosis factor-&#x3b1;, interleukin-6, interleukin-1&#x3b2;, and alleviated oxidative stress. In mice, XPQG (15.2 g/kg) lowered the liver/body weight ratio, alanine aminotransferase, aspartate aminotransferase, &#x3b3;-glutamyl transferase; H&amp;E and Oil Red O demonstrated a reduction in steatosis. Network pharmacology and RNA-seq converged on MAPK signaling, suggesting DDIT3 as a likely key effector in XPQG-mediated protection. DDIT3 knockdown in HepG2 cells attenuated the benefits of XPQG, supporting DDIT3 as a critical effector mechanism in XPQG-mediated protection. The use of NAC further illustrates the correlation of drugs to oxidative stress in disease effects.<br><br>CONCLUSION: In summary, the results of the study suggest that XPQG is effective in improving ethanol-induced acute liver injury (ALD). Its mechanism involves the suppression of DDIT3 and the enhancement of Nrf2/HO-1 pathway activity.},
}
@article {pmid41808863,
year = {2026},
author = {Yin, Y and Wu, X and Liu, Z and Luo, Y and Jing, M and Jing, K and Li, Q and Wang, F and Huang, J},
title = {Network meta-analysis of pharmacological treatments for idiopathic pulmonary fibrosis: evaluating effects on lung function.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1761899},
pmid = {41808863},
issn = {1663-9812},
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic interstitial lung disease of unknown cause. Its main feature is a steady decline in lung function, which is also the primary target for treatment. Existing research has investigated various drugs to slow IPF progression, but their effectiveness and how they affect key pulmonary function indicators need to be systematically evaluated and analysed.<br><br>METHODS: This systematic review and network meta-analysis searched eight databases to identify randomised controlled trials assessing the effects of various pharmacological treatments on lung function in patients with IPF. The risk of bias in the included studies was evaluated using tools from the Cochrane Handbook. Network meta-analysis was conducted using Stata 19.0 and R 4.5.1 software. The study protocol was registered in PROSPERO (CRD420251148658).<br><br>RESULTS: This study included 121 publications comprising 162 studies, covering 16,525 IPF patients across nine countries. The overall risk of bias assessment showed that while most studies had a low risk of bias in random sequence generation, concerns regarding allocation concealment and blinding were identified in a substantial proportion of the included studies. Network meta-analysis revealed that Nerandomilast was the most effective intervention for improving Forced Vital Capacity (FVC) (SUCRA: 98.85%). N-acetylcysteine (NAC) combined with Roxithromycin (RXM) was the most effective intervention for improving Vital Capacity (VC) (SUCRA: 88.8%) and Forced Expiratory Volume in 1&#xa0;s/Forced Vital Capacity (FEV1/FVC) (SUCRA: 97.45%). Ambroxol was the most effective intervention for improving Total Lung Capacity (TLC) (SUCRA: 82.52%), while Thalidomide was the most effective intervention for improving Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) (SUCRA: 90.93%).<br><br>CONCLUSION: The results suggest that drugs targeting different pulmonary function parameters have corresponding mechanisms of action. Nerandomilast shows potential for improving FVC, while NAC combined with RXM may enhance VC and FEV1/FVC. Ambroxol appears effective in increasing TLC, and Thalidomide may boost DLCO. Nonetheless, these findings need validation through higher-quality studies in the future. Additionally, future research should examine the long-term effectiveness of new drugs like Nerandomilast and Pamrevlumab, while also improving comprehensive assessments of synergistic changes across various pulmonary function indicators.<br><br>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251148658.},
}
@article {pmid41807727,
year = {2026},
author = {Tan, LX and Zhang, YY and Liu, ZJ and Cao, Y and Liu, JJ and Mo, MH and Liu, T},
title = {The fungistatic mechanism of benzaldehyde against the nematophagous fungus Arthrobotrys oligospora suggests a method for manipulating soil fungistasis.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-09836-z},
pmid = {41807727},
issn = {2399-3642},
support = {32160022//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Germination and growth of biocontrol microorganisms in soil are often inhibited by soil fungistasis (SF), resulting in unsatisfactory control efficacy. Therefore, exploring mechanisms underlying SF is important for developing efficient biocontrol agents. Benzaldehyde has a strong fungistatic effect against the nematophagous fungus Arthrobotrys oligospora. Our transcriptome analysis suggested a fungistatic model by which benzaldehyde induces reactive oxygen species (ROS), leading to energy deficiency and in turn activating the AMPK-mTOR pathway. The ROS-inducing compound retinol enhanced benzaldehyde fungistasis (BF), whereas the antioxidant substance N-acetyl cysteine reduced ROS production and enhanced BF resistance in A. oligospora. Inhibiting the glutathione antioxidant system by blocking the supply of NADPH decreased BF resistance in A. oligospora. Furthermore, the AMPK activator acadesine bolstered BF resistance in A. oligospora, while the AMPK inhibitor dorsomorphin dihydrochloride or knocking out the AMPK gene had the opposite effect. These results strongly support a fungistatic mechanism of action for benzaldehyde. Finally, we found that the fungistatic mechanism of benzaldehyde similarly underlies SF, with the AMPK activators acadesine or metformin effectively increasing the SF resistance of A. oligospora. This study suggests a mechanism by which soil inhibits fungi and offers a potential method for improving SF resistance of fungal biocontrol agents.},
}
@article {pmid41801306,
year = {2026},
author = {Xie, M and Weng, J and Li, C and Liu, Q and Feng, Y and Zhang, H and Chang, Q and Chung, KF and Adcock, IM and Li, F and Fan, X},
title = {Mechanisms of Anti-Oxidants, N-Acetylcysteine and Elamipretide (SS-31), on Ozone-Induced Airway Hyperresponsiveness and Mucus Hypersecretion.},
journal = {Lung},
volume = {204},
number = {1},
pages = {},
pmid = {41801306},
issn = {1432-1750},
support = {81870031//National Natural Science Foundation of China/ ; U1803126//National Natural Science Foundation of China/ ; YG2019ZDA24//Shanghai Jiao Tong University/ ; 202304295107020044//Anhui Provincial Institute of Translational Medicine/ ; },
mesh = {Animals ; Ozone ; *Acetylcysteine/pharmacology ; Mice, Inbred C57BL ; *Antioxidants/pharmacology ; *Mucus/metabolism ; Oxidative Stress/drug effects ; NLR Family, Pyrin Domain-Containing 3 Protein ; *Oligopeptides/pharmacology ; Reactive Oxygen Species/metabolism ; Mice ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Disease Models, Animal ; Male ; Cell Line ; Carrier Proteins/metabolism ; *Bronchial Hyperreactivity/chemically induced/metabolism/prevention &amp; control/physiopathology ; Phosphatidylinositol 3-Kinases/metabolism ; *Lung/drug effects/metabolism/physiopathology ; Humans ; Mitochondria/metabolism/drug effects ; Caspase 1/metabolism ; Bronchoalveolar Lavage Fluid/cytology ; Inflammation Mediators/metabolism ; },
abstract = {BACKGROUND: Ozone (O3) exposure induces acute airway injury characterized by airway hyperresponsiveness (AHR) and airway mucus hypersecretion (AMH). Oxidative stress and mitochondria-derived reactive oxygen species (mtROS) are key contributors. We investigated and compared the protective mechanisms of N-acetylcysteine (NAC) and the mitochondria-targeted antioxidant Elamipretide (SS-31) in O3-induced airway inflammation, AHR and AMH.<br><br>METHODS: Wild-type C57BL/6J mice received intraperitoneal NAC or SS-31 1&#xa0;h before a single O&#x2083; exposure. AHR, bronchoalveolar lavage (BAL) inflammatory cells, mucus production and mucin expression, inflammatory mediators, oxidative stress indices, and PI3K/AKT and NLRP3/caspase-1/GSDMD pathway activation were assessed in vivo. BEAS-2B cells were pretreated with NAC, SS-31, or the PI3K/AKT inhibitor LY294002 before O&#x2083; exposure, and pathway activation was evaluate d in vitro.<br><br>RESULTS: NAC and SS-31 comparably attenuated O&#x2083;-induced AHR, reduced BAL inflammatory cell influx, and decreased AMH and MUC5B expression. Both treatments improved redox balance by reducing ROS/mtROS, lowering malondialdehyde (MDA), increasing superoxide dismutase (SOD) activity, and improving GSH/GSSG. NAC and SS-31 also suppressed O&#x2083;-induced inflammatory gene expression and inhibited activation of PI3K/AKT and NLRP3/caspase-1/GSDMD signaling in mouse lungs and BEAS-2B cells. PI3K inhibition recapitulated these protective effects in vitro, supporting a mechanistic role for PI3K/AKT signaling during acute O&#x2083; exposure.<br><br>CONCLUSIONS: NAC and SS-31 protect against acute O&#x2083;-induced AHR and AMH by alleviating oxidative stress and suppressing PI3K/AKT-driven inflammatory and pyroptotic pathways. Targeting oxidative stress, including mitochondrial ROS, may represent a viable strategy to mitigate airway damage caused by acute O&#x2083; exposure.},
}
@article {pmid40398422,
year = {2025},
author = {Sonar, SA and Bhat, R and Thompson, HL and Coplen, CP and Uhrlaub, JL and Jergovic, M and Nikolich, J&#x17d;},
title = {Age-Related Oxidative Stress and Mitochondrial Dysfunction in Lymph Node Stromal Cells Limit the Peripheral T Cell Homeostatic Maintenance and Function.},
journal = {Aging cell},
volume = {24},
number = {8},
pages = {e70100},
pmid = {40398422},
issn = {1474-9726},
support = {P01 AG052359/AG/NIA NIH HHS/United States ; P30 CA023074/CA/NCI NIH HHS/United States ; //Bowman Professorship in Medical Sciences/ ; },
mesh = {*Oxidative Stress ; Animals ; *Mitochondria/metabolism/drug effects/pathology ; *Stromal Cells/metabolism ; *Lymph Nodes/metabolism/cytology/pathology/immunology ; Mice ; Reactive Oxygen Species/metabolism ; *Homeostasis ; *Aging ; *T-Lymphocytes/metabolism/immunology ; Mice, Inbred C57BL ; },
abstract = {Lymph nodes (LN) are the key organs in charge of long-term maintenance of naïve lymphocytes and their initial, primary activation upon infection. Accumulating evidence indicates that LN stromal cells undergo degenerative changes with aging that critically impair LN function, including the generation of protective primary immune responses. The nature of these defects remains incompletely understood. We here demonstrate that age-related LN stromal changes manifest themselves in mitochondrial dysfunction and oxidative stress. Ex vivo, all three major stromal cell subsets, fibroblastic reticular cells (FRC), lymphatic endothelial cells (LEC), and blood endothelial cells (BEC) exhibit elevated mitochondrial reactive oxygen species (ROS) stress, reduced mitochondrial potential, and elevated mitochondrial mass with aging. Old FRC also exhibited elevated cytoplasmic ROS production. This was accompanied by the reduced ability of old LN stromal cells to support Tn survival in vitro, a defect alleviated by pretreating old LN stroma with the general antioxidant N-acetyl cysteine (NAC) as well as by mitochondrial ROS-reducing (mitoquinone) and mitophagy-inducing (urolithin A) compounds. Mitochondrial dysfunction and, in particular, reduced mitochondrial potential in old FRC were also seen upon vaccination or infection in vivo. Consistent with these results, in vivo antioxidant treatment of old mice with NAC restored to adult levels the numbers of antigen-specific CD8[+] effector T cells and their production of granzyme B in response to antigenic challenge.},
}
@article {pmid41663723,
year = {2026},
author = {Zhang, XD and Atalla, N and Rodriguez, E and Teng, C and Bai, X and Teng, JMC},
title = {Development of a controlled ex vivo human skin platform for quantitative evaluation of age-related functional biomarkers following application of topical treatments.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41663723},
issn = {2045-2322},
mesh = {Humans ; *Biomarkers/metabolism ; *Skin Aging/drug effects/radiation effects ; *Zinc Oxide/pharmacology/administration &amp; dosage ; *Skin/drug effects/metabolism/radiation effects/pathology ; Adult ; Middle Aged ; Female ; Male ; Aged ; Cellular Senescence/drug effects ; Ultraviolet Rays/adverse effects ; Administration, Topical ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Tumor Suppressor Protein p53/metabolism ; Acetylcysteine/pharmacology/administration &amp; dosage ; Interleukin-1beta/metabolism ; },
abstract = {Targeting cellular senescence presents a promising approach to slow visible skin aging and promote tissue repair. However, most preclinical models fail to capture the full architecture of human skin or accommodate diverse skin types, limiting their translational relevance. To address this gap, we developed a controlled ex vivo human skin explant platform using freshly acquired tissues from donors of varying ages and Fitzpatrick skin types. This model applies standardized UVA and UVB doses to induce reproducible photodamage, enabling the assessment of both preventative and reparative effects of topical treatments. The results showed that ND-ZnO and NAC reduced levels of p16^INK4a and p53, which are key biomarkers measuring cellular senescence; ND-ZnO and exosomes lowered IL-1β expression, which is a biomarker measuring inflammation. Histological analysis confirmed these findings, with ND-ZnO-treated skins preserved epidermal structure, reduced inflammatory features, and maintained dermal collagen organization. We then conducted a four-week single-patient case study using the same ND-ZnO formulation. Visible improvements in redness, pigmentation, and texture were observed, aligned with the molecular and histological changes seen ex vivo. These findings suggested that the ex vivo platform has the potential to be used as a more inclusive, human-relavent model for evaluating and quantifying the anti-aging efficacies of topical treatments across diverse skin types and age groups.},
}
@article {pmid41661511,
year = {2026},
author = {Appell, MB and Kanan, Y and Malmberg, K and Appidi, T and Khan, M and Campochiaro, PA and Ensign, LM},
title = {A gel-forming antioxidant eye drop for photoreceptor protection in retinitis pigmentosa.},
journal = {Drug delivery and translational research},
volume = {16},
number = {4},
pages = {1052-1063},
pmid = {41661511},
issn = {2190-3948},
support = {R01EY031041/EY/NEI NIH HHS/United States ; P30EY001765/EY/NEI NIH HHS/United States ; T32EY007143/EY/NEI NIH HHS/United States ; R01EY031041/EY/NEI NIH HHS/United States ; P30EY001765/EY/NEI NIH HHS/United States ; T32EY007143/EY/NEI NIH HHS/United States ; },
mesh = {Animals ; *Retinitis Pigmentosa/drug therapy/pathology ; *Antioxidants/administration &amp; dosage/chemistry ; Ophthalmic Solutions/administration &amp; dosage ; *Acetylcysteine/administration &amp; dosage/analogs &amp; derivatives/chemistry ; Mice ; Gels ; Disease Models, Animal ; Rats ; Male ; *Photoreceptor Cells, Vertebrate/drug effects ; Mice, Inbred C57BL ; },
abstract = {Retinitis pigmentosa (RP) is a chronic genetic condition that leads to progressive loss of photoreceptor cells and vision. While gene therapy is available for a small subset of patients with specific mutations, developing a therapeutic that broadly targets the cellular stresses that lead to cell death could address a major unmet need. One such option would be utilizing antioxidant therapies to neutralize reaction oxygen species (ROS) in the retina that underlie RP progression. Here, we describe an approach for delivering the antioxidants N-acetyl cysteine (NAC) or N-acetyl cysteine ethyl ester (NACET) with a gel-forming eye drop previously demonstrated to provide therapeutic drug delivery in the posterior segment in animals. We demonstrated therapeutic protection of photoreceptor structure and function in a chemically-induced rat model of RP (48% increase in photopic b-wave amplitude), as well as some limited protection in an aggressive genetic mouse model (rd10) of retinal degeneration (~ 31% increase in photopic b-wave amplitude) with once daily application. However, antioxidants have inherent stability issues when stored in solution, so we investigated the use of additional excipients to improve stability and retain potency. While a promising approach, future work to address product stability and efficacy in larger eyes is needed for further development.},
}
@article {pmid41790529,
year = {2026},
author = {Ommi, NB and Mattocks, DAL and Horowitz, MC and Nichenametla, SN},
title = {D, L-Buthionine-(S, R)-sulfoximine recapitulates the anti-obesity effects of sulfur amino acid restriction without the associated deleterious effects on bone in male mice.},
journal = {Aging},
volume = {18},
number = {1},
pages = {82-99},
doi = {10.18632/aging.206358},
pmid = {41790529},
issn = {1945-4589},
abstract = {Sulfur amino acid restriction (SAAR), a diet low in methionine and lacking cysteine, reduces obesity but also lowers bone mineral density (BMD) and increases marrow adipose tissue. Because the SAAR diet lacks cysteine, it exerts cysteine restriction (CysR), in addition to methionine restriction (MetR). We previously reported that the anti-obesity effect of the SAAR diet was exclusively due to CysR. Follow-up studies revealed that CysR decreases obesity by lowering glutathione (GSH), and that D, L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH biosynthesis, recapitulates the SAAR-induced lean phenotype on a methionine-replete diet. Here, we investigated whether the detrimental effects of the SAAR diet on bone are mediated solely by CysR and whether BSO, similar to the SAAR diet, exerts deleterious effects. Male obese C57BL6/NTac mice were fed high-fat diets with 0.86% methionine (control diet, CD), 0.12% methionine (SAAR diet), SAAR diet supplemented with a GSH precursor, N-acetylcysteine (NAC) in water, and CD supplemented with BSO in water. Femurs and tibiae of SAAR mice had lower trabecular and cortical BMD, fewer osteoblasts, reduced biomechanical strength, and more marrow adipocytes than in CD mice. NAC reversed all these effects, suggesting that CysR mediates the detrimental effects of the SAAR diet on bone. Despite its anti-obesity effects, BSO did not exert any detrimental effects on bones. Future studies should investigate mechanisms, age-at-onset, tissue-specific, and gender-specific effects of BSO on bone health. Long-term studies to establish the therapeutic efficacy and off-target effects of BSO are critical for developing it as an anti-obesity drug in humans.},
}
@article {pmid41780686,
year = {2026},
author = {Sun, W and Xie, L and Jiang, X and Zhu, Q and Feng, H and Cun, D and Wu, L and Yang, M},
title = {A functional lyoprotectant platform enables storage-stable, mucus-penetrating siRNA delivery to the lung.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114749},
doi = {10.1016/j.jconrel.2026.114749},
pmid = {41780686},
issn = {1873-4995},
abstract = {Respiratory diseases remain a major global health concern, where pathological mucus accumulation and chronic inflammation severely compromise lung function. RNA therapeutics have emerged as a transformative modality to address underlying molecular pathologies beyond the capabilities of small-molecule drugs. However, effective delivery of RNA therapeutics to the lungs remains hindered by significant challenges. The instability of lipid nanoparticles (LNPs) in liquid formulations compromises their storage and cold-chain transport, while the pathological mucus hypersecretion characteristic of chronic airway diseases impedes nanoparticle penetration and delivery efficacy. Herein, we propose a functional lyoprotectant strategy that bridges formulation stability and biological functionality within a single design. Specifically, N-acetylcysteine (NAC), a clinically used mucolytic, was incorporated into a sucrose-based lyoprotectant matrix as a functional additive, enabling lyophilization while introducing mucus-modulating capability. The lyophilized LNPs preserved physicochemical integrity, maintained siRNA encapsulation, and achieved efficient mucus penetration and gene silencing in vitro and in vivo. In murine models of mucus-hypersecretory lung disease, a single-dose administration achieved enhanced therapeutic outcomes through a sequential and dual-action complementary mechanism, including extracellular NAC-mediated mucolysis and intracellular RNAi-mediated inflammation suppression. This work pioneers the concept of a functional lyoprotectant, offering a generalizable platform for storage-stable and biologically active inhaled RNA therapeutics.},
}
@article {pmid41780678,
year = {2026},
author = {Cai, YY and Yang, LJ and Pan, MM and Nurtay, N and Yu, YP and Xie, M and Jiang, M and Wang, Y and Yu, X and Xu, L},
title = {PtCu-bimetallic modified MOF nanozyme composites for alleviating acute liver injury via reactive oxygen species elimination and inflammation regulation.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114774},
doi = {10.1016/j.jconrel.2026.114774},
pmid = {41780678},
issn = {1873-4995},
abstract = {Excessive reactive oxygen species (ROS) accumulation and dysregulated inflammation drive acetaminophen (APAP)-induced acute liver injury (ALI), yet the therapeutic effect of the commonly used clinical drug N-acetylcysteine (NAC) still has certain limitations at present. Here, we engineered a multifunctional nanozyme nanocomposite, MPCNH, by in situ deposition of bimetallic PtCu nanoparticles onto UiO-66 metal-organic frameworks (MOFs), loading NAC, and coating with hyaluronic acid (HA) to enhance biocompatibility. MPCNH exhibited cascade superoxide dismutase (SOD)-like and catalase (CAT)-like catalytic activities, enabling rapid ROS clearance and mitochondrial protection in APAP-challenged hepatocytes. Meanwhile, the delivery of the therapeutic drug NAC was achieved. In vivo, MPCNH lowered serum transaminases, activated the Keap1-Nrf2 antioxidant pathway, shifted macrophages polarization toward an anti-inflammatory M2 phenotype and restored metabolic balance. By integrating catalytic and pharmacological functions, MPCNH offers a synergistic strategy to simultaneously eliminate oxidative stress and regulate inflammation, providing a promising therapeutic platform for oxidative stress-driven liver injury.},
}
@article {pmid41780618,
year = {2026},
author = {Ge, Y and Luo, N and Zhang, M and Shi, J and Xu, X and Wang, Y},
title = {Advances on botanicals targeting programmed cell death in acetaminophen-induced liver injury.},
journal = {Journal of ethnopharmacology},
volume = {363},
number = {},
pages = {121466},
doi = {10.1016/j.jep.2026.121466},
pmid = {41780618},
issn = {1872-7573},
abstract = {Acetaminophen (APAP), a widely used analgesic and antipyretic drug, poses a significant clinical challenge worldwide due to its potential to induce hepatotoxicity following overdose. At present, limited therapeutic options exist for APAP overdose. Moreover, N-acetylcysteine (NAC), the first-line clinical agent in routine use, suffers from a narrow therapeutic window and numerous adverse effects, which limits its clinical utility. Plants constitute a rich reservoir of phytochemicals that engage in multiple pharmacological processes, positioning them as a cornerstone in pharmaceutical innovation. The therapeutic use of herbs for liver conditions is historically recognized in classical works such as the "Treatise on Febrile Diseases," "Compendium of Materia Medica," and "Thousand Golden Prescriptions."<br><br>AIM OF THE REVIEW: Chinese herbal medicines and their extracts have garnered significant attention for the prevention and treatment of acetaminophen (APAP)-induced liver injury (AILI), largely due to their therapeutic efficacy and favorable safety profile. The programmed cell death (PCD) induced by APAP, and the impact and potential mechanism on the pathogenesis of AILI are discussed in this review. Furthermore, various botanicals that can be used to prevent AILI, as well as the structure-activity relationships and potential mechanisms, are discussed.<br><br>METHODS: Articles published over the past decade were retrieved from databases including Web of Science, PubMed, and CNKI, using the keywords APAP, AILI, natural products, and traditional Chinese medicine. Studies that failed to clearly characterize the components of plant extracts were excluded. Subsequently, a preliminary classification was performed based on the chemical structures of the included natural products, with priority given to relatively novel agents supported by robust research data or notable research advances. Following a systematic review and synthesis of key study details, including experimental design, phenotypic alterations, and mechanism elucidation, the decision was made to conduct further in-depth analysis focusing on the type of PCD. Ultimately, more than 160 papers were selected and discussed in this review.<br><br>RESULTS: A systematic review of the literature identified plant extracts with anti-AILI properties, which can be categorized into nine distinct classes based on their bioactive structures. By comparing the experimental research evidence from 44 natural compounds, not only were several more promising compounds such as sinomenine, dihydromyricetin, tannic acid and pterostilbene obtained, but it also helped to clarify the protective mechanisms of these extracts. Studies have found that numerous derivatives of natural products are capable of concurrently modulating multiple signaling pathways, such as Nrf2-HO1, NF-&#x3ba;B, and RIPK/MLKL, to alleviate PCD caused by APAP, thereby offering potential strategies for the prevention or treatment of AILI.<br><br>CONCLUSION: This review systematically elucidates the mechanisms by which structurally diverse phytochemicals alleviate APAP-induced hepatotoxicity, with a specific focus on their modulatory roles in programmed cell death pathways implicated in AILI. These findings provide valuable insights for the development of novel hepatoprotective therapeutics.},
}
@article {pmid41779942,
year = {2026},
author = {Lucas, D and Munoz, C and Muller, CR and Gu, X and Wolfe, SR and Cuddington, CT and Palmer, AF and Cabrales, P},
title = {Acellular Hemoglobin Impairs Cardiomyocyte Excitation-Contraction Coupling.},
journal = {ASAIO journal (American Society for Artificial Internal Organs : 1992)},
volume = {},
number = {},
pages = {},
doi = {10.1097/MAT.0000000000002668},
pmid = {41779942},
issn = {1538-943X},
abstract = {Heart failure is a significant complication of chronic intravascular hemolysis, a condition characterized by red blood cells (RBCs) breakdown, leading to the release of acellular hemoglobin (Hb) and its oxidized form, methemoglobin (MetHb), into the bloodstream. Acellular Hb promotes nitric oxide (NO) scavenging, oxidative stress, inflammation, iron overload, and functional tissue impairment. This study investigates the direct impact of Hb and MetHb on cardiomyocyte function by assessing calcium transients, fractional shortening, and reactive oxygen species (ROS) formation. The study also evaluated the effects of polymerized Hb, NO scavenging, and antioxidant therapy using N-acetylcysteine (NAC) on cardiomyocyte contractility. Our results show that acellular Hb and MetHb impair cardiomyocyte function by prolonging calcium transient half-life, reducing contractility, and increasing ROS production. Polymerization of Hb and antioxidant supplementation offered partial protection but did not fully mitigate these effects. Inhibiting NO synthase did not increase Hb toxicity, indicating that NO scavenging is not the sole toxicity pathway. These findings demonstrate that Hb-induced cardiomyocyte dysfunction involves a multifactorial mechanism, including NO scavenging, oxidative stress, and disrupted calcium dynamics. Although Hb polymerization and antioxidants offer limited protection, novel multi-target strategies are essential to address Hb toxicity in hemolytic disorders and the use of Hb-based oxygen carriers.},
}
@article {pmid41771427,
year = {2026},
author = {Lu, Y and Cheng, S and Zhang, Y and Li, Y and Liu, L},
title = {Novel 1,2,3-triazole-based compound triggers apoptosis through DNA damage response involving ATM/ATR signaling in liver cancer cells.},
journal = {Biochemical pharmacology},
volume = {248},
number = {},
pages = {117856},
doi = {10.1016/j.bcp.2026.117856},
pmid = {41771427},
issn = {1873-2968},
abstract = {1,2,3-Triazole-substituted cabotegravir analogues, i.e., KJ-9, have been developed as lead structures to explore their potential as antitumor agents. The new analogue exhibited significant anti-proliferative activity against various human cancer cell lines, with particularly strong effects on the HepG2 and HCCLM3 liver cancer lines, as it induced a marked loss of colony-forming ability and triggered apoptosis upon KJ-9 exposure. Furthermore, treatment with KJ-9 increased the Bax-to-Bcl-2 protein ratio and activated cleaved caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP). Meanwhile, KJ-9 treatment induced a blockage in the cell cycle (G2/M), increased DNA damage levels, and induced the accumulation of histone variant H2AX (γ-H2AX) protein. Furthermore, there was strong induction of p-ATM and p-ATR proteins, along with their downstream effectors p-CHK1 and p-CHK2. Additionally, KJ-9 treatment increased phosphorylation levels of the tumor suppressor protein p53 and inhibited components of the PI3K/AKT pathway. Although it did not significantly affect AKT phosphorylation, the ATM/ATR inhibitor CGK733 significantly reversed KJ-9-induced upregulation of p-ATM, p-ATR, p-p53, γ-H2AX, and activated caspase-3. Moreover, reactive oxygen species (ROS) were generated in greater quantities by KJ-9 treatment. After KJ-9 treatment, ROS were suppressed by the addition of the antioxidant N-Acetylcysteine (NAC), leading to increased levels of p-AKT and reduced levels of p-ATM, p-ATR, p-p53, cleaved caspase-3, and γ-H2AX. These findings suggest that KJ-9 promotes oxidative stress, which further inhibits AKT activation while activating the ATM/ATR pathway, leading to p53 accumulation, sustained DNA damage responses, G2/M-phase cell cycle arrest, and apoptosis in both HepG2 cells and HCCLM3 cells.},
}
@article {pmid41761803,
year = {2026},
author = {Nasir, W and Ul Hassan, S and Aslam, B and Majeed, W},
title = {Unfolding protection: Terminalia arjuna targets UPR pathways to counteract ER stress in hepatotoxicity.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {4},
pages = {1073-1082},
doi = {10.36721/PJPS.2026.39.4.REG.14749.1},
pmid = {41761803},
issn = {1011-601X},
mesh = {Animals ; *Terminalia/chemistry ; *Endoplasmic Reticulum Stress/drug effects ; Rats, Wistar ; *Plant Extracts/pharmacology/isolation &amp; purification ; Acetaminophen/toxicity ; *Chemical and Drug Induced Liver Injury/metabolism/prevention &amp; control/pathology ; Oxidative Stress/drug effects ; Rats ; Male ; *Liver/drug effects/pathology/metabolism ; *Unfolded Protein Response/drug effects ; Apoptosis/drug effects ; Signal Transduction/drug effects ; Plant Bark/chemistry ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; },
abstract = {BACKGROUND: Drug-induced liver injury (DILI) from acetaminophen (APAP) overdose involves ER stress, oxidative damage, apoptosis, and inflammation.<br><br>OBJECTIVE: This study assesses Terminalia arjuna bark extract (TAE) against APAP-induced toxicity in rats, comparing its efficacy with N-acetylcysteine (NAC) through key signaling and inflammatory markers.<br><br>METHODS: Twenty-four Wistar rats were equally divided into four groups: Control Negative (CN, no treatment), Control Positive (CP, acetaminophen 350&#x202f;mg/kg), N-acetylcysteine (NAC, 150&#x202f;mg/kg), and Terminalia arjuna bark extract (TAE, ethanolic, 80&#x202f;mg/kg). Over 14 days, liver injury was induced in the CP group via acetaminophen, while the NAC and TAE groups received their respective treatments. Animals were decapitated on day 15, and biological samples were collected for analysis. Biochemical assessments included liver function markers (ALT, AST) and oxidative stress parameters (SOD, TAC, TBARS, TOS). Gene expression studies were performed for oxidative stress regulators (Keap1, Nrf2) and ER stress signaling molecules (ERK, JNK, PPAR-&#x3b1;, AKT). Histopathological examination evaluated liver architecture and cellular integrity.<br><br>RESULTS: Acetaminophen induced significant hepatotoxicity, as reflected by elevated liver enzymes, increased oxidative stress, altered gene expression, and disrupted liver histology. APAP toxicity resulted in elevated oxidative stress, apoptosis, inflammation, and ER stress, leading to significant hepatic damage (p < 0.0001 vs CN). NAC and TAE treatments mitigated these effects, with TAE demonstrating superior improvement in oxidative stress markers (p < 0.0001 vs CP). Gene expression analysis revealed a protective shift in the Keap1-Nrf2 pathways in the treated groups. Histopathology confirmed reduced necrosis and preserved hepatic architecture in the NAC and TAE groups.<br><br>CONCLUSION: T. arjuna exhibits potent hepatoprotective effects, comparable to NAC, through modulation of oxidative stress, apoptosis, and ER stress pathways. Further studies are needed to explore its clinical applicability in acute liver injury management.},
}
@article {pmid41754714,
year = {2026},
author = {Xie, Y and Ruan, B and Yin, Y and Fan, L and Tang, H and Dai, H and You, S and Yao, S and Wang, G and Xu, Y},
title = {A Biomimetic NAC-Loaded PCL/Modified Chitosan/dECM Fibrous Scaffold for Accelerating Diabetic Wound Healing and Minimizing Scarring.},
journal = {Polymers},
volume = {18},
number = {4},
pages = {},
pmid = {41754714},
issn = {2073-4360},
support = {ZDYF2025GXJS148//2025 Provincial Key R&amp;D Sanya Yazhou Bay Science and Technology City Joint Innovation Project/ ; ZDYF2024GXJS016//2024 Key R &amp; D projects in Hainan Province/ ; ZR202306010004//Natural Science Foundation of Shandong Province/ ; BZLX2023004//Research projects of the University Institute in the construction period of Shangyu District, Shaoxing City/ ; N/A//The 2024 Chu Tian Talent Plan Science and Technology Innovation Team Project/ ; },
abstract = {The development of innovative wound dressings capable of accelerating diabetic wound healing while simultaneously reducing scar formation is a significant clinical challenge. In this study, we designed and fabricated a multifunctional nanofibrous scaffold PCL/Az-CS/dECM/NAC by incorporating decellularized extracellular matrix (dECM) and N-acetylcysteine (NAC) into a composite backbone of polycaprolactone (PCL) and azidobenzoic acid-modified chitosan (AZCS). The scaffold exhibited ideal hydrophilicity and swelling capacity, and demonstrated excellent biocompatibility. In vitro studies demonstrated that the scaffold effectively scavenged reactive oxygen species (ROS) and promoted the polarization of macrophages from the M1 phenotype to the M2 phenotype; in vivo studies confirmed that the PCL/AZ-CS/dECM/NAC scaffold significantly accelerated wound closure, promoted mature angiogenesis, and facilitated orderly collagen deposition. The PCL/AZ-CS/dECM/NAC scaffold mitigated scar formation by increasing the proportion of regenerative type III collagen, optimizing the collagen I/III ratio. Our findings suggest that the PCL/AZ-CS/dECM/NAC scaffold is a highly promising candidate for a multifunctional dressing designed to treat recalcitrant diabetic wounds and prevent excessive scarring.},
}
@article {pmid41754089,
year = {2026},
author = {Dawi, J and Affa, S and Au, S and Misakyan, Y and Gonzalez, E and Chorbajian, A and Hammi, M and Dave, P and Qumsieh, K and Venketaraman, V},
title = {Efficacy and Safety of Glutathione Supplementation in Patients with HIV Infection and HIV-Tuberculosis Co-Infection.},
journal = {Nutrients},
volume = {18},
number = {4},
pages = {},
pmid = {41754089},
issn = {2072-6643},
abstract = {Glutathione (GSH), the most abundant intracellular non-protein thiol, is a central regulator F redox homeostasis, immune function, and mitochondrial integrity. In human immunodeficiency virus (HIV) infection, persistent oxidative stress and impaired precursor availability result in sustained glutathione deficiency, contributing to immune dysfunction, inflammation, and disease progression despite effective antiretroviral therapy. This redox imbalance is further exacerbated in HIV-tuberculosis co-infection, where compounded inflammatory and metabolic stress increases susceptibility to opportunistic infections and treatment-related complications. This review examines the efficacy and safety of glutathione supplementation and precursor-based strategies in HIV infection and HIV-tuberculosis co-infection. Evidence from mechanistic studies, clinical trials, and translational research suggests that glutathione repletion, achieved through direct supplementation or precursor approaches such as N-acetylcysteine, Glycine and N-acetylcysteine (GlyNAC), and cysteine-rich dietary interventions, can restore intracellular thiol balance, improve immune cell function, enhance mitochondrial performance, and reduce systemic oxidative stress. These interventions have shown consistent safety and tolerability across diverse populations, including individuals receiving complex antiretroviral and antitubercular regimens, with gastrointestinal discomfort being the most commonly reported adverse effect and serious toxicities remaining rare. Despite encouraging findings, translation into routine clinical practice remains limited by methodological heterogeneity, short study durations, and lack of standardized biomarkers and long-term outcome data. Future research should prioritize rigorously designed trials incorporating mechanistic endpoints, standardized redox measurements, and clinically meaningful outcomes. Collectively, the available evidence supports glutathione-centered strategies as promising adjuncts to existing HIV and tuberculosis treatment paradigms, warranting further investigation to define their role in improving immune resilience and long-term clinical outcomes.},
}
@article {pmid41753798,
year = {2026},
author = {Wang, F and Wang, W and Gu, H},
title = {Intrinsic Acidity of N-Acetylcysteine Mediates Enhanced Inhibition of Klebsiella pneumoniae and Its Biofilms by Polymyxin B.},
journal = {Microorganisms},
volume = {14},
number = {2},
pages = {},
pmid = {41753798},
issn = {2076-2607},
abstract = {This study investigated the combined antibacterial and anti-biofilm activity of polymyxin B (PB) with intrinsically acidic N-acetylcysteine (NAC) against Klebsiella pneumoniae. The minimum inhibitory concentrations (MICs) of PB, acidic NAC, and neutralized NAC against 34 K. pneumoniae strains were determined using the broth microdilution. Drug interactions were assessed by checkerboard assays and the fractional inhibitory concentration index (FICI), while biofilm inhibition was quantified using crystal violet staining. Polymyxin B resistance was identified in the reference multidrug-resistant strain K. pneumoniae ATCC BAA-1705. The PB-NAC combination showed an additive effect (FICI 0.53-0.63) against PB-resistant and PB-intermediately susceptible strains, whereas indifferent interactions were observed in PB-susceptible strains. Furthermore, sub-inhibitory concentrations of the combination produced significantly stronger biofilm inhibition than either agent alone. Neutralization of NAC markedly reduced its antibacterial and anti-biofilm activities, with substantial inhibition observed only at concentrations ≥ 32 mg/mL. These findings demonstrate that the combination of PB and acidic NAC exerts additive antibacterial effects, particularly against resistant K. pneumoniae strains, and enhances biofilm inhibition. Notably, the intrinsic acidity of NAC is essential for its antimicrobial and anti-biofilm activity.},
}
@article {pmid41752465,
year = {2026},
author = {Hu, C and Xu, P and Hu, J and Fang, B and Meng, J and Tang, Y},
title = {A Novel Pyrazole Pyrimidine Derivative MBP346 Induces Cell Death via ROS-Mediated Mitochondrial Damage in Human Head and Neck Squamous Cell Carcinoma.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {4},
pages = {},
pmid = {41752465},
issn = {1420-3049},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Pyrazoles/pharmacology/chemistry ; *Pyrimidines/pharmacology/chemistry ; Cell Line, Tumor ; *Mitochondria/drug effects/metabolism/pathology ; Cell Proliferation/drug effects ; *Squamous Cell Carcinoma of Head and Neck/metabolism/drug therapy/pathology ; *Head and Neck Neoplasms/metabolism/drug therapy/pathology ; Apoptosis/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Cell Survival/drug effects ; *Antineoplastic Agents/pharmacology/chemistry ; Cell Death/drug effects ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; },
abstract = {Background: Head and neck squamous cell carcinoma (HNSCC) represents almost 95% of head and neck cancer cases and ranks as the sixth most prevalent malignant tumor globally. Several treatment strategies, such as surgery, radiation, and chemotherapy, are implemented to boost the outcomes for patients with HNSCC. However, the overall survival rate for patients with HNSCC has remained poor. MBP346 is a novel pyrazole pyrimidine compound that is cytotoxic to HNSCC cells. Therefore, this study aims to investigate its effect on HNSCC and to explore its possible molecular mechanism. Methods: Cell viability of HNSCC (Cal33 and Scc15) cells and normal NOK cells treated with MBP346 was determined by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Colony formation assay and Edu assay were used to detect cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was used for detecting cell cycle-related and cell apoptotic-related proteins. Immunofluorescence assay was performed to analyze the effect of MBP346 on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Results: MBP346 significantly inhibited the proliferation of Cal33 and Scc15 cells, with half inhibitory concentrations of 1.56 ± 0.13 μmol·L[-1] and 4.41 ± 0.28 μmol·L[-1], respectively. The cell cycle-related proteins CyclinD1, CyclinA2, and CDK2 were downregulated, and P21 was upregulated in Cal33 and Scc15 cells treated with MBP346, which blocked the cell cycle in the S phase. MBP346 induced cell apoptosis in Cal33 and Scc15 cells by inducing ROS production. In addition, the elevated ROS decreased MMP to accelerate apoptosis. N-acetylcysteine (NAC), an ROS inhibitor, suppressed MBP346-induced cell apoptosis. Conclusions: MBP346 may serve as a therapeutic agent in HNSCC by inducing cell death. It achieves this by halting cell proliferation through cell cycle arrest and enhancing apoptosis due to increased ROS, which results in mitochondrial dysfunction.},
}
@article {pmid41750648,
year = {2026},
author = {Han, JS and Park, K and Kim, YL and Lim, JH and Park, SY and Park, SN},
title = {Evaluation of Intratympanic Alpha-Lipoic Acid and Diltiazem as Alternatives to Dexamethasone in Noise-Induced Hearing Loss in a Murine Model.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
pmid = {41750648},
issn = {2076-3921},
support = {RS-2022-NR075243 and RS-2024-00340841//National Research Foundation of Korea/ ; },
abstract = {This study evaluates the protective effects of alpha-lipoic acid (ALA), diltiazem (DIL), and N-acetylcysteine (NAC) as potential adjunctive agents to enhance intratympanic dexamethasone (IT-DEX) therapy in noise-induced hearing loss. A two-phase experiment using C57BL/6J mice was conducted. In phase 1, candidate drugs were screened by perilymph concentration analysis using ultra-high-performance liquid chromatography, auditory brainstem response (ABR) threshold, and organ of Corti (OC) morphology. Western blot analysis evaluated inflammatory markers. Phase 2 investigated the synergistic effects of co-administration of the most promising candidates with DEX. All drugs successfully penetrated the inner ear via IT injection. In the noise-induced hearing loss model, ALA and DIL individually demonstrated significant improvements in ABR thresholds and OC morphology compared to DEX alone, while NAC showed no therapeutic benefit. Western blot analysis revealed that ALA and DIL suppressed inflammatory markers through distinct antioxidant-mediated mechanisms, contrasting with DEX's anti-inflammatory pathway. However, combination therapy with DEX + ALA or DEX + DIL increased middle ear inflammation and failed to produce synergistic therapeutic effects. While ALA and DIL showed individual therapeutic promise through complementary mechanisms, combination with DEX did not enhance efficacy, suggesting that simple drug combinations may not translate to improved IT therapy outcomes.},
}
@article {pmid41750596,
year = {2026},
author = {Sun, M and Feng, Z and Wang, Z and Wu, R and Du, K and Zhu, J and Liu, K and Zhang, L and Zhang, M and Qiu, Z},
title = {BACH1-CHAC1-Glutathione Axis Aggravates Myocardial Ischemia-Reperfusion Injury by Enhancing Ferroptosis and Oxidative Stress.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
pmid = {41750596},
issn = {2076-3921},
support = {82370282//National Natural Science Foundation of China/ ; },
abstract = {Myocardial ischemia-reperfusion injury (MIRI) is a pathological process in which reperfusion-induced oxidative stress and metabolic derangement further aggravate myocardial damage and blunt the benefit of reperfusion. Ferroptosis is increasingly implicated in MIRI, with the glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis constituting a key antioxidant barrier. Although GSH depletion is recognized as a critical event, its upstream regulation in MIRI remains unclear. Against this background, we investigate the BACH1-CHAC1-GSH pathway as a putative upstream regulatory axis of ferroptosis in MIRI and a potential molecular target. Here, using an oxygen-glucose deprivation/reoxygenation (OGD/R) model in AC16 and the reversibility conferred by the ferrostatin-1, RNA sequencing identified the GSH-degrading enzyme CHAC1 as a modulator that is induced by stress and promotes ferroptosis. Experiments showed that CHAC1 overexpression aggravated OGD/R-induced injury, depleted GSH, suppressed GPX4 and enhanced lipid peroxidation, whereas CHAC1 knockdown was partially protective. N-acetylcysteine (NAC) replenished GSH, restored GPX4 activity and partially rescued CHAC1-driven injury. In a mouse myocardial I/R model, cardiotropic adeno-associated virus-mediated CHAC1 overexpression worsened cardiac dysfunction, enlarged infarct and fibrosis areas, and increased myocardial iron deposition. Dual-luciferase assays revealed that the transcription factor BACH1 activates the CHAC1 promoter, and BACH1 silencing attenuated ferroptosis by suppressing CHAC1 and restoring the GSH-GPX4 axis. Collectively, our data identify the BACH1-CHAC1-GSH axis as an upstream amplifier of ferroptosis in MIRI through glutathione depletion and impairment of GPX4-dependent antioxidant defense. These findings refine the mechanistic link between reperfusion-phase redox imbalance and ferroptosis and highlight BACH1/CHAC1 inhibition or augmentation of GSH precursors as potential cardioprotective strategies in ischemic heart disease.},
}
@article {pmid41749341,
year = {2026},
author = {Mudzengi, D and Mashatole, S and Xiang, Q and Adrion, C and Glover, N and Ngwanto, T and Mdluli, J and Boniface, S and Rassool, M and Matome, B and Paramo, L and Svensson, E and Fasanmi, A and Angelo, S and Moyo, M and Marx, C and Khosa, C and Mokaba, L and Mofokeng, N and Lalashowi, J and Nacy, C and Charalambous, S and Fumane, E and Maphossa, V and Beattie, T and Brumskine, W and Venter, C and Mapamba, D and Heinrich, N and Rajaram, S and Kooverjee, S and Botha, L and Nell, M and Easton, A and Foraida, S and Warren, RM and Sabi, I and Ntinginya, N and Wallis, RS and , },
title = {panTB-HM: a multi-arm clinical trial of a pan-TB regimen targeting both host and microbe.},
journal = {Trials},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13063-026-09568-9},
pmid = {41749341},
issn = {1745-6215},
support = {RIA2019AMR-2647//EDCTP/ ; },
abstract = {BACKGROUND: Newer oxazolidinones will be required to advance regimens in pan-TB indications. The addition of host-directed agents may help promote the recovery of lung function during TB treatment and prevent post-TB lung disease.<br><br>METHODS: The panTB-HM trial assesses the capacity of three novel regimens containing the oxazolidinone sutezolid and the antioxidant N-acetylcysteine (NAC) to meet the target criteria proposed by WHO for pan-TB indications (including use without rifamycin susceptibility testing and of 4&#xa0;months or less duration) in a phase 2C trial.<br><br>DISCUSSION: This trial is ground-breaking in its objectives and design for a 4-month pan-TB indication (in a non-inferiority comparison to standard treatment) and its evaluation of lung function recovery (in a superiority comparison).<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT05686356. Registered on 13 Jan 2023.},
}
@article {pmid41740408,
year = {2026},
author = {Wang, HZ and Xiong, YM and Song, SL and Zhao, QC and Chen, XY and Gao, JR and Li, YY and Qin, ZF},
title = {Low doses of chlorothalonil cause testicular impairment in mammals through the antimicrobial-like mechanism.},
journal = {Journal of hazardous materials},
volume = {506},
number = {},
pages = {141563},
doi = {10.1016/j.jhazmat.2026.141563},
pmid = {41740408},
issn = {1873-3336},
abstract = {Chlorothalonil is a widely used fungicide that exerts activity through interacting with glutathione (GSH) and thiol-containing proteins or other nucleophilic molecules due to its electrophilicity. However, it remains little known whether chlorothalonil exerts similar actions in mammals and causes male reproductive damage. Here, we detected reduced cell viability and glycolytic impairment coupled with the redox imbalance including ROS accumulation in GC-1 cells (testicular germ cell line) treated with chlorothalonil; however, the nucleophilic antioxidant N-acetylcysteine (NAC) rescued chlorothalonil-caused cell damage. In animal experiments, exposure to chlorothalonil (30, 300, and 3000 μg/kg/d) from gestational day 10 to postnatal day (PND) 10 caused slight effects on testicular development in suckling male mice. However, extended exposure to postnatal week (PNW) 15 resulted in testicular impairment in male offspring, including germ cell apoptosis, reduced sperm count, and increased sperm tail malformation, along with reduced GSH content and altered expression of redox-related genes, and certain significant alterations even occurred in the low-dose group. Furthermore, we also observed reduced motility and redox disturbance in mouse sperm in vitro, and NAC exerted significant rescue effects. Moreover, surface plasmon resonance (SPR) analysis revealed the binding of chlorothalonil to β-actin, a sensitive target of electrophilic substances. Taken together, all data indicate that low dose of chlorothalonil caused testicular impairment in mice possibly through interacting with nucleophilic molecules. This study challenges the acceptable daily intake (20 or 30 μg/kg/d) of chlorothalonil established previously, and calls for great attention on male reproductive hazards of more electrophilic pollutants.},
}
@article {pmid41737465,
year = {2026},
author = {Jiang, M and Lu, W and Zhuang, J and Song, J and Zhao, Y and Zhou, C and Zhou, Y and Shu, W and Zhu, Z and Jiang, L and Wu, P and Wu, A and Sheng, S and Zhu, S and Wang, Z},
title = {A bioinspired anisotropic anti-inflammatory scaffold enhances spinal nerve regeneration and neural circuit reconstruction via FGF13/Ca[2+]/CaMK2A/CREB pathway.},
journal = {Materials today. Bio},
volume = {37},
number = {},
pages = {102929},
pmid = {41737465},
issn = {2590-0064},
abstract = {Spinal cord injury (SCI) induces severe neurological impairment, exacerbated by secondary inflammation and disrupted neural circuitry. Inspired by the spinal cord's electromechanical microenvironment, we developed a biomimetic conductive nerve scaffold via directional freeze-casting of gelatin methacryloyl (GelMA) hydrogel incorporated with N-acetylcysteine-modified silver nanowires (NAC-AgNWs). The scaffold exhibits axially aligned microchannels, tunable mechanical strength, and conductivity akin to native spinal tissue. In a rat model of complete spinal cord transection (2 mm), the scaffold exhibited dual therapeutic effects: (1) early-stage anti-inflammatory modulation (mediated by the synergistic interplay between AgNWs and NAC), and (2) sustained neural reconstruction, evidenced by robust axonal bridging across the lesion, synapse reformation, and significant functional recovery. Integrated transcriptomic analyses revealed the FGF13/Ca[2+]/CaMK2A/CREB axis as the activated pathway driving neurite outgrowth and neural circuit reconstruction. This biomaterial design establishes a novel therapeutic paradigm for SCI repair, integrating structural guidance, immunomodulation, and activation of pro-regenerative signaling.},
}
@article {pmid41722831,
year = {2026},
author = {Perera, KDC and Vasta, AK and Menon, JU},
title = {Mucopenetrative Lipid-Polymer nanoparticles show Potent Anti-Inflammatory activity in a human Lung-on-Chip model.},
journal = {International journal of pharmaceutics},
volume = {693},
number = {},
pages = {126688},
doi = {10.1016/j.ijpharm.2026.126688},
pmid = {41722831},
issn = {1873-3476},
abstract = {Airway mucus presents a significant barrier to inhaled drug delivery, particularly for nanoparticle-based interventions, with this barrier exacerbated in chronic respiratory diseases (CRDs) due to hyperviscous secretions and persistent inflammation. In this study, a dual-functional lipid-polymer hybrid nanoparticle was developed to combine rapid mucolysis with sustained anti-inflammatory activity, and its performance was evaluated using both conventional in vitro assays and a physiologically relevant lung-on-a-chip model. Dipalmitoylphosphatidylcholine (DPPC)-coated PLGA nanoparticles (hydrodynamic diameter 378.1 ± 23.0 nm; 58-61 wt% lipid; ζ ≈ +3 mV) encapsulated N-acetylcysteine (NAC) within the lipid shell for rapid release and all-trans retinoic acid (ATRA) within the core for sustained delivery. NAC exhibited a burst release of 44.2-52.5% within 6 h and significantly reduced the viscosity of cystic fibrosis-mimetic mucus, enabling a 26.5-fold higher penetration across a ∼ 0.6 mm mucus plug compared to NAC-free controls. The formulation was well tolerated by pulmonary epithelial and fibroblast cells and demonstrated high cellular uptake driven by the DPPC coating. To assess efficacy under physiologically relevant airway conditions, a human lung-on-a-chip model incorporating air-liquid interface, flow, and cyclic stretch was employed. In this model, repeated dosing of NAC + ATRA nanoparticles resulted in a 2.6-fold reduction in IL-6 and a 2.3-fold reduction in IL-8 levels compared to diseased controls at 72 h, outperforming NAC-free nanoparticles at early timepoints and maintaining suppression over 9 days. These findings demonstrate the therapeutic promise of dual-functional mucopenetrative nanoparticles and establish the utility of lung disease-on-chip platforms for evaluating inhaled nanotherapeutics under physiologically relevant conditions.},
}
@article {pmid41720502,
year = {2026},
author = {Afşar, E and Öz, M and Eranıl, I},
title = {Hepato-Cardiac Axis in Epirubicin Toxicity: Role of Kynurenine Pathway and N-Acetylcysteine Antioxidant Intervention.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70118},
pmid = {41720502},
issn = {1099-1263},
abstract = {Epirubicin (EPI) is a widely used chemotherapeutic agent; however, its clinical utility is limited by severe side effects, particularly the production of reactive oxygen species (ROS). Among these, cardiotoxicity is one of the most critical issues, and it is worsened by impaired hepatic clearance resulting from liver dysfunction. This study aimed to investigate molecular changes induced by EPI in the liver within the kynurenine pathway (KP), their possible contribution to cardiotoxicity, and the protective effects of N-acetylcysteine (NAC). Rats received intraperitoneal injections of 50 or 300 mg/kg NAC, followed 1 h later by 9.6 mg/kg EPI. Tryptophan (Trp), kynurenine (Kyn), kynurenic acid (KYNA), quinolinic acid (QA), kynureninase, and kynurenine 3-monooxygenase (KMO) levels in the liver and cleaved caspase-3 levels in the liver and heart tissue were measured using ELISA. Hepatic and cardiac total antioxidant status (TAS) and total oxidant status (TOS) were determined using a colorimetric method. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), creatine kinase-MB isoenzyme (CK-MB), high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (T-chol), and triglyceride (TG) were analyzed with a clinical biochemistry analyzer. Cardiac morphology was examined using hematoxylin-eosin staining. EPI administration was associated with increases in plasma CK-MB, the AST/ALT ratio, LDL, T-chol, and TG, with these increases partially attenuated by NAC treatment. Hepatic levels of Trp, QA, and KMO were positively correlated with plasma CK-MB and the AST/ALT ratio. Additionally, EPI appeared to increase oxidative stress in heart tissue and induce morphological changes. At the same time, NAC treatment was associated with partial improvement in these parameters, suggesting that alterations in the hepatic KP may be linked to possible cardiac involvement. Our findings suggest that EPI-induced alterations in hepatic KP may impair hepatic clearance, and NAC administration may provide partial protection, warranting further investigation of a possible hepato-cardiac interaction.},
}
@article {pmid41713986,
year = {2026},
author = {Li, S and Xia, L and Wang, S and Ju, R and Han, Z and Lv, X and Han, B and Chi, J},
title = {N-acetylcysteine-functionalized biodegradable polysaccharide hydrogel patches for the repair of acute liver injury.},
journal = {Carbohydrate polymers},
volume = {379},
number = {},
pages = {124983},
doi = {10.1016/j.carbpol.2026.124983},
pmid = {41713986},
issn = {1879-1344},
mesh = {Animals ; *Hydrogels/chemistry/pharmacology ; *Acetylcysteine/chemistry/pharmacology ; Mice ; Humans ; Acetaminophen ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology/metabolism ; Male ; Human Umbilical Vein Endothelial Cells/drug effects ; Liver/drug effects/pathology ; Cell Proliferation/drug effects ; Hepatocytes/drug effects ; Chondroitin Sulfates/chemistry ; Apoptosis/drug effects ; Mice, Inbred C57BL ; Biocompatible Materials/chemistry/pharmacology ; *Polysaccharides/chemistry ; },
abstract = {Acute liver injury (ALI) caused by acetaminophen (APAP) has a high incidence rate worldwide, and severe cases may cause liver failure or even death. N-acetylcysteine (NAC), as an effective treatment drug approved for clinical application in ALI, has limitations such as a short half-life and the requirement for high-dose injections. Consequently, it is imperative to optimize new administration method of NAC and promote alternative therapeutic strategies for ALI. Herein, hydrogel patches ONC composed of oxidized chondroitin sulfate (OCS) and NAC-grafted CMCS were developed, and their reparative effects on APAP-induced ALI were investigated. ONC hydrogels exhibited excellent biocompatibility and appropriate biodegradability, and favorable hemostatic effects in the liver. In vitro experiments demonstrated that ONC could promote the proliferation and migration of hepatocytes, as well as the angiogenesis of HUVECs. By establishing an APAP-induced ALI model in mice, liver enzymes after ONC hydrogel patches treatment recovered to near-normal levels. Moreover, histological examination, RT-qPCR, and transcriptome sequencing results demonstrated that ONC patches could reduce the expression of inflammatory factors and apoptosis in the liver, while simultaneously activating antioxidant-related signaling pathways, thereby promoting the regeneration and functional repair of damaged tissues. Therefore, ONC hydrogel patches may be a promising alternative strategy for treating ALI.},
}
@article {pmid41708253,
year = {2026},
author = {Wang, P and Zhong, Y and Liu, J and Gao, L and Long, T and Li, Z},
title = {Dietary titanium dioxide particles (E171) promote colitis-associated colorectal cancer development in mice through macrophage-derived S100A8/S100A9secretion mediated by NLRP3/Caspase 1/GSDMD pathway.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {2},
pages = {215-226},
doi = {10.1016/S1875-5364(26)61092-8},
pmid = {41708253},
issn = {1875-5364},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Calgranulin A/metabolism/genetics ; Mice ; *Titanium/adverse effects/administration &amp; dosage ; *Calgranulin B/metabolism/genetics ; *Macrophages/metabolism/drug effects ; *Caspase 1/metabolism/genetics ; Mice, Inbred C57BL ; RAW 264.7 Cells ; Male ; *Colitis-Associated Neoplasms/chemically induced/genetics/metabolism ; Humans ; Signal Transduction/drug effects ; *Colorectal Neoplasms/genetics/etiology/chemically induced/metabolism ; },
abstract = {Colitis-associated colorectal cancer (CAC) is a major contributor to cancer-related mortality worldwide. Titanium dioxide (TiO2, E171), a widely used food additive, has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development. In this study, CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo, while lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro. We found that dietary E171 intake accelerated CAC development, exacerbated inflammatory responses and oxidative stress, and upregulated CAC-associated genes, including S100a8, S100a9, Lcn2, S100a11, Cxcl2, and interleukin-1α (Il-1α). E171 also increased the expression of S100A8, S100A9, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and gasdermin-D N-terminal (GSDMD-N) in macrophages within colon tumors. In inflammatory macrophages, E171 exposure enhanced cell viability, increased reactive oxygen species (ROS) levels, and elevated the expression and secretion of S100A8 and S100A9, consistent with in vivo histological observations. Furthermore, E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors, including N-acetylcysteine (NAC, ROS inhibitor), MCC950 (NLRP3 inhibitor), Z-YVAD-FMK (caspase 1 inhibitor), disulfiram (GSDMD inhibitor), and transfection of NLRP3 small interfering ribonucleic acid (siRNA). These results indicate that dietary E171 promotes CAC development by activating macrophages, with S100A8 and S100A9 serving as key mediators, and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.},
}
@article {pmid41704764,
year = {2026},
author = {Huang, X and Meng, Y and Song, J and Zhu, Y and Li, J and Xi, Y and Peng, X and Xiong, Y},
title = {KNSTRN knockdown impairs autophagy flux to inhibit bladder cancer progression.},
journal = {iScience},
volume = {29},
number = {2},
pages = {114734},
pmid = {41704764},
issn = {2589-0042},
abstract = {Bladder cancer (BLCA) is a common malignant tumor of the urinary system. Kinetochore-localized astrin-binding protein (KNSTRN) has been implicated in the initiation and progression of multiple cancers. Furthermore, abnormal autophagy levels have been shown to significantly impact tumor development. However, the mechanism by which KNSTRN regulates autophagy in BLCA remains unclear. This study reveals that KNSTRN knockdown inhibits autophagy flux in BLCA. The mechanism involves ROS-dependent disruption of lysosomal function upon KNSTRN knockdown, thereby impeding autophagosome-lysosome fusion. Clioquinol restores lysosomal activity by regulating lysosomal pH, subsequently reestablishing autophagy flux. The ROS scavenger N-acetylcysteine (NAC) reverses lysosomal dysfunction and reactivates the autophagic flux. Furthermore, the autophagy activator rapamycin (Rapa) effectively counteracts KNSTRN knockdown-induced cell death in both in vitro and in vivo experiments. Collectively, we demonstrate that KNSTRN knockdown induces intracellular ROS accumulation and lysosomal dysfunction, thereby disrupting autophagic flux and inhibiting BLCA progression.},
}
@article {pmid41701447,
year = {2026},
author = {Sabry, S and Ammar, MK and Taeima, M and Nassar, N and ElFiky, A and Saleh, A},
title = {Preventing Contrast-Induced Acute Kidney Injury in Egyptian Patients Undergoing Coronary Angiography: A Randomized Controlled Trial.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {41701447},
issn = {1179-1918},
abstract = {BACKGROUND AND OBJECTIVES: Contrast-induced acute kidney injury (CI-AKI) observed after coronary angiography (CAG) requires preventive strategies guided by clinical judgment. Evidence is still lacking regarding the prevention of CI-AKI in patients undergoing coronary angiography. This study aimed to compare the effect of a high dose of N-acetylcysteine (NAC) plus preprocedural hydration, a high dose of atorvastatin (HDS) plus preprocedural hydration, or preprocedural hydration alone on the prevention of CI-AKI in patients undergoing elective coronary angiography.<br><br>METHODS: A prospective multi-armed randomized comparative study was conducted on elective patients undergoing CAG. Patients were randomly assigned to either control group [n = 40], who received hydration with 0.9% saline started just before contrast media injection and continued for 12 h at a rate 1.0 mL/kg/min after angiography; NAC group [n = 40], who received oral NAC 1200 mg daily started 5 days before angiography and good hydration; or HDS group [n = 40], receiving one oral dose of atorvastatin 80 mg 24 h before angiography and good hydration. CI-AKI was defined as an increase in serum creatinine of > 25% of baseline or an absolute increase of 0.5 mg/dL above baseline after 48 h. Incidence of CI-AKI and incidence of complications were assessed for all groups.<br><br>RESULTS: The study included 120 patients. The incidence of CI-AKI was [32.5%] in the control group, [20%] in the NAC group, and [12.5%] in the HDS group. The incidence of CI-AKI was significantly lower in the high-dose statin group compared with the control group (risk ratio = 1.658; 95% CI 1.050-2.433). In-hospital clinical outcomes showed no statistical significance among the three groups.<br><br>CONCLUSIONS: Both NAC and high-dose statins may reduce CI-AKI incidence in patients undergoing CAG, with statins showing more promising results. These findings support prophylactic strategies for CI-AKI prevention in high-risk patients undergoing CAG. In-hospital outcomes were comparable.<br><br>CLINICAL TRIAL REGISTRATION: Clinical-Trials.gov (ID; NCT06139952, Date; December 2023).},
}
@article {pmid41700562,
year = {2026},
author = {Gregory, E and Wilkinson, EP and Leyngold, I},
title = {N-acetylcysteine and Vitamin C oral antioxidant therapy for teprotumumab-related hearing dysfunction: case series and review of literature.},
journal = {Orbit (Amsterdam, Netherlands)},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/01676830.2025.2608253},
pmid = {41700562},
issn = {1744-5108},
abstract = {We report three cases of successful treatment of teprotumumab-related hearing dysfunction with N-acetylcysteine (NAC) and ascorbic acid (Vitamin C). To investigate NACs effectiveness in the treatment of other types of auditory symptoms through a review of available literature. Three patients with thyroid eye disease (TED) developed symptoms of ear fullness and hearing loss during infusions of teprotumumab. Audiogram revealed above-normal pure tone average hearing threshold frequencies. They were treated with once-daily oral administration of 600 mg N-acetyl cysteine and 500 mg ascorbic acid (Vitamin C). All patients experienced nearly complete resolution of their ear symptoms prior to completing their teprotumumab therapy. They continued to remain symptom-free throughout the remaining teprotumumab infusions and onwards. This study showcases that antioxidant therapy with N-acetylcysteine and Vitamin C appears to be a promising, safe, and inexpensive potential treatment option for teprotumumab-related hearing dysfunction in our patient group.},
}
@article {pmid41686281,
year = {2026},
author = {Moon, UY and Kim, YE and Nguyen, HD and Choi, HJ},
title = {CREB2 Functions as a Central Mediator of Oxidative Neuronal Death Triggered by Microglial Glutamate Release Under Neuroinflammatory Conditions.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01695-w},
pmid = {41686281},
issn = {1573-6830},
support = {2710086662/RS-2025-02213662//Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare/ ; RS-2023-00246655 and RS-2024-00356135//National Research Foundation of Korea/ ; },
abstract = {Glutamate-induced oxidative cytotoxicity is a major driver of neuronal loss in neurodegenerative diseases, yet the upstream transcriptional regulators linking oxidative stress to neuronal death remain unclear despite the known involvement of the p53-GADD45α pathway. CREB2 (ATF4) is a stress-responsive transcription factor, but its role in microglia-mediated oxidative neurotoxicity has not been fully defined. Here, we investigated CREB2 function in oxidative glutamate toxicity using HT22 hippocampal neurons, primary mouse hippocampal cells, and a kainic acid (KA)-injected rat model. Oxidative stress was induced by glutamate, intracellular ROS levels were quantified with DCFDA, and the antioxidant N-acetylcysteine (NAC) was used to confirm oxidative dependency. Microglia-derived glutamate was assessed by stimulating BV2 cells with lipopolysaccharide (LPS) and applying glutamate-containing conditioned medium (LPS-CM) to HT22 cells. Exogenous glutamate robustly increased CREB2 expression in HT22 and primary neurons, accompanied by ROS accumulation and cell death, whereas NAC suppressed these effects. Inhibition of p53 by siRNA or pifithrin-α (PFT-α) attenuated glutamate-induced CREB2 upregulation, and CREB2 knockdown blocked GADD45α induction and protected neurons. In Vivo, KA injection caused robust CREB2 upregulation in the damaged CA3 region. Importantly, conditioned medium from LPS-activated BV2 microglia increased CREB2 expression and ROS levels in HT22 cells in an NAC-sensitive manner, supporting a glutamate-associated oxidative mechanism rather than receptor-mediated excitotoxicity. Collectively, these results suggest that CREB2 functions between upstream p53 signaling and downstream GADD45α activation as a redox-sensitive mediator of oxidative neuronal death, and may represent a potential therapeutic target in neurodegenerative diseases associated with oxidative stress and neuroinflammation.},
}
@article {pmid41683511,
year = {2026},
author = {Hikisz, P and Adamus-Grabicka, AA and Budzisz, E},
title = {Multifaceted Anticancer Activity of Flavanone/Chromanone Intermediates for Five-Membered Heterocyclic Derivatives: Targeting Oxidative Stress, Apoptosis, and MAPK Signaling in Colorectal Cancer.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {3},
pages = {},
pmid = {41683511},
issn = {1420-3049},
support = {503/3-066-02/503-31-001//Medical University of Lodz/ ; 2024/08/X/NZ7/01232//National Science Center/ ; 2023/07/X/NZ3/01404//National Science Center/ ; },
mesh = {Humans ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; *Flavanones/pharmacology/chemistry ; *Colorectal Neoplasms/metabolism/drug therapy/pathology ; *Antineoplastic Agents/pharmacology/chemistry ; Cell Line, Tumor ; *MAP Kinase Signaling System/drug effects ; Reactive Oxygen Species/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; *Heterocyclic Compounds/pharmacology/chemistry ; },
abstract = {This study explores the multifaceted anticancer mechanisms of flavanone analogues and spiropyrazoline condensed with flavanone ring against colorectal cancer (CRC) cell lines. Five-membered heteroaromatic scaffolds, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. Building upon previous findings, we investigated three lead derivatives (1, 3, and 5) with potent antiproliferative activity (IC50 < 35 μM). The compounds induced pronounced oxidative stress, evidenced by increased lipid peroxidation and reduced membrane fluidity, primarily within the hydrophobic layers of cell membranes. Preincubation with the antioxidant N-acetylcysteine (NAC) significantly attenuated these effects, confirming the pivotal role of reactive oxygen species (ROS) in their cytotoxicity. Mechanistic studies revealed that the derivatives triggered intrinsic apoptosis, characterized by the cleavage of PARP and the activation of caspase-9 and caspase-3. Furthermore, the compounds modulated key signaling pathways involved in cell survival and proliferation. Specifically, they inhibited the pro-oncogenic ERK1/2 MAPK pathway while inducing cell line-dependent alterations in p38 and JNK activity. Concurrently, all derivatives reduced the level of the transcription factor Nrf2, a master regulator of antioxidant defense and a mediator of chemoresistance in CRC. Collectively, these findings indicate that flavanone/chromanone derivatives exert their anticancer activity through a synergistic mechanism involving ROS generation, disruption of redox homeostasis, inhibition of Nrf2 signaling, and modulation of MAPK-dependent apoptotic pathways. These results highlight the therapeutic potential of flavanone-based compounds and their spiropyrazoline analogues as multifunctional anticancer agents targeting oxidative stress and survival signaling in colorectal cancer.},
}
@article {pmid41681844,
year = {2026},
author = {Rodriguez, V and Villani, A and Sénica, M and Panebianco, C and Pazienza, V and Preto, A},
title = {Harnessing Postbiotics to Boost Chemotherapy: N-Acetylcysteine and Tetrahydro β-Carboline Carboxylic Acid as Potentiators in Pancreatic and Colorectal Cancer.},
journal = {Cancers},
volume = {18},
number = {3},
pages = {},
pmid = {41681844},
issn = {2072-6694},
support = {ID. 23006 project//Associazione Italiana Ricerca sul Cancro (AIRC) under IG 2019/ ; UIDB/04050/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; UID/04050//Centro de Biologia Molecular e Ambiental/ ; },
abstract = {BACKGROUND: Pancreatic cancer (PC) and colorectal cancer (CRC) are among the most lethal malignancies, with growing evidence pointing to the gut microbiota's role in their progression. This study aimed to explore the anticancer potential of two microbiota-derived postbiotics, N-acetylcysteine (NAC) and tetrahydro β-carboline carboxylic acid (THC), in targeting some hallmark traits of PC and CRC, both as standalone agents and in combination with standard chemotherapeutics (gemcitabine for PC and 5-fluorouracil (5-FU) for CRC).<br><br>METHODS: Cell viability assays and IC50 determination was assessed using either the Muse&#x2122; Count &amp; Viability Kit or the Sulforhodamine B assay; cell death was determined by Annexin V/Propidium Iodide and cell cycle assessed by Propidium Iodide was analyzed by flow cytometry.<br><br>RESULTS: Here, we found that NAC selectively reduced the viability of PC cells BxPC-3 without triggering apoptosis, while effectively inducing apoptosis in PC cells Panc-1 and in CRC cell lines. THC exhibited stronger anticancer activity, inhibiting proliferation and promoting apoptosis in all tested PC and CRC cells, even at lower concentrations. Combination treatments yielded promising enhancement effects. NAC enhanced the cytotoxicity of gemcitabine in Panc-1 cells through increased apoptosis. NAC, when combined with 5-FU, also increased apoptosis of CRC cells. THC further potentiated gemcitabine's impact on Panc-1 cells by increasing apoptosis and by inducing cell cycle changes in BxPC-3. In the CRC model, THC co-treatment with 5-FU reduced cell viability and increased apoptosis in all cells.<br><br>CONCLUSIONS: These findings provide preliminary in vitro evidence supporting the potential of integrating microbiota-derived postbiotics with conventional chemotherapy both in PC and CRC.},
}
@article {pmid41678124,
year = {2026},
author = {Batsaikhan, T and Lee, HS and Yang, H and Ferdushi, R and Key, J and Seo, YJ},
title = {Therapeutic Effects of N-Acetylcysteine-Primed, Iron Oxide Nanoparticle-Enhanced Mesenchymal Stem Cell Exosomes in Ototoxicity Hearing Loss.},
journal = {Tissue engineering and regenerative medicine},
volume = {},
number = {},
pages = {},
pmid = {41678124},
issn = {2212-5469},
abstract = {BACKGROUND: Sensorineural hearing loss caused by ototoxic agents remains irreversible due to the limited regenerative capacity of cochlear hair cells. Exosome-based therapies derived from mesenchymal stem cells (MSCs) offer a promising, cell-free alternative to protect auditory structures by modulating oxidative stress and inflammation. In this study, we evaluated the therapeutic potential of exosomes isolated from nanoparticle (NP) labeled, N-acetylcysteine primed tonsil-derived mesenchymal stem cells (T-MSCs), hereafter referred to as SPISOME-NAC, in kanamycin-induced ototoxicity models.<br><br>METHODS: T-MSCs were labeled with positively charged PLGA-PEI clustered SPIONs, with or without NAC pretreatment. Antioxidant enzyme activity (SOD, CAT, GSH), ROS levels, and PRDX1 expression were assessed in vitro. Exosomes were isolated and analyzed via nanoparticle tracking analysis. Their therapeutic efficacy was evaluated in both ex vivo cochlear explants and mouse model of kanamycin-induced ototoxicity. Hair cell survival was quantified via Myosin VIIa immunostaining, and auditory function was assessed using auditory brainstem responses (ABR). Pro-inflammatory cytokines (TNF-&#x3b1;, IL-1, IL-6) were measured via qRT-PCR.<br><br>RESULTS: NAC pretreatment significantly enhanced cell viability, increased GSH activity, and reduced intracellular ROS and PRDX1 levels in NP-labeled T-MSCs. Exosomes derived from NAC-pretreated cells (SPISOME-NAC) conferred superior protection to cochlear hair cells, particularly in the basal turn, and significantly improved hearing thresholds in vivo. Furthermore, SPISOME-NAC treatment downregulated inflammatory cytokines in cochlear tissue.<br><br>CONCLUSION: SPISOME-NAC exhibit enhanced antioxidant and anti-inflammatory properties, providing functional protection in an ototoxicity-induced hearing loss model. By preventing ROS-mediated mitochondrial damage and apoptosis in cochlear hair cells, NAC interrupts a key pathogenic mechanism in ototoxicity, preserving auditory structure and function. These findings support NAC-primed exosomes as a novel therapeutic strategy for sensorineural hearing loss.},
}
@article {pmid41677644,
year = {2026},
author = {Khamineh, Y and Panahi-Alanagh, S and Zolghadri, S and Mavaddatiyan, L and Ryszkiel, I and Stanek, A and Talkhabi, M},
title = {Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
pmid = {41677644},
issn = {2073-4409},
mesh = {Humans ; Female ; *Acetylcysteine/pharmacology ; *Ovarian Neoplasms/pathology/genetics/drug therapy ; *Ketoglutaric Acids/pharmacology ; Cell Line, Tumor ; *Computational Biology/methods ; Apoptosis/drug effects ; Cell Movement/drug effects ; Cell Survival/drug effects ; Cell Proliferation/drug effects ; Protein Interaction Maps/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; },
abstract = {Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; however, their combined effects in ovarian cancer are not well characterized. In this study, we applied an integrative approach combining network pharmacology analysis with in vitro experiments to investigate the effects of NAC and AKG on OVCAR3 ovarian cancer cells. Common molecular targets of NAC and AKG were identified by intersecting predicted compound targets with ovarian cancer-associated genes, followed by protein-protein interaction network construction and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Experimental validation assessed the effects of NAC and AKG, alone and in combination, on cell viability, apoptosis, migration, and clonogenic capacity. Network analysis identified 70 shared target genes enriched in pathways related to apoptosis, cellular stress responses, and cell migration. In vitro experiments demonstrated that combined treatment with NAC (10 mM) and AKG (100 µM) significantly reduced cell viability, increased apoptotic cell death, and markedly suppressed cell migration and colony formation compared with single-agent treatments. Overall, these findings indicate that the combination of NAC and AKG exerts enhanced inhibitory effects on ovarian cancer cell growth and motility in vitro.},
}
@article {pmid41677304,
year = {2026},
author = {Higazy, D and Vergauwe, F and Coenye, T and Ciofu, O},
title = {Evolutionary adaptations of Pseudomonas aeruginosa biofilms to ciprofloxacin and antioxidant co-treatment in synthetic sputum medium.},
journal = {Microbiology spectrum},
volume = {14},
number = {3},
pages = {e0314925},
pmid = {41677304},
issn = {2165-0497},
support = {//Egyptian Ministry of Higher Education/ ; BOF20/GOA/002//Ghent University Special Research Fund/ ; },
mesh = {*Ciprofloxacin/pharmacology ; *Biofilms/drug effects/growth &amp; development ; *Pseudomonas aeruginosa/drug effects/genetics/physiology ; *Antioxidants/pharmacology ; *Sputum/microbiology ; *Anti-Bacterial Agents/pharmacology ; Microbial Sensitivity Tests ; Humans ; Cystic Fibrosis/microbiology ; Pseudomonas Infections/microbiology ; Drug Resistance, Bacterial/drug effects/genetics ; Bacterial Proteins/genetics ; Culture Media/chemistry ; Mutation ; Acetylcysteine/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {UNLABELLED: Antimicrobial resistance (AMR) is a growing public health concern, particularly in biofilm-related infections, where microbial aggregates display high levels of tolerance. Oxidative stress has been hypothesized to accelerate the development of resistance, whereas antioxidants (AOs) may mitigate this process. In this study, we investigated the impact of AOs on the evolution of ciprofloxacin (CIP) resistance in Pseudomonas aeruginosa PAO1 using synthetic cystic fibrosis sputum medium (SCFM2), which mimics the physiochemical conditions of cystic fibrosis (CF) respiratory infections. Experimental evolution was performed over six passages with CIP alone or in combination with edaravone (ED), N-acetyl-cysteine (NAC), or thiourea (THU). Population analysis profiles and minimum inhibitory concentration (MIC) assays demonstrated that CIP treatment produced high-level resistance (MIC 8-32 mg/L), whereas CIP + AO treatments markedly suppressed resistance development (MIC 0.75-2 mg/L). Whole-genome sequencing revealed distinct mutational patterns. CIP-treated isolates carried mutations in mexR and nalC (efflux pump regulators), and gyrA (fluoroquinolone target), consistent with elevated resistance, along with additional mutations in rocR and dnaX. In contrast, evolved isolates in the presence of CIP + AO harbored nfxB mutations associated with lower resistance, while CIP + ED uniquely produced a mutation in parS. These findings support the role of reactive oxygen species (ROS) in driving resistance evolution under CF-like conditions and suggest that antioxidants can suppress this process, providing a potential strategy for limiting antimicrobial resistance in biofilm-associated infections.<br><br>IMPORTANCE: Fighting antimicrobial resistance (AMR) is one of the greatest health challenges of our time. To find new ways to stop it, we need to better understand how resistance develops. Our study suggests that antioxidants may help slow down the process that allows bacteria to become resistant. We also show that resistance develops more quickly, and in a different way, when bacteria grow in conditions that resemble the human body rather than in standard laboratory media. In particular, the synthetic sputum medium promoted the formation of aggregated biofilms-sticky communities of cells that often occur in chronic and hard-to-treat infections.},
}
@article {pmid41666086,
year = {2026},
author = {Babayigit, Z and Yiğider, AP and Yiğit, O and Algün Gedik, A and Dumur, S and Uzun, H},
title = {Effect of intratympanic N-acetylcystein (NAC) on vestibulotoxicity model formed with intratympanic gentamicin in Guinea pigs.},
journal = {Acta oto-laryngologica},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/00016489.2025.2600090},
pmid = {41666086},
issn = {1651-2251},
abstract = {BACKGROUND: N-acetylcysteine (NAC) can protect against this damage.<br><br>AIM: To evaluate the effect of intratympanic NAC on the vestibulotoxicity model formed with intratympanic gentamicine in guinea pigs.<br><br>DESIGN: Experimental Animal Study.<br><br>METHODS: Guinea pigs were randomly divided into three groups. Group1 (control), group2 was treated with intratympanic(IT) gentamicin and group3 was treated with IT gentamicin&#x2009;+&#x2009;NAC. A single dose of NAC was applied on the 1st,3rd, and5th days. Cervical-vestibular evoked myogenic potentials (c-VEMP) measurements and blood samples were taken from the guinea pigs on the day 0,10,30.<br><br>RESULTS: In group2 on day 10 c-VEMP latency was prolonged and on day 30 c-VEMP responses were lost in half of animals. A partial loss of c-VEMP values was observed in the group3. Serum total antioxidant capacity (TAC) and superoxide dismutase (SOD) activity in group3 (on the 7th and 30th day) were significantly higher than those in the group2. Tissue SOD and glutathione (GSH) were lower, while the malondialdehyde (MDA) and lipid hydroperoxide (LOOH) were the higher in group2.<br><br>CONCLUSION: Gentamicin induced loss in c-VEMP responses and NAC played an effective role in reducing this loss which were confirmed by oxidative capacity at tissue and serum level.},
}
@article {pmid41663453,
year = {2026},
author = {Heshmati, ZS and Amiri-Yekta, A and Khosravifar, M and Akbarian, F and Moini, A and Eftekhari-Yazdi, P and Hafezi, M and Afsharian, P},
title = {Administration of N-acetylcysteine influence the expression of apoptotic genes in the granulosa cells of infertile women diagnosed with endometriosis.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41663453},
issn = {2045-2322},
support = {401000042//Royan Institute for Reproductive Biomedicine, ACECR, Iran/ ; 2447/1400/D//Royan Lotus Charity Foundation, Iran/ ; },
mesh = {Humans ; Female ; *Acetylcysteine/administration &amp; dosage/pharmacology ; *Endometriosis/complications/drug therapy/genetics ; *Granulosa Cells/metabolism/drug effects ; Adult ; *Apoptosis/drug effects/genetics ; *Infertility, Female/drug therapy/genetics/etiology ; Superoxide Dismutase/blood ; Antioxidants ; Caspase 3/genetics/metabolism ; Oxidative Stress/drug effects ; Gene Expression Regulation/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; },
abstract = {Endometriosis is a chronic, multifactorial disorder. Reactive oxygen species (ROS) and oxidative stress (OS) contribute to the development of endometriosis by affecting apoptosis-related genes in granulosa cells. N-acetylcysteine (NAC) is an antioxidant that reduces OS. This randomized controlled trial aimed to investigate the effects of NAC on serum levels of superoxide dismutase (SOD) and total antioxidant capacity (TAC), as well as the expression of apoptotic genes in granulosa cells. Infertile women with endometriosis were enrolled and administered either NAC (1200 mg/day; n = 11) or placebo (n = 14). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum SOD and TAC levels. The expression of Bcl-2, Bax, and Caspase-3 genes in granulosa cells was evaluated by Real-Time Polymerase Chain Reaction. NAC treatment increased serum SOD and TAC levels. Additionally, the expression of pro-apoptotic genes Bax and Caspase-3 in granulosa cells decreased compared to the placebo group, while the expression of the anti-apoptotic gene Bcl-2 increased. We conclude that administration of N-acetylcysteine (NAC) can reduce apoptosis in granulosa cells of women with infertility due to endometriosis.},
}
@article {pmid41659018,
year = {2025},
author = {Spurrier-Best, L and Butcher, D and Blackham-Hayward, E and Kertesz, Z and Chichger, H},
title = {Nicotine-free electronic vape fluid stimulates angiogenic processes in vitro through ARF6-mediated oxidative stress.},
journal = {Frontiers in toxicology},
volume = {7},
number = {},
pages = {1699112},
pmid = {41659018},
issn = {2673-3080},
abstract = {INTRODUCTION: The increase in e-cigarette use in the population has led to substantial interest in the health impacts associated with e-cigarette smoking. E-cigarette smoking represents a key external environmental cell stressor. Whilst there have been several studies to investigate the effect of nicotine-containing e-cigarette fluid, there is still a significant lack of understanding of how nicotine-free e-cigarette smoking can impact individuals. However, preliminary studies indicate that nicotine-free e-cigarette smoking can cause impaired endothelial function in humans.<br><br>MATERIALS AND METHODS: In the present study, we therefore used a common brand of nicotine-free e-cigarette and human umbilical vein endothelial cells to assess angiogenic processes in vitro.<br><br>RESULTS: We observed a significant upregulation in endothelial cell adhesion, migration and new tube formation with exposure to nicotine-free e-cigarette condensate (eVape) which was abrogated with exposure to the antioxidant, N-acetyl cysteine. Proteome analysis demonstrated that eVape exposure increased expression of the pro-angiogenic factors, angiogpoeitin-2, endoglin (CD105), PIGF and VEGF, as well as the ADP ribosylation factor, ARF6, and ARF6-GEF, ARNO. Chemical inhibition of ARNO reduced eVape-induced oxidative stress, angiogenic processes, and release of angiogpoeitin-2, endoglin (CD105) and VEGF.<br><br>DISCUSSION: These findings demonstrate that nicotine-free eVape causes aberrant upregulated angiogenesis in an in vitro model of the human endothelium through ARNO-dependent signalling. This study is the first to demonstrate the molecular mechanisms in response to the cellular stressor, nicotine-free eVape which underlie impaired vascular function.},
}
@article {pmid41657721,
year = {2026},
author = {Peerapen, P and Putpeerawit, P and Boonmark, W and Thongboonkerd, V},
title = {Systematic evaluation and comparison of the in vitro inhibitory activities of dietary supplements against calcium oxalate crystal formation, growth and aggregation: Implications for kidney stone prevention.},
journal = {Current research in food science},
volume = {12},
number = {},
pages = {101326},
pmid = {41657721},
issn = {2665-9271},
abstract = {Kidney stone disease (KSD), particularly calcium oxalate (CaOx) type, remains a global health problem. Many efforts have been made to prevent KSD, including the use of some dietary supplements. However, mechanisms underlying their anti-KSD properties have remained poorly understood, and their relative anti-KSD properties have previously been unknown. Herein, we systematically evaluated and compared the inhibitory effects of five well-known dietary supplements on CaOx crystals. Caffeine (CAF), epigallocatechin-3-gallate (EGCG), N-acetylcysteine (NAC), resveratrol (RES) and trigonelline (TRIG) (at 1, 10 and 100 μM, which are within their physiologic levels in the urine) were subjected to CaOx crystallization, growth and aggregation assays. Degrees of their CaOx crystal-inhibitory activities were then compared. CAF inhibited crystal formation, EGCG inhibited crystal formation and growth, NAC inhibited crystal aggregation, RES inhibited crystal growth, and TRIG inhibited crystal formation and growth. However, RES promoted crystal aggregation and thus served as a dual modulator (acting as an inhibitor and promoter at different steps of stone formation). Almost all of these inhibitory effects were concentration-dependent. Comparing the CaOx-inhibitory activities of these compounds revealed that EGCG was the most potent inhibitor against CaOx crystal formation (with the crystal abundance-inhibitory activity of 85.61 ± 5.12 %), whereas RES was the most potent inhibitor against CaOx crystal growth (with the crystal growth-inhibitory activity of 92.99 ± 1.67 %). NAC was the only inhibitor against CaOx crystal aggregation (with the crystal aggregation-inhibitory activity of 22.97 ± 0.75 %). These data indicate the direct inhibitory effects of various dietary supplements against CaOx crystal formation, growth and aggregation, supporting their roles in KSD prevention.},
}
@article {pmid41654163,
year = {2026},
author = {Thakur, M and Mutyala, D and Amoliga, AA and Kondati, R and Batra, S},
title = {ROS-Driven Rewiring of Hippo-Inflammation-Polycomb Axis by PFOA in 2D and 3D Lung Epithelial Models.},
journal = {Toxicology},
volume = {},
number = {},
pages = {154426},
doi = {10.1016/j.tox.2026.154426},
pmid = {41654163},
issn = {1879-3185},
abstract = {Perfluorooctanoic acid (PFOA), a persistent organic pollutant and prominent member of the per- and polyfluoroalkyl substances (PFAS) family, continues to raise global concern due to its bioaccumulation and potential for chronic human exposure. While hepatic and systemic toxicities of PFOA are well documented, its effects on lung epithelial integrity, particularly at environmentally relevant concentrations, remain incompletely understood. In this study, we investigated the cellular and molecular responses to PFOA in human alveolar lung epithelial cells (A549) cultured under both 2D submerged monolayer and 3D air-liquid interface (ALI) conditions, representing systemic and barrier-relevant exposure models. Cells were exposed to 10-1000nM PFOA for 24h to assess changes in pro-inflammatory mediators, including transcription factors-NF-κB and STAT3, pattern recognition receptors (TLR4 and RAGE), cytokine/chemokine production (IL-6, IL-8, CCL2, CCL5), and damage-associated molecular patterns (HSP70, HMGB1). PFOA also appeared to trigger translational stress responses, including stress granule and P-body formation, along with alterations in Hippo signaling via YAP/TAZ overactivation. PFOA-challenged cells exhibited activation of Polycomb Repressive Complexes and associated silencing histone marks (H3K27me3, H2AK119Ub), along with HDACs and SIRT family members, indicative of a redox-driven Polycomb-mediated gene silencing program. Oxidative stress was identified as the central driver of epigenetic and Hippo pathway disruptions, as observed in cells pre-exposed to 1 mM N-acetylcysteine (NAC). Despite these molecular alterations, epithelial cell migration capacity remains unaffected under acute exposure. Our results provide key mechanistic insights into PFOA-mediated disruption of redox homeostasis, immune signaling, and epigenetic plasticity in A549 cells, as well as identifying biomarkers for future biomonitoring efforts and studying regulatory frameworks.},
}
@article {pmid41654007,
year = {2026},
author = {Dutta, D and Behera, A and Roy, D and Sukla, S and Banerjee, S},
title = {Mechanistic exploration of methylglyoxal-induced hepatotoxicity involving oxidative stress, apoptosis, and gluconeogenic modulation.},
journal = {Chemico-biological interactions},
volume = {428},
number = {},
pages = {111954},
doi = {10.1016/j.cbi.2026.111954},
pmid = {41654007},
issn = {1872-7786},
mesh = {*Pyruvaldehyde/toxicity ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; Humans ; Animals ; *Gluconeogenesis/drug effects ; Hep G2 Cells ; Reactive Oxygen Species/metabolism ; Mice, Inbred BALB C ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Liver/drug effects/metabolism/pathology ; Male ; Sirtuin 1/metabolism ; Acetylcysteine/pharmacology ; Chemical and Drug Induced Liver Injury/pathology/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Cell Survival/drug effects ; },
abstract = {Methylglyoxal (MG) is a precursor of advanced glycation end-products produced during glycolysis. MG accumulation is linked to various pathophysiological conditions through the production of reactive oxygen species (ROS). This investigation uncovers the mechanism of MG-induced hepatotoxicity in vitro and in vivo. We assessed MG's dose- and time-dependent cytotoxicity (0.001-10 μM) in HepG2 cells using the cell viability assay. We examined the protective effects of N-acetylcysteine (NAC) against MG toxicity using MTT reagent, monitoring ROS generation, apoptosis (via flow cytometry), and mitochondrial membrane potential (with JC1 dye staining). For the in vivo study, BALB/c mice received MG (290 mg/kg and 400 mg/kg) at 6 h and 14 h intervals to induce hepatotoxicity. We conducted liver histopathology and protein expression analysis for apoptotic markers (Bax, Bcl-2, and caspase-3) and gluconeogenesis regulators (SIRT1, PGC1α, and glucose 6-phosphatase or G6Pase) in both cell lines and liver tissues. MG caused significant dose- and time-dependent toxicity in HepG2 cells by promoting cell death, increasing ROS and apoptosis, and altering the mitochondrial membrane potential at 5 μM. NAC (5 and 10 mM) protected against MG-induced toxicity. In mice, MG led to elevated spleen and liver weight, aspartate transferase (AST), alanine transaminase (ALT), glucose, malondialdehyde, and decreased superoxide dismutase levels. MG upregulated pro-apoptotic and gluconeogenic proteins in HepG2 cells, while NAC significantly reduced their levels. MG also increased the expression of proteins involved in apoptosis and gluconeogenesis. MG-induced caspase-dependent hepatotoxicity was mediated by the production of ROS and the activation of gluconeogenesis via SIRT1-dependent PGC1α activation.},
}
@article {pmid41653207,
year = {2026},
author = {Zhang, M and Guan, C and Sheng, G and Ding, Z and Zhao, Y and Zhao, G and Li, W and Hu, Z and Peng, Y and Zheng, J},
title = {Pyrazinamide-induced hepatotoxicity mediated by aldehyde oxidase and xanthine oxidase.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {41653207},
issn = {1432-0738},
support = {ZK[2023]319//Guizhou Provincial Science and Technology Department/ ; },
abstract = {Pyrazinamide (PZA) has been approved for the treatment of tuberculosis in clinical practice. However, its adverse effects, particularly hepatotoxicity, have raised concerns. The present study aimed at exploring the potential relationship between PZA-induced hepatotoxicity and its metabolites resulting from metabolic activation. Glutathione (GSH) conjugates with confirmed structures were detected in mouse cytosol incubations containing PZA or pyrazinoic acid (POA, a major metabolite of PZA) supplemented with glutathione (GSH). Such GSH metabolites were also observed in both liver homogenates from mice administered with PZA and mouse primary hepatocytes exposed to PZA. Aldehyde oxidase (AO) and xanthine oxidase (XOD) were identified as key enzymes in the metabolic activation of PZA and POA. Both vitamin C (VC) and N-acetylcysteine (NAC) were found to reduce the generation of GSH conjugates derived from PZA and POA in incubation systems. Additionally, VC alleviated the susceptibility of hepatocytes to PZA-induced cytotoxicity. Consecutive administration of PZA for 7 days resulted in a marked elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice, and PZA-derived hepatic protein adduction was detected. Allopurinol administration attenuated the elevated serum ALT and AST in company with a reduction in the formation of GSH conjugates. This work provides solid evidence for the correlation between the metabolic activation of PZA and PZA-induced hepatotoxicity, enhancing the understanding of the underlying mechanisms of PZA toxicity in terms of molecular chemical structure.},
}
@article {pmid41642676,
year = {2026},
author = {Anandakrishnan, A and O'Halloran, A and Diamond, T},
title = {Successful Heat Stroke-Induced Pediatric Acute Liver Failure Treatment With N-Acetylcysteine Case Report.},
journal = {Critical care explorations},
volume = {8},
number = {2},
pages = {e1371},
pmid = {41642676},
issn = {2639-8028},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Heat Stroke/complications ; Male ; Child ; *Liver Failure, Acute/drug therapy/etiology ; *Free Radical Scavengers/therapeutic use ; },
abstract = {BACKGROUND: Previously healthy children are at risk of developing exertional heat stroke when experiencing extreme heat. Pediatric clinicians in primary care, emergency department, and critical care settings should be versed in the management of complications of exertional heat stroke. Pediatric acute liver failure (PALF) in the setting of heat stroke is rarely reported in published literature.<br><br>CASE SUMMARY: A 9-year-old male presented with heat stroke-induced PALF. He initially presented to an emergency department for altered mental status. During his clinical course, despite appropriate identification and initial treatment of exertional heat stroke, his symptoms progressed, including ongoing agitation, hepatic encephalopathy, coagulopathy, and severe transaminase elevation meeting clinical criteria for PALF.<br><br>CONCLUSIONS: He was treated with N-acetylcysteine (NAC) with resolution of his PALF without complications. In this article, we review the patient's clinical course, the rationale for treatment with NAC, and the management of heat stroke-induced PALF.},
}
@article {pmid41642111,
year = {2026},
author = {Dos Santos, IWR and Souza-Monteiro, D and Frazão, DR and da Silva, ZAL and de Moura, JDM and Cruz, JN and Collares, FM and de Souza-Rodrigues, RD and Cintra, LT&#xc2; and Lima, RR},
title = {N-Acetylcysteine Reduces Alveolar Bone Loss and Mitigates Systemic Oxidative Damage in Rats With Apical Periodontitis.},
journal = {International endodontic journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/iej.70108},
pmid = {41642111},
issn = {1365-2591},
support = {307747/2025-5//Cient&#xed;fico e Tecnol&#xf3;gico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 408329/2022-0//Cient&#xed;fico e Tecnol&#xf3;gico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 404431/2024-0//Cient&#xed;fico e Tecnol&#xf3;gico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 400706/2024-5//Cient&#xed;fico e Tecnol&#xf3;gico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 409576/2025-5//Cient&#xed;fico e Tecnol&#xf3;gico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 001//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior (CAPES, Brazil), Ministry of Education/ ; 406436/2022-3//National Institute of Science and Technology in 3D Printing and Advanced Materials Applied to Human and Veterinary Health/ ; },
abstract = {AIM: This study aimed to evaluate the effects of N-acetylcysteine (NAC) supplementation in apical periodontitis (AP) induced in rats.<br><br>METHODOLOGY: Eighteen male Wistar rats were randomly assigned to three groups: control, AP, and AP plus NAC. NAC was administered by oral gavage (100&#x2009;mg/kg/day), beginning 1 day after lesion induction and continued daily until the day preceding euthanasia. AP induction was performed by exposing the dental pulp of the lower first molars bilaterally, maintaining this condition for 28&#x2009;days. After this period, the animals were euthanized, and the following biological materials were collected: blood (for systemic oxidative stress analysis) and hemimandibles for histopathological and histochemical, and micro-computed tomography analyses, aiming to measure bone quality parameters and periapical volume. Statistical analyses were performed using one-way ANOVA and Tukey's post hoc test. In addition, correlation analyses and multivariate analyses of variance (MANOVA) were performed on the biochemical parameters.<br><br>RESULTS: The study results showed that animals supplemented with NAC had greater preservation of bone quality parameters and a reduction in periapical volume progression when compared to the only apical periodontitis group. Additionally, in the analysis of systemic oxidative stress, supplemented animals showed higher antioxidant parameter levels and lower oxidant levels compared to non-supplemented animals, which also showed reduced preservation of bone collagen content.<br><br>CONCLUSIONS: The study findings suggest that NAC supplementation promoted greater preservation of bone quality, reduced periapical volume development, and modulation of endogenous antioxidant and oxidant aspects. This indicates that NAC can decrease local and systemic damage caused by AP, highlighting its potential as an adjunctive agent in processes involving systemic oxidative stress and the preservation of biological structures.},
}
@article {pmid41637640,
year = {2026},
author = {Pandey, AM and Zhou, R and Singh, D and Li, F and He, M and Le, A and Herdrich, J and Chen, Y and Shah, R and Adusei-Poku, S and Rohlwing, NJ and Koo, J and Ong, ZY and Oldfield, E},
title = {Antifungal Activity of Lipophilic Bisphosphonates.},
journal = {ACS infectious diseases},
volume = {12},
number = {2},
pages = {766-780},
doi = {10.1021/acsinfecdis.5c00838},
pmid = {41637640},
issn = {2373-8227},
mesh = {*Antifungal Agents/pharmacology/chemistry ; *Diphosphonates/pharmacology/chemistry ; Humans ; Microbial Sensitivity Tests ; *Candida glabrata/drug effects/growth &amp; development ; Drug Resistance, Fungal ; Drug Synergism ; },
abstract = {We investigated the activity of a series of 75 lipophilic bisphosphonates against Candida glabrata. Thirty-six compounds had MIC < 1 μg/mL, 18 had MIC < 0.5 μg/mL, and 2 had MIC = 0.13 μg/mL, comparable to amphotericin B and caspofungin. The lipophilic bisphosphonates were ∼20-fold more potent against C. glabrata than the most potent hydrophilic bisphosphonate, zoledronate. The most active compounds were pyridinium bisphosphonates followed by imidazolium bisphosphonates, while aryl bisphosphonates were less active. Several compounds had selectivity index values against a human cell line in the 1000-3600 range, the most selective compounds being para-substituted pyridinium bisphosphonates. We also found similar activity against a caspofungin-resistant FKS2 (F659S) mutant. Some combinations of lipophilic bisphosphonates had synergistic activity with FICI values in the ∼0.3-0.5 range, and similar synergies were observed with fluconazole, implicating ergosterol biosynthesis inhibition leading to compromised membrane structure and function. Cell growth inhibition was rescued by ascorbic acid, glutathione, and N-acetyl cysteine, indicating a ROS-based killing mechanism. There was also synergy with other antifungals but very strong antagonism with verapamil (FICI ∼4), which blocks calcium channels. Unlike hydrophilic bisphosphonates, which target farnesyl diphosphate synthase, lipophilic bisphosphonates also target squalene synthase, suggesting that the combination of multitargeting bisphosphonates is one origin of the synergistic interactions observed. Given that one of the lipophilic bisphosphonates studied here (BPH-1237) has been shown to have activity against many other human fungal pathogens, combinations with the compounds described here may be of interest as antifungal leads.},
}
@article {pmid41632564,
year = {2026},
author = {Zhang, J and Yan, M and Tang, Y and Liu, M and Yao, W and Zhang, Q and Chen, H},
title = {A First-Aid Nanomedicine Endowed with Microenvironment Self-Adaptive Regulation Ability to Facilitate Acute Liver Failure Prophylaxis and Therapy.},
journal = {ACS nano},
volume = {20},
number = {6},
pages = {4989-5006},
doi = {10.1021/acsnano.5c18314},
pmid = {41632564},
issn = {1936-086X},
mesh = {Animals ; *Liver Failure, Acute/prevention &amp; control/drug therapy/metabolism/pathology ; *Nanomedicine ; Mice ; *Copper/chemistry/pharmacology/therapeutic use ; Macrophages/drug effects/metabolism ; Humans ; Oxidative Stress/drug effects ; *Sulfides/chemistry/pharmacology/therapeutic use ; *Nanoparticles/chemistry ; Male ; Mice, Inbred C57BL ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; },
abstract = {Acute liver failure (ALF) represents a life-threatening medical emergency with high mortality, yet limited treatment is available clinically. Here, we report albumin-biomineralized nonstoichiometric copper sulfide nanoparticles serving as first-aid nanomedicine to combat ALF, conceptualized as NanoAID. The NanoAID exhibits an electron-donor nanoantioxidant property to scavenge reactive oxygen species and concurrent anti-inflammatory capacity to reprogram pro-inflammatory M1 macrophages into anti-inflammatory M2-phenotype, thereby mitigating excessive oxidative and inflammatory stress in ALF lesions. More interestingly, we found Cu ions release under an in situ oxidative stress switch and the resulting H2S gas generation by NanoAID degradation, which further enhance the biosynthesis of intrahepatic antioxidant enzyme SOD1 and the repolarization of M1-to-M2 macrophages, respectively, thereby self-reinforcing ALF therapy. Such microenvironment self-adaptive regulation confers NanoAID with effective prophylactic efficacy and significant ALF survival advantages over the FDA-approved N-acetyl cysteine in multiple animal models, extending the first-aid window to 6 h post APAP intoxication. Transcriptomics results reveal the molecular mechanisms of NanoAID by promoting antioxidative and inhibiting inflammatory pathways, underscoring its great potential as a next-generation first-aid nanomedicine for ALF management.},
}
@article {pmid41630014,
year = {2026},
author = {Ali̇hossei̇ni̇, H and Çolakoğlu, E&#xc7; and Haydardedeoğlu, AE and Özen, D},
title = {N-acetylcysteine reduces serum creatinine, blood urea nitrogen, symmetric dimethylarginine and urine protein to creatinine ratio in cats with chronic kidney disease: a double-blind, placebo-controlled clinical trial.},
journal = {BMC veterinary research},
volume = {22},
number = {1},
pages = {},
pmid = {41630014},
issn = {1746-6148},
abstract = {BACKGROUND: Oxidative stress is considered a significant contributing factor of chronic kidney disease (CKD). To date, there is a paucity of clinical data in the literature regarding the effect of N-Acetylcysteine (NAC) in cats with naturally developing CKD. The aim of the study is to evaluate whether the addition of NAC in the treatment of cats with acute exacerbations of CKD could improve kidney function biomarkers over the use of intravenous fluid therapy alone.<br><br>METHODS: A total of 50 client-owned cats were included in the study. The inclusion criteria comprised cats previously diagnosed with azotemic CKD (IRIS stage 2-4) in addition to ultrasonographic evidence of bilaterally decreased renal mass, rough surface contours, and alteration of renal cortical echogenicity. All cats were examined using standard clinical procedures, including clinical examination, blood analyses, abdominal ultrasonography, dipstick urinalysis and urine culture. Computer-generated randomisation was utilised to assign the cats into the following groups: NAC (n:40): N-acetylcysteine (70&#xa0;mg/kg, diluted in 50&#xa0;ml 0.9% saline solution, administered intravenously over a period of seven days, and a placebo group (n:10) 50&#xa0;ml 0.9% saline solution, IV for 7 days. Blood analyses and dipstick urinalysis were repeated on the eighth day of treatment. Between-group differences in baseline age and weight were assessed using the Student's t-test, while sex distribution was evaluated with the Fisher's exact test. Treatment effects across time were analysed using a two-way mixed-design ANOVA, with "Group" and "Time" entered as fixed factors and their interaction term included in the model.<br><br>RESULTS: SDMA and creatinine concentrations decreased significantly in both groups, but the concentrations of both were significantly lower in the NAC group after treatment (Day 8 values: SDMA NAC 16.5&#x2009;&#xb1;&#x2009;1.21&#xa0;&#xb5;g/dl versus placebo 27&#x2009;&#xb1;&#x2009;3.89&#xa0;&#xb5;g/dl; P&#x2009;=&#x2009;0.04 and Creatinine NAC 4.01&#x2009;&#xb1;&#x2009;0.25&#xa0;mg/dl versus placebo 6.44&#x2009;&#xb1;&#x2009;0.9&#xa0;mg/dl; P&#x2009;<&#x2009;0.001). UPC and BUN decreased significantly in the NAC group, but no change was observed in the placebo group.<br><br>CONCLUSION: The incorporation of NAC into treatment regimens demonstrates potential as a treatment strategy for cats with acute-on-chronic kidney disease.},
}
@article {pmid41624281,
year = {2025},
author = {Pas, D and Oltmanns, H and Meißner, J},
title = {In vitro characterization of antimicrobial efficacy and cytotoxicity of polyvinylpyrrolidone-iodine, N-acetylcysteine, methylglyoxal, and N-chlorotaurine as alternative antimicrobials in treating bovine clinical endometritis.},
journal = {Frontiers in veterinary science},
volume = {12},
number = {},
pages = {1699857},
pmid = {41624281},
issn = {2297-1769},
abstract = {Bovine clinical endometritis (CE) is a common indication for antibiotic use in dairy cows. The increase in bacterial resistance and the aspired decrease in antibiotic use under the One Health concept call for alternatives in treatment. Polyvinylpyrrolidone-iodine (PVP), N-acetylcysteine (NAC), methylglyoxal (MGO), and N-chlorotaurine (NCT) are known substances with antibacterial properties that could potentially serve as those alternatives. In a broth microdilution assay, their efficacy against the common cause of endometritis, Trueperella pyogenes, was investigated. By cytotoxicity testing on a primary bovine endometrial epithelial cell culture, potential adverse effects on cell proliferation, viability, and immune response (IL-6) were examined. While all four substances had an antibacterial effect on T. pyogenes, PVP, MGO, and NCT also showed cytotoxic effects. In contrast, NAC was tolerated well by the cells. In sum, the four tested substances can be considered potential alternatives to antibiotic treatments. Further research is, however, necessary to investigate their toxic effects in ex vivo or in vivo models and to identify effective dosages in animals.},
}
@article {pmid41620910,
year = {2026},
author = {Bai, X and Luo, Y and Huang, J and Liu, G},
title = {Effect of linezolid combined with N-acetylcysteine on lung function, blood gas and inflammation in patients with severe pneumonia.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {3},
pages = {803-808},
doi = {10.36721/PJPS.2026.39.3.REG.13264.1},
pmid = {41620910},
issn = {1011-601X},
mesh = {Humans ; *Linezolid/therapeutic use/adverse effects ; *Acetylcysteine/therapeutic use/adverse effects ; Male ; Female ; Middle Aged ; *Pneumonia/drug therapy/physiopathology/blood ; Blood Gas Analysis ; *Anti-Bacterial Agents/therapeutic use/adverse effects ; Aged ; Drug Therapy, Combination ; *Lung/drug effects/physiopathology ; Adult ; Treatment Outcome ; Respiratory Function Tests ; Inflammation/drug therapy ; C-Reactive Protein/metabolism ; },
abstract = {BACKGROUND: Severe pneumonia is a serious lung disease. The continuous and regular administration of antibiotics is currently used for severe pneumonia. However, the single antibiotic may enhance the drug resistance and the overall efficacy is not ideal.<br><br>OBJECTIVES: This study aimed to investigate the efficacy and safety of linezolid combined with N-acetylcysteine (NAC) on lung function, blood gas and inflammation in patients with severe pneumonia.<br><br>METHODS: Eighty-four severe pneumonia patients were divided into linezolid group and linezolid +NAC group, which received the treatment using linezolid and linezolid combined with NAC for ten days, respectively. The total treatment efficacy was assessed. Before and after treatment, the pulmonary function indexes, blood gas indexes inflammatory response indexes were determined.<br><br>RESULTS: Compared with linezolid group, in linezolid +NAC group the disappearance time of cough, sputum and lung rales were shortened, the total effective rate, peak expiratory flow, forced expiratory volume in one second/forced vital capacity, arterial oxygen partial pressure and blood oxygen saturation were increased, the arterial carbon dioxide partial pressure and serum tumor necrosis factor &#x3b1;, interleukin 6 and hypersensitive C-reactive protein levels were decreased (all P < 0.05).<br><br>CONCLUSION: In treating severe pneumonia, linezolid combined with NAC can significantly improve the lung function of patients, improve the blood gas indicators and reduce the inflammatory response, thus alleviating the clinical symptoms.},
}
@article {pmid41619526,
year = {2026},
author = {Monti, DA and Zabrecky, G and Kremens, D and Liang, TW and Wintering, NA and Vedaei, F and Navarreto, E and Gupta, M and Steinmetz, A and Bazzan, AJ and Mohammed, F and Newberg, AB},
title = {N-Acetylcysteine is associated with changes in functional connectivity in patients with Parkinson's disease.},
journal = {Parkinsonism &amp; related disorders},
volume = {144},
number = {},
pages = {108216},
doi = {10.1016/j.parkreldis.2026.108216},
pmid = {41619526},
issn = {1873-5126},
abstract = {INTRODUCTION: This study assessed the changes in functional connectivity from resting functional magnetic resonance imaging (fMRI) in patients with Parkinson's disease (PD) given N-Acetylcysteine (NAC), the prodrug to L-cysteine and a precursor to the natural biological antioxidant glutathione (GSH). The aim of this study was to determine whether NAC is associated with changes in functional connectivity, particularly in the basal ganglia, and improvements in Parkinson's symptoms.<br><br>METHODS: Forty-four patients with PD were randomized to either weekly intravenous infusions of NAC (50&#xa0;mg/kg) plus oral doses (500&#xa0;mg twice per day) for six months plus standard of care, or standard of care only. Participants received pre and post brain imaging with resting Blood Oxygen Level Dependent (BOLD) MRI to measure functional connectivity between key brain regions involved with PD. These findings were compared to changes in PD symptoms as measured by the Unified Parkinson's Disease Rating Scale (UPDRS).<br><br>RESULTS: There were significant differences in the NAC group compared to the control group in functional connectivity measures after NAC. Specifically, there was significantly different functional connectivity between basal ganglia structures and the precuneus, precentral gyrus, postcentral gyrus, and particularly the Rolandic operculum. Changes in the precuneus also correlated with changes in UPDRS scores.<br><br>CONCLUSION: The results suggest that NAC may positively affect brain functional connectivity in PD patients, with corresponding positive clinical effects. Larger scale studies are warranted.},
}
@article {pmid41617440,
year = {2026},
author = {Choi, SH and Seo, J and Jeong, SM},
title = {Splicing Factor SF3B4 Suppresses Pancreatic Cancer Growth and Migration by Inhibiting Autophagy.},
journal = {Anticancer research},
volume = {46},
number = {2},
pages = {737-747},
doi = {10.21873/anticanres.17983},
pmid = {41617440},
issn = {1791-7530},
mesh = {Humans ; *Autophagy/drug effects ; *RNA Splicing Factors/metabolism/genetics ; Cell Movement/drug effects ; *Pancreatic Neoplasms/pathology/genetics/metabolism/drug therapy ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Fluorouracil/pharmacology ; *Carcinoma, Pancreatic Ductal/pathology/genetics/metabolism/drug therapy ; Apoptosis/drug effects ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; },
abstract = {BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, characterized by aggressive progression, profound chemoresistance and unique metabolic adaptations such as elevated autophagy. Although the splicing factor SF3B4 has been reported to function as an oncogene in other malignancies, its role in PDAC remains unclear. This study aimed to elucidate the functional and mechanistic significance of SF3B4 in PDAC.<br><br>MATERIALS AND METHODS: SF3B4 expression in PDAC was analyzed using patient datasets and experimental models. Functional assays including cell proliferation, colony formation, migration, and autophagy analyses were performed in PDAC cells. Reactive oxygen species (ROS) levels were evaluated. Sensitivity to 5-fluorouracil (5-FU) and apoptotic responses were also evaluated.<br><br>RESULTS: SF3B4 acts as a tumor suppressor in PDAC by inhibiting autophagy, a process that this cancer uniquely depends on for survival. SF3B4 overexpression inhibited proliferation, colony formation and migration of PDAC cells. Mechanistically, SF3B4 suppressed autophagic flux, resulting in increased ROS accumulation and subsequent inhibition of tumorigenic phenotypes. Treatment with the antioxidant N-acetylcysteine (NAC) rescued the tumor suppressive effects of SF3B4 overexpression. Moreover, SF3B4 overexpression sensitized PDAC cells to 5-FU, accompanied by enhanced apoptotic responses.<br><br>CONCLUSION: SF3B4 is a context-dependent splicing factor that functions as a tumor suppressor in PDAC by regulating autophagy and redox homeostasis. Targeting the SF3B4-autophagy-ROS axis may represent a promising strategy to suppress PDAC progression and overcome chemoresistance.},
}
@article {pmid41616897,
year = {2026},
author = {Shirpoor, A and Zarrini, Z and Naderi, R},
title = {N-acetyl-cysteine alleviates nandrolone decanoate-induced hippocampal cell apoptosis in rats via reversing protein expressions of S1P1, Akt and FOXO3a signaling pathway.},
journal = {Steroids},
volume = {228},
number = {},
pages = {109759},
doi = {10.1016/j.steroids.2026.109759},
pmid = {41616897},
issn = {1878-5867},
mesh = {Animals ; *Hippocampus/drug effects/cytology/metabolism ; *Apoptosis/drug effects ; Male ; *Forkhead Box Protein O3/metabolism ; Rats, Wistar ; *Signal Transduction/drug effects ; Rats ; *Proto-Oncogene Proteins c-akt/metabolism ; Nandrolone Decanoate ; *Acetylcysteine/pharmacology ; *Nandrolone/analogs &amp; derivatives/pharmacology ; },
abstract = {Illicit use of nandrolone can result in apoptosis in the hippocampus tissue but the underlying mechanism is unknown. The present study evaluated the role of S1P1/Akt/FOXO3a pathway in hippocampus cell apoptosis following exposure to nandrolone decanoate either alone or in combination with N-acetyl-cysteine. Twenty-four male Wistar rats were randomly divided into three groups (n = 8): control, nandrolone (10 mg/kg; intramuscularly; three times per week), and nandrolone + N-acetyl-cysteine (150 mg/kg; intraperitoneally). After six weeks of treatment, the number of apoptotic cells was significantly increased in the nandrolone treated group compared with the control group. Compared to control group, nandrolone group showed significant upregulation of NOX2, iNOS, 8-OHdG, P-FOXO3a/FOXO3a and lactate dehydrogenase (LDH) protein expression in rat hippocampus cells. Conversely, the protein expressions of P-Akt/Akt and S1P1 were significantly downregulated in hippocampus tissue of rats treated with nandrolone compared with control rats. Co-administration of N-acetyl-cysteine with nandrolone significantly reduced the apoptotic index and reversed the expressions of S1P1, P-Akt/Akt and P-FOXO3a/FOXO3a in the hippocampus neurons compared with the nandrolone group. These findings suggest that S1P1/Akt/FOXO3a signaling pathway may at least in part play an important role in the progression of apoptosis induced by nandrolone exposure, providing new insights into the pathogenesis and potential treatment of nandrolone-induced hippocampal damage.},
}
@article {pmid41613139,
year = {2025},
author = {Gao, W and Lin, Z and Bao, Y and Liu, M and Ma, G and Chen, X and Yu, S and Zeng, Y},
title = {A stage specific NETs-related signature in alcoholic steatohepatitis: from molecular subtyping to therapeutic vulnerabilities.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1711388},
pmid = {41613139},
issn = {1664-3224},
mesh = {Humans ; *Fatty Liver, Alcoholic/genetics/immunology/diagnosis/metabolism/drug therapy ; Animals ; Mice ; Matrix Metalloproteinase 7/genetics/metabolism ; *Neutrophils/immunology/metabolism ; Gene Expression Profiling ; Proto-Oncogene Proteins c-fos/genetics/metabolism ; Male ; Transcriptome ; Gene Regulatory Networks ; Molecular Docking Simulation ; },
abstract = {BACKGROUND: Alcohol-associated steatohepatitis (ASH) is a globally prevalent liver disease, with robust evidence implicating neutrophil extracellular traps (NETs) as a central pathological phenomenon driving inflammation and progression. However, the core genomic signatures that govern NETs and underlying molecular mechanisms within the ASH microenvironment remain poorly defined.<br><br>METHODS: Building on the prominent NETs formation phenomenon in ASH, we established a core pool of NETs-related hub genes through intersection of ASH-derived differentially expressed genes (DEGs), key WGCNA modules, and a curated NETs gene set. From this NET-focused pool, a consensus of three machine learning algorithms (LASSO, SVM, RF) distilled a final diagnostic signature, which was rigorously validated in training and external cohorts via ROC analysis and neural networks. Patient heterogeneity was then investigated using consensus clustering with this signature, followed by immune profiling and functional validation in human and mouse ASH models. Therapeutic potential was explored through drug database enrichment and molecular docking.<br><br>RESULTS: A NETs-focused three-gene signature (FOS, MMP7, CXCL6) achieved exceptional diagnostic accuracy for ASH (AUC = 1.00 in training; 0.983 in validation). It stratified ASH into a Metabolic-dominant (C1) subtype and a Pro-inflammatory (C2) subtype, the latter exhibiting higher MMP7/CXCL6, lower FOS, and enriched cytotoxic infiltration. In vivo, FOS rose in acute injury but declined in chronic models and human ASH, whereas MMP7/CXCL6 remained elevated, suggesting a temporal shift from acute FOS-dominant response to sustained MMP7/CXCL6-mediated inflammation. Finally, drug-gene interaction analysis identified several potential therapeutic modulators, including N-acetylcysteine (NAC), with predicted high binding affinities to FOS and MMP7.<br><br>CONCLUSION: FOS, MMP7, and CXCL6 constitute a clinically actionable signature capturing the stage-specific dynamics of NETs-driven inflammation in ASH. Beyond its diagnostic and stratifying utility, this signature highlights potential therapeutic avenues for clinical intervention.},
}
@article {pmid41607252,
year = {2026},
author = {Huang, R and Wu, Y and Liu, X and Zou, L and Li, J and He, J and Yang, L and Yang, X},
title = {Sulfur-Fumigation Engineered Ceria Nanoparticles With Augmented Oxygen Vacancies for Enhanced Therapy of Drug-Induced Liver Injury.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e13609},
doi = {10.1002/smll.202513609},
pmid = {41607252},
issn = {1613-6829},
support = {CSTB2024NSCQ-MSX0554//Natural Science Foundation of Chongqing/ ; },
abstract = {The excessive generation of reactive oxygen species (ROS) and its synergistic interplay with inflammation and apoptosis play a critical role in the progression of drug-induced liver injury (DILI). Ceria nanoparticles are potential DILI therapy candidates due to their self-renewable ROS scavenging activity. However, the clinical translation of ceria nanoparticles for DILI therapy is challenged by enhanced ROS scavenging activity and prolonged hepatic retention. Herein, the sulfur-fumigation approach is used to modulate the ROS scavenging activity of ceria nanoparticles through the surface microstructure reconfiguration mechanism. The sulfur-fumigation induces nanoparticle contraction and crystalline fusion. Crucially, sulfur-fumigation decreases (111) plane exposure but increases (200) and (220) plane exposure. These changes cause the generation of abundant oxygen vacancies, which significantly enhances the ROS scavenging activity of ceria nanoparticles, even when the surface area is decreased. Together with an appropriate hydrodynamic diameter (135.9 nm) for liver targeting, the sulfur-fumigated ceria nanoparticles can easily accumulate in the liver and alleviate ROS, inflammation, and apoptosis in DILI mice. Compared to the clinical standard N-acetylcysteine (NAC), the sulfur-fumigated ceria nanoparticles show better therapeutic efficacy across most of the detected parameters. These findings suggest that sulfur-fumigation is a potent surface reconfiguration strategy to engineer highly active ceria nanoparticles for DILI therapy.},
}
@article {pmid41606955,
year = {2026},
author = {Wang, C and Zhang, H and Guan, C and Li, Y and Yang, S and Huang, L},
title = {Glutamine transporter SLC1A5 inhibits autophagy-mediated CD276 degradation to promote esophageal cancer progression.},
journal = {Cancer biology &amp; therapy},
volume = {27},
number = {1},
pages = {2621606},
pmid = {41606955},
issn = {1555-8576},
mesh = {Humans ; Animals ; *Amino Acid Transport System ASC/metabolism/genetics/antagonists &amp; inhibitors ; Mice ; *Esophageal Neoplasms/pathology/metabolism/genetics ; *Autophagy ; *Minor Histocompatibility Antigens/metabolism/genetics ; Cell Proliferation ; Disease Progression ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Female ; Xenograft Model Antitumor Assays ; Male ; Glutamine/metabolism ; Mice, SCID ; Mice, Inbred NOD ; Proteolysis ; },
abstract = {BACKGROUND: CD276/B7-H3 is an immune checkpoint molecule often overexpressed in cancers, representing a potential therapeutic target. The underlying mechanisms for CD276 upregulation remain unclear. This study investigates how glutamine metabolism affects CD276 protein stability and esophageal squamous cell carcinoma (ESCC) progression.<br><br>METHODS: CD276 and SLC1A5 expression were analyzed in 90 ESCC clinical tissues and TCGA/GEO datasets. CCK-8, colony formation, wound healing and transwell assays were performed in KYSE150 and KYSE450 cells. Autophagy was quantified by immunofluorescence and western blot. Mitochondrial reactive oxygen species (ROS) levels measured by flow cytometry. Rescue experiments used N-acetylcysteine (NAC) and chloroquine (CQ). Finally, antitumor effects of SLC1A5 inhibitor V9302 in the presence or absence of CD276 were evaluated in NOD/SCID mice (n&#x2009;=&#x2009;5 per group) bearing KYSE150 xenografts.<br><br>RESULTS: CD276 and SLC1A5 upregulated in ESCC tissues (P&#x2009;<&#x2009;0.05). CD276 overexpression enhanced ESCC cell proliferation and migration by 42.3% and 58.7%, respectively (P&#x2009;<&#x2009;0.01). CQ but not MG-132 increased CD276 expression in ESCC cells. SLC1A5 stabilized CD276 protein without altering CD276 mRNA levels, by suppressing ROS-dependent autophagic degradation. NAC reversed ROS-induced CD276 degradation, while CQ abrogated CD276 downregulation upon glutamine metabolism inhibition. Inhibiting glutamine metabolism could reverse ESCC cell proliferation induced by CD276 overexpression. Moreover, combination of V9302 and CD276 knockout significantly reduced KYSE150 cell-derived xenograft tumor volume by 65.2% (95% CI 58.3-72.1%, P&#x2009;<&#x2009;0.001) in NOD/SCID mice, without affecting mouse body weight (P&#x2009;>&#x2009;0.05).<br><br>CONCLUSION: SLC1A5 enhances CD276 stability by suppressing ROS-autophagy signaling, promoting ESCC progression. Targeting glutamine metabolism to enhance CD276 degradation might be a novel therapeutic strategy for ESCC.},
}
@article {pmid41603285,
year = {2026},
author = {Karimi-Dehkordi, M and Saghaei, F and Saberian, M and Nejad, HS and Sohrabi, F and Zabihi, N},
title = {Feselol Ameliorates Acetaminophen-Induced Hepatotoxicity Through Multi-Pathway Modulation of Oxidative Stress, Inflammation, and Apoptosis in Mice.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {2},
pages = {e70710},
doi = {10.1002/jbt.70710},
pmid = {41603285},
issn = {1099-0461},
mesh = {Animals ; *Acetaminophen/adverse effects/toxicity ; *Oxidative Stress/drug effects ; Mice ; *Apoptosis/drug effects ; *Chemical and Drug Induced Liver Injury/metabolism/pathology/drug therapy/prevention &amp; control ; Male ; *Inflammation/drug therapy/metabolism/chemically induced/pathology ; Liver/metabolism/pathology/drug effects ; },
abstract = {BACKGROUND AND AIM: Acetaminophen (APAP) overdose is a major cause of drug-related acute liver failure around the world. The limited treatment options beyond N-acetylcysteine (NAC) show a clear need for new liver-protective agents. Feselol, a natural compound known for its strong antioxidant effects, has become a potential candidate. This research aimed to evaluate feselol's anti-inflammatory, anti-apoptotic, and protective qualities against APAP-induced acute liver damage in a mouse model.<br><br>MATERIAL AND METHOD: The experiment included 42 mice divided into 7 groups, with some being administered a toxic dose of APAP only and others being given APAP in combination with 25 or 50&#x2009;mg/kg of feselol. Serum levels of AST (serum aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase), and GGT (gamma-glutamyl transferase) were examined. SOD (superoxide dismutase), CAT (catalase), GPx (glutathione peroxidase) activities and MDA (malondialdehyde) levels were measured by colorimetric method. The liver tissue was analyzed through H&amp;E staining. The expression of IL-1&#x3b2;, TNF-&#x3b1;, Bax, Caspase 3, and Bcl-2 genes was also examined by Real-time PCR.<br><br>RESULTS: The results showed that treatment of feselol at different doses with APAP led to a decrease in MDA levels to 23.25 nmol/mg (p&#x2009;<&#x2009;0.05). Also, the activities of SOD, CAT and GPx enzymes in the group treated with a dose of 50&#x2009;mg/kg of feselol with APAP were 33.09, 109.86, and 109.80, respectively, which was significant compared to the APAP group (p&#x2009;<&#x2009;0.05). The results showed that simultaneous treatment with feselol and APAP resulted in a decrease in IL-1&#x3b2; and TNF-&#x3b1; gene expression by 1.67 and 1.015 fold, respectively (p&#x2009;<&#x2009;0.05). Also, the expression of Bax (3.22-fold) and Caspase 3 (1.26-fold) genes decreased in the feselol-treated group and the expression of Bcl-2 (0.59-fold) gene increased. In the group that received APAP and feselol, the liver tissue was close to that of the control group. Feselol (50&#x2009;mg/kg) coadministered with APAP significantly reduced ALT, AST, ALP, and GGP enzyme activity compared to the APAP-treated group (p&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: This study is notable for the discovery of feselol's pharmacological effects as a preventive drug against oxidative stress-associated hepatic impairment.},
}
@article {pmid41602262,
year = {2025},
author = {Zacharia, GS and Ravte, V and Jyala, A and Shehi, E},
title = {Complementary and Alternative Medicine-Induced Combined Hepatorenal Toxicity: A Case Report.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e100197},
pmid = {41602262},
issn = {2168-8184},
abstract = {Drug-induced liver injury (DILI) is a leading cause of liver disease globally, with complementary and alternative medicine (CAM) representing a significant contributor due to its widespread use and limited regulation. CAM encompasses diverse practices and products, with regional and ethnic diversity, many of which are used to treat liver disease. Even though a few natural remedies have been utilized for centuries, most lack scientific evidence for their safety and efficacy. This report describes a 42-year-old male who self-treated his fatty liver with CAM, culminating in severe concomitant hepatic and renal dysfunctions. Comprehensive evaluation excluded viral, autoimmune, metabolic liver diseases, and obstructive biliary diseases. The Roussel Uclaf Causality Assessment Method (RUCAM) score indicated a probable causal link between CAM and DILI of hepatocellular pattern. The constituents of the CAM, extracts of Carica papaya, Alstonia boonei, and Tetrapleura tetraptera, have been implicated in hepatotoxicity in animal models. Discontinuing the supplements and supportive care, including N-acetyl cysteine, led to symptomatic and biochemical improvement. This case highlights the importance of clinicians' awareness of CAM-related DILI, emphasizing the need for vigilance and patient education about the potential risks associated with herbal products.},
}
@article {pmid41602127,
year = {2025},
author = {Zeng, Q and Sun, Y and Lei, M and Liu, Z and Yan, X and Li, R and Zheng, J and Zha, J and Zhang, L and Guan, X and Yao, J},
title = {Nicotinic acid protects against hepatic ischemia-reperfusion injury via suppressing mitochondrial damage-induced ferroptosis.},
journal = {Liver research (Beijing, China)},
volume = {9},
number = {4},
pages = {324-337},
pmid = {41602127},
issn = {2542-5684},
abstract = {BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (HIRI) is a major contributor to liver dysfunction and failure, particularly in the context of liver transplantation. Its pathogenesis is primarily driven by ferroptosis, oxidative stress, and mitochondrial dysfunction. Given the interplay among these mechanisms through redox imbalance and disrupted energy metabolism, nicotinic acid (NA)-recognized for its antioxidative and metabolic regulatory properties-emerges as a promising therapeutic candidate. This study aims to investigate the protective effects of NA on HIRI and elucidate its underlying mechanisms.<br><br>METHODS: An HIRI model in mice and a hypoxia/reoxygenation (H/R) model in primary hepatocytes were established to evaluate the effects of NA treatment on oxidative stress. NA was administered prior to model induction. N-acetylcysteine (NAC) was used as a comparator. Comprehensive assessments of ferroptosis, oxidative stress, mitophagy, and mitochondrial biogenesis markers were conducted using Western blotting, immunohistochemistry, immunofluorescence, and biochemical assays.<br><br>RESULTS: NA pretreatment reduced serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase (LDH) levels, suppressed inflammation by decreasing neutrophil infiltration and macrophage activation, and mitigated oxidative stress by lowering reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It enhanced antioxidant defenses, inhibited ferroptosis, and improved mitochondrial health through increased mitophagy, mitochondrial biogenesis, and mitochondrial permeability transition pore (mPTP) stabilization, leading to enhanced ATP production and mitochondrial function in HIRI.<br><br>CONCLUSIONS: NA improves mitochondrial function by promoting mitophagy and mitochondrial biogenesis, which reduces ferroptosis and oxidative stress, thereby alleviating HIRI.},
}
@article {pmid41601049,
year = {2026},
author = {Firouzjaei, Y and Hajizadeh Moghaddam, A and Sohabatzadeh, F and Khanjani Jelodar, S and Farhadi, M},
title = {Neuroprotective effects of plasma-activated N-acetylcysteine against streptozotocin-induced behavioral deficits in rats: Attenuation of oxidative stress and cholinergic dysfunction.},
journal = {Ecotoxicology and environmental safety},
volume = {309},
number = {},
pages = {119619},
doi = {10.1016/j.ecoenv.2025.119619},
pmid = {41601049},
issn = {1090-2414},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Male ; *Oxidative Stress/drug effects ; Rats ; *Neuroprotective Agents/pharmacology ; Streptozocin/toxicity ; Behavior, Animal/drug effects ; *Cognitive Dysfunction/chemically induced/drug therapy ; Plasma Gases ; },
abstract = {N-Acetylcysteine (NAC), a thiol-containing antioxidant, has demonstrated neuroprotective potential in various neurological disorders. Recently, cold atmospheric plasma (CAP) technology has emerged as a promising approach for modifying the physicochemical properties of biomolecules. This study investigated the neuroprotective effects of plasma-activated N-acetylcysteine (PAN) in a rat model of intracerebroventricular streptozotocin (icv-STZ)-induced cognitive impairment, with particular emphasis on redox homeostasis and cholinergic function. The physicochemical properties of PAN were characterized using FTIR, LC-MS/MS, and DPPH assay. Male rats received a single icv-STZ injection (3 mg/kg) on day 0, followed by oral administration of NAC or PAN (50 mg/kg) every other day for three weeks. Cognitive performance and anxiety-like behaviors were assessed using the shuttle box, novel object recognition, and elevated plus maze tests. Subsequently, oxidative stress indices (TAC, GSH, SOD, CAT, MDA, NO), cholinergic markers (AChE activity, ACh levels), and the expression of AChE, α7 nAChR, Nrf2, Keap1 and BDNF genes were quantified in the hippocampus and cerebral cortex. FTIR and LC-MS/MS analyses revealed plasma-induced chemical modifications in NAC, resulting in the generation of novel compounds. The DPPH assay further demonstrated superior radical scavenging activity of PAN compared with NAC. Behaviorally, PAN administration significantly alleviated STZ-induced cognitive deficits and anxiety-like behaviors. Biochemically, PAN normalized TAC, GSH, MDA, NO, and ACh levels, increased CAT and SOD activities, and reduced AChE activity. At the transcriptional level, PAN upregulated α7 nAChR, Nrf2 and BDNF expression while downregulating AChE and Keap1. Collectively, these findings suggest that PAN mitigates behavioral impairments in the icv-STZ rat model of Alzheimer's disease, potentially through attenuation of oxidative stress and restoration of cholinergic neurotransmission.},
}
@article {pmid41597285,
year = {2026},
author = {Chung, YY and Kim, B and Lee, J and Kwak, S and Jung, M and Kim, YS and Baek, SK},
title = {Establishing a Non-Surgical Mouse Model of Laryngopharyngeal Reflux Disease: Acid-Induced Epithelial Disruption and Protective Role of N-Acetylcysteine.},
journal = {Cells},
volume = {15},
number = {2},
pages = {},
pmid = {41597285},
issn = {2073-4409},
support = {2021R1F1A1056645 (RS-2021-NR063002)//National Research Foundation of Korea/ ; 2023R1A2C1004538 (RS-2023-NR076554)//National Research Foundation of Korea/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Female ; Disease Models, Animal ; Mice, Inbred C57BL ; *Laryngopharyngeal Reflux/pathology/drug therapy/metabolism ; Mice ; Cadherins/metabolism ; Matrix Metalloproteinase 7/metabolism ; *Acids ; Epithelial Cells/drug effects/pathology/metabolism ; *Protective Agents/pharmacology ; },
abstract = {Laryngopharyngeal reflux disease (LPRD) results from the retrograde flow of gastric contents into the upper aerodigestive tract, causing epithelial injury. Progress in its management has been limited by the lack of objective biomarkers and reproducible in vivo models. This study aimed to establish a chronic, non-surgical mouse model of LPRD and to investigate the protective effect of N-acetylcysteine (NAC). Female C57BL/6 mice were randomly assigned to three groups: control (standard drinking water), study (acidified water, pH 3.0, for 12 weeks), and treatment (acidified water for 12 weeks plus NAC supplementation during the final 4 weeks). Body weight, food intake, and water consumption were monitored weekly. Pharyngeal tissues were analyzed by immunohistochemistry and Western blotting. Chronic acid exposure resulted in loss of membrane-localized E-cadherin, cytoplasmic redistribution, and upregulation of matrix metalloproteinase-7 (MMP-7). These molecular alterations were accompanied by enhanced phosphorylation of ERK and c-Jun, consistent with activation of the ROS-ERK-c-Jun signaling pathway. NAC supplementation was associated with partial restoration of E-cadherin, reduced MMP-7 expression, and attenuation of ERK/c-Jun phosphorylation. No systemic toxicity or weight loss was observed, indicating good tolerability of the model. This non-surgical ingestion-based model faithfully recapitulates key epithelial features of LPRD and provides a feasible platform for mechanistic investigation and exploratory therapeutic studies. NAC may exert protective effects against acid-induced epithelial injury in this model.},
}
@article {pmid41596085,
year = {2025},
author = {Chen, X and Gao, D and Wang, M and Wang, L and Hu, H and Wen, C and Tang, Y},
title = {Neutrophil Extracellular Traps in Systemic Lupus Erythematosus: Pathogenic Mechanisms, Crosstalk with Oxidative Stress, and Antioxidant Therapeutic Potential.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {1},
pages = {},
pmid = {41596085},
issn = {2076-3921},
support = {82305145//National Natural Science Foundation of China/ ; LQ23H270006//Zhejiang Provincial Natural Science Foundation of China/ ; },
abstract = {Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and the formation of immune complexes (ICs), which lead to widespread inflammation and tissue damage. Neutrophil extracellular traps (NETs), web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils, play a crucial role in innate immunity by defending against pathogens. However, excessive NET formation and ineffective clearance of these structures contribute to the development of SLE. This review explores the mechanisms behind NET formation in SLE, their relationship with oxidative stress, and the potential role of antioxidants in treatment. Research indicates that SLE patients exhibit two key abnormalities: excessive NET formation and impaired NET clearance. Excessive NET formation is driven by proinflammatory low-density granulocytes (LDGs) and immune complexes (ICs). Impaired NET clearance stems from reduced DNase1/DNase1L3 activity or anti-nuclease autoantibodies. These two abnormalities lead to elevated circulating NETs. These NETs act as autoantigen reservoirs, forming pathogenic NET-ICs that amplify autoimmune responses. Oxidative stress drives NET formation by activating NADPH oxidase. In contrast, various antioxidants, including enzymatic and non-enzymatic types, can inhibit NET formation via scavenging reactive oxygen species (ROS) and blocking NADPH oxidase activation. Preclinical studies show that antioxidants such as curcumin, resveratrol, and mitochondrial-targeted MitoQ reduce NET formation and ameliorate lupus nephritis; clinical trials confirm that curcumin and N-acetylcysteine (NAC) lower SLE disease activity and reduce proteinuria, supporting their role as safe adjuvant therapies. However, high-dose vitamin E may exacerbate autoimmunity, highlighting the need for dose optimization. Future research should aim to clarify the mechanisms underlying NET formation in SLE and to optimize new antioxidant therapies, including assessments of their long-term efficacy and safety.},
}
@article {pmid41595622,
year = {2025},
author = {Dinç, M and Bayrak, H&#xc7; and Karasu, R and Aykaç, B and Soydemir, &#xd6;C and Saricetin, A},
title = {Intra-Articular N-Acetylcysteine Reduces Synovitis Without Preventing Cartilage Degeneration in Experimental Osteoarthritis.},
journal = {Biomedicines},
volume = {14},
number = {1},
pages = {},
pmid = {41595622},
issn = {2227-9059},
abstract = {Background/Objectives: Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized by synovial inflammation, oxidative stress, and progressive cartilage degeneration. This study investigated whether intra-articular N-acetylcysteine (NAC) attenuates synovial inflammation and oxidative stress and whether these effects translate into structural cartilage protection. Methods: OA was induced in rats by anterior cruciate ligament transection (ACLT). NAC (5 mg/50 µL) was administered intra-articularly once weekly for three weeks post-ACLT. Inflammatory cytokines (IL-1β, IL-6, TNF-α), oxidative stress markers (iNOS, TAS, TOS, OSI), and cartilage degradation markers (MMP-13, COMP, CTX-II) were quantified in synovial fluid and cartilage homogenates using ELISA. Cartilage integrity was evaluated histologically using the modified Mankin scoring system. Results: Compared with controls, NAC significantly reduced synovial IL-1β, IL-6, TNF-α, MMP-13, and iNOS levels and improved the synovial redox profile by increasing TAS and reducing TOS and OSI (all p < 0.05). In contrast, NAC did not significantly alter cartilage homogenate levels of inflammatory cytokines, oxidative stress indices, or degradation markers (COMP, CTX-II, MMP-13). Histological analysis demonstrated persistent cartilage fissuring, hypocellularity, and proteoglycan loss in both groups (p > 0.05). Conclusions: Intra-articular NAC exerts potent anti-inflammatory and antioxidative effects within the synovial compartment but fails to prevent cartilage degeneration in the ACLT model. These findings indicate a compartment-specific therapeutic profile, suggesting that NAC may function as a symptom-modifying agent in synovitis-dominant OA rather than a structure-modifying therapy. Future studies should focus on optimized delivery systems or combination strategies targeting cartilage and subchondral bone to achieve disease modification.},
}
@article {pmid41593603,
year = {2026},
author = {Jiang, Y and Ma, P and Yang, Y and Shi, X and Liu, X and Sun, M},
title = {The Achilles' heel of hepatocellular carcinoma: ginsenoside compound K as a novel GPX4 degrader promotes ferroptosis in hepatocellular carcinoma.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {277},
pmid = {41593603},
issn = {1479-5876},
support = {20DZ2272200//Key Laboratory of Chronic Deficiency Liver Disease of the State Administration of Traditional Chinese Medicine of the People's Republic of China/ ; shslczdzk01201//Shanghai Key Specialty of Traditional Chinese Clinical Medicine/ ; zyyzdxk-2023060//National Administration of Traditional Chinese Medicine/ ; },
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) remains a major therapeutic challenge, highlighting the need for agents that engage non-apoptotic regulated cell death pathways. Ginsenoside compound K (CK), a bioactive metabolite derived from ginseng saponins, has demonstrated antitumor activity, however, its efficacy and underlying mechanisms in HCC are not well defined. Given the emerging role of ferroptosis in HCC, we investigated whether CK suppresses HCC by inducing this iron-dependent form of cell death.<br><br>METHODS: The antitumor effects of CK were evaluated in HepG2 and Hep3B cells and in a xenograft mouse model. Ferroptotic cell death was assessed by measuring reactive oxygen species (ROS), ferrous iron (Fe&#xb2;&#x207a;), malondialdehyde (MDA), and glutathione (GSH) levels, and by rescue experiments using ferroptosis inhibitors (N-acetylcysteine, NAC; Trolox) or GPX4 overexpression. Mechanistic studies were performed using RNA sequencing, ubiquitination assays, and genetic manipulation of OTUB2 expression.<br><br>RESULTS: CK inhibited HCC cell proliferation in a dose-dependent manner and robustly induced ferroptosis hallmarks, including ROS accumulation, enhanced lipid peroxidation, and GSH depletion. These cytotoxic effects were largely abrogated by ferroptosis inhibitors or GPX4 overexpression, confirming a ferroptosis-dependent mechanism. In vivo, CK significantly reduced tumor growth in xenograft models and recapitulated key ferroptosis features. Mechanistically, CK was identified as a functional inhibitor of the deubiquitinase OTUB2. Suppression of OTUB2 promoted ubiquitin-dependent degradation of GPX4, a central negative regulator of ferroptosis, thereby sensitizing HCC cells to ferroptosis.<br><br>CONCLUSIONS: Our findings identify CK as a novel OTUB2 inhibitor that induces ferroptosis in HCC by destabilizing GPX4. This work delineates a previously unrecognized OTUB2/GPX4 regulatory axis in ferroptosis and supports CK as a promising candidate for further translational development for HCC therapy.<br><br>GRAPHICAL ABSTRACT: [Image: see text]<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07587-9.},
}
@article {pmid41593161,
year = {2026},
author = {Ozhan, O and Ekici, C and Ates, B and Yildiz, A and Balcioglu, S and Vardi, N and Parlakpinar, H},
title = {N-acetyl cysteine amide mitigates oxidative stress and apoptosis in a rat model of renal ischemia-reperfusion injury.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {6323},
pmid = {41593161},
issn = {2045-2322},
support = {2209a//T&#xfc;rkiye Bilimsel ve Teknolojik Ara&#x15f;t&#x131;rma Kurumu/ ; },
abstract = {Renal ischemia–reperfusion (IR) injury is a major cause of acute kidney injury, in which oxidative stress (OS) and apoptosis play central roles. N-acetyl cysteine amide (NACA), a lipophilic derivative of N-acetylcysteine, exhibits improved cellular penetration and antioxidant activity. This study investigated the renoprotective effects of NACA in a rat model of renal IR injury. Twenty-eight female Wistar albino rats were randomized into four groups (n = 7): Control, IR, NACA + IR (100 mg/kg i.p., 30 min before ischemia), and IR + NACA (100 mg/kg i.p., immediately after ischemia). Following right nephrectomy, the left renal pedicle was clamped for 60 min and reperfused for 24 h. Serum renal function markers, kidney OS parameters, histopathological injury, and caspase-3 immunoreactivity were evaluated. Renal IR injury significantly increased serum blood urea nitrogen and creatinine levels and induced histopathological damage characterized by tubular dilatation, cast formation, and degeneration. Catalase (CAT) and superoxide dismutase (SOD) activities were significantly altered; malondialdehyde increased after IR and was reduced by NACA pretreatment, whereas myeloperoxidase and total glutathione did not differ significantly among groups. NACA pretreatment attenuated inflammatory cell infiltration, tubular dilatation, and caspase-3 immunoreactivity, while partially restoring CAT and SOD activity. Post-ischemic NACA administration was less effective, particularly in reducing apoptosis and inflammatory infiltration. NACA confers partial renoprotection against renal IR injury, with pretreatment providing superior efficacy. These findings highlight the importance of antioxidant timing and suggest NACA as a potential prophylactic strategy when renal ischemia is predictable.},
}
@article {pmid41593024,
year = {2026},
author = {Chen, Z and Zhang, X and Li, J and Feng, C and Xiong, Y and Yan, L},
title = {Facile Synthesis of Thioketal-Functionalized Poly(amino acid) Nanocarriers for ROS-Triggered Drug Release in Cancer Therapy.},
journal = {ACS macro letters},
volume = {15},
number = {2},
pages = {259-266},
doi = {10.1021/acsmacrolett.5c00731},
pmid = {41593024},
issn = {2161-1653},
mesh = {*Reactive Oxygen Species/metabolism ; Animals ; *Doxorubicin/chemistry/pharmacology/administration &amp; dosage/therapeutic use ; *Drug Carriers/chemistry/chemical synthesis ; Mice ; Drug Liberation ; Humans ; *Amino Acids/chemistry ; *Nanoparticles/chemistry ; *Polymers/chemistry/chemical synthesis ; Cell Line, Tumor ; *Antineoplastic Agents/chemistry ; Micelles ; Female ; Mice, Inbred BALB C ; Antibiotics, Antineoplastic/chemistry ; },
abstract = {Polymer nanocarriers offer significant advantages in antitumor drug delivery; however, achieving a balance between minimizing nonspecific drug release in blood circulation and maximizing specific intracellular drug release remains a critical challenge. To address this, this study developed a cross-linked poly(amino acid) nanocarrier sensitive to intracellular reactive oxygen species (ROS). A novel thioketal-functionalized, ROS-sensitive bicyclic amino acid N-carboxyanhydride (NCA) monomer was designed and synthesized, and ROS-responsive poly(amino acid)s were prepared via ring-opening polymerization. Polymeric nanomicelles loaded with doxorubicin (DOX) were successfully fabricated using a microemulsion method, and their ROS-responsive properties were systematically evaluated. In vitro release experiments demonstrated that the nanocarrier exhibited H2O2 concentration-dependent, ROS-triggered drug release characteristics. The oxidative response behavior of the drug-loaded nanomicelles was further validated in cellular and animal models by introducing the ROS scavenger N-acetylcysteine (NAC). In a 4T1 tumor-bearing mouse model, these drug-loaded nanomicelles showed enhanced tumor retention and superior tumor suppression compared to free DOX. This study demonstrates that thioketal-functionalized poly(amino acid) nanocarriers hold promise in balancing blood circulation stability and intracellular specific drug release, providing a novel design strategy for developing efficient and safe poly(amino acid)-based anticancer nanomedicines.},
}
@article {pmid41586115,
year = {2025},
author = {Jafarzadeh, E and Pashaei-Asl, R and Hakimi, P and Pashaiasl, M},
title = {The Effect of Letrozole and N-Acetylcysteine on the Expression Levels of Genes Involved in Glucose Metabolism in Patients with Polycystic Ovary Syndrome: A Clinical Trial Study.},
journal = {Journal of reproduction &amp; infertility},
volume = {26},
number = {2},
pages = {81-89},
pmid = {41586115},
issn = {2228-5482},
abstract = {BACKGROUND: N-acetylcysteine (NAC) is a supplement commonly used in patients with polycystic ovary syndrome (PCOS). The expansion of oocyte-associated cumulus cells (CCs) and the quality of the oocyte are critical factors influencing fertilization rates and clinical pregnancy outcomes in assisted reproductive techniques (ARTs). Genes such as phosphofructokinase (PFKP) and pyruvate kinase isoform M2 (PKM2) are involved in glucose metabolism and are crucial in the regulation of oocyte competence and developmental potential. The purpose of the current study was to evaluate the effects of letrozole and NAC on the expression of PFKP and PKM2 in CCs of PCOS patients undergoing ART.<br><br>METHODS: The study evaluated 20 PCOS women undergoing ART to assess the effect of letrozole and NAC on the expression levels of PKM2 and PFKP genes in cumulus cells. Women were randomly assigned using a simple randomization method into four groups: control, NAC, letrozole, and NAC plus letrozole, with five women in each group. Gene expression levels of PKM2 and PFKP were measured using real-time PCR.<br><br>RESULTS: The expression level of PKM2 was significantly higher in the letrozole plus NAC group compared to the control group (p<0.05). In NAC group, PFKP was significantly expressed compared to the control group (p<0.05). There were no significant differences among the other groups compared to the control group.<br><br>CONCLUSION: NAC can improve the quality of oocytes by increasing the expression level of genes involved in the glucose metabolism (PKM2, PFKP) of CCs, thereby potentially improving ART success rate in PCOS patients. Therefore, administering NAC along with letrozole can have a synergistic effect on increasing the expression level of genes associated with blastocyst quality in PCOS patients.},
}
@article {pmid41582130,
year = {2026},
author = {Li, C and Yuan, Y and Bao, Y and Ni, Y and Chen, N and Piao, J and Wang, L and Zhu, Z},
title = {Synergistic regulation of TGF-β1/Smad2/3 signaling and inflammatory pathways via SA/NAC-based nanoplatforms: a novel strategy to enhance anti-fibrotic therapeutic outcomes in idiopathic pulmonary fibrosis.},
journal = {Journal of nanobiotechnology},
volume = {24},
number = {1},
pages = {173},
pmid = {41582130},
issn = {1477-3155},
support = {LQ20H270014//National Natural Science Foundation of Zhejiang Province/ ; LY23H280010//Zhejiang Provincial Natural Science Foundation of China/ ; 2023JKZKTS23//Research Project of Zhejiang Chinese Medical University/ ; },
mesh = {Animals ; *Transforming Growth Factor beta1/metabolism ; *Idiopathic Pulmonary Fibrosis/drug therapy/metabolism ; Mice ; Signal Transduction/drug effects ; *Smad2 Protein/metabolism ; Smad3 Protein/metabolism ; *Acetylcysteine/pharmacology/chemistry ; Humans ; Mice, Inbred C57BL ; Inflammation/drug therapy/metabolism ; Macrophages/metabolism ; Male ; Disease Models, Animal ; Bleomycin ; Nanoparticles/chemistry ; Fibroblasts/drug effects ; RAW 264.7 Cells ; },
abstract = {Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by progressive fibrosis and poor prognosis, with no current therapies capable of reversing the fibrotic changes. The aberrant repair driven by fibroblast activation and an inflammatory microenvironment results in irreversible IPF. In this work, a macrophage-derived apoptotic body delivery system (SA + NAC@AB) co-loaded with sodium arsenite (SA) and N-acetylcysteine (NAC) was developed to exert synergistic antifibrotic activity against IPF via coordinated regulation of TGF-β1 signaling and inflammation. Apoptotic bodies derived from macrophages inherit inflammation-homing capability, enabling targeted delivery to fibrotic lesions. In vivo evaluation in a bleomycin-induced IPF mouse model demonstrated that SA + NAC@AB effectively targeted the lungs, significantly improved body weight and survival, and alleviated pulmonary fibrosis. Immunofluorescence and Western blot analyzes revealed that SA + NAC@AB reduced Smad2/3 phosphorylation and M2 macrophage polarization, indicating regulation of the TGF-β1/Smad2/3 pathway and inflammation as part of its mechanism of action. Furthermore, in vitro studies validated the enhanced efficacy of SA + NAC@AB, which significantly promoted fibroblast uptake, thereby potentiating its inhibitory effects on fibroblast viability, as well as TGF-β1-induced migration and differentiation. In conclusion, our study demonstrates that SA + NAC@AB represents an effective therapeutic strategy for IPF, offering a promising novel approach by modulating both the TGF-β1/Smad2/3 signaling pathway and the inflammatory response.},
}
@article {pmid41579736,
year = {2026},
author = {Mah, E and Gallagher, D and Gao, F and Ramirez, J and Rabin, JS and Survilla, K and Vieira, D and Chen, JJ and Kang, Y and Andreazza, A and Herrmann, N and Kiss, A and Marzolini, S and Oh, P and Swardfager, W and Black, SE and Lanctôt, KL},
title = {Frontal white matter hyperintensity burden predicts cognitive response to N-acetylcysteine and exercise in vascular mild cognitive impairment.},
journal = {Neurobiology of aging},
volume = {161},
number = {},
pages = {39-46},
doi = {10.1016/j.neurobiolaging.2026.01.005},
pmid = {41579736},
issn = {1558-1497},
mesh = {Humans ; *Cognitive Dysfunction/therapy/pathology/psychology/diagnostic imaging/etiology ; *White Matter/pathology/diagnostic imaging ; Male ; Female ; Aged ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Cognition/drug effects ; Magnetic Resonance Imaging ; Executive Function ; *Exercise Therapy ; Treatment Outcome ; Middle Aged ; Aged, 80 and over ; *Frontal Lobe/pathology/diagnostic imaging ; },
abstract = {Vascular mild cognitive impairment (vaMCI) is a prodromal stage of dementia defined by cognitive deficits due to cerebrovascular disease. Increased white matter hyperintensity (WMH) volume has been associated with reduced executive function (EF). We explored whether lower baseline frontal and global WMH volume predicted an improvement in EF in vaMCI participants treated with N-acetylcysteine (NAC) and exercise as compared to placebo and exercise. Fifty-eight individuals with vaMCI received exercise therapy and were randomized to NAC or placebo. EF was assessed using the Trail Making Test Part B (TMT-B), Digit Symbol-Coding Test (DSCT), and a test of phonemic fluency, at baseline, 3 months, and 6 months. WMH volumes were measured from baseline magnetic resonance imaging scans. Linear mixed models were used. All participants improved on TMT-B (β = -0.185, SE = 0.046, p < 0.001) and phonemic fluency (β = 4.440, SE = 0.911, p < 0.001) over 6 months. A significant three-way interaction between baseline frontal WMH volume, treatment group, and timepoint predicted TMT-B performance at 3 months (β = 0.160, SE = 0.076, p = 0.039), but not at 6 months. No significant interactions were found for DSCT or phonemic fluency. Global WMH did not predict treatment response. Participants demonstrated improvement in EF regardless of treatment group and WMH volume. Lower frontal WMH volume predicted a greater improvement in TMT-B performance at 3 months in those treated with NAC versus placebo. These findings underscore the importance of considering participant heterogeneity in trials for vaMCI.},
}
@article {pmid41579706,
year = {2026},
author = {Madhavan, A and Schiano-Visconte, M and Dutton, L and Cantalupo, M and Balasco, L and Mavillonio, A and Chelini, G and Bozzi, Y and Pangrazzi, L},
title = {Astaxanthin improves behavioural and immune dysfunction in the Shank3b mouse model of autism spectrum disorder.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {195},
number = {},
pages = {119051},
doi = {10.1016/j.biopha.2026.119051},
pmid = {41579706},
issn = {1950-6007},
mesh = {Animals ; *Autism Spectrum Disorder/drug therapy/immunology/psychology/genetics/metabolism ; *Nerve Tissue Proteins/genetics ; Disease Models, Animal ; Mice ; *Behavior, Animal/drug effects ; Mice, Knockout ; Cytokines/metabolism ; Male ; Oxidative Stress/drug effects ; Xanthophylls/pharmacology/therapeutic use ; *Antioxidants/pharmacology ; Mice, Inbred C57BL ; *Anti-Inflammatory Agents/pharmacology ; Social Interaction/drug effects ; Microfilament Proteins ; },
abstract = {Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviours. Numerous studies have associated ASD with immune dysregulation and inflammation, with neuroinflammatory processes reported in ASD individuals and mouse models. Altered immune cell profiles and cytokine levels have been observed in the peripheral blood (PB), supporting systemic immune dysfunction. Recently we showed that the administration of antioxidant molecule N-acetylcysteine (NAC) reduced oxidative stress and inflammation and counteracted behavioural deficits in two mouse models of ASD, providing a rationale for exploring other redox-active compounds. Here, we investigated the effects of astaxanthin (AST), potent antioxidant and anti-inflammatory molecule, in the Shank3b model (Shank3b[-/-] mice). AST treatment significantly improved core ASD-like behaviours, including social interaction deficits, motor incoordination, and repetitive grooming. In the cerebellum, AST reduced pro-inflammatory cytokines and counteracted microglial hyperactivation. In peripheral immune compartments, AST modulated cytokine expression. Pro-inflammatory markers were downregulated in Shank3b[-/-] mice in the bone marrow and spleen while they were elevated in Shank3b controls, suggesting immune rebalancing (i.e. adaptive modulation suppressing harmful inflammation while supporting protective immunity). As a limitation, oxidative stress assays were not performed here. Receiver operating characteristic (ROC) analysis suggests that TNF and IFNγ expression in peripheral immune cells may be promising biomarkers of treatment response. Notably, unlike NAC, AST did not induce pro-inflammatory effects in Shank3b[+/+] animals. These findings show that AST administration may counteract behavioural deficits and immune dysfunction in Shank3b[-/-] mice, therefore suggesting its potential as a safe immunomodulatory therapy for ASD.},
}
@article {pmid41577060,
year = {2026},
author = {Abdeltawab, M and Ebid, AH and Ahmed, O and Mobarez, MA and Ibrahim, M},
title = {N-acetylcysteine reduces incidence and duration of linezolid-associated thrombocytopenia in critically ill patients: A randomized controlled trial.},
journal = {Environmental toxicology and pharmacology},
volume = {122},
number = {},
pages = {104944},
doi = {10.1016/j.etap.2026.104944},
pmid = {41577060},
issn = {1872-7077},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Thrombocytopenia/chemically induced/prevention &amp; control/epidemiology/drug therapy ; Male ; Critical Illness ; Middle Aged ; Female ; *Linezolid/adverse effects ; Aged ; Double-Blind Method ; Incidence ; Adult ; *Anti-Bacterial Agents/adverse effects ; Aged, 80 and over ; },
abstract = {Linezolid-associated thrombocytopenia (LAT) limits its use in critically ill patients. This double-blind, randomized, placebo-controlled trial evaluated intravenous N-acetylcysteine (IV NAC) for LAT prevention in 250 critically ill adults receiving linezolid for ≥ 48 h. Patients received IV NAC (600 mg every 12 h) or placebo. The primary endpoint was LAT incidence (platelet count <150 × 10 [3]/mm[3] or >50 % reduction from baseline). NAC significantly reduced LAT incidence (16.8 % vs. 41.6 %; p < 0.001), platelet transfusions (1.6 % vs. 11.2 %; p = 0.003), and linezolid discontinuations (6.4 % vs. 32.0 %; p < 0.001). NAC delayed LAT onset (adjusted hazard ratio 0.24; p < 0.001) and accelerated platelet recovery (adjusted hazard ratio 3.88; p = 0.011), with greatest benefit in moderate-severity cases. These findings suggest IV NAC may offer a preventive benefit against LAT in critically ill patients, though multicenter validation is needed to confirm generalizability across diverse clinical settings. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05944458. Registered on July 6, 2023.},
}
@article {pmid41575655,
year = {2026},
author = {Li, B and Liu, P and Yang, X and Li, M and Lei, L and Meng, Z and Song, Y and Lan, J and Ouyang, C and Ma, J and Liu, Q},
title = {NAC and DNase I synergistically reduce NETs to attenuate severe acute pancreatitis via suppressing the NETs/NF-κB/CXCL3 pathway.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {2},
pages = {58},
pmid = {41575655},
issn = {1573-675X},
mesh = {*Deoxyribonuclease I/pharmacology/therapeutic use ; *Extracellular Traps/drug effects/metabolism ; *NF-kappa B/metabolism/genetics ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Pancreatitis/drug therapy/metabolism/pathology ; Mice ; Signal Transduction/drug effects ; Male ; Humans ; Neutrophils/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Neutrophil extracellular traps (NETs) drive severe acute pancreatitis (SAP) progression by promoting pancreatic injury, duct obstruction, and systemic inflammation. Reactive oxygen species (ROS) are critical for NETs formation, while NETs degradation remains therapeutically challenging. This study investigates whether combined N-acetylcysteine (NAC) and deoxyribonuclease I (DNase I) therapy mitigates SAP and associated lung injury by suppressing NETs formation and degradation, respectively, and explores the underlying molecular mechanisms. NETs were elevated in SAP pancreatic tissue. In vitro, NAC reduced NETs formation by inhibiting oxidative stress, while DNase I degraded preformed NETs. Combined therapy surpassed monotherapy efficacy, synergistically attenuating NETs burden. In vivo, Early dual intervention degraded NETs, reduced neutrophil infiltration and apoptosis, and lowered inflammatory cytokines, thereby alleviating pancreatitis and lung injury. Mechanistically, dual therapy suppressed NF-κB activation in pancreatic tissue, decreasing CXCL3 release and subsequent CXCR2-positive neutrophil recruitment, ultimately ameliorating SAP. NAC and DNase I synergistically target NETs generation and clearance, offering a promising redox-based therapeutic strategy for SAP.},
}
@article {pmid41574386,
year = {2026},
author = {Yadav, N and Singh, R and Mondal, SK and Mandal, AK},
title = {Molecular insights of p-benzoquinone-induced red blood cell dysfunction: probable implications to cigarette smoke-associated pathologies.},
journal = {Free radical research},
volume = {60},
number = {1},
pages = {67-90},
doi = {10.1080/10715762.2026.2620638},
pmid = {41574386},
issn = {1029-2470},
mesh = {Humans ; *Erythrocytes/drug effects/metabolism/pathology ; *Benzoquinones/adverse effects/toxicity ; Oxidation-Reduction ; *Cigarette Smoking/adverse effects ; },
abstract = {Cigarette smoke (CS) is a complex mixture of numerous chemicals, including p-benzosemiquinone (pBSQ), which oxidizes to p-benzoquinone (pBQ) in the lungs of smokers and enters circulation. Despite its high reactivity, the direct impact of pBQ on human red blood cells (RBC) remains underexplored. Herein, we investigated the molecular insights into how pBQ compromises human RBC physiology and its role in mediating CS-associated pathologies by integrating redox biochemistry, membrane integrity, and omics-based approaches. Our findings reveal that pBQ disrupted redox homeostasis, evidenced by glutathione depletion, elevated reactive oxygen species, lipid peroxidation, and reduced antioxidant enzyme activity. pBQ also triggered methemoglobin formation, hemoglobin aggregation, and reduced oxygen-binding capacity. Biophysical analysis of RBCs revealed reduced membrane fluidity, alterations in membrane proteins and lipids, disrupted zeta potential, and sedimentation dynamics, suggesting altered deformability, an indication of impaired microvascular transit. Untargeted metabolomics and lipidomics profiling revealed metabolic reprogramming and remodeling of the membrane lipids. Depletion of polyunsaturated fatty acids alongside accumulation of saturated species in the membrane points toward membrane stiffening. Pathway analysis highlighted perturbations in fatty acid biosynthesis and redox homeostasis. Disease enrichment analysis linked these changes to hypertension and other pathologies that are previously linked to redox imbalance and CS exposure. Notably, NAC co-treatment mitigated these effects, preserving RBC integrity and redox homeostasis. These findings underscore that pBQ is a critical mediator of CS-induced RBC dysfunction and establish a mechanistic link to its contribution to smoking-associated complications.},
}
@article {pmid41563857,
year = {2026},
author = {Race, NS and Uchida, K and Burcham, PC and Shi, R},
title = {Multimodal Toxicity of Acrolein and Associated Therapeutic Strategies in Central Nervous System Trauma and Disease.},
journal = {Annual review of biomedical engineering},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-bioeng-103023-035352},
pmid = {41563857},
issn = {1545-4274},
abstract = {Acrolein is a highly reactive α,β-unsaturated aldehyde produced endogenously through lipid peroxidation and enzymatic metabolism and exogenously via environmental exposures. Acrolein covalently adducts to DNA and proteins, leading to oxidative stress, mitochondrial dysfunction, and inflammation, including innate immune response activation via natural antibodies. Acrolein is difficult to measure in biological systems, but acrolein-bound covalent products can be measured reliably. Therapeutically, nucleophilic small molecules that scavenge acrolein such as hydralazine, phenelzine, dimercaprol, carnosine, and N-acetylcysteine (NAC) have shown neuroprotective effects in animal models of multiple sclerosis, Parkinson's disease, spinal cord injury, and traumatic brain injury. These effects include preserved membrane and mitochondrial integrity, reduced inflammation, reduced pain, and improved motor, sensory, and cognitive outcomes. Alternative strategies that enhance clearance or inhibit production of acrolein show promise but face limitations. Acrolein is a key pathophysiological mediator and a viable therapeutic target in central nervous system trauma and neurodegenerative diseases.},
}
@article {pmid41562319,
year = {2026},
author = {Hossen, F and Kouwaki, T and Fujiwara, Y and Tsutsuki, H and Zhang, T and Guo, C and Rahman, A and Komohara, Y and Oshiumi, H and Sawa, T},
title = {Therapeutic Efficacy of the Supersulfide Donor NAC-S2 in Influenza Virus Pneumonia via Suppression of Excessive Inflammatory Responses.},
journal = {Microbiology and immunology},
volume = {70},
number = {3},
pages = {148-159},
pmid = {41562319},
issn = {1348-0421},
support = {21H05267//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 21H05258//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 25H01029//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 25K02477//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 23K06362//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 23K07942//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 25K22315//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 23gm161001h001//Japan Agency for Medical Research and Development/ ; },
abstract = {Influenza pneumonia is characterized by excessive inflammatory responses that contribute to severe lung injury and mortality. Supersulfides, endogenously produced cysteine-derived persulfides and polysulfides, exert potent antioxidant, anti-ferroptotic, and anti-inflammatory activities; however, their therapeutic potential after disease onset remains unclear. Here, we investigated the efficacy of N-acetylcysteine tetrasulfide (NAC-S2), a highly water-soluble and cell-permeable supersulfide donor, in a mouse model of influenza A virus (IAV)-induced pneumonia. Subcutaneous administration of NAC-S2 rapidly elevated systemic levels of cysteine- and glutathione-derived supersulfides. In therapeutic treatment starting 2 days post-infection, when body weight loss and clinical signs had already developed, NAC-S2 significantly improved survival and mitigated body weight loss compared with vehicle and oxidized NAC controls. Metabolomic analysis revealed that influenza virus infection depleted lung glutathione persulfide (GSSH), while NAC-S2 effectively restored tissue GSSH levels. NAC-S2 treatment markedly reduced pulmonary interleukin (IL)-1β and IL-6 production without affecting viral load or Type-I interferon responses. Furthermore, NAC-S2 suppressed NLRP3 inflammasome activation and gasdermin D expression, leading to decreased infiltration of CD3[+] T cells and myeloperoxidase-positive neutrophils. Histopathological analyses confirmed that NAC-S2 ameliorated epithelial injury, interstitial edema, and hemorrhage in infected lungs. Collectively, our findings demonstrate that NAC-S2 exerts therapeutic benefit even after the onset of severe influenza pneumonia, primarily by replenishing supersulfides and alleviating excessive inflammatory responses. Supersulfide donors represent a promising class of adjunctive therapeutics for severe viral pneumonia.},
}
@article {pmid41559638,
year = {2026},
author = {Li, H and Shen, H and Duan, X and Guo, M and Liu, X},
title = {Efficacy and safety of anti-inflammatory drug-assisted treatment of symptoms in patients with schizophrenia: a meta-analysis.},
journal = {BMC psychiatry},
volume = {26},
number = {1},
pages = {161},
pmid = {41559638},
issn = {1471-244X},
support = {Grant No. 202101BA070001-119//the Special Basic Research Cooperative Research Programs of the Yunnan Provincial Undergraduate Universities' Association/ ; Grant No. 202305AS350001//the Program for Innovative Research Team of Yunnan Province/ ; Grant No. AT2024002//the Yunnan Province Insect Biomedicine Research and Development Key Laboratory Open Project/ ; },
abstract = {BACKGROUND: Although anti-inflammatory agents have been explored as adjunctive treatments for schizophrenia, findings remain inconsistent. While some meta-analyses suggest benefit, concerns persist regarding methodological heterogeneity, language bias, and the influence of publication bias on reported effect sizes (ES). This updated meta-analysis aims to re-evaluate the efficacy and safety of anti-inflammatory drugs in schizophrenia, with a critical focus on robustness after accounting for these biases.<br><br>METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating anti-inflammatory drugs as adjunctive therapy in schizophrenia. Databases (PubMed, Embase, Scopus, Web of Science) were searched from inception to December 31, 2024, with restriction to English-language publications. Standardized mean differences (Hedges&#x2019;s g) were calculated using a random-effects model. Heterogeneity was assessed using I&#xb2;, and publication bias was evaluated via Egger&#x2019;s test and trim-and-fill analysis. Sensitivity analyses were performed to assess robustness.<br><br>RESULTS: Seventy-four RCTs involving 5,484 participants were included. Initial analyses suggested significant benefits for aspirin (ES&#x2009;=&#x2009;0.64), celecoxib (ES&#x2009;=&#x2009;0.49), estrogens (ES&#x2009;=&#x2009;0.59), fatty acids (ES&#x2009;=&#x2009;0.25), minocycline (ES&#x2009;=&#x2009;0.38), N-acetylcysteine (NAC; ES&#x2009;=&#x2009;0.60), monoclonal antibodies (mAbs; ES&#x2009;=&#x2009;0.49), and pregnenolone (ES&#x2009;=&#x2009;0.20). However, substantial heterogeneity (I&#xb2; > 50%) and significant publication bias were detected for several agents, including estrogens (p&#x2009;<&#x2009;0.001) and minocycline (p&#x2009;=&#x2009;0.01). Trim-and-fill analysis indicated that the observed effects for estrogens and minocycline were likely inflated, with adjusted ES falling below conventional thresholds for statistical significance in some cases. Sensitivity analyses excluding high-risk-of-bias studies further weakened the evidence for several compounds. No significant benefit was found for statins or varenicline.<br><br>CONCLUSION: While some anti-inflammatory agents initially appear beneficial as adjunctive treatments in schizophrenia, these findings are tempered by high heterogeneity, potential language bias (due to exclusive inclusion of English-language studies), and significant publication bias. After correction for these biases, the clinical significance of many reported effects diminishes. Current evidence does not robustly support routine clinical use of these agents outside of research settings. Future large-scale, long-term, and globally representative RCTs with rigorous reporting standards are needed to determine whether any anti-inflammatory strategy offers reproducible and clinically meaningful benefits.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12888-026-07774-y.},
}
@article {pmid41558638,
year = {2026},
author = {Moseanko, A and Ginwalla, C and Eidman, M and Dash, S and Lewis, J and Albertson, TE},
title = {Pediatric Intravenous Acetaminophen Overdoses: A Continuing Iatrogenic Problem.},
journal = {Hospital pediatrics},
volume = {16},
number = {2},
pages = {e114-e118},
doi = {10.1542/hpeds.2025-008624},
pmid = {41558638},
issn = {2154-1671},
mesh = {Humans ; *Acetaminophen/poisoning/administration &amp; dosage ; *Drug Overdose/epidemiology/drug therapy ; Retrospective Studies ; Child, Preschool ; Male ; Female ; Child ; *Iatrogenic Disease/epidemiology ; Acetylcysteine/therapeutic use ; California/epidemiology ; Infant ; *Analgesics, Non-Narcotic/poisoning/administration &amp; dosage ; Adolescent ; Administration, Intravenous ; *Medication Errors/statistics &amp; numerical data ; Poison Control Centers/statistics &amp; numerical data ; Antidotes/therapeutic use ; },
abstract = {OBJECTIVE: To determine if intravenous (IV) acetaminophen use in children remains a source of iatrogenic overdosing.<br><br>METHODS: A cluster of 3 index cases in early 2025 stimulated a 14-year (2011-2024) retrospective study of calls from health care facilities to the California Poison Control System (CPCS) involving IV acetaminophen dosing errors in children aged 16&#xa0;years or younger. All calls during this period that involved pediatric IV acetaminophen were reviewed and data abstracted. Date of call, age of child, location in the hospital, laboratory results, acetaminophen levels, intended dose, dose given, use of N-acetylcysteine (NAC), and outcomes were recorded. Descriptive statistics were used.<br><br>RESULTS: The 3 index pediatric cases of IV acetaminophen overdose ranged from 3 to 10 times the desired dose. Two of the 3 patients were treated with NAC. The retrospective review of CPCS calls resulted in 42 additional cases in which intravenous dosing errors occurred with mean doses of 45.5&#x2009;&#xb1;&#x2009;36.7&#xa0;mg/kg (range, 14.7-147.1&#xa0;mg/kg) and mean age of 4.9&#xa0;years&#x2009;&#xb1;&#x2009;4.0 (1&#xa0;day to 16&#xa0;years). Two additional patients were treated with NAC. These adverse events happened in operative/perioperative areas (13 cases), 11 cases on the pediatric inpatient units, 5 in intensive care units, 12 in the emergency department, and 4 in unknown areas. No long-term adverse effects were seen in the 45 children.<br><br>CONCLUSION: Rare pediatric iatrogenic IV acetaminophen overdoses continue to be seen in acute care settings. Determining potential toxicity and the need for NAC remains challenging. Further efforts are needed to prevent this infrequent serious medication error.},
}
@article {pmid41558404,
year = {2026},
author = {Aral, H and Aral, T and Sunkur, M and Çolak, M and Bağcık, M},
title = {N-acetylcysteine-functionalised a multimodal HPLC stationary phase for broad-range separations.},
journal = {Talanta},
volume = {302},
number = {},
pages = {129397},
doi = {10.1016/j.talanta.2026.129397},
pmid = {41558404},
issn = {1873-3573},
abstract = {In this study, a new multimodal HPLC stationary phase derived from N-acetyl-l-cysteine was synthesized and comprehensively evaluated across a broad polarity spectrum. In chromatographic stationary phase design, two fundamental criteria are particularly important: a facile, low-cost synthesis and broad applicability across diverse analyte classes. The present stationary phase fulfils both requirements, as it is prepared from a commercially available starting material via a simple single-step immobilisation onto silica, providing a practical and economical synthetic route alongside wide analytical utility. The molecular architecture of the ligand, incorporating a pH-responsive carboxyl group, a hydrogen-bond-donating and -accepting amide moiety, a polarisation-sensitive sulfur atom, and hydrophobic methyl and methylene units, creates a versatile interaction environment capable of mediating hydrophobic, polar, dispersive, and weak cation-exchange processes. This multifunctional design enables the stationary phase to adapt its selectivity according to analyte structure and mobile-phase conditions, supporting both reversed-phase-like and HILIC-like retention behaviour within a single chromatographic platform. The chromatographic performance of the NAC-derived stationary phase was systematically evaluated using a wide range of chemically and biologically relevant analytes. Under HILIC conditions, the column successfully resolved 7 of the 9 highly polar nucleobases and nucleosides. In reversed-phase mode, compounds with high hydrophobicity-including 6 alkyl benzenes, 4 polycyclic aromatic hydrocarbons, 6 Sudan dyes, 8 anilines, and 7 benzoic acid derivatives-were efficiently separated. Under the same reversed-phase conditions, the stationary phase successfully resolved 10 analytes from a twelve-analyte plant growth regulator mixture and 9 sulphonamides. In addition, a 6 herbicide was also effectively separated, highlighting the multimodal selectivity of the stationary phase. Retention trends were interpreted using analyte logD and pKa values, clarifying the combined contributions of hydrophobic, polar, and weak ion-exchange interactions to overall selectivity. The N-acetyl-l-cysteine-based stationary phase provides a finely balanced interaction profile, enabling high separation performance for analytes spanning from extreme polarity to pronounced hydrophobicity and demonstrating broad analytical utility.},
}
@article {pmid41553565,
year = {2026},
author = {Altındağ, F and İgit, T},
title = {Berberine and N-Acetylcysteine ameliorate diabetes-induced hippocampal damage by inhibiting apoptosis and neuroinflammation, and improve synaptic plasticity in rats.},
journal = {Journal of molecular histology},
volume = {57},
number = {1},
pages = {54},
pmid = {41553565},
issn = {1567-2387},
support = {TDK-2021-9565//Van Yuzuncu Yil University Scientific Research Coordination Unit/ ; TDK-2021-9565//Van Yuzuncu Yil University Scientific Research Coordination Unit/ ; },
mesh = {Animals ; *Apoptosis/drug effects ; *Berberine/pharmacology/therapeutic use ; *Acetylcysteine/pharmacology/therapeutic use ; *Diabetes Mellitus, Experimental/complications/pathology/drug therapy ; Rats ; *Hippocampus/drug effects/pathology/metabolism ; Male ; *Neuronal Plasticity/drug effects ; *Neuroinflammatory Diseases/drug therapy/pathology/etiology ; },
abstract = {Diabetes Mellitus (DM) is a metabolic disease characterized by hyperglycemia resulting from impaired insulin secretion and resistance. Berberine (BBR) and N-acetylcysteine are anti-inflammatory and antiapoptotic compounds that have beneficial effects on diabetic complications. This study aimed to investigate the effects of BBR and NAC on the Hippocampus in an experimental diabetes model in rats. Rats were divided into 5 groups: control, diabetes (D), D + NAC, D + BBR, and D + BBR + NAC. STZ (45 mg/kg, i.p.) was administered to the other four groups except the control group. BBR and NAC (50 mg/kg/day) were given intragastrically (i.g.) to the treatment groups for 28 days. Decreased cell body size, pyknotic cells and necrotic neurons were observed in the D group. However, these pathological changes were largely improved in the D + BBR, D + NAC, and D + BBR + NAC. Stereologically, there was no significant difference between the groups in terms of hippocampus volume. The number of pyramidal neurons in CA1 was significantly decreased in the D group. But the number of CA1 pyramidal neurons was higher in both the alone and combined BBR and NAC treatment groups than in the D group. Expressions of Caspase-3, TNF-α, and IL-1β increased in the D group, while expressions of Bcl-2 and SYP decreased. But, BBR and NAC treatments decreased Caspase-3, TNF-α, and IL-1β expressions and increased Bcl-2 and SYP expressions. These results revealed that BBR and NAC can have an antidiabetic effect against the neuronal damage caused by diabetes in the hippocampus CA1 region, suppressing inflammation and apoptosis and preventing the decrease in the number of pyramidal neurons. Also, they reveal that they may modulate synaptic plasticity by increasing synaptophysin expression.},
}
@article {pmid41552353,
year = {2025},
author = {Wu, Y and Yao, J and Zhang, Y},
title = {Effects of acetylcysteine combined with bronchoalveolar lavage under fiberoptic bronchoscopy on blood oxygenation and inflammation in elderly severe pneumonia patients.},
journal = {American journal of translational research},
volume = {17},
number = {12},
pages = {9317-9326},
pmid = {41552353},
issn = {1943-8141},
abstract = {OBJECTIVE: To determine the effects of acetylcysteine (NAC) plus bronchoalveolar lavage (BAL) under fiberoptic bronchoscopy (FB) on blood oxygenation and inflammation in elderly severe pneumonia patients.<br><br>METHODS: The data of 180 elderly patients with severe pneumonia treated in the Affiliated Hospital 2 of Nantong University between January 2022 and January 2024 were analyzed retrospectively. Eighty-six patients were treated with BAL under FB (BAL group) and 94 patients were treated with NAC based on BAL under FB (BAL + NAC group). Outcomes included pre-/post-treatment blood gas, pulmonary function, inflammatory factors, correlation between inflammatory markers and blood gas parameters, clinical efficacy, symptom resolution time, and adverse reactions.<br><br>RESULTS: After treatment, both groups exhibited an increase in arterial partial pressure of oxygen (PaO2), arterial oxygen saturation (SaO2), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and decreased C-reactive protein (CRP) and interleukin-6 (IL-6), with more significant changes in the BAL + NAC group (all P < 0.05). Inflammatory markers (CRP/IL-6) were negatively correlated with oxygenation parameters (PaO2/SpO2, all P < 0.01). Additionally, the BAL + NAC group had earlier resolution time of chest pain, expectoration, cough, and lung rales, a higher overall response rate, and no significant difference in adverse reaction incidence versus the BAL group.<br><br>CONCLUSION: NAC combined with BAL under FB is effective for elderly patients with severe pneumonia. It can strongly improve the blood gas indexes and lung function, relieve inflammatory reactions, and quickly relieve clinical symptoms, without increasing adverse reactions. Thus it is worthy of clinical promotion.},
}
@article {pmid41550647,
year = {2025},
author = {Zheng, Z and Chen, Z and Zhang, C and Peng, S and Hu, J and Wang, C and Liu, L and Yang, MX and Chen, H},
title = {Enhancing ferroptosis and inhibiting ABCB1 make the novel aldose reductase inhibitor 5F-E a promising sensitizer in liver cancer.},
journal = {Pharmaceutical science advances},
volume = {3},
number = {},
pages = {100088},
pmid = {41550647},
issn = {2773-2169},
abstract = {Multidrug resistance (MDR) poses a critical barrier to chemotherapy efficacy. While the promising agents, aldose reductase inhibitors (ARIs), to overcome multidrug resistance (MDR) has been investigated over recent decades, their underlying mechanisms remain unclear and clinically viable candidates are still lacking. In our study, we identified a novel ARI, 5F-E, which exhibited a more potent sensitizing effect on doxorubicin (DOX) resistant HepG2 cells (HepG2/ADR) compared to epalrestat (EPA). Both 5F-E and EPA were observed to decrease intracellular GSH levels while elevating reactive oxygen species (ROS), Fe[2+] and lipid peroxidation; these effects could be reversed by N-acetyl cysteine (NAC), suggesting that enhanced ferroptosis may be involved in restoring DOX sensitivity. Furthermore, inhibition of AKR1B1 by either compound led to marked reductions in p-STAT3 and SLC7A11 expression, an outcome that was recapitulated by AKR1B1 gene knockdown. The results demonstrate that ARIs exert antitumor effects on HepG2/ADR cells by triggering ferroptosis, a process dependent on AKR1B1/STAT3/SLC7A11 signaling. And, 5F-E, but not EPA, was found to increase intracellular DOX accumulation by inhibiting ABCB1. Our integrated experimental approach reveals that 5F-E exhibits strong chemosensitizing effects against multidrug-resistant liver cancer, highlighting its therapeutic promise.},
}
@article {pmid41547222,
year = {2026},
author = {Su, H and Wu, F and Haque, K and Sha, SH},
title = {Furosemide prevents noise-induced hearing loss and enhances the preventive effect of N-acetylcysteine.},
journal = {Hearing research},
volume = {471},
number = {},
pages = {109537},
doi = {10.1016/j.heares.2026.109537},
pmid = {41547222},
issn = {1878-5891},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Hearing Loss, Noise-Induced/prevention &amp; control/physiopathology/metabolism/pathology ; *Furosemide/pharmacology/administration &amp; dosage ; Mice ; Disease Models, Animal ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Auditory Threshold/drug effects ; Reactive Oxygen Species/metabolism ; *Antioxidants/pharmacology ; Male ; Drug Synergism ; *Cochlea/drug effects/physiopathology/metabolism ; Hair Cells, Auditory, Outer/drug effects/metabolism/pathology ; *Hearing/drug effects ; },
abstract = {Disruption of reactive oxygen species (ROS) homeostasis is a key mechanism underlying noise-induced sensory hair cell damage. Antioxidant treatments such as N-acetylcysteine (NAC) have been shown to attenuate noise-induced hearing loss (NIHL), supporting the role of ROS accumulation. However, no FDA-approved pharmaceutical therapy currently exists for the prevention or treatment of NIHL, likely due to the complexity of the damaging mechanisms and the presence of the blood-labyrinth barrier (BLB), which limits drug permeability and prevents therapeutic compounds from reaching effective concentrations via systemic administration. Furosemide (FRS) has demonstrated potential to reduce NIHL and facilitate drug delivery into inner ear by transiently opening the BLB. In this study, we investigated the mechanisms by which FRS pretreatment prevents NIHL. A single dose of 200 mg/kg FRS administered immediately before noise exposure significantly reduced NIHL in FVB/NJ mice. One hour after FRS treatment, the endocochlear potential (EP) was temporarily reduced without altering cochlear sensitivity (ABR thresholds), outer hair cell function (DPOAE amplitudes), or synaptic transmission integrity between hair cells and auditory nerve fibers (suprathreshold ABR wave I amplitudes). Furthermore, this dose of FRS selectively increased stria vascularis permeability to small molecules but not to large protein-bound tracers. Combined treatment with FRS and NAC enhanced NAC's antioxidant effect and additively prevented noise-induced outer hair cell (OHC) loss and NIHL, with OHC loss almost entirely prevented. These findings provide important insight into future strategies for the prevention and treatment of NIHL.},
}
@article {pmid41546819,
year = {2026},
author = {Elhence, A and Mishra, P and Rai, P},
title = {N‑acetylcysteine for post-ERCP pancreatitis prophylaxis: A systematic review and meta-analysis.},
journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology},
volume = {},
number = {},
pages = {},
pmid = {41546819},
issn = {0975-0711},
abstract = {BACKGROUND: Oxidative stress is an early step in the cascade of events triggering post-ERCP pancreatitis (PEP). N-acetylcysteine (NAC), a free radical scavenger, can be used to check this oxidative stress for PEP prophylaxis. METHODS: A systematic search of MEDLINE, EMBASE and Scopus was undertaken from inception to May 30, 2025. The relative risks (RR) of PEP and severe PEP were pooled using a random effects model with the inverse variance method. Funnel plot and Egger's test were used to evaluate publication bias. The quality of studies was assessed using the Cochrane risk of bias tool. Further sensitivity analysis was undertaken to evaluate oral route dosing and a leave-alone-one sensitivity analysis was done to confirm the robustness of the results (PROSPERO ID CRD420251062268).<br><br>RESULTS: The five studies meeting the inclusion criteria included 784 participants of which 388 received NAC and 396 received placebo. PEP occurred in 50 participants in the NAC group as compared to 68 participants in the placebo group with a pooled RR of 0.74 (95% confidence interval [CI] 0.48 to 1.15) with moderate heterogeneity, I[2] 35%. Severe PEP occurred in none of the participants administered NAC as compared to three participants administered placebo with a pooled RR of 0.27 (95% CI of 0.03 to 2.43), with I[2] of 0% and no publication bias confirmed by no funnel plot visual asymmetry or Egger's test (p&#x2009;=&#x2009;0.220). Sensitivity analysis confirmed the robustness of the results.<br><br>CONCLUSION: The pooled results of the meta-analysis suggest that NAC prophylaxis does not prevent the occurrence of PEP or severe PEP as compared to placebo.},
}
@article {pmid41546041,
year = {2026},
author = {Wu, PH and Cheng, N and Lo, WC and Chang, CM and Cheng, PW and Liu, SH},
title = {Functional and biochemical protection by combined N-acetylcysteine and D-methionine in guinea pig noise-induced hearing loss.},
journal = {Head &amp; face medicine},
volume = {22},
number = {1},
pages = {},
pmid = {41546041},
issn = {1746-160X},
abstract = {PURPOSE: This study examined whether combining antioxidants could enhance protection and permit lower dosing for treating noise-induced hearing loss (NIHL). The therapeutic effects of D-methionine (DMET) and N-acetylcysteine (NAC) were evaluated in a guinea pig model.<br><br>METHODS: Ninety-six guinea pigs were randomly assigned to eight groups: control, saline, three NAC-only groups (100, 150, 200&#xa0;mg/kg), and three NAC&#x2009;+&#x2009;DMET groups (100, 200, 400&#xa0;mg/kg). One hour after six hours of broadband noise exposure, treatments were administered intraperitoneally every 12&#xa0;h for seven days. Auditory brainstem responses (ABR) were measured before exposure and on day 14. Cochlear tissues were analyzed for Na&#x207a;/K&#x207a;-ATPase and Ca&#xb2;&#x207a;-ATPase activities and lipid peroxidation (LPO) levels.<br><br>RESULTS: No significant body weight differences were observed between saline and treated groups. NAC alone and in combination with DMET improved ABR thresholds in a dose-dependent manner. The combined NAC (200&#xa0;mg/kg)&#x2009;+&#x2009;DMET (400&#xa0;mg/kg) group achieved complete ABR recovery. Noise-induced reductions in ATPase activities were dose-dependently reversed by both treatments. The highest-dose combination restored 87.3% of Na&#x207a;/K&#x207a;-ATPase and 94.7% of Ca&#xb2;&#x207a;-ATPase activity compared to controls. LPO levels declined with increasing NAC doses, with NAC 200&#xa0;mg/kg alone showing the greatest reduction.<br><br>CONCLUSIONS: Combined NAC (200&#xa0;mg/kg) and DMET (400&#xa0;mg/kg) yielded the most substantial functional protection against NIHL. This combination was accompanied by lower LPO levels and higher Na&#x207a;/K&#x207a;-ATPase and Ca&#xb2;&#x207a;-ATPase activities in the cochlear lateral wall, indicating a potential role in maintaining cochlear homeostasis following acoustic injury.},
}
@article {pmid41541699,
year = {2026},
author = {Ahmad, F and Rendina, BP and Chen, C and Ren, H and Brantner, C and Dukic, T and Miles, D and Winkles, JA and Woodworth, GF and Bhetawal, S and Stone, E and Bar, EE},
title = {Systemic cyst(e)inase administration induces ferroptosis and synergizes with temozolomide in glioblastoma.},
journal = {iScience},
volume = {29},
number = {1},
pages = {114350},
pmid = {41541699},
issn = {2589-0042},
abstract = {Glioblastoma exhibits profound therapeutic resistance, driven by tumor heterogeneity and highly plastic glioma stem cells (GSCs). This study exploits GSC metabolic dependence on cysteine using systemic cyst(e)inase, a cysteine-degrading enzyme. In patient-derived GSCs and orthotopic xenograft models, cyst(e)inase potently inhibited GSC proliferation and extended animal survival by inducing ferroptosis. Mechanistically, cyst(e)inase triggered elevated reactive oxygen species (ROS), glutathione (GSH) depletion, and significant lipid peroxidation. Crucially, these effects were reversed by N-acetylcysteine (NAC), and lipid peroxidation was abrogated by the iron chelator deferoxamine (DFX), unequivocally confirming iron-dependent ferroptosis. Characteristic mitochondrial morphological changes further validated ferroptosis induction. Acyl-CoA synthetase long-chain family member-4 (ACSL4) was identified as essential for this process. Critically, cyst(e)inase synergized with temozolomide (TMZ), markedly enhancing its anti-tumor efficacy and prolonging survival, even in TMZ-resistant xenografts. These findings establish cysteine metabolism as a promising therapeutic target and position cyst(e)inase, especially with TMZ, as a potent strategy to overcome GBM resistance.},
}
@article {pmid41537173,
year = {2026},
author = {Wang, S and Zhang, F and Zhou, X and Yang, J and Li, Z and Li, S and Lu, Q and Sun, H and Liu, P},
title = {Chondrocyte-Targeted Nanoparticles Loaded with N-Acetylcysteine Protect Articular Cartilage and Attenuate Osteoarthritis by Inhibiting Ferroptosis via Glutathione Maintenance.},
journal = {Small science},
volume = {6},
number = {1},
pages = {e202500440},
pmid = {41537173},
issn = {2688-4046},
abstract = {Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation. Abnormal mechanical loading exacerbates intracellular ROS accumulation and glutathione (GSH) depletion. While N-acetylcysteine (NAC) has potent antioxidant properties, its therapeutic potential in OA is limited by rapid degradation and poor intraarticular retention. In this study, chondrocyte-targeted, chondroitin sulfate (CS)-modified PLGA nanoparticles (CS-NAC-NPs) is developed for sustained and localized delivery of NAC. These nanoparticles exhibit excellent physical and chemical properties, biocompatibility, and chondrocyte targeting capabilities. In vitro, CS-NAC-NPs attenuated mechanical stress-induced ROS accumulation, preserved mitochondrial integrity, restored GSH levels, and suppressed ferroptosis, as evidenced by increased GPX4 expression and improved chondrocyte viability. In a murine model of OA, intraarticular injection of CS-NAC-NPs significantly reduced cartilage degradation and osteophyte formation, improved histological scores, and maintained extracellular matrix homeostasis more effectively than free NAC or nontargeted NAC-NPs. Notably, the therapeutic effect is abolished in GPX4-deficient mice, confirming that CS-NAC-NPs act via GPX4-mediated ferroptosis inhibition. Furthermore, in vivo tracking demonstrated excellent joint retention and no off-target toxicity, underscoring their translational safety. This study introduces a novel nanotherapeutic platform that couples biomechanical targeting with redox-responsive delivery to modulate ferroptosis, offering a promising disease-modifying approach for OA treatment.},
}
@article {pmid41535111,
year = {2026},
author = {Afşar, E and Öz, M and Özkan, E and Eranıl, I},
title = {Maternal Immune Activation Disrupts Autophagy and Glucose Homeostasis: Experimental Evidence for the Protective Effects of N-Acetylcysteine on Maternal and Offspring Outcomes in a Rat Model.},
journal = {Journal of applied toxicology : JAT},
volume = {46},
number = {4},
pages = {1372-1388},
doi = {10.1002/jat.70063},
pmid = {41535111},
issn = {1099-1263},
support = {K&#xdc;N.2025-BAGP-005//Kapadokya University/ ; },
mesh = {Animals ; Female ; *Acetylcysteine/pharmacology ; *Autophagy/drug effects/immunology ; Pregnancy ; Rats, Wistar ; Homeostasis/drug effects ; Rats ; Male ; Lipopolysaccharides/toxicity ; *Glucose/metabolism ; *Prenatal Exposure Delayed Effects/immunology ; *Blood Glucose/drug effects ; Insulin Resistance ; },
abstract = {Maternal immune activation during pregnancy has been shown to disrupt maternal glucose regulation, predisposing the mother to postpartum diabetic conditions while also exerting long-lasting metabolic effects on the offspring. This study aimed to investigate the impact of lipopolysaccharide (LPS)-induced maternal immune activation on glucose homeostasis at different postpartum stages, the modulatory role of N-acetylcysteine (NAC), and the effects on the offspring, including sex-specific differences. Albino Wistar female and male rats were used; pregnant females received a single intraperitoneal injection of LPS (0.5 mg/kg) on gestational day 16, with a subset pretreated with NAC (300 mg/kg). Mothers were sacrificed at the end of gestation or on postpartum day 21 (PP21), and offspring were analyzed at PP21. Maternal glucose tolerance was assessed using OGTT, and HOMA-IR and HOMA-β indices were used to determine insulin resistance and β-cell function. Maternal and offspring tissues were analyzed for key markers of signaling, autophagy, proliferation, apoptosis, and inflammation. Phosphorylated protein kinase B (p-Akt), mammalian target of rapamycin (mTOR), Ki-67 (a proliferation marker), phosphorylated AMP-activated protein kinase (p-AMPK), Beclin-1, and microtubule-associated protein 1 light chain 3 beta (LC3B) were measured in tissue homogenates; pancreatic insulin and pro-insulin levels were determined; plasma cytokines, including interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), as well as cleaved caspase-3. All of them were quantified using enzyme-linked immunosorbent assay (ELISA) kits. Total antioxidant capacity (TAC) and total oxidant status (TOS) were measured in plasma using colorimetric assays. At PP0, LPS decreased muscle glucose uptake, increased hepatic gluconeogenesis and glucose output, and enhanced pancreatic insulin production, autophagy, apoptosis, and proliferation while maintaining plasma glucose levels, indicating an adaptive response. NAC improved muscle glucose uptake, suppressed hepatic gluconeogenesis, and normalized pancreatic changes. At PP21, LPS exposure led to increased hepatic gluconeogenesis, impaired pancreatic function, and higher plasma glucose levels. NAC reduced hepatic gluconeogenesis but did not restore glucose balance and worsened pancreatic dysfunction. In offspring of LPS-treated dams, IL-6, TNF-α, and IFN-γ levels decreased, whereas IL-10 increased only in females. Markers of pancreatic apoptosis, autophagy, and proliferation were reduced in both sexes. NAC exposure decreased IL-10 and increased IL-6, TNF-α, and IFN-γ in all offspring and selectively enhanced pancreatic markers in males. Maternal LPS exposure differentially affected glucose regulation through the muscle, liver, and pancreas across postpartum stages. NAC exerted beneficial effects mainly in the early postpartum period but was insufficient later. Furthermore, NAC induced sex-specific effects in the offspring, with a more substantial impact observed in males.},
}
@article {pmid41534829,
year = {2026},
author = {Yadav, A and Richartz, N and Bhagwat, S and Burman, MM and Munthe-Kaas, MC and Skålhegg, BS and Wik, JA and Naderi, S and Blomhoff, HK},
title = {Starvation of leukemic cells enhances DNA damage-induced apoptosis in vitro via ROS/p38 MAPK and prevents leukemia progression in fasting xenograft mice.},
journal = {The Journal of biological chemistry},
volume = {302},
number = {3},
pages = {111143},
pmid = {41534829},
issn = {1083-351X},
abstract = {Most children with acute lymphoblastic leukemia (ALL) achieve long-term survival due to intensive multimodal chemotherapy. However, the use of cytotoxic DNA-damaging agents is frequently associated with severe long-term side effects, prompting continued efforts to improve treatment strategies. This study explores the potential of starving the leukemic cells to enhance the efficacy of DNA-damaging therapy in ALL. Previous work demonstrated that cAMP signaling attenuates DNA damage-induced apoptosis in ALL cells, both in vitro and in a xenograft model. The current findings show that glucose and serum deprivation reverse the effect of cAMP, converting it from a survival factor to a promoter of DNA damage-induced apoptosis in ALL-derived cell lines and patient-derived leukemic cells in vitro. The starvation-induced sensitization was independent of p53 but was shown to require increased levels of reactive oxygen species (ROS). In turn, the elevated ROS levels enhanced the activation of the mitogen-activated protein kinase p38 (p38 MAPK). The resulting augmented cell death was inhibited both by the ROS scavenger N-acetyl cysteine and the p38 MAPK inhibitor SB 202190. The translational potential of increasing the efficacy of DNA damaging agents in starving ALL cells was supported by in vivo data showing that intermittent fasting, combined with subtherapeutic doses of irradiation, significantly inhibits the leukemia progression in a xenograft model of severe combined immunodeficiency mice.},
}
@article {pmid41534554,
year = {2026},
author = {Fu, W and Yan, Y and Shu, C and Xu, C and Chen, Y and Xia, Y and Chen, J and Chen, Y and Cui, R and Zou, P and Ni, D},
title = {6-Methoxydihydrosanguinarine synergizes with cisplatin to enhance lung cancer cell death via ROS-mediated autophagy, ER stress, and JNK activation.},
journal = {European journal of pharmacology},
volume = {1014},
number = {},
pages = {178544},
doi = {10.1016/j.ejphar.2026.178544},
pmid = {41534554},
issn = {1879-0712},
mesh = {Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Cisplatin/pharmacology ; *Lung Neoplasms/pathology/metabolism/drug therapy ; *Autophagy/drug effects ; Drug Synergism ; Cell Line, Tumor ; *Carcinoma, Non-Small-Cell Lung/pathology/drug therapy/metabolism ; *Isoquinolines/pharmacology ; *Benzophenanthridines/pharmacology ; MAP Kinase Signaling System/drug effects ; *Antineoplastic Agents/pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Animals ; },
abstract = {6-Methoxydihydrosanguinarine is a natural alkaloid derived from medicinal plants that exhibits significant antitumor activity, making it a promising candidate for cancer therapy. However, the exact molecular mechanisms underlying its effects require further investigation. In this study, we investigated the cytotoxicity and underlying mechanisms of 6-Methoxydihydrosanguinarine in human non-small cell lung cancer (NSCLC) cells. Our findings reveal that reactive oxygen species (ROS) accumulation is the key driver of its antitumor activity. Mechanistically, 6-Methoxydihydrosanguinarine activates the JNK signaling pathway and induces endoplasmic reticulum (ER) stress, both of which can be reversed by the ROS scavenger N-acetylcysteine (NAC). Interestingly, 6-Methoxydihydrosanguinarine also activates autophagy, and inhibition of autophagy reverses the JNK and ER stress pathway activation induced by 6-Methoxydihydrosanguinarine. Notably, 6-Methoxydihydrosanguinarine synergistically enhances cisplatin-induced NSCLC cell death, and this synergistic effect is abolished by NAC, highlighting the critical role of ROS accumulation in their combined efficacy. This study systematically elucidates the molecular mechanisms of 6-Methoxydihydrosanguinarine against NSCLC, revealing that, in addition to the JNK and autophagy pathways, ER stress also mediates its antitumor effects. Moreover, our data establish a rationale for exploring 6-Methoxydihydrosanguinarine in NSCLC therapy and highlight its combination with cisplatin as a potentially effective strategy.},
}
@article {pmid41534303,
year = {2026},
author = {Feng, J and Carreño, M and Jung, H and Dayalan Naidu, S and Arroyo-Diaz, N and Ang, AD and Kulkarni, B and Kisielewski, D and Suzuki, T and Yamamoto, M and Hayes, JD and Honda, T and Wilson, L and Leon-Ruiz, B and Eggler, AL and Vitturi, DA and Dinkova-Kostova, AT},
title = {The electrophilic metabolite of kynurenine, kynurenine-CKA, requires C151 in Keap1 to derepress Nrf2.},
journal = {Redox biology},
volume = {90},
number = {},
pages = {104009},
pmid = {41534303},
issn = {2213-2317},
mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics/chemistry ; Animals ; Humans ; Mice ; Receptors, Aryl Hydrocarbon/metabolism/genetics ; *Kynurenine/analogs &amp; derivatives/metabolism/pharmacology ; NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism ; },
abstract = {The Kelch-like ECH-associated protein 1/Nuclear factor-erythroid 2 p45-related factor 2 (Keap1/Nrf2) system responds to a wide array of structurally diverse small molecules, of both exogenous and endogenous origin, by inducing a robust cytoprotective program that allows adaptation during oxidative, metabolic and inflammatory stress. Here, we report that exposure to the tryptophan metabolite kynurenine and its electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA) leads to an increase in the abundance of transcription factor Nrf2 and induction of Nrf2-target genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), in murine and human cells. Additionally, both kynurenine and Kyn-CKA activate the aryl hydrocarbon receptor (AhR). Using cellular thermal shift assays, we found that Kyn-CKA increases the thermal stability of Keap1-mCherry fusion protein, but not free mCherry, indicating target engagement of Keap1, the principal repressor of Nrf2. Critically, the ability of Kyn-CKA to increase the abundance of Nrf2 and expression of NQO1 in mouse embryonic fibroblasts (MEFs) expressing wild-type Keap1 was greatly diminished in C151S-Keap1 mutant MEFs. Furthermore, Kyn-CKA reacts with Keap1 C151 much faster in vitro than with the small molecule thiol N-acetyl cysteine, suggesting that Kyn-CKA is targeted to C151 by the surrounding active site. Experiments in wild-type, AhR-knockout, and Nrf2-knockout primary murine bone marrow-derived macrophages showed that Nrf2 is required for the acute anti-inflammatory activity of Kyn-CKA, whereas AhR is dispensable. Together, these findings demonstrate that Kyn-CKA requires C151 in Keap1 to derepress Nrf2 and reveal that Nrf2, but not AhR, is a main contributor to the anti-inflammatory activity of Kyn-CKA in macrophages.},
}
@article {pmid41533906,
year = {2026},
author = {Guo, Y and Luo, S and Li, W and Wang, X and Sun, W and Zha, W and Zhang, R and Liu, D and Wei, M and Zhang, H and Liu, Q and Liu, Z},
title = {Ferroptosis in Meibomian Gland Progenitor Cells Contributes to Pathogenesis of Meibomian Gland Dysfunction.},
journal = {Investigative ophthalmology &amp; visual science},
volume = {67},
number = {1},
pages = {9},
pmid = {41533906},
issn = {1552-5783},
mesh = {*Ferroptosis/physiology ; Animals ; Mice ; *Meibomian Glands/pathology/metabolism ; Disease Models, Animal ; *Meibomian Gland Dysfunction/metabolism/pathology/etiology ; *Stem Cells/pathology/metabolism ; Mice, Inbred C57BL ; Humans ; Hydrogen Peroxide ; Male ; Epithelial Cells/metabolism/pathology ; Cells, Cultured ; },
abstract = {PURPOSE: Meibomian gland (MG) atrophy in Meibomian gland dysfunction (MGD) is critically linked to progenitor cell (PC) abnormalities. However, the mechanisms underlying PC abnormalities during MGD pathogenesis remain unclear. This study investigates the role of ferroptosis in MG PC abnormalities during MGD pathogenesis.<br><br>METHODS: Three mouse MGD models were established: alkali burn-induced MGD (AK-MGD), blue light-induced MGD (BL-MGD), and age-related MGD (AR-MGD). All exhibited MG atrophy and Lrig1-positive PC abnormalities. Dihydroethidium (DHE) and immunofluorescent staining for Gpx4 and Ptgs2 in MGs were applied to observe the distribution of ferroptotic cells during MGD. Ferroptosis was evaluated in H2O2-treated human MG epithelial cells (HMGECs) by measuring intracellular Fe2+, iron metabolism gene expression, and levels of Gpx4, Slc7a11, and Ptgs2. Ferroptosis signatures were evaluated across models. Ferroptosis inhibitors including Ferrostatin-1 (Fer-1), deferoxamine (DFO), and N-acetylcysteine (NAC) targeting different ferroptosis pathways were applied therapeutically in these MGD models.<br><br>RESULTS: All MGD models demonstrated lipid peroxidation and ferroptosis in MG PCs. In HMGECs, we confirmed that H2O2 treatment induced ferroptosis, which was rescued by ferroptosis inhibitors. Acute and chronic MGD models exhibited distinct ferroptosis signatures. Therapeutic intervention with ferroptosis inhibitors ameliorated MGD manifestations to varying degrees in MGD models.<br><br>CONCLUSIONS: Ferroptosis in MG PCs contributes to the pathogenesis of MGD. MG PCs are preferentially susceptible to ferroptosis. Pharmacological inhibition of ferroptosis represents a promising therapeutic strategy for MGD.},
}
@article {pmid41531336,
year = {2026},
author = {Azuma, R and Yamasaki, T and Sano, K and Mukai, T},
title = {Development of a radioiodinated boronic acid probe for the detection of hydrogen peroxide and peroxynitrite.},
journal = {Free radical research},
volume = {60},
number = {1},
pages = {28-38},
doi = {10.1080/10715762.2026.2617613},
pmid = {41531336},
issn = {1029-2470},
mesh = {*Peroxynitrous Acid/analysis ; *Hydrogen Peroxide/analysis ; Animals ; *Boronic Acids/chemistry ; Mice ; *Iodine Radioisotopes/chemistry ; Male ; Tissue Distribution ; },
abstract = {Hydrogen peroxide and peroxynitrite play important roles as signaling molecules to maintain the biological functions; however, excess levels of these oxidants are associated with various diseases. Despite their important roles in vivo, effective methods to measure these oxidants in the body with high sensitivity have not yet been established. Therefore, in this study, we aimed to design a radioiodinated boronic acid probe for the in vivo detection of hydrogen peroxide and peroxynitrite. The probe contained boronic acid, a well-known substructure that reacts with hydrogen peroxide and peroxynitrite, at positions 3 and 6 of the xanthene moiety and radioiodine at the phthalide moiety of fluorescein. I-125 labeling was successful, resulting in a radiochemical yield of 60% and radiochemical purity of >95%. In vitro selectivity studies demonstrated that the probe showed significant responses to both hydrogen peroxide and peroxynitrite while exhibiting minimal reactivity toward other reactive oxygen species including superoxide, nitric oxide, and peroxy radicals. In biodistribution studies using lipopolysaccharide (LPS)-treated mice generating reactive oxidants, the boronic acid probe was significantly accumulated in various organs damaged by LPS. However, this phenomenon was inhibited by administration of the antioxidant, N-acetylcysteine, to LPS-treated mice. These results highlight the potential of the developed radioiodinated boronic acid probe to detect hydrogen peroxide and peroxynitrite in living organisms, suggesting it as a candidate for the in vivo detection and functional evaluation of these oxidants in various diseases.},
}
@article {pmid41524784,
year = {2026},
author = {Penney, C and Piper, AK and Holliday, J and Tincknell, G and Joosse, SA and Pantel, K and Brungs, D and Ranson, M},
title = {Adaphostin-induced oxidative stress in oesophageal neuroendocrine carcinoma: a potential therapeutic strategy.},
journal = {Medical oncology (Northwood, London, England)},
volume = {43},
number = {2},
pages = {109},
pmid = {41524784},
issn = {1559-131X},
support = {RSP-316-FY2023//Tour de Cure/ ; RSP-316-FY2023//Tour de Cure/ ; RSP-316-FY2023//Tour de Cure/ ; },
mesh = {Humans ; *Esophageal Neoplasms/drug therapy/pathology/metabolism ; *Carcinoma, Neuroendocrine/drug therapy/pathology/metabolism ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Apoptosis/drug effects ; *Antineoplastic Agents/pharmacology ; Cell Survival/drug effects ; DNA Damage/drug effects ; },
abstract = {Advanced oesophageal neuroendocrine carcinoma (ENEC) is a highly aggressive and rare malignancy with poor prognosis. Due to the rarity of this cancer there are currently no standardised treatment regimens for ENEC, and models to study this disease are difficult to obtain. To address this, we screened our established circulating tumour cell line from a patient with metastatic ENEC, termed UWG01CTC, using the LOPAC[®][1280] drug repurposing library. The redox modulatory agent adaphostin was identified as a potent cytotoxin against UWG01CTC but not non-ENEC cell lines. Secondary adaphostin cell viability screens returned IC50 values of 0.201 ± 0.024 µM confirming the high sensitivity of this ENEC CTC line to the drug. Inclusion of the antioxidant N-acetyl cysteine significantly protected the UWG01CTCs against the cytotoxic effects of adaphostin (IC50 = 0.928 ± 0.425 µM), corroborating a mechanism mediated through the generation of reactive oxygen species (ROS). The expression of DNA damage marker phospho-γH2AX and apoptotic marker cleaved PARP1 were both elevated in cells treated with adaphostin, suggesting that the increased intracellular ROS levels induced by the drug causes downstream DNA damage and ultimately apoptosis. Thus, adaphostin shows promise as a potential new and selective treatment for ENEC.},
}
@article {pmid41523401,
year = {2025},
author = {Rasheed, A and Hassan, SH and Mehmood Qadri, H and Ahmed, AB and Ahmed, M and Khan, H and Fatima, N and Azam, A and Dar, SA and Khawaja, AA},
title = {Neurological Manifestations of Aluminum Phosphide (Wheat-Pill/Rice-Pill) Poisoning: A Narrative Review.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e98910},
pmid = {41523401},
issn = {2168-8184},
abstract = {The clinical manifestations of Aluminium Phosphide (AlP) that stem from its misdirected human consumption range from nausea and vomiting to acute respiratory failure, cardiotoxicity and hepatotoxicity, causing sudden death. Currently, there is no standard regimen to deal with this menacing product. This review aimed to highlight the neurological manifestations and treatment options for dealing with wheat pill poisoning. After the literature search, a total of eight studies were included in this study. Study types included five case reports, a prospective case series, a retrospective review, and an autopsy with sample sizes ranging from a single patient to 471 patients. The major symptoms included were dizziness, headache, and weakness in both upper and lower extremities. Reported neurological findings included progressive decline in consciousness, anisocoria with non-reactive pupils, loss of consciousness, convulsions, variable coma grades, and motor deficits. The CT brain findings mentioned in one case report were significant for diffuse bilateral hypoattenuation in the cerebellar hemispheres, midbrain, thalamus, and globus pallidus nuclei. MRI brain revealed multiple cortical and subcortical diffusion restrictions in cerebral hemispheres, consistent with prior global hypoperfusion injury in one case report, while the other showed an acute ischemic infarct in the left posterior cerebral artery (PCA) territory involving left medial temporal, parieto-occipital lobes, left half of the splenium of the corpus callosum and left thalamus. There is some evidence that paraffin oil, co-enzyme Q10, hyperinsulinemia euglycemia, and N-acetylcysteine (NAC) decrease mortality in this poisoning. However, further large-scale randomised controlled trials are needed to definitively evaluate their mortality benefit.},
}
@article {pmid41523131,
year = {2025},
author = {Kim, J and Yi, S and Kang, S and Yae, C and Choi, JM and Kim, SB and Kim, HK},
title = {Liquiritigenin, a licorice-derived flavanone, reduces dry eye pathology via dual anti-inflammatory and antioxidant action.},
journal = {Taiwan journal of ophthalmology},
volume = {15},
number = {4},
pages = {598-610},
pmid = {41523131},
issn = {2211-5072},
abstract = {PURPOSE: Liquiritigenin (LIQ), an active flavanone derived from Glycyrrhiza uralensis, is known to possess potent antioxidant and anti-inflammatory properties. This study aimed to evaluate the antioxidative and anti-inflammatory effects of LIQ on experimental dry eye disease (DED) models.<br><br>MATERIALS AND METHODS: In vitro effects of LIQ were assessed using a hyperosmotic stress model with assays including quantitative polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, and immunofluorescent staining. The antioxidative effect was compared with n-acetyl cysteine (NAC) and the anti-inflammatory effect with dexamethasone (DEX). In vivo, DED was induced by desiccation stress in a controlled environmental chamber mouse model. Tear production rate, corneal staining scores, pro-inflammatory cytokine expression, conjunctival goblet cell density, infiltration of T-helper (Th) 17 cells, and reactive oxygen species (ROS) levels in the lacrimal gland were evaluated.<br><br>RESULTS: In vitro studies demonstrated that LIQ significantly reduced ROS levels, comparable to NAC, and exhibited anti-inflammatory effects similar to DEX. In the mouse model, LIQ treatment significantly increased tear production and reduced corneal staining scores compared to controls, decreased the expression of Interleukin (IL)-1&#x3b2;, IL-4, IL-6, IL-8, IL-13, tumor necrosis factor &#x3b1;, Interferon &#x3b3;, restored conjunctival goblet cell density, reduced Th17 cell infiltration, and lowered ROS levels in the lacrimal gland Microarray analysis revealed LIQ regulated cytokine expression and ROS levels through the modulation of the aldo-keto reductase (AKR) superfamily in hyperosmotic stress conditions.<br><br>CONCLUSION: LIQ shows potential as a therapeutic agent for DED through its dual anti-inflammatory and antioxidative actions, primarily through modulation of the AKR superfamily.},
}
@article {pmid41520042,
year = {2026},
author = {Liu, PK and Chi, YC and Chang, YC and Lin, YH and Chen, CY and Liu, C and Tyan, YC and Chang, KC},
title = {Quercetin attenuates high glucose-induced VEGFA expression in ARPE-19 cells by inhibiting ROS generation, p38 MAPK phosphorylation, and NF-κB activation.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {4987},
pmid = {41520042},
issn = {2045-2322},
support = {114-2314-B-037-115//NSTC/ ; 113-3R45//Kaohsiung Medical University Chung-Ho Memorial Hospital/ ; P30-EY008098/GF/NIH HHS/United States ; unrestricted research grant//Research to Prevent Blindness/ ; P30 EY008098/EY/NEI NIH HHS/United States ; },
abstract = {UNLABELLED: Hyperglycemia-driven oxidative stress and inflammatory signaling in retinal pigment epithelium (RPE) promote overexpression of vascular endothelial growth factor A (VEGFA), contributing to the pathogenesis of diabetic retinopathy (DR). Quercetin, a dietary flavonoid with antioxidant and anti-inflammatory properties, has not been fully evaluated for its ability to counteract high glucose–induced VEGFA upregulation in RPE. Here, ARPE-19 cells were exposed to high glucose (30 mM) with or without quercetin (5 or 20 µM) treatment. VEGFA expression was measured by qPCR and ELISA; intracellular reactive oxygen species (ROS) were assessed using a DCFH-DA probe; and pathway activation was examined by immunoblotting for p38 MAPK and ERK1/2 phosphorylation, IκBα stability, and NF-κB p65 nuclear translocation. N-acetylcysteine (NAC) served as an antioxidant control, and cell viability was monitored using the CCK-8 assay. Quercetin at non-cytotoxic concentrations significantly suppressed high glucose–induced VEGFA mRNA and protein expression, reduced ROS accumulation, and attenuated p38 MAPK phosphorylation without altering ERK1/2 activation. Quercetin also prevented IκBα degradation and diminished p65 nuclear translocation, indicating inhibition of NF-κB signaling. These findings support a model in which quercetin mitigates hyperglycemia-induced VEGFA upregulation in RPE cells at least in part by modulating a ROS–p38 MAPK–NF-κB axis, while not excluding contributions from other glucose- and ROS-sensitive pathways. Quercetin may therefore represent a readily accessible adjunctive strategy to address oxidative stress, inflammation, and VEGFA dysregulation in DR, warranting further in vivo validation.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-35409-5.},
}
@article {pmid41519441,
year = {2026},
author = {Li, Z and Xue, Y and Li, K and Qian, M and Wang, F and Luo, JL and Gao, XJ},
title = {Dietary zinc deficiency regulates the ROS/TLR4/NF-κB pathway to induce pancreatic inflammation and cell death in mice.},
journal = {The Journal of nutritional biochemistry},
volume = {151},
number = {},
pages = {110262},
doi = {10.1016/j.jnutbio.2026.110262},
pmid = {41519441},
issn = {1873-4847},
mesh = {Animals ; *Zinc/deficiency ; *Reactive Oxygen Species/metabolism ; *NF-kappa B/metabolism ; *Toll-Like Receptor 4/metabolism ; Mice ; Signal Transduction ; Cell Death ; *Pancreas/metabolism/pathology ; *Pancreatitis/metabolism/etiology/pathology ; Oxidative Stress ; Male ; Inflammation/metabolism ; Diet ; },
abstract = {Zinc (Zn) deficiency disrupts redox homeostasis in the body. The pancreas is a vital digestive and endocrine organ of the body, and its normal functional operation cannot proceed without the involvement of Zn. In this study, we established in vivo mouse models, including the normal Zn group (CG, 34 mg Zn/kg), Zn-deficient group (LZn, 2 mg Zn/kg), and Zn-supplemented group (HZn, 100 mg Zn/kg), as well as an in vitro Zn-deficient model of Mouse INsulinoma 6 (MIN6) cells. We systematically investigated the effects of Zn deficiency on pancreatic oxidative stress, inflammation, and cell death. The results showed that Zn deficiency significantly decreased the activities of α-amylase and lipase in the pancreas, and led to pancreatic histological damage. Through flow cytometry and detection of antioxidant enzyme activities, it was found that Zn deficiency induces excessive accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA) in the pancreas, and inhibits antioxidant enzyme activities. Using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot, it was observed that Zn deficiency activates the TLR4/NF-κB pathway and significantly increases the expression of the NLRP3 inflammasome and inflammatory factors. Furthermore, Zn deficiency significantly upregulates the expression of apoptosis-related factors (Bax, Caspase-3, Caspase-7, Caspase-9) and necroptosis-related factors (RIPK1, RIPK3, MLKL). Treatment with the antioxidant N-acetylcysteine (NAC) reduces the level of ROS and inhibits the activation of the TLR4/NF-κB pathway, thereby alleviating Zn deficiency-induced inflammation and cell death. Taken together, Zn deficiency induces pancreatic inflammation and cell death by regulating the ROS/TLR4/NF-κB pathway.},
}
@article {pmid41519036,
year = {2026},
author = {Yang, X and Zhou, J and Shangguan, D},
title = {Self-oxidation and proximity crosslinking of G-quadruplex in G-quadruplex /hemin peroxidase system.},
journal = {Talanta},
volume = {302},
number = {},
pages = {129344},
doi = {10.1016/j.talanta.2025.129344},
pmid = {41519036},
issn = {1873-3573},
mesh = {*G-Quadruplexes ; *Hemin/chemistry/metabolism ; Oxidation-Reduction ; *DNA, Catalytic/chemistry/metabolism ; Hydrogen Peroxide/chemistry/metabolism ; Biosensing Techniques ; *Peroxidase/chemistry/metabolism ; *Peroxidases/metabolism/chemistry ; },
abstract = {G-quadruplex (G4)/hemin peroxidase has emerged as a robust platform for signal amplification in biosensors. While offering distinct advantages over protein enzymes, its susceptibility to inactivation often results in low apparent catalytic activity, thereby limiting broader applications. To address this, we investigated the side reactions occurring during the catalytic process of G4/hemin DNAzyme in both N-acetyl-cysteine (NAC) and H2O2 systems. Notably, high-molecular-weight products were observed when the hemin/G4 ratio exceeded 10. Further analysis revealed that these products primarily resulted from the self-oxidation of G4 sequences or proximity cross-linking with hemin fractions, substrates, and coexisting DNA sequences. Our findings provide critical insights into the inactivation mechanism and offer guidance for enhancing the catalytic efficiency of G4-based biosensors.},
}
@article {pmid41516400,
year = {2026},
author = {Zhang, J and Wang, D and Wang, H and Wu, Q and Liu, M and Li, Q and Gong, Z},
title = {Antioxidant N-Acetylcysteine Facilitates Breast Cancer Metas-Tasis via Immunosuppressive Reprogramming of Neutrophils.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
pmid = {41516400},
issn = {1422-0067},
support = {2023KYQD002//Institute of Health and Medicine, Hefei Comprehensive National Science Center/ ; 32400758//National Natural Science Foundation of China/ ; 32470974//National Natural Science Foundation of China/ ; 82472960//National Natural Science Foundation of China/ ; },
mesh = {*Acetylcysteine/pharmacology ; Animals ; *Neutrophils/immunology/drug effects ; Female ; Mice ; *Breast Neoplasms/pathology/immunology/drug therapy ; *Antioxidants/pharmacology ; Humans ; T-Lymphocytes/immunology/drug effects ; Cell Line, Tumor ; *Lung Neoplasms/secondary/immunology ; },
abstract = {N-acetylcysteine (NAC) is a widely used antioxidant. It has also attracted significant research interest with regard to its role in cancer progression, although the mechanisms involved remain controversial and poorly understood. Here, using murine models of breast cancer metastasis, we found that systemic NAC administration significantly enhanced pulmonary metastasis without altering primary tumor growth in immunocompetent mice, whereas this metastasis-promoting property of NAC was abrogated in T cell-deficient mice. This phenomenon was not due to the direct effects of NAC on T cells or tumor cells, since in vitro studies indicated that NAC exhibited no impact on the effector functions of T cells or the malignant behavior of breast cancer cells. Mechanistically, we demonstrated that NAC endows neutrophils with an immunosuppressive phenotype, which is characterized by the upregulation of immunosuppressive genes, and these NAC-educated neutrophils potently suppress the activation and effector functions of T cells. Collectively, our study reveals a previously unrecognized role played by NAC in regulating breast cancer lung metastasis by orchestrating the myeloid-dependent suppression of anti-tumor T cell immunity and suggests a need to consider immune-mediated mechanisms when evaluating the systemic impact of antioxidant agents in cancer patients.},
}
@article {pmid41516202,
year = {2025},
author = {Chrószcz-Porębska, M and Waśkiewicz, S and Gołofit, T and Gadomska-Gajadhur, A},
title = {Synthesis and Characterization of Bioactive Oligoitaconates with Amino Acid Functional Groups for Tissue Engineering.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
pmid = {41516202},
issn = {1422-0067},
support = {504/04496/1020/45.010045//Warsaw University of Technology/ ; },
mesh = {*Tissue Engineering/methods ; Cysteine/chemistry ; *Amino Acids/chemistry ; Spectroscopy, Fourier Transform Infrared ; Acetylcysteine/chemistry ; *Biocompatible Materials/chemistry/chemical synthesis ; },
abstract = {Improving the hydrophilicity and tissue adhesion of polymers remains a significant challenge in tissue engineering and is often addressed by introducing functional groups that enhance polymer-tissue interactions. In this field, L-cysteine (Cys) and N-acetyl-L-cysteine (NAC) are particularly interesting due to their functional carboxyl and amine groups, which are prone to hydrogen bonding. Following this trend, this study (i) investigated the feasibility of grafting Cys or NAC onto the linear oligoitaconates via thio-Michael addition and (ii) examined the influence of amino acid incorporation on the material's physicochemical properties. NMR-based calculations confirmed nearly 100% addition efficiency for Cys and a slightly lower, but still high, efficiency for NAC. FT-IR spectra confirmed thiol-based addition, as signal from the Cys/NAC S-H stretching vibrations was not observed in the adduct's spectra. The obtained adducts showed thermal stability up to 200 °C and glass transition temperatures below -20 °C. They were soluble in common organic solvents, except for Cys adducts with oligo(propylene itaconate) and oligo(hexylene itaconate), which were water-soluble only. Due to the low molecular weight (below 1000 g/mol) of oligoitaconates, their adducts cannot serve as standalone scaffold components. However, they showed potential for use as modifiers for high-molecular-weight polylactide or poly(ɛ-caprolactone)-based scaffolds.},
}
@article {pmid41512939,
year = {2026},
author = {Lei, Y and Xu, R and Zhan, J and Liu, J},
title = {Activation of the Nrf2-Keap1 pathway is associated with NAC-mediated alleviation of nitrite-induced oxidative and endoplasmic reticulum stress and apoptosis in Marsupenaeus japonicus.},
journal = {Fish &amp; shellfish immunology},
volume = {170},
number = {},
pages = {111114},
doi = {10.1016/j.fsi.2026.111114},
pmid = {41512939},
issn = {1095-9947},
mesh = {*Penaeidae/cytology/drug effects ; Animals ; *Nitrites/toxicity ; Oxidative Stress/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Apoptosis ; *Acetylcysteine/pharmacology ; Signal Transduction ; Gene Expression ; Hepatopancreas/drug effects ; Gills/drug effects ; },
abstract = {Nitrite accumulation poses a serious threat to aquatic animals in intensive aquaculture systems. Although the antioxidant role of the Nrf2-Keap1 pathway is well established, its regulatory mechanisms under nitrite stress in crustaceans remain poorly understood. This investigation focused on the protective impact of N-acetylcysteine (NAC) on Marsupenaeus japonicus exposed to nitrite toxicity. Shrimp were injected with NAC or PBS and then exposed to 100 mg/L of nitrite nitrogen for 72 h. The findings revealed that pretreatment with NAC markedly reduced tissue damage in both the hepatopancreas and gills, in comparison to the PBS control group. Additionally, the NAC-treated M. japonicus exhibited upregulated mRNA levels of Nrf2 and its associated antioxidant genes including NQO1, HO-1, CAT, GPx, GST, and SOD, while Keap1 expression was notably suppressed. Additionally, the NAC group downregulated endoplasmic reticulum stress (ERS)-related genes (PERK, eIF2α, ATF4, GRP78, CHOP, IRE1, XBP1, ATF6) and apoptosis-related genes (Caspase-3, Caspase-9, p53, Bax, Apaf-1), while upregulating Bcl-2. Additionally, the NAC group improved total antioxidant capacity (T-AOC) and SOD activity, reduced malondialdehyde (MDA) content and Caspase-3 activity, and decreased the apoptosis rate in the hepatopancreas. The results indicate that NAC alleviates oxidative stress, ERS, and apoptosis triggered by nitrite in M. japonicus. This protective effect is associated with the activation of the Nrf2-Keap1 signaling pathway, suggesting its potential as a therapeutic strategy for nitrite toxicity in crustacean aquaculture.},
}
@article {pmid41510997,
year = {2026},
author = {Du, Z and Wu, J and Zhang, T and Ma, X and Li, Z and Xu, J and You, J and Chen, N and Wu, J},
title = {Lack of receptor for advanced glycation end products attenuates obesity-induced adipose tissue senescence in mice.},
journal = {Adipocyte},
volume = {15},
number = {1},
pages = {2611481},
pmid = {41510997},
issn = {2162-397X},
mesh = {Animals ; *Obesity/metabolism/genetics ; *Receptor for Advanced Glycation End Products/metabolism/genetics/deficiency ; Mice ; *Adipose Tissue/metabolism/pathology ; *Cellular Senescence ; Reactive Oxygen Species/metabolism ; Diet, High-Fat/adverse effects ; Mice, Knockout ; Male ; Sirtuin 1/metabolism ; Mice, Inbred C57BL ; Adipocytes/metabolism ; },
abstract = {The receptor for advanced glycation end products (RAGE) and its ligands are critical drivers of adipose tissue inflammation. While RAGE expression increases in ageing cells and pathological conditions, its specific role in high-fat diet (HFD)-induced adipose tissue senescence remains to be fully elucidated. In this study, we investigated the function of RAGE in the development of adipose tissue senescence associated with obesity. We observed that HFD-fed RAGE-deficient (RAGE[-/-]) mice exhibited significantly reduced body weight and adipocyte hypertrophy compared to wild-type (WT) controls. At the molecular level, RAGE[-/-] mice displayed lower mRNA expression of cell cycle regulators and markers of the senescence-associated secretory phenotype. This anti-senescent phenotype was accompanied by decreased reactive oxygen species (ROS) production and elevated expression of anti-oxidant genes. Mechanistically, the lack of RAGE resulted in the upregulation of silent information regulator type 1 (SIRT1) in adipose tissues. Notably, the inhibition of SIRT1 reversed these anti-senescent effects and attenuated anti-oxidant gene expression in RAGE-deficient mice. Furthermore, while antioxidant treatment with N-acetylcysteine (NAC) reduced p53 in WT mice, it failed to fully suppress p16 and p21, whereas NAC treatment in RAGE[-/-] mice significantly downregulated all senescence markers, suggesting a synergistic protective effect. In conclusion, our results demonstrated that RAGE deficiency improved anti-oxidant properties and prevents adipocyte senescence via the SIRT1 signalling pathway, highlighting a potential therapeutic target for obesity-associated tissue dysfunction.},
}
@article {pmid41509112,
year = {2025},
author = {Esparham, F and Rajabian, F and Ghasemzadeh Rahbardar, M and Razavi, BM and Khajavi Rad, A and Amoueian, S and Hosseinzadeh, H},
title = {Evaluating the effect of rutin on contrast-induced nephropathy in rats.},
journal = {Avicenna journal of phytomedicine},
volume = {15},
number = {6},
pages = {1726-1740},
pmid = {41509112},
issn = {2228-7930},
abstract = {OBJECTIVE: Contrast-induced nephropathy is a common cause of acute kidney injury, and oxidative stress plays an important role in its development. The flavonoid rutin is of interest for its potential antioxidant properties. This study aimed to assess the protective effects of rutin against contrast-induced renal toxicity in rats.<br><br>MATERIALS AND METHODS: Eight groups of male Wistar rats (n=6 in each group) were designed: (1) Sham, (2) Premedication-control (N(&#x3c9;)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.)+indomethacin (10 mg/kg, i.p.)), (3) Contrast medium (L-NAME+indomethacin+diatrizoate (12.5 ml/kg, i.p)), (4-6) Rutin (25, 50, and 100 mg/kg, p.o., for 7 days)+L-NAME+indomethacin+ diatrizoate, (7) N-acetylcysteine (NAC, 125 mg/kg, i.p.), L-NAME+indomethacin+diatrizoate, and (8) Rutin-alone (100 mg/kg). All study groups except for the sham and rutin-alone were subjected to 48 hr of water deprivation. On day 8, blood and kidney samples were isolated to evaluate oxidative stress, biochemical and histopathological changes.<br><br>RESULTS: The levels of serum blood urea nitrogen (BUN), creatinine, and malondialdehyde (MDA) were raised by diatrizoate, while glutathione (GSH) levels in renal tissue were reduced. Rutin (25, 50, and 100 mg/kg) improved biochemical parameters and oxidative stress. Diatrizoate also resulted in interstitial edema, medullary congestion, proteinaceous casts, and severe tubular necrosis in kidney tissue. Rutin (100 mg/kg) reduced tubular necrosis and interstitial edema but had no significant effect on the formation of medullary congestion and proteinaceous casts in renal tissue.<br><br>CONCLUSION: Oxidative stress triggered by contrast-induced nephropathy is caused by a rise in MDA and a decline in GSH amounts. Rutin protects kidney tissue against contrast-induced damage through its antioxidant effect.},
}
@article {pmid41504138,
year = {2026},
author = {Singh, P and Kumari, S and Singh, R},
title = {Intranasal Curcumin and N-Acetyl l-Cysteine (NAC) Attenuates Dibutyl Phthalate (DBP)-Aggravated Airway Inflammation by Targeting Ferroptosis via Nrf-2/GPx4-SLC7A11.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.70035},
pmid = {41504138},
issn = {1522-7278},
support = {//Department of Biotechnology, Ministry of Science and Technology, India/ ; //Institute of Eminence (IOE), Banaras Hindu University/ ; },
abstract = {Ferroptosis plays a significant role in the pathophysiological development of several diseases. It is an iron-dependent type of controlled cell death triggered by oxidative stress and lipid peroxidation. Nrf2, a key regulator of the antioxidant response, protects cells from ferroptosis by regulating genes involved in iron metabolism and the synthesis and breakdown of glutathione (GSH). This study was undertaken to investigate the relationship between Nrf2-mediated oxidative stress and ferroptosis in allergic asthmatic mice, particularly when the environmental toxin DBP is present. DBP disrupts iron homeostasis and causes asthma exacerbation by inducing iron accumulation and increasing hemosiderin-loaded macrophage numbers in the lungs. N-acetylcysteine (NAC) and curcumin antioxidant treatments significantly reduced ferroptotic damage, increased downstream targets such as GPx4, SLC7A11, and SLC40A1, and activated the Nrf2 pathway. On the other hand, ferroptosis and lung damage were exacerbated by Nrf2 suppression. In addition to elevating reactive oxygen species (ROS), nitric oxide (NO), and 8-oxoguanine (8-oxodG), DBP exposure also decreased GSH, GPx, and SOD, which led to lipid peroxidation and increased levels of malondialdehyde (MDA). These results demonstrate the therapeutic potential of Nrf2 targeting to prevent oxidative lung injury and ferroptosis in asthma triggered by DBP.},
}
@article {pmid41504037,
year = {2025},
author = {Qiao, W and Huang, M and Chen, L and Goltzman, D and Miao, D},
title = {Active Vitamin D Insufficiency Accelerates Skeletal Aging via Oxidative Stress and p16-Mediated Senescence.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {12},
pages = {46123},
doi = {10.31083/FBL46123},
pmid = {41504037},
issn = {2768-6698},
support = {81730066//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Oxidative Stress ; *Vitamin D Deficiency/metabolism ; Male ; Mice ; *Cellular Senescence ; *Aging/metabolism ; *Cyclin-Dependent Kinase Inhibitor p16/metabolism/genetics ; DNA Damage ; Reactive Oxygen Species/metabolism ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics ; *Bone and Bones/metabolism/pathology ; Acetylcysteine/pharmacology ; Vitamin D ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Vitamin D is essential for skeletal health, but its role in redox homeostasis and cellular senescence during aging in vivo is unclear. We therefore investigated whether active vitamin D insufficiency accelerates bone loss via oxidative stress and senescence pathways.<br><br>METHODS: Male wild-type (WT) and Cyp27b1 haploinsufficient mice (modeling vitamin D insufficiency) were treated with N-acetylcysteine (NAC) or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Double-mutant p16[-/-]Cyp27b1[+/-] mice were used to assess the role of the tumor suppressor protein p16. Mice were maintained until 8 months of age in a specific pathogen-free facility. Outcomes included lifespan (n = variable per group, monitored daily); generation of oxidative stress (determined by serum malondialdehyde [MDA] levels via assay kit); generation of bone reactive oxygen species [ROS] (determined via flow cytometry), development of DNA damage (indicated by 8-hydroxy-2'-deoxyguanosine [8-OHdG] and &#x3b3;-H2A.X generation and determined via immunohistochemistry and Western blot); and senescence (assessed by generation of &#x3b2;-galactosidase [&#x3b2;-gal], p16, and senescence-associated secretory phenotype [SASP] cytokines as determined via staining, blot, and real-time reverse transcription polymerase chain reaction). Additionally, bone microarchitecture was examined via micro-computed tomography and histomorphometry. Data from at least 5 mice per group were analyzed using unpaired Student's t-test for two-group comparisons and two-way analysis of variance for multi-group comparisons, with significance at p < 0.05.<br><br>RESULTS: Compared with wild-type controls, Cyp27b1[+/-] mice showed a significantly shorter lifespan, higher oxidative stress, greater DNA damage, increased senescence markers, and lower trabecular bone volume (all p < 0.05). In Cyp27b1[+/-] mice, treatment with either N-acetylcysteine or 1,25(OH)2D3 significantly improved survival, reduced oxidative stress and DNA damage, attenuated senescence markers, and increased bone volume relative to untreated Cyp27b1[+/-] mice (p < 0.05 for all relevant comparisons; n = 5 per group). Genetic deletion of p16 in Cyp27b1[+/-]mice similarly increased bone volume and reduced senescence-associated readouts compared with Cyp27b1[+/-] controls (p < 0.05; n = 5).<br><br>CONCLUSIONS: Active vitamin D insufficiency accelerates skeletal aging in vivo through a pathway involving reactive oxygen species-DNA damage-p16/senescence-associated secretory phenotype. Antioxidants, vitamin D repletion, or p16 inhibition rescued bone loss, highlighting redox-senescence axes as potential therapeutic targets for osteoporosis.},
}
@article {pmid41503729,
year = {2026},
author = {Yu, T and Wang, B},
title = {N-acetylcysteine attenuates benzo[a]pyrene-exacerbated asthma lung injury by inhibiting mucous hypersecretion and apoptosis via the ROS/CREB/ERK pathway.},
journal = {The Journal of asthma : official journal of the Association for the Care of Asthma},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/02770903.2025.2612521},
pmid = {41503729},
issn = {1532-4303},
abstract = {OBJECTIVE: To investigate the protective effect of N-acetylcysteine (NAC) against benzo[a]pyrene (BaP)-aggravated lung injury in asthma and to elucidate whether it is mediated through the ROS/CREB/ERK signaling pathway.<br><br>METHODS: Twenty-four BALB/c mice were randomly divided into Control, Model (OVA&#x2009;+&#x2009;BaP), and Intervention (OVA&#x2009;+&#x2009;BaP&#x2009;+&#x2009;NAC) groups. An aggravated asthma model was established by ovalbumin (OVA) sensitization/challenge combined with intratracheal instillation of BaP. The NAC group received NAC via gavage. Airway inflammation and mucus secretion were assessed by H&amp;E and PAS staining. Serum IgE levels were measured by ELISA. SOD activity and MDA content were detected using commercial kits. ROS levels in lung tissue were observed by fluorescence staining. The mRNA expression of mucin genes (MUC5AC, MUC5B, MUC16, etc.) was detected by qPCR. The protein expression of apoptosis-related markers (Bax, Bcl-2) and signaling pathway components (p-ERK1/2, p-CREB) was measured by Western Blot.<br><br>RESULTS: Compared with the Model group, NAC intervention significantly alleviated airway inflammatory cell infiltration, mucus hypersecretion, and epithelial damage, and reduced serum IgE levels. Meanwhile, NAC effectively decreased ROS and MDA levels, increased SOD activity in lung tissue, reversed the BaP-induced upregulation of MUC5AC, MUC5B, and MUC16 genes, and modulated the Bax/Bcl-2 ratio to inhibit apoptosis. Mechanistically, NAC significantly inhibited BaP-induced phosphorylation of ERK1/2 and CREB.<br><br>CONCLUSION: NAC can mitigate BaP-induced airway mucus hypersecretion and apoptosis, thereby alleviating asthma lung injury, by scavenging ROS and inhibiting the overactivation of the ROS/CREB/ERK signaling pathway. This study provides experimental evidence supporting NAC as a potential therapeutic strategy for preventing and treating air pollution-associated asthma.},
}
@article {pmid41503441,
year = {2026},
author = {Gu, HJ and Han, GU and Kim, SG and Moon, SH and Shin, SH and Ryu, BY},
title = {Bisphenol AF induces mouse spermatogonia apoptosis via reactive oxygen species-mediated Beclin-1 cleavage.},
journal = {Toxicological research},
volume = {42},
number = {1},
pages = {113-125},
pmid = {41503441},
issn = {1976-8257},
abstract = {Oxidative stress plays an essential role in homeostasis, cell signaling, and host defense mechanisms. However, excessive levels are harmful and cause DNA damage, lipid peroxidation, and mitochondrial dysfunction, ultimately causing cell death. Oxiapoptophagy, a cell death mechanism driven by excessive reactive oxygen species (ROS), involves both apoptosis and autophagy. This study investigated the mechanisms underlying bisphenol AF (BPAF)-induced cell death in mouse GC-1 spermatogonia (spg), using 7-ketocholesterol (7KC) as a reference oxiapoptophagy inducer. Both 7KC and BPAF inhibited GC-1 spg proliferation with comparable half-maximal inhibitory concentration (IC50): 16.9 µM for 7KC and 16.5 µM for BPAF. However, BPAF induced significantly higher ROS levels than 7KC. At 20 µM, BPAF predominantly triggered apoptosis, whereas 7KC mainly promoted autophagy. BPAF evidently increased cleaved Beclin-1 levels, suggesting a transition from autophagy to apoptosis and implicating Beclin-1 cleavage as key modulator of apoptosis. Furthermore, the ROS scavenger N-acetyl cysteine (NAC) reduced BPAF-induced ROS production, suppressed Beclin-1 cleavage, and partially restored GC-1 spg proliferation. Collectively, these findings demonstrate that BPAF-induced spermatogonia toxicity is mediated by ROS and regulated through Beclin-1 cleavage, underscoring the need for further investigation of BPAF's reproductive toxicity and the development of strategies to protect male reproductive health.},
}
@article {pmid41502527,
year = {2025},
author = {Shi, H and Chen, L and Huang, J and Lin, X and Huang, L and Tang, M and Lu, K and Wang, W and Zhu, M},
title = {CSRNP1 Promotes Apoptosis and Mitochondrial Dysfunction via ROS-Mediated JNK/p38 MAPK Pathway Activation in Hepatocellular Carcinoma.},
journal = {Oncology research},
volume = {34},
number = {1},
pages = {17},
pmid = {41502527},
issn = {1555-3906},
mesh = {Humans ; *Carcinoma, Hepatocellular/pathology/genetics/metabolism ; *Liver Neoplasms/pathology/genetics/metabolism ; Apoptosis/genetics ; *Reactive Oxygen Species/metabolism ; *Mitochondria/metabolism/pathology ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Cell Proliferation ; *MAP Kinase Signaling System ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Prognosis ; JNK Mitogen-Activated Protein Kinases/metabolism ; Cell Movement ; },
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms, with a particular focus on mitochondrial function and apoptosis.<br><br>METHODS: Differential expression analyses were performed across three datasets-The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC), GSE36076, and GSE95698-to identify overlapping differentially expressed genes (DEGs). A prognostic risk model was then constructed. Cysteine/serine-rich nuclear protein 1 (CSRNP1) expression levels in HCC cell lines were assessed via western blot (WB) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effects of CSRNP1 knockdown or overexpression on cell proliferation, migration, and apoptosis were evaluated using cell counting-8 (CCK-8) assays, Transwell assays, and flow cytometry. Mitochondrial ultrastructure was examined by transmission electron microscopy, and intracellular and mitochondrial reactive oxygen species (mROS) levels were measured using specific fluorescent probes. WB was used to assess activation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathway, and pathway dependence was examined using the ROS scavenger N-Acetylcysteine (NAC) and the JNK inhibitor SP600125.<br><br>RESULTS: A six-gene prognostic model was established, comprising downregulated genes (NR4A1 and CSRNP1) and upregulated genes (CENPQ, YAE1, FANCF, and POC5) in HCC. Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis. Conversely, CSRNP1 overexpression impaired mitochondrial integrity, increased both mitochondrial and cytoplasmic ROS levels, and activated the JNK/p38 MAPK pathway. Notably, treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.<br><br>CONCLUSION: CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC. It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner. These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.},
}
@article {pmid41500430,
year = {2026},
author = {Zhang, W and Lin, H and Xiao, Z and Shen, D and Xia, D and Qiu, Z and Zhang, X and Zhao, Q},
title = {Trichlorfon induces damage of growth and development of Bombyx mori through ferroptosis pathway.},
journal = {Insect biochemistry and molecular biology},
volume = {188},
number = {},
pages = {104488},
doi = {10.1016/j.ibmb.2026.104488},
pmid = {41500430},
issn = {1879-0240},
mesh = {Animals ; *Bombyx/growth &amp; development/drug effects/metabolism/genetics ; *Ferroptosis/drug effects ; *Insecticides/toxicity ; Larva/drug effects/growth &amp; development ; },
abstract = {Trichlorfon (TCF), an organophosphorus pesticide, has long been used in agriculture as an insecticide for crop protection. However, its residual presence has caused significant economic losses to the sericulture industry, hindering the development of Bombyx mori (B. mori) farming. Although previous studies have investigated the toxicity of TCF to silkworms, the detailed toxic effects and molecular mechanisms remain poorly understood. In this study, the potential molecular targets and mechanisms of TCF-induced injury in silkworms were investigated in vivo and in vitro by combining RNA sequencing, qRT-PCR and other techniques. It is found that TCF exposure leads to damage of growth and development in silkworms, as evidenced by reduced body weight, increased mortality, and decline of cluster, cocooning, pupation and egg production. Further RNA sequencing analysis identified several differentially expressed genes, particularly LOC101744260, as well as altered pathways, notably the glutamine metabolism pathway-both of which are closely associated with ferroptosis. In vivo and in vitro experiments have confirmed that the expression levels of ferroptosis-related genes, including Fer HCH, Fer 2LCH, Keap1, Tf, Gtpx and SOD1 exhibited significant changes in expression levels. These changes are accompanied by elevated intracellular Fe[2+] and Fe[3+] levels and oxidative stress. Moreover, N-acetylcysteine (NAC) treatment partially reverses TCF-induced growth and developmental impairments at the individual and cellular levels. Taken together, these results indicate for the first time that TCF exposure induces damage of growth and development in silkworms by activating the ferroptosis pathway. This study provides a new insight into the toxic mechanisms of TCF in silkworms and offers a theoretical basis for the prevention and control of pesticide pollution in silkworms industry.},
}
@article {pmid41496214,
year = {2026},
author = {Seomoon, K and Lee, H and Hong, T and Park, J and Ying, W and Song, G and Jeong, W and Lim, W},
title = {Multi-organ toxicity via oxidative stress and disrupting mitochondrial plasticity induced by bendiocarb in zebrafish.},
journal = {Redox biology},
volume = {89},
number = {},
pages = {104001},
pmid = {41496214},
issn = {2213-2317},
mesh = {Animals ; *Zebrafish/metabolism/genetics ; *Oxidative Stress/drug effects ; *Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Animals, Genetically Modified ; *Insecticides/toxicity ; Larva/drug effects ; },
abstract = {Bendiocarb, a carbamate insecticide, is widely applied in various circumstances; however, it poses a potential threat to various non-target organisms. Although many researchers have focused on defining the toxic effects of bendiocarb, those associated with early and organ development remain poorly understood. In this study, we evaluated the developmental and organ-specific toxic mechanisms of bendiocarb in a zebrafish model. Exposure of bendiocarb decreased viability of zebrafish larvae by changing morphology and inducing production of reactive oxygen species with a decrease of the expression of antioxidant genes cat and sod2. In addition, bendiocarb affected mitochondrial bioenergetics and plasticity with reduction of mitochondrial complexes I, III, and V related genes leading to suppression of ATP generation. To investigate multi-organ toxic effects of bendiocarb, various transgenic zebrafish were utilized, for example, cardiac toxicity, impaired vasculature, and interfered blood flow were confirmed using cmlc2:dsRed, fli1a:EGFP, and gata1a:dsRed. Hepatotoxicity was examined using the fabp10a:dsRed model, and pancreatic toxicity was elucidated using the elastase:EGFP and insulin:EGFP models. Additionally, abnormal neuronal development was observed following treatment with olig2:dsRed and gad1b:EGFP. Moreover, changes at the molecular level by whole mount in situ hybridization and qPCR analyses were consistent with our observations. Furthermore, N-acetylcysteine (NAC) co-treatment substantially ameliorated developmental toxicity across multiple organ systems, including the cardiovascular, metabolic, and nervous systems. Taken together, this study provides novel perspectives on the system-level toxicity of bendiocarb and its molecular mechanisms of action in zebrafish.},
}
@article {pmid41493763,
year = {2026},
author = {He, Q and Hu, X and Li, X and Li, N and Wu, JL},
title = {Covalently Active Metabolites of Bisphenol A Analogs by Mass Spectrometry Diagnostic Ions: Possible Mechanisms of Their Toxicity.},
journal = {Chemical research in toxicology},
volume = {39},
number = {1},
pages = {157-167},
pmid = {41493763},
issn = {1520-5010},
mesh = {*Phenols/metabolism/chemistry/toxicity ; *Benzhydryl Compounds/metabolism/chemistry/toxicity ; Mass Spectrometry ; Molecular Structure ; Cysteine/chemistry/metabolism ; Ions/chemistry/metabolism ; Acetylcysteine/chemistry ; Humans ; Bisphenol A Compounds ; },
abstract = {Bisphenol A analogs (BPs), used as BPA alternatives, have drawn great concerns due to their potential adverse effects. Studies have shown that reactive metabolites (RMs) formed in vitro and in vivo could covalently bind to nucleophilic macromolecules to elicit toxicity. However, the bioactivation potential of BPs and their capacity to covalently modify amino acid residues within proteins have been poorly characterized. Thus, this study systematically characterized the metabolic activation of eight BPs and their reactivity toward cysteine. Using N-acetylcysteine (NAC) as a trapping agent to capture RMs, we developed a novel nontargeted fragment screening strategy for cysteine adduct identification and mechanistic exploration. Integrating calculated electron affinity results, mechanistic analyses revealed a common activation pathway across multiple BPs involving oxidation, ipso-addition, and ipso-substitution. Also, the abundances of cysteine adducts correlated with metabolic rates of individual BPs, underscoring structure-reactivity relationships. These results provided critical mechanistic insight into BPs bioactivation, implicating their potential toxicity risk and supporting environmental risk evaluation.},
}
@article {pmid41492367,
year = {2026},
author = {Zhang, Y and Jin, Z and Xu, L and Zhong, Z and Wang, X and Gao, C and Li, L},
title = {ROS-scavenging nanoparticles loaded with tectorigenin protect against acetaminophen-induced hepatotoxicity by interrupting the calcium/ROS-mediated pathogenic endoplasmic reticulum-Mitochondrial signaling cascade.},
journal = {Bioactive materials},
volume = {58},
number = {},
pages = {408-421},
pmid = {41492367},
issn = {2452-199X},
abstract = {Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI) and acute liver failure (ALF) worldwide, representing a major clinical and public health challenge due to its rapid onset and high morbidity. Current clinical treatment is limited to N-acetylcysteine (NAC), but its efficacy is highly time-dependent and the prolonged regimen imposes additional clinical burdens and side effects. Natural compounds hold tremendous promise for hepatoprotection, but their clinical translation is limited by unfavorable physicochemical and pharmacokinetic properties. In this study, tectorigenin (Tec), an isoflavone possessing anti-inflammatory and antioxidative activity, was encapsulated within a reactive oxygen species (ROS)-responsive nanoplatform (PBHB@Tec) to enhance bioavailability and enable site-selective hepatoprotection. PBHB@Tec possessed diameters compatible with passage through hepatic sinusoidal fenestrae into the space of Disse enabling direct hepatocyte interaction, while exhibiting potent ROS scavenging activity and undergoing ROS-triggered morphological degradation that accelerated Tec release under oxidative conditions. In an APAP-induced ALI mouse model, PBHB@Tec markedly attenuated ALI phenotypes. Mechanistically, PBHB@Tec reduced endoplasmic reticulum (ER) stress, which alleviated ER Ca[2+] leak and subsequently prevented mitochondrial Ca[2+] overload. This, in turn, lowered mitochondrial ROS production and restored antioxidant defenses, collectively disrupting the feedforward calcium/ROS apoptotic cascade. These broad improvements in ER-mitochondrial homeostasis positioning PBHB@Tec as a promising ROS-responsive nanotherapy for APAP-induced hepatotoxicity.},
}
@article {pmid41490888,
year = {2026},
author = {Wei, Y and Sun, D and Wu, F and Zhang, S and Cai, B and Ma, Y and Zheng, H and Shi, X and Li, Y and Le, S and Zhou, X and Jin, L and Wang, J},
title = {Mitochondrial retrograde signaling initiates HIF-1α/BNIP3/NIX-mediated mitophagy in Tibetan high-altitude adaptation.},
journal = {Cell death discovery},
volume = {12},
number = {1},
pages = {81},
pmid = {41490888},
issn = {2058-7716},
support = {U23A20475, 32288101, 82300574, 31871436//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Genome-wide studies have identified the nuclear gene EPAS1 and the mitochondrial M9a haplogroup as pivotal contributors to hypoxia adaptation in Tibetans. However, the interaction between these two genetic components is not yet clear. In this study, we demonstrate that cells harboring the Tibetan-specific M9a haplogroup with downregulated EPAS1 (M9a+shEPAS1) exhibit enhanced cellular function under hypoxic conditions. These cells display improved mitochondrial function and proliferation, alongside reduced apoptosis and mtDNA-mediated inflammation, driven by the activation of HIF-1α-BNIP3/NIX-mediated mitophagy and an increase in reactive oxygen species (ROS) levels. Furthermore, treatment with N-acetylcysteine (NAC), PX-478, or Mdivi-1 significantly attenuated BNIP3/NIX-mediated mitophagy, leading to an aggravation of mtDNA-mediated inflammation and apoptosis in M9a+shEPAS1 cells during hypoxia. This study first reveals that ROS-driven HIF-1α-BNIP3/NIX-mediated mitophagy mitigates hypoxia-induced inflammation and apoptosis, contributing to the enhanced hypoxia adaptation observed in Tibetans. HIF-1α-BNIP3/NIX-mediated mitophagy may offer potential therapeutic targets for high-altitude illnesses by regulating cellular energy metabolism and inflammation.},
}
@article {pmid41486713,
year = {2025},
author = {Shruthi, T and Govindan, L and Kanagarajan, SS},
title = {Fluoxetine versus N-acetylcysteine in reducing craving in Indian men with alcohol dependence syndrome: a randomised controlled trial.},
journal = {East Asian archives of psychiatry : official journal of the Hong Kong College of Psychiatrists = Dong Ya jing shen ke xue zhi : Xianggang jing shen ke yi xue yuan qi kan},
volume = {35},
number = {4},
pages = {224-228},
doi = {10.12809/eaap2591},
pmid = {41486713},
issn = {2224-7041},
mesh = {Humans ; Male ; *Acetylcysteine/therapeutic use/adverse effects ; Adult ; *Craving/drug effects ; *Alcoholism/drug therapy/psychology ; Middle Aged ; *Fluoxetine/therapeutic use/adverse effects ; India ; Young Adult ; Treatment Outcome ; Adolescent ; Recurrence ; Aged ; },
abstract = {OBJECTIVES: To compare the efficacy of fluoxetine and N-acetylcysteine (NAC) in reducing craving, relapse, and improving treatment adherence in men with alcohol dependence syndrome (ADS).<br><br>METHODS: Men aged 18 to 65 years with a diagnosis of ADS who had maintained &#x2265;7 days of abstinence from alcohol were recruited. Participants were randomised in a 1:1 ratio to receive either oral fluoxetine 20 mg/day or NAC 600 mg twice/day for 12 weeks. Participants were followed up at weeks 4, 8, and 12. Outcome measures included the Penn Alcohol Craving Scale (PACS), relapse rate, treatment adherence, and adverse effects.<br><br>RESULTS: In total, 100 men were equally randomised to receive either fluoxetine or NAC. Both fluoxetine and NAC were effective in lowering PACS scores over 12 weeks, with scores being lower in the NAC group than in the fluoxetine group at week 4 (15.4 vs 17.6, p = 0.03), week 8 (11.3 vs 14.2, p = 0.002), and week 12 (7.8 vs 11.1, p < 0.001). The reduction in PACS scores was significantly greater in the NAC group from week 4 onward. Relapse rates were lower in the NAC group (18.0% vs 32.0%, p = 0.049). Treatment adherence was higher (but not significantly) in the NAC group (90.0% vs 84.0%, p = 0.38). Both medications were well tolerated. All adverse effects were mild.<br><br>CONCLUSION: Both fluoxetine and NAC were effective in reducing alcohol craving over 12 weeks, with greater reduction in the NAC group at each follow-up assessment. The NAC group also had a lower relapse rate and better adherence and tolerability.},
}
@article {pmid41486682,
year = {2026},
author = {Kiel, A and Luty, M and Kralemann-Köhler, A and Helweg, LP and Schürstedt-Seher, J and Kotlinowski, J and Pospíšil, J and Lekka, M and Ly, TD and Huser, T and Schulte Am Esch, J and Hübner, W and Szafranska, K and Zapotoczny, B},
title = {Offsetting ROS-Mediated Arrest of Endothelial Fenestration Dynamics Permits Long-Term Optical Super-Resolution Imaging Validated by AFM.},
journal = {ACS applied materials &amp; interfaces},
volume = {18},
number = {1},
pages = {927-940},
pmid = {41486682},
issn = {1944-8252},
mesh = {*Reactive Oxygen Species/metabolism ; *Endothelial Cells/metabolism/cytology ; *Microscopy, Atomic Force ; Animals ; Microscopy, Fluorescence ; Liver/cytology ; Humans ; },
abstract = {Advances in cell biology create the demand for developing methods capable of resolving the structure and dynamics of subcellular organelles in living cells, which are beyond the reach of classical microscopy. Live-cell super-resolution fluorescence imaging provides this capability; however, in practice, its application is limited by phototoxicity, which perturbs cellular features and interferes with natural mechanisms of biological processes, providing a biased interpretation. Liver Sinusoidal Endothelial Cells (LSECs), with their nanoscale fenestrations that are physiologically critical and highly dynamic structures in the native state, represent a particularly demanding system for fluorescence-based microscopy. Here, we identify that photoactivation-generated reactive oxygen species (ROS) are the principal cause of fenestration arrest in fluorescence microscopy. By implementing three-dimensional super-resolution structured illumination microscopy (3D SR-SIM), we systematically evaluate a range of fluorophores and ROS scavengers to optimize imaging conditions. By combining BioTracker staining, carbon dioxide-independent medium supplemented with N-acetylcysteine (NAC), we preserved fenestration dynamics without altering the number/size of fenestrations. Complementary atomic force microscopy (AFM) validated that the combination of light and dye exposure impairs fenestration dynamics through ROS, in the absence of antioxidant supplementation. Additionally, AFM provides insights into the cells' nanomechanical changes upon illumination. Our findings confirm the mechanism underlying imaging-induced artifacts in LSECs observed in the literature and provide a broadly applicable framework for extending live-cell super-resolution microscopy of living cells.},
}
@article {pmid41485463,
year = {2026},
author = {Patwardhan, UM and Soni, C and Mannava, S and Campwala, I and Vacaru, A and Cope, J and Soundappan, SV and Moores, D and Radulescu, A and Cromeens, BP and Waltz, P and Gollin, G},
title = {Operative Management of Meconium Ileus With Needle Injection of N-Acetylcysteine.},
journal = {The Journal of surgical research},
volume = {318},
number = {},
pages = {9-13},
doi = {10.1016/j.jss.2025.12.001},
pmid = {41485463},
issn = {1095-8673},
mesh = {Humans ; Retrospective Studies ; *Acetylcysteine/administration &amp; dosage ; Male ; Female ; Infant, Newborn ; *Meconium Ileus/surgery/therapy ; Treatment Outcome ; Operative Time ; Needles ; Injections/instrumentation/methods ; Meconium ; Enteral Nutrition/statistics &amp; numerical data ; *Ileus/etiology ; },
abstract = {INTRODUCTION: The operative management of meconium ileus in infants often includes enterotomy or appendectomy with N-acetylcysteine (NAC) instillation. Some have adopted an approach whereby NAC is instead injected directly into the meconium-bearing ileum at multiple sites with a small-gauge needle. We hypothesized that this technique would facilitate the mobilization of meconium without an enterotomy or even appendectomy.<br><br>METHODS: A retrospective study of neonates who underwent operative management of meconium ileus at 6 hospitals in the United States and Australia between 2010 and 2021 was conducted. Outcomes after NAC instillation at multiple sites with a 27G needle injection versus enterotomy or the appendiceal stump were assessed. The primary outcomes were operative duration and time to full enteral feedings.<br><br>RESULTS: Inclusion criteria were met in 52 patients and 9 (17.3%) underwent needle injection of NAC. Meconium was evacuated via the appendiceal stump (33%) or colon and passed via rectum (67%) in all patients in whom NAC was injected via a needle but in only 4 (9%) of those who were administered NAC via an enterotomy. Time to first stool, first enteral feeding, goal enteral feedings, and postoperative length of stay did not differ based on the operative approach. The median operative time in the needle injection group was significantly shorter (90 versus 133 min, P = 0.009).<br><br>CONCLUSIONS: Needle injection of NAC appears to be safe and effective in clearing inspissated meconium in neonates who required operative management. It obviated the need for enteral violation in the majority of cases and resulted in reduced operative time.},
}
@article {pmid41483163,
year = {2026},
author = {Nicholson, SE and Hewitt, KA and Brauen, CS and Henricks, AM},
title = {Prenatal antioxidant treatment suppresses maternal immune activation induced increases in alcohol self-administration in a sex-specific manner.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41483163},
issn = {1432-2072},
support = {Alcohol and Drug Abuse Research Program//Alcohol and Drug Abuse Research Program/ ; },
abstract = {RATIONALE: Prenatal exposure to infection is a risk factor for neuropsychiatric disorders that often co-occur with alcohol misuse. However, the mechanisms by which early exposure to infection might increase the risk of such disorders remains unclear. One hypothesis is that prenatal stressors interact with adolescent stressors (i.e., "two-hits") to promote alcohol misuse development.<br><br>OBJECTIVES: The current project tested whether maternal immune activation (MIA) combined with adolescent alcohol exposure (AA) increases the motivation to work for alcohol and negative affect in adulthood, and whether prenatal antioxidant treatment prevents these effects.<br><br>METHODS: Pregnant Sprague-Dawley rats were exposed to poly(I: C) (4&#xa0;mg/kg) or saline on gestational day 15, and the antioxidant n-acetylcysteine (NAC; 100&#xa0;mg/kg) or saline 24&#xa0;h before and after poly(I: C). Offspring had 24-hour access to 10% ethanol and water during adolescence. In adulthood, offspring were trained to self-administer 10% ethanol and tested on escalating schedules of reinforcement. Elevated plus maze (EPM) behavior was assessed on non-self-administration days.<br><br>RESULTS: Poly(I: C) and NAC treatment independently led to an increased willingness to work for alcohol in males, but not females, relative to same-sex controls. NAC treatment suppressed the MIA-induced increase in alcohol-seeking. Poly(I: C) increased locomotor activity in the EPM in both sexes, independent of NAC, without altering open or closed arm time.<br><br>CONCLUSIONS: These data support the hypothesis that MIA-induced oxidative stress negatively influences development, leaving the brain more susceptible to the negative effects of AA, and increasing the risk of alcohol misuse in adulthood, particularly in males.},
}
@article {pmid41482855,
year = {2026},
author = {Benna-Doyle, S and Grant, S and Maunder, A and Liu, J and Ibrahim, M and Cave, A and Pandey, C and Tang, M and Koh, ES and Delaney, G and Bhuyan, DJ and Choi, V and Kwon, K and Gonzalez, M and Graham, S and Malalasekera, A and Ee, C},
title = {The Efficacy and Safety of Nutritional Supplements for Cancer Supportive Care: An Umbrella Review and Hierarchical Evidence Synthesis.},
journal = {Integrative cancer therapies},
volume = {25},
number = {},
pages = {15347354251405267},
pmid = {41482855},
issn = {1552-695X},
mesh = {Humans ; *Dietary Supplements/adverse effects ; *Neoplasms/therapy ; },
abstract = {Cancer survivors experience a range of side effects during and after treatment. There is a need for a rigorous synthesis of the most recent and best available evidence on the role of nutritional supplements for supportive care in cancer, to inform shared decision-making. We searched 5 databases for umbrella reviews, meta-analyses and systematic reviews on nutritional supplements for supportive cancer care, excluding studies on pain, anxiety and depression, which are covered in recent guidelines. We found 52 reviews that reported on 250 RCTs on 18 supplements for 16 indications. Almost all reviews were of low/critically low quality (assessed using A MeaSurement Tool to Assess systematic Reviews version 2). There was moderate-certainty evidence for benefit from the following supplements: amino acids and oral proteolytic enzymes for severity of radiation-induced dermatitis, N-acetyl cysteine for prevention of chemotherapy-induced peripheral neuropathy (CIPN) in individuals with gastrointestinal cancers. There was low to very low certainty evidence that glutamine, zinc, probiotics and melatonin may be effective for oral mucositis; Vitamin E, omega-3 fatty acids, glutamine and other amino acids may be effective for preventing CIPN. Serious adverse events were reported for high-dose Vitamin A, and dose-related adverse events were reported with zinc and Vitamin E. However, the majority of nutritional supplements were associated with only minor adverse events. Due to the low to very low certainty of the majority of evidence, firm clinical recommendations cannot be made. Further research to conclusively evaluate benefit and harm, including potential impact on efficacy of standard treatments, should be conducted.},
}
@article {pmid41479169,
year = {2026},
author = {Li, Z and Yang, X and Mao, J and Zeng, P and Qi, Y and Shi, Y and Guo, J and Zhou, J and Wang, D and Liu, J and Hou, L},
title = {Senecavirus a VP2 protein orchestrates PRDX1 degradation through dual autophagy pathways: macroautophagy and chaperone-mediated autophagy.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/15548627.2025.2610449},
pmid = {41479169},
issn = {1554-8635},
abstract = {Co-adaptation between viruses and autophagy has equipped viruses with diverse strategies to regulate host redox homeostasis, thereby facilitating viral replication. However, the mechanisms by which viruses manipulate PRDX1 (peroxiredoxin 1), a key antioxidative enzyme, via autophagy remain poorly understood. Here, we demonstrate that infection by Senecavirus A (SVA), an emerging picornavirus, induces PRDX1 degradation, and that PRDX1 negatively regulates viral replication. Decreased PRDX1 expression impairs cellular antioxidant defenses, leading to enhanced reactive oxygen species generation that facilitates SVA replication. Screening of viral proteins revealed that SVA VP1, VP2, and 3A induce PRDX1 degradation through vesicle formation-dependent macroautophagy. Notably, viral VP2 can also recruit HSPA8/HSC70 to specifically target PRDX1, directing it for degradation via LAMP2A-mediated chaperone-mediated autophagy (CMA). Collectively, these findings demonstrate that the SVA VP2 protein plays a central role in orchestrating both macroautophagy- and CMA-mediated PRDX1 degradation, establishing PRDX1 as a potential intervention target for countering SVA infection.Abbreviations: AKT/protein kinase B: AKT serine/threonine kinase; ATP: adenosine triphosphate; BHK-21: baby hamster kidney-21; CAT: catalase; CCCP: BMDMs: bone marrow-derived macrophages; CMA: chaperone-mediated autophagy; co-IP: co-immunoprecipitation; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CQ: chloroquine; DCFH-DA: 2',7'-dichlorodihydrofluorescein diacetate; DMSO: dimethyl sulfoxide; GFP: green fluorescent protein; GPX: glutathione peroxidase; GSH: glutathione; HEK-293T: human embryonic kidney 293T; hpi: hours post-infection; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KO: knockout; LAMP2A: lysosomal associated membrane protein 2A; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mdivi-1: mitochondrial division inhibitor-1; mM: millimole; MMP: mitochondrial membrane potential; mPTP: mitochondrial permeability transition pore; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetylcysteine; PI3K: phosphoinositide 3-kinase; PRDX1: peroxiredoxin 1; RT-qPCR: real-time quantitative reverse transcription polymerase chain reaction; ROS: reactive oxygen species; SD: standard deviation; SOD: superoxide dismutase; SQSTM1: sequestosome 1; SVA: Senecavirus A; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; WT: wild-type; μg: microgram; μm: micrometer; μM: micromolar.},
}
@article {pmid41475676,
year = {2026},
author = {Eskafinoghani, A and Palomares, AR and Hao, X and Mohammadi, R and Lundberg, A and Rodriguez-Walberg, KA},
title = {Early gonadotoxic effects of cyclophosphamide on the prepubertal testis and the feasibility of reducing toxicity through combined antioxidant therapy.},
journal = {Reproductive toxicology (Elmsford, N.Y.)},
volume = {140},
number = {},
pages = {109156},
doi = {10.1016/j.reprotox.2025.109156},
pmid = {41475676},
issn = {1873-1708},
mesh = {Male ; Animals ; *Cyclophosphamide/toxicity ; *Testis/drug effects/pathology/metabolism ; *Antioxidants/pharmacology/therapeutic use ; *Antineoplastic Agents, Alkylating/toxicity ; Carnitine/pharmacology/therapeutic use ; Mice, Inbred CBA ; *Acetylcysteine/pharmacology/therapeutic use ; Mice ; },
abstract = {Early chemotherapy-induced gonad toxicity threatens future fertility in boys, yet early in-vivo testicular responses are poorly defined. To characterize acute effects of cyclophosphamide (CPA) on the prepubertal testis and explore whether combined antioxidants (AO; L-carnitine [LC] and N-acetyl cysteine [NAC]) modulate these changes. CBA/B6 F1 male pups (postnatal day 7-9) were randomized to saline control, CPA (100 mg/kg i.p.), AO, or CPA+AO. Testes were collected every 8 h to 48 h for histology/immunostaining and were pooled (n = 3 per group/time point) for bulk RNA-seq per group/time point. Histology showed emerging degeneration from ∼32 h with prominent effects by 48 h after CPA, including reduced germ cell layers, increased γH2AX/CC3, and decreased Ki67. Transcriptionally, CPA perturbed apoptosis/developmental pathways as early as 16 h, preceding overt histological change. AO and CPA+AO groups displayed partial transcriptional shifts toward control profiles, consistent with mitigation of CPA-associated signatures, but not full normalization. In neonatal mouse testis, CPA elicits rapid transcriptomic reprogramming within 16 h, before morphological injury at ∼32-48 h. Concomitant AO shows preliminary, partial protective transcriptional effects. These proof-of-concept data support transcriptomics as an early, sensitive readout of testicular toxicity and motivate follow-up studies with independent validation and long-term outcomes prior to clinical translation.},
}
@article {pmid41472557,
year = {2026},
author = {Wu, QN and Feng, ZR and Tang, Q and Jin, JP and Liu, XH and Mai, ZB and Zhao, SN and Lan, YQ and Chen, KX and Lin, JD and Xu, PC and Fu, JJ},
title = {Redox-Active Cerium Oxide Nanoparticles Protect Against Acetaminophen-Induced Acute Liver Injury by Modulating Oxidative Stress and Inflammatory Pathways.},
journal = {Molecular pharmaceutics},
volume = {23},
number = {2},
pages = {1263-1275},
doi = {10.1021/acs.molpharmaceut.5c01647},
pmid = {41472557},
issn = {1543-8392},
mesh = {*Cerium/chemistry/pharmacology ; Animals ; *Acetaminophen/adverse effects ; *Oxidative Stress/drug effects ; Mice ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention &amp; control/metabolism ; *Nanoparticles/chemistry ; Oxidation-Reduction/drug effects ; Apoptosis/drug effects ; Antioxidants/pharmacology/chemistry ; Reactive Oxygen Species/metabolism ; RAW 264.7 Cells ; Male ; Inflammation/drug therapy ; Anti-Inflammatory Agents/pharmacology ; Liver/drug effects ; Mice, Inbred C57BL ; Lipopolysaccharides ; },
abstract = {Acute liver injury (ALI), often triggered by an acetaminophen (APAP) overdose, is characterized by severe oxidative stress, inflammation, and hepatocyte apoptosis. Current therapies, such as N-acetylcysteine (NAC), are limited by narrow treatment windows, highlighting the need for more effective antioxidant strategies. In this study, cerium oxide nanoparticles (CeO2 NPs, nanoceria) were synthesized and comprehensively characterized using the transmission electron microscopy (TEM), dynamic light scattering method (DLS), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) to confirm their branched morphology, high crystallinity, and mixed Ce[3+]/Ce[4+] valence states. Their enzyme-mimetic antioxidant activities were evaluated through superoxide, hydrogen peroxide, and hydroxyl radical scavenging assays. Nanoceria exhibited excellent cytocompatibility and effectively suppressed the generation of lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) and lipid peroxidation and caspase-3-mediated apoptosis in macrophages. They also downregulated pro-inflammatory mediators (nitric oxide synthase (iNOS), TNF-α, IL-1β, and NLRP3) while enhancing anti-inflammatory markers (Arg1 and IL-10). In an APAP-induced ALI mouse model, nanoceria preferentially accumulated in the liver, alleviated oxidative stress and inflammation, and significantly reduced aspartate aminotransferase (AST) levels, showing hepatoprotective efficacy comparable to NAC. Nanoceria protect against APAP-induced ALI via synergistic antioxidative and anti-inflammatory mechanisms based on reversible Ce[3+]/Ce[4+] redox cycling. These findings underscore nanoceria's potential as a next-generation nanotherapeutic for oxidative stress-related liver diseases.},
}
@article {pmid41469142,
year = {2025},
author = {Wang, H and Fan, Y and Liang, Q and Tao, W and Chen, X and Wang, J and Cao, S and Ye, J and Zuo, S and Zhang, C and Shen, D and Gao, Y and Huang, Q and Ma, X and Zhang, X and Huang, Y and Yang, M},
title = {MAVS/CMTM6 axis couples mitochondrial homeostasis to immunogenic senescence via CCL3-driven T-cell recruitment in renal carcinoma.},
journal = {Journal for immunotherapy of cancer},
volume = {13},
number = {12},
pages = {},
pmid = {41469142},
issn = {2051-1426},
mesh = {Humans ; *Kidney Neoplasms/immunology/pathology/metabolism/genetics ; *Mitochondria/metabolism ; Animals ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Carcinoma, Renal Cell/immunology/pathology/metabolism ; Cellular Senescence/immunology ; Homeostasis ; Female ; },
abstract = {BACKGROUND: Mitochondrial antiviral signaling protein (MAVS), a central adaptor in cytosolic RNA sensing, is critical for antitumor innate immunity and maintains mitochondrial homeostasis via its mitochondrial localization. Mitochondrial dysfunction acts as a key driver and amplifier of the senescence-associated secretory phenotype (SASP), a double-edged sword in tumor progression. However, whether tumor-intrinsic MAVS can regulate antitumor immunity via cellular senescence independently of its well-established interferon signaling remains unclear.<br><br>METHODS: Our study employed an integrated strategy. Clinically, we profiled MAVS expression and its association with prognosis and immune infiltration in renal tumor specimens. Mechanistic insights into tumor-intrinsic MAVS were gained through a battery of techniques spanning quantitative PCR, immunoblotting, RNA sequencing, senescence and mitochondrial function assays, confocal imaging, immunohistochemical, mass spectrometry, and co-immunoprecipitation. In vivo, we used MAVS-deficient models combined with CD8[+] T-cell depletion, programmed cell death protein-1 (PD-1) blockade, or reactive oxygen species (ROS) scavenging by N-acetylcysteine (NAC), with immune infiltration characterized by flow cytometry.<br><br>RESULTS: Clinical evidence links elevated MAVS expression in renal tumors to poor prognosis and diminished CD8[+] T-cell infiltration. Strikingly, tumor-intrinsic MAVS deficiency curbed malignant progression by triggering cellular senescence and fostering a permissive niche for CD8[+] T-cell activation and recruitment. Mechanistically, MAVS orchestrates mitochondrial integrity by co-localizing with and stabilizing chemokine-like factor-like MARVEL transmembrane domain-containing 6 (CMTM6), thereby shielding it from lysosomal degradation. Disruption of this axis provoked mitochondrial dysfunction and ROS accumulation, culminating in senescence and an SASP marked by chemokine C-C motif ligand 3 (CCL3). Thus, despite dampening canonical innate immune signaling, MAVS deletion unleashed potent antitumor immunity via CCL3-mediated CD8[+] T-cell recruitment, an effect abolished by CD8[+] T-cell depletion or ROS scavenging with NAC. Leveraging this paradigm, we demonstrated that tumor-specific MAVS deficiency acts synergistically with PD-1 blockade to achieve robust therapeutic efficacy.<br><br>CONCLUSIONS: Our findings establish the tumor-intrinsic MAVS/CMTM6/CCL3 axis as a previously unrecognized critical regulator of senescence-driven antitumor immunity in renal carcinoma. Therapeutic targeting of this axis presents a promising strategy to curtail tumor progression and potentiate immunotherapy.},
}
@article {pmid41467082,
year = {2025},
author = {Wolie, AA and Mengistie, BT and Mengistie, CT and Genet, A and Wakie, SA and Alebachew, EA and Bonus, SM},
title = {Overlapping Hepatic and Neurological Toxicity Following Intentional Multidrug Poisoning with Acetaminophen, Metoclopramide, and Metronidazole: A Case Report.},
journal = {Clinical medicine insights. Case reports},
volume = {18},
number = {},
pages = {11795476251410404},
pmid = {41467082},
issn = {1179-5476},
abstract = {INTRODUCTION: Polydrug overdose, defined as the simultaneous ingestion of multiple toxic substances, is increasingly encountered in emergency departments. Overlapping toxidromes often obscure the causative agents, complicating diagnosis and management. Acetaminophen (APAP) overdose can cause hepatotoxicity through N-acetyl-p-benzoquinone imine (NAPQI) formation, metoclopramide may precipitate acute extrapyramidal symptoms, and metronidazole can induce neurotoxicity, typically a cerebellar syndrome.<br><br>CASE SUMMARY: Young adult male medical student intentionally ingested 12&#x2009;g of APAP, 170&#x2009;mg of metoclopramide, and 8&#x2009;g of metronidazole. He presented 24&#x2009;hours later with repeated vomiting, tremor, rigidity, dysarthria, gait ataxia, and transient confusion. Vital signs were stable; laboratory tests showed transaminase elevation and coagulopathy. Peak AST/ALT were 100/76&#x2009;U/L and INR peaked at 1.74. Management included oral N-acetylcysteine for APAP toxicity, intravenous diphenhydramine and diazepam for extrapyramidal symptoms, supportive ICU care, and psychiatric intervention. Coagulopathy was corrected with fresh frozen plasma. Neurological and hepatic abnormalities resolved within 72&#x2009;hours, and the patient remained asymptomatic at 2-week follow-up. The patient recovered fully after N-acetylcysteine and supportive care, illustrating the diagnostic challenges of overlapping toxidromes.<br><br>CONCLUSION: This case highlights the diagnostic and therapeutic challenges of polydrug overdose with overlapping toxidromes. Rapid identification and agent-specific management, including NAC for APAP, symptomatic therapy for metoclopramide and metronidazole toxicity, and supportive care, resulted in full recovery without long-term sequelae. Emergency clinicians should maintain high suspicion for multiple co-ingestants and use targeted interventions to optimize outcomes.},
}
@article {pmid41462060,
year = {2025},
author = {Kim, JW and Won, HR and Kim, CS and Choi, JS and Woo, SH and Lee, DW and Kwon, M and Joo, YH and Koo, BS and Cho, KJ},
title = {Effects of topically applied liquid N-acetylcysteine for the management of burning mouth syndrome.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44889},
pmid = {41462060},
issn = {2045-2322},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/therapeutic use ; *Burning Mouth Syndrome/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Administration, Topical ; Quality of Life ; Prospective Studies ; Clonazepam/administration &amp; dosage/therapeutic use ; Treatment Outcome ; Pain Measurement ; Adult ; },
abstract = {Burning Mouth Syndrome (BMS) is a chronic neuropathic pain condition with limited treatment options. N-acetylcysteine (NAC), a thiol-based antioxidant with neuroprotective properties, has not been clinically evaluated as a topical agent for BMS. This study aimed to evaluate the efficacy of topically applied liquid NAC in reducing symptoms and improving quality of life of patients with BMS. In a multicenter, prospective, nonrandomized, open-label study, 114 patients with BMS were allocated to receive liquid NAC oral rinse, oral clonazepam, or combination therapy for eight weeks. Symptoms were assessed at baseline, week 4, and week 8 using the visual analog scale (VAS) and the Korean version of the Oral Health Impact Profile-14 (OHIP-14 K). Across all three groups, VAS scores declined significantly within groups from baseline to week 4 and to week 8; however, the magnitude of VAS change did not differ between groups at either time point. For OHIP‑14 K, significant within‑group decreases were observed in the liquid NAC and combination groups from baseline to weeks 4 and 8, whereas the clonazepam group showed a significant decrease only from week 4 to week 8 and not from baseline. At week 4, the combination group achieved a larger OHIP‑14 K reduction than either monotherapy; by week 8, between‑group differences were no longer significant. Topically applied liquid NAC, alone or in combination with clonazepam, effectively reduced pain and enhanced patient-reported outcomes. These findings support the potential of a localized and safe strategy targeting neuropathic mechanisms in BMS. Topically administered liquid NAC demonstrates potential as an effective and well-tolerated therapeutic strategy for managing BMS, offering symptom relief with minimal systemic burden. Although the combination with clonazepam did not demonstrate sustained superiority at 8 weeks, its principal advantage is a faster onset of improvement in OHIP‑14 K, evident by week 4.},
}
@article {pmid41460361,
year = {2025},
author = {Yang, CW and Yen, CH and Chien, TM and Yu, SY and Chang, FR and Sheu, JH and Chang, HW},
title = {Excavatolide E triggers oxidative stress-associated apoptosis and DNA damage to inhibit bladder cancer cell proliferation.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {234},
pmid = {41460361},
issn = {1573-4978},
support = {NSTC 114-2314-B-037-032//National Science and Technology Council/ ; NSTC 114-2320-B-037-015//National Science and Technology Council/ ; KMU-DK(A)113003 and KMU-TB114009//Kaohsiung Medical University/ ; KMU-TC114A04//Kaohsiung Medical University Research Center/ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Urinary Bladder Neoplasms/drug therapy/metabolism/genetics/pathology ; Cell Proliferation/drug effects ; *DNA Damage/drug effects ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Cell Survival/drug effects ; Animals ; Mitochondria/drug effects/metabolism ; Anthozoa/chemistry ; },
abstract = {BACKGROUND: Excavatolide E (EXCE), a biocompound extracted from the gorgonian octocoral Briareum excavatum, has received limited attention for its anticancer properties, especially in the context of bladder cancer.<br><br>METHODS: Cell viability, flow cytometry, and Western blotting were performed to assess the antiproliferative effects and mechanisms against bladder cancer cells.<br><br>RESULTS: In the present study, the impacts and mechanisms of EXCE's antiproliferative effects on bladder cancer cells were assessed, along with its impacts on normal cells. EXCE selectively inhibited proliferation of bladder cancer cells, as compared to normal cells, i.e., selectivity index&#x2009;>&#x2009;2, and induced greater oxidative stress in bladder cancer cells than normal cells, regarding the induction of cellular and mitochondrial ROS, as well as the depletion of mitochondrial membrane potential. Moreover, EXCE triggered higher levels of apoptosis, both extrinsic and intrinsic caspase activation, and DNA damage in bladder cancer cells than in normal cell; these EXCE-triggered antiproliferative mechanisms were alleviated by N-acetylcysteine (NAC), a ROS inhibitor.<br><br>CONCLUSION: Therefore, EXCE's antiproliferative activity offers a promising therapeutic approach for targeting bladder cancer cells by modulating oxidative stress, while preserving the safety of normal cells.},
}
@article {pmid41458194,
year = {2026},
author = {Alajab, MB and Elameen, SAO and Mohamed, FAY and Eisa, MGM and Omer, EOM and Elmubarak, MAH and Elmubarak, MAH and Abdalazim Dafallah, M},
title = {Fulminant Hepatic Failure in Dengue Infection: Two Survivors From a Resource-Limited Outbreak in Sudan.},
journal = {Clinical case reports},
volume = {14},
number = {1},
pages = {e71721},
pmid = {41458194},
issn = {2050-0904},
abstract = {Dengue is a leading cause of viral hemorrhagic fever globally, with hepatic involvement being common but usually mild. Rarely, dengue can progress to fulminant hepatic failure, a life-threatening complication requiring prompt recognition especially in resource-limited settings. We report two Sudanese male patients (aged 29 and 18) who presented with jaundice, markedly elevated liver enzymes, hepatic encephalopathy, and coagulopathy. Both fulfilled criteria for fulminant hepatic failure with hepatic encephalopathy. One patient had concurrent hepatitis B infection and developed acute kidney injury requiring hemodialysis. Both patients received supportive management including intravenous N-acetylcysteine, correction of coagulopathy, glucose infusion, hypertonic saline, lactulose/rifaximin, and appropriate transfusions. Renal replacement therapy was initiated in the patient with acute kidney injury. Despite severe presentation and limited resources, both patients demonstrated progressive clinical and biochemical improvement. Follow-up showed complete recovery of liver and renal parameters. These cases underscore that early recognition and intensive supportive management, including N-acetylcysteine, are critical for survival in dengue-associated fulminant hepatic failure, even in constrained settings.},
}
@article {pmid41452363,
year = {2025},
author = {Chen, Y and Wu, W and Zhao, L and Shen, L and Tao, D and Liang, Y and Zheng, X and Zheng, Z and Luo, C and Peng, F and Long, H and Chen, X},
title = {GATA1 controls metadherin transcription to promote oxidative stress-induced podocyte injury.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {14},
pmid = {41452363},
issn = {1432-1440},
support = {82000682//National Natural Science Foundation of China/ ; 82374198//National Natural Science Foundation of China/ ; 82570842//National Natural Science Foundation of China/ ; 2024A1515030266//Basic and Applied Basic Research Foundation of Guangdong Province/ ; yzjj2022ms01//President Foundation of Zhujiang Hospital, Southern Medical University/ ; 2021XM08//Science and Technology Action of Erdos High-tech Industrial Development Commission of Inner Mongolia/ ; },
mesh = {*Podocytes/metabolism/pathology ; *Oxidative Stress ; Animals ; RNA-Binding Proteins/genetics ; Mice ; *Membrane Proteins/genetics/metabolism ; *Renal Insufficiency, Chronic/metabolism/pathology/genetics ; *GATA1 Transcription Factor/metabolism/genetics ; beta Catenin/metabolism ; Male ; Humans ; Advanced Oxidation Protein Products ; *Transcription, Genetic ; Mice, Inbred C57BL ; *Cell Adhesion Molecules/genetics/metabolism ; Signal Transduction ; Gene Expression Regulation ; },
abstract = {Oxidative stress has been demonstrated to induce damage to podocytes, which play a pivotal role in the pathogenesis of chronic kidney disease (CKD). Metadherin (MTDH), an oncogene that has been extensively investigated in various malignancies, also contributes to podocyte injury in CKD. However, the relationship between oxidative stress and MTDH remains poorly elucidated. Here, we show that elevated oxidative stress in CKD serum induced MTDH expression and activated β-catenin signaling in podocytes, which were reversed by N-acetyl cysteine (NAC), a pharmacological antioxidant agent. Therefore, we established the oxidative stress model by administration of Advanced Oxidation Protein Products (AOPPs). As for the mechanism, oxidative stress enhanced MTDH expression both in mRNA and protein levels in podocytes. Furthermore, transcription factor prediction analysis and the Chip-qPCR assay identified that GATA1 was capable of directly binding to the MTDH promoter following AOPP stimulation. Silencing GATA1 repressed MTDH expression induced by AOPPs, while overexpressing GATA1 enhanced MTDH expression and subsequently activated β-catenin signaling. In conclusion, GATA1 induced by oxidative stress triggers MTDH transcription to activate β-catenin signaling, thereby promoting podocyte injury. Thus, targeting the GATA1/MTDH axis may present a promising therapeutic strategy for attenuating oxidative stress-induced damage in podocytes during CKD. KEY MESSAGES: Advanced Oxidative Protein Products (AOPPs) promote the accumulation of oxidative stress in circulation Metadherin is elevated in kidneys of AOPP-induced oxidative stress CKD model mice GATA1 controls transcription of MTDH in renal podocyte of CKD Silencing GATA1/MTDH axis interrupts β-catenin signaling and ameliorates podocyte injury and CKD pathology.},
}
@article {pmid41446880,
year = {2025},
author = {van Brummelen, R and van Brummelen, AC},
title = {The role of neuro-supportive substances of natural origin in neurological conditions-A literature-based formulators' perspective.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1647092},
pmid = {41446880},
issn = {1664-2295},
abstract = {Products of natural origin are seldom tested up to a point of full acceptance, mainly due to a lack of financial viability for commercialization. Yet many come with a rich history of use and proof of concept testing. We investigated literature regarding the possible role and function of the best known of these nutraceuticals in relationship to three neurological conditions i.e. stroke, Alzheimer's - (AD) and Parkinson's disease (PD), and their potential as supportive therapies. Current studies suggest that citicoline has a neuroprotective effect in ischemic conditions, playing a role in the restoration of the barrier function of endothelial cells, activating repair mechanisms and possibly decreasing ischemic lesion size in stroke, as well as increasing dopamine availability in PD. Citicoline was also demonstrated to increase the levels of sirtuin 1 (SIRT1), thus reducing inflammation-leading to improved cognitive status and a better quality of life in cognitive impairment. N-Acetylcysteine (NAC) shows pro-cognitive effects, increasing glutathione (GSH) levels that are decreased in AD and PD patients, possibly decreasing neuroinflammation. Mechanistic studies indicate the potential neuroprotective and neurorestorative effects of resveratrol by its anti-inflammatory and anti-apoptotic activity, also increasing SIRT1 levels and promoting the outgrowth of neurite protrusions and synaptogenesis. Curcumin's anti-inflammatory effects via inhibition of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can potentially delay progression of PD. Some nutraceuticals, e.g., citicoline, show synergism in combination with current therapies. We propose a renewed, risk-benefit approach for inclusion of the investigated nutraceuticals with limited indications in certain neurological treatment regimens.},
}
@article {pmid41445121,
year = {2025},
author = {Mehrpour, O and Soltani, M and Karami-Mohajeri, S and Khanamani Falahatipour, S},
title = {Acetaminophen poisoning: contemporary intravenous acetylcysteine regimens and early discharge pathways.},
journal = {Expert opinion on pharmacotherapy},
volume = {26},
number = {18},
pages = {1997-2012},
doi = {10.1080/14656566.2025.2610370},
pmid = {41445121},
issn = {1744-7666},
mesh = {*Acetylcysteine/administration &amp; dosage ; Humans ; *Acetaminophen/poisoning/administration &amp; dosage ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/etiology ; Drug Overdose/drug therapy ; *Analgesics, Non-Narcotic/poisoning/administration &amp; dosage ; *Antidotes/administration &amp; dosage ; Administration, Intravenous ; },
abstract = {INTRODUCTION: Acetaminophen (paracetamol, APAP) overdose remains a leading cause of drug-induced acute liver failure, yet N-acetylcysteine (NAC) prevents hepatic injury.<br><br>AREAS COVERED: We conducted a narrative search of PubMed/MEDLINE, Embase, and Google Scholar (January 2000-August 2025) and reviewed NAC regimens, including the 3-bag protocol (21&#x2009;h), the U.S. FDA-labeled 2-bag regimen (20&#x2009;h), and the 12-h Scottish and Newcastle Acetylcysteine Protocol (SNAP), as well as early-stop pathways. Across regimens, efficacy is broadly similar, but simplified protocols reduce non non-immunoglobulin E reactions and dosing errors. SNAP delivers 300&#x2009;mg/kg over 12&#x2009;h and is extended only when stopping criteria are not met, whereas early-stop pathways (NACSTOP/SARPO) are restricted to selected low-risk patients. In most acute overdoses, NAC can be stopped when APAP is&#x2009;<&#x2009;10&#x2009;mg/L, ALT/AST are stable or falling, and INR is acceptable.<br><br>EXPERT OPINION: A protocolized NAC pathway with clear stop/extend rules is the most impactful way to improve care. Escalation (higher or prolonged dosing, early hepatology/transplant referral, and consideration of ECTR) should be reserved for high-risk cases. In low- and middle-income countries (LMICs), dose and timing history can guide empiric NAC when levels are delayed. Biomarkers and artificial intelligence remain useful adjuncts, not substitutes, for laboratory-based decisions.},
}
@article {pmid41441921,
year = {2025},
author = {Yavuz, M and Acer, S and Celik, O and Argun, M and Ozmen, O and Tok, L},
title = {Assessment of neuroprotective efficacy of N-acetylcysteine compared with brimonidine in an experimental glaucoma model.},
journal = {International ophthalmology},
volume = {46},
number = {1},
pages = {53},
pmid = {41441921},
issn = {1573-2630},
mesh = {Animals ; *Brimonidine Tartrate/therapeutic use ; Female ; Rats ; Disease Models, Animal ; Rats, Wistar ; *Glaucoma/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use ; *Acetylcysteine/therapeutic use/pharmacology ; Retinal Ganglion Cells/pathology/drug effects ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Intraocular Pressure/drug effects ; Adrenergic alpha-2 Receptor Agonists ; },
abstract = {PURPOSE: To investigate the neuroprotective effects of N-acetylcysteine (NAC) in comparison with brimonidine in an experimental glaucoma model.<br><br>METHODS: Thirty-two adult female Wistar albino rats were randomly assigned to five groups: Control, Sham, NAC, Brimonidine, and Combination (NAC&#x2009;+&#x2009;Brimonidine). Glaucoma was induced in the right eye by optic nerve crush in all groups except Control. Treatments were administered intraperitoneally every 72&#xa0;h for 30&#xa0;days. Neuroprotection was assessed histopathologically by measuring ganglion cell layer (GCL) thickness and total retinal thickness. Apoptotic activity and glial activation were evaluated by quantifying B-cell lymphoma/leukemia-2 (BCL-2), BCL-2-associated X protein (BAX) and glial fibrillary acidic protein (GFAP) expression. Oxidative stress and antioxidant capacity were assessed using malondialdehyde (MDA), total oxidant status (TOS), glutathione (GSH) and total antioxidant capacity (TAC) levels.<br><br>RESULTS: NAC significantly preserved GCL and total retinal thickness compared with the Sham group (P&#x2009;<&#x2009;0.001), with neuroprotective efficacy comparable to brimonidine (P&#x2009;>&#x2009;0.05). The combination therapy group demonstrated the most pronounced neuroprotective effects. NAC treatment increased antiapoptotic BCL-2 and GSH levels while reducing BAX, GFAP, MDA, and TOS levels (P&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: NAC exhibited substantial neuroprotective effects in an intraocular pressure-independent glaucoma model, likely mediated through its antioxidant properties and modulation of apoptotic pathways. These findings suggest that NAC may serve as a promising adjunctive therapy for glaucomatous optic neuropathy and other retinal neurodegenerative disorders characterized by oxidative stress and apoptosis.},
}
@article {pmid41440725,
year = {2025},
author = {Hong, M and Kedeshian, K and Hoffman, L and Kita, A},
title = {Preliminary Evaluation of an Injectable Therapeutic for Cisplatin Ototoxicity Using Neuronal SH-SY5Y Cells.},
journal = {Medicines (Basel, Switzerland)},
volume = {12},
number = {4},
pages = {},
pmid = {41440725},
issn = {2305-6320},
support = {K08 DC019957/DC/NIDCD NIH HHS/United States ; 1K08DC019957-01/NH/NIH HHS/United States ; Not applicable//American Neurotology Society/ ; },
abstract = {BACKGROUND/OBJECTIVES: Though ototoxic, cisplatin is a mainstay of chemotherapy for a variety of cancers. One suggested mechanism of cisplatin ototoxicity involves damage to the spiral ganglion afferent neurons in the inner ear. There is a need for a high-throughput model to screen medications for efficacy against cisplatin and to develop a local therapeutic to mitigate cisplatin's debilitating side effects. Microparticles encapsulating a therapeutic medication are an injectable and tunable method of sustained drug delivery, and thus a promising treatment.<br><br>METHODS: SH-SY5y human neuroblastoma cells were used as a cell line model for the spiral ganglion neurons. The cells were dosed with cisplatin and four potential therapeutics (melatonin, metformin, cyclosporine, and N-acetylcysteine), with cell viability measured by CCK-8 assay. The most promising therapeutic, N-acetylcysteine (NAC), was then encapsulated into multiple poly(lactic-co-glycolic acid) (PLGA) microparticle subtypes of varied lactide-glycolide (L:G) ratios and NAC amounts. The elution profile of each microparticle subtype was determined over two months.<br><br>RESULTS: Of the therapeutics screened, only cells dosed with 1 or 10 mM NAC prior to cisplatin injury demonstrated an improvement in cell viability (73.8%, p < 1 &#xd7; 10[-8]) when compared to cells dosed with cisplatin alone. The 75:25 L:G microparticles demonstrated an increase in the amount of NAC released compared to the 50:50 L:G microparticles.<br><br>CONCLUSIONS: NAC is a potential therapeutic agent for cisplatin toxicity when tested in a neuronal cell line model. NAC was encapsulated into PLGA microparticles and eluted detectable concentrations of NAC for 6 days, which is a first step towards otoprotection for the weeks long duration of chemotherapy treatment. This work describes a method of screening potential therapeutics and a strategy to develop local drug eluting treatments to protect against cisplatin ototoxicity.},
}
@article {pmid41440550,
year = {2025},
author = {Parpoudi, S and Mantzoros, I and Ioannidis, O and Zapsalis, K and Gamali, T and Kyziridis, D and Gekas, C and Anestiadou, E and Symeonidis, S and Bitsianis, S and Kotidis, E and Pramateftakis, MG and Miliaras, D and Bikouli, A and Iosifidis, G and Angelopoulos, S},
title = {Effect of N-Acetyl-L-Cysteine (NAC) on Inflammation After Intraperitoneal Mesh Placement in an Escherichia coli Septic Rat Model: A Randomized Experimental Study.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {13},
number = {4},
pages = {},
pmid = {41440550},
issn = {2076-3271},
mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Escherichia coli/drug effects ; *Surgical Mesh/adverse effects ; Rats ; *Escherichia coli Infections/drug therapy ; Disease Models, Animal ; *Inflammation/drug therapy/etiology ; *Sepsis/drug therapy/microbiology ; Male ; Tissue Adhesions ; Cytokines/blood ; },
abstract = {Background/Objectives: The safety of intraperitoneal mesh placement in contaminated fields remains controversial because of the increased risk of inflammation and adhesion formation. N-acetyl-L-cysteine (NAC) has antioxidant, pro-fibrinolytic and antibiofilm actions that could attenuate this response. The aim of this study is to determine whether NAC reduces mesh-related inflammation in a septic model created by intraperitoneal Escherichia coli (E.coli) inoculation. The primary comparison was prospectively defined between E. coli-inoculated animals treated with NAC (D) and those without NAC (B). Groups without E. coli (A,C,E) are presented for context and were compared previously. Methods: In this randomized, double-blind experimental model (five groups, n = 20 per group), all rats underwent midline laparotomy with intraperitoneal placement of a composite mesh, followed by standardized ciprofloxacin administration. The septic groups received intraperitoneal E. coli, while the NAC-treated groups additionally received intraperitoneal NAC (150 mg/kg). Serum levels of IL-1α, IL-6, and TNF-α were measured on postoperative days 7, 14, and 21. On day 21, adhesions were graded using the Modified Diamond system, histology (inflammatory infiltration, fibrosis, neovascularization) was scored, and mesh cultures were obtained. Cytokine data were analyzed with repeated-measures ANOVA, while categorical or ordinal outcomes were assessed using χ[2] or Fisher's exact tests with Bonferroni-adjusted pairwise comparisons. Results: E. coli inoculation significantly increased adhesion burden and worsened histologic scores compared with controls (both p < 0.001). NAC administration in the septic model significantly reduced adhesions and improved all histologic domains relative to E. coli alone (all p ≤ 0.003), with values comparable to controls (non-significant across domains). For cytokines, there was a significant overall group effect for IL-1α, IL-6, and TNF-α (all p < 0.001), without a main effect of time or time × group interaction. Pairwise contrasts showed lower IL-1α (p = 0.024), IL-6 (p < 0.001), and TNF-α (p < 0.001) levels in group D versus B, and lower IL-6 and TNF-α in group D versus A (both p < 0.001). Mesh culture positivity rate was higher in group B than A (p < 0.001) and showed a non-significant reduction in group D versus B (p = 0.10). No perioperative deaths occurred. Conclusions: NAC attenuated septic, mesh-associated inflammation-normalizing adhesions and histology and reducing IL-6 and TNF-α- supporting its role as a host-directed adjunct alongside antibiotics. Further translational studies are warranted to define the optimal dose, timing, and clinical indications.},
}
@article {pmid41440263,
year = {2025},
author = {Liu, Z and Li, X and Liu, S and Cai, Y and Xu, X and Gao, S and Yao, C and Wang, L and Xie, X and Cai, Y and Jiang, L and Liu, J and Li, M and Li, Y and Huang, X and Chen, H},
title = {Transcriptomic Evaluation of Hollow Microneedles-Mediated Drug Delivery for Rheumatoid Arthritis Therapy.},
journal = {Biosensors},
volume = {15},
number = {12},
pages = {},
pmid = {41440263},
issn = {2079-6374},
support = {32171456, 82100430//National Natural Science Foundation of China/ ; 2024YFB3211600//National Key R&amp;D Program of China/ ; 2023A1515111139, 2025A1515010608, 2020A1515111139//Guangdong Basic and Applied Basic Research Foundation/ ; 2024B03J0121, 2024B03J1284//Science and Technology Program of Guangzhou, China/ ; 2023A03J1008//Science and Technology Projects in Guangzhou/ ; 24xkjc011//Fundamental Research Funds for the Central Universities, Sun Yat-sen University/ ; 2024-skllmd-11//Open Fund of the State Key Laboratory of Luminescent Materials and Devices (South China University of Technology)/ ; JCYJ20220818102201003//Shenzhen Science and Technology Program/ ; },
mesh = {*Arthritis, Rheumatoid/drug therapy ; *Drug Delivery Systems/methods ; Animals ; Needles ; *Transcriptome ; Pyrimidines/administration &amp; dosage/therapeutic use ; Piperidines/administration &amp; dosage/therapeutic use ; Acetylcysteine/administration &amp; dosage ; Humans ; Pyrroles/administration &amp; dosage ; Gene Expression Profiling ; },
abstract = {Microneedle array-based drug delivery offers a minimally invasive and safe approach for breaching the skin barrier, enabling localized and targeted treatment-an advantage particularly valuable in chronic condition management, such as rheumatoid arthritis (RA). RA presents a multifaceted pathophysiology, often necessitating long-term pharmacological management. However, conventional oral administration may lead to systemic drug distribution, increasing the likelihood of adverse effects, and ultimately undermining therapeutic efficacy. In this study, a hollow microneedle array was employed for effective delivery of Tofacitinib and the antioxidant N-acetylcysteine (NAC). A comprehensive evaluation was conducted across multiple levels, in which inflammation and cartilage degradation were assessed histologically using hematoxylin-eosin (H&amp;E) and Safranin O-Fast Green staining. Radiologically, micro-computed tomography (micro-CT) was employed to visualize bone structure alterations. On the molecular level, enzyme-linked immunosorbent assay (ELISA) was used to quantify inflammatory cytokines and oxidative stress markers. Furthermore, differentially expressed genes and enriched signaling pathways were identified through transcriptomic profiling pre- and post-treatment. And the potential regulatory targets and mechanistic insights into the therapeutic response were elucidated through correlation analyses between gene expression profiles and pathological indicators. This study provides a mechanistic and computational basis for precision targeted therapy, validates the efficacy and safety of microneedle delivery in a rheumatoid arthritis (RA) model, and demonstrates its potential application in local drug delivery strategies.},
}
@article {pmid41440136,
year = {2025},
author = {Mulè, S and Parini, F and Galla, R and Uberti, F},
title = {Neuroinflammation-Modulating Properties Combining Glutathione, N-Acetylcysteine, and Uridine Monophosphate in a Formulation Supplement: An In Vitro Study.},
journal = {Brain sciences},
volume = {15},
number = {12},
pages = {},
pmid = {41440136},
issn = {2076-3425},
abstract = {Background: Neuropathic pain is a complex condition often resistant to current therapies due to limited efficacy and adverse effects. Nutraceuticals offer promising alternatives, combining antioxidant and anti-inflammatory properties with good tolerability. This study aimed to compare the effects of a commercial nutraceutical formulation, SUPERALA CARNITINE[®] (Pharma Suisse Laboratories SpA, Milan, Italy), containing Alpha-Lipoic Acid (ALA), with a novel formulation, called SUPERALA CARNITINE[®] Forte, where ALA and vitamin B6 were replaced by N-acetylcysteine (NAC), Glutathione (GSH), and Uridine monophosphate (UMP). Methods: An indirect gut-peripheral nerve axis was employed to simulate oral absorption, metabolism, and effect on nervous tissues using 3D in vitro models. Both formulations and their individual components were assessed for cytotoxicity and permeability in the gut model (Caco-2 cells in Transwell[®]) and, after gut metabolism, for antioxidant capacity, anti-inflammatory activity, and neuroprotective potential in the peripheral nerve model. Results: SUPERALA CARNITINE[®] Forte improved cell viability and favoured the maintenance of intestinal integrity, showing enhanced permeability, and significantly reduced oxidative stress (OS) and pro-inflammatory cytokines (TNF-α, IL-2) at the peripheral nervous system. In addition, it increased levels of neuronal markers (p75, MPZ, NRG1, ERβ) and decreased NaV1.7 and NaV1.8 activity, indicating greater neuroprotection and analgesic modulation than the ALA-based formula. Conclusions: The replacement of ALA and vitamin B6 with NAC, GSH, and UMP produced favorable responses in vitro on neuronal cells, supporting a hypothetical potential interest in this nutraceutical combination and justifying further future in vivo investigations.},
}
@article {pmid41431629,
year = {2025},
author = {Sinaeinejad, M and Karimi, M and Razavizadeh, M and Arj, A and Tabatabaei, SH and Mortezazadeh, M and Shirsalimi, N and Pirzad, S and Mofidi, A and Kashani, M},
title = {Efficacy of N-Acetylcysteine on Liver Function and Metabolic Profiles in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Double-Blind, Randomized Controlled Trial.},
journal = {Addiction &amp; health},
volume = {17},
number = {},
pages = {1667},
pmid = {41431629},
issn = {2008-4633},
abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is a common liver disorder associated with metabolic abnormalities. This study aimed to evaluate the effectiveness of N-acetylcysteine (NAC) in improving liver function and metabolic profile in patients with MASLD.<br><br>METHODS: In this randomized controlled trial (RCT), 69 patients with MASLD were randomly assigned to either the NAC group (600 mg, administered three times daily, n=34) or the placebo group (n=35) for eight weeks. The severity of hepatic steatosis, liver enzymes, and metabolic profile were measured at baseline and the final trial. Data were analyzed using SPSS.<br><br>FINDINGS: Following eight weeks of NAC administration in patients with MASLD, no significant changes were observed compared to the placebo in hepatic steatosis grade (P=0.215), serum aspartate aminotransferase (AST) (P=0.21), alanine transaminase (ALT) (P=0.28), malondialdehyde (MDA) (P=0.79), total antioxidant capacity (TAC) (P=0.56), triglycerides (P=0.15), total cholesterol (P=0.28), low-density lipoprotein cholesterol (P=0.32), and high-density lipoprotein cholesterol (P=0.16). However, NAC administration resulted in significant reductions in fasting blood glucose (FBG) (P=0.01), fasting insulin levels (P<0.001), homeostatic model assessment for insulin resistance (HOMA-IR) (P<0.001), and C-reactive protein (CRP) (P<0.001), along with a significant increase in total glutathione levels (P=0.003), compared to the placebo group.<br><br>CONCLUSION: NAC administration in patients with MASLD does not significantly impact hepatic steatosis, liver enzymes, or lipid profiles; however, it improves oxidative, glycemic, and inflammatory markers. Therefore, NAC may be a beneficial adjunct therapy for managing metabolic parameters and reducing inflammation and oxidative stress in MASLD patients.<br><br>TRIAL REGISTRATION: The trial was registered with the Iranian Registry of Clinical Trials (IRCT20201220049772N1) on February 20, 2021.},
}
@article {pmid41428714,
year = {2025},
author = {Rocha, MBM and Assis, EIT and Azevedo, VAN and Lima Neto, MF and Silva, AWB and Godinho, AN and Freire, JMO and Félix, EDS and Ribeiro, RP and Gomes, GA and Silva, JRV},
title = {Piperine protects ovarian follicles and stromal cells against doxorubicin-induced adverse effects in mouse ovaries.},
journal = {JBRA assisted reproduction},
volume = {},
number = {},
pages = {},
doi = {10.5935/1518-0557.20250187},
pmid = {41428714},
issn = {1518-0557},
abstract = {OBJECTIVE: This study investigates the effects of Piperine (PIP) on doxorubicin (DOX)-induced changes in mouse ovarian follicles, stromal cells, collagen fibers, and mRNA expression of nuclear factor erythroid 2-related factor (NRF2), superoxide dismutase (SOD), and catalase (CAT).<br><br>METHODS: The mice were randomly divided into seven groups. In the first three groups, they received saline (1), both DOX and N-acetylcysteine (2), or DOX only (3). In groups 4 and 5, mice were treated with DOX in combination with 0.1 or 10.0mg/kg PIP. In groups 6 and 7, mice received 0.1 or 10.0mg/kg PIP alone. After 10 days, ovaries were collected and used to evaluate follicular morphology and growth, collagen fibers, stromal cells, and mRNA for NRF2, SOD, and CAT.<br><br>RESULTS: Mice treated with DOX showed reduced percentage of normal follicles, but the combination of DOX with PIP or NAC prevented this effect, maintaining follicle integrity similar to untreated animals. Ovaries of mice treated with PIP alone had similar percentage of normal follicles compared to control group. Additionally, the association of DOX and PIP preserved collagen levels similar to control, while PIP or NAC alone did not influence collagen distribution. Ovaries of mice treated with both DOX and NAC showed a reduction in stromal cells, but those treated with both DOX and PIP maintained the levels of collagens similar to control.<br><br>CONCLUSIONS: The DOX and PIP preserved the integrity of follicles and collagen fibers in mouse ovaries, which opens a new possibility to protect primordial follicles during chemotherapy.},
}
@article {pmid41424200,
year = {2026},
author = {Sadri, H and Shahrokhi, N and Ebrahimi-Rad, M and Mardani, M and Sadeghi, S and Pooya, M},
title = {Synergistic antibacterial and antibiofilm activity of N-acetylcysteine combined with niosomal recombinant lysostaphin against MRSA Staphylococcus aureus.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/1061186X.2025.2607397},
pmid = {41424200},
issn = {1029-2330},
abstract = {Wound infections significantly impair healing and often result in chronic wounds, burdening healthcare systems substantially. The principal pathogen in such infections is Staphylococcus aureus (S. aureus), which forms biofilms that resist host defences and conventional therapies. To overcome these challenges, recombinant lysostaphin (rLyso) was encapsulated in niosomes using thin-film hydration and evaluated with N-acetylcysteine (NAC) against standard and clinical S. aureus strains. Antibacterial and antibiofilm activities were assessed by determining the minimum inhibitory concentration (MIC) and minimum biofilm eradication concentration (MBEC), complemented by fluorescence and confocal microscopy. Cytotoxicity was assessed in L929 fibroblasts, and in vivo efficacy was investigated in BALB/c mouse wound models. The NAC/niosomal rLyso formulation exhibited the most potent antibacterial and antibiofilm effects, significantly lowering the MIC values (standard: 1250/5.9 μg/ml; clinical: 1250/2 μg/ml) and achieving notable biofilm eradication (MBEC: standard: 5000/23.6 μg/ml; clinical: 1250/2 μg/ml). Cytotoxicity assays confirmed high bio-compatibility, with nearly 100% cell viability at MIC, while NAC alone was highly toxic. The combination of two agents achieved full bacterial clearance in vivo and accelerated wound healing. These findings suggest that NAC combined with niosomal rLyso synergistically disrupts S. aureus biofilms, enhances antimicrobial activity, and promotes wound repair, making it a promising therapeutic strategy against resistant staphylococcal infections.},
}
@article {pmid41422903,
year = {2026},
author = {Chaabani, H and Ayed, I and Rjiba, K and Abid, S and Eyer, J and Arnoult, D},
title = {Trifloxystrobin induces oxidative stress-dependent activation of the OMA1-DELE1-HRI integrated stress response leading to apoptosis in human neuroblastoma cells.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {390},
number = {},
pages = {127562},
doi = {10.1016/j.envpol.2025.127562},
pmid = {41422903},
issn = {1873-6424},
mesh = {Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Strobilurins/toxicity ; Cell Line, Tumor ; *Fungicides, Industrial/toxicity ; *Imines/toxicity ; *Acetates/toxicity ; Neuroblastoma/metabolism ; *Methacrylates/toxicity ; Mitochondria/drug effects ; },
abstract = {Trifloxystrobin (TFX), a potent inhibitor of complex III in the mitochondrial respiratory chain, is a widely used strobilurin fungicide whose neurotoxic mechanisms remain poorly defined. This study investigated the molecular pathways underlying TFX-induced toxicity in human SH-SY5Y neuronal-like neuroblastoma cells, with particular emphasis on oxidative stress, mitochondrial dysfunction, and activation of the Integrated Stress Response (ISR). TFX exposure (24 h) exhibited an IC50 of approximately 100 μM, induced G0/G1 cell cycle arrest, and triggered mitochondria-mediated apoptosis, as evidenced by loss of mitochondrial membrane potential (ΔΨm), Bax activation, cytochrome c release, DNA fragmentation, phosphatidylserine exposure, and caspase-3 activation. These effects were accompanied by increased mitochondrial superoxide levels and decreased ATP production, indicating profound mitochondrial impairment. Pretreatment with N-acetylcysteine (NAC) markedly restored cell viability, reduced ROS accumulation, prevented ΔΨm dissipation, and diminished apoptotic damage. Mechanistically, TFX activated the ISR through the OMA1-DELE1-HRI mitochondrial stress signaling axis, as confirmed by loss-of-function experiments targeting these proteins. Importantly, both NAC and the ISR inhibitor ISRIB (Integrated Stress Response InhiBitor) significantly attenuated ISR activation and the resulting apoptosis, demonstrating that oxidative stress serves as an upstream trigger for ISR engagement and cell death. Collectively, these findings reveal that TFX induces oxidative stress-dependent activation of the OMA1-DELE1-HRI ISR pathway, linking mitochondrial dysfunction to apoptosis in human neuroblastoma cells. To our knowledge, this is the first report identifying ISR activation as a mechanistic component of strobilurin fungicide-induced neurotoxicity.},
}
@article {pmid41422364,
year = {2025},
author = {Xing, HB and Li, HY and Zheng, GZ and Zhang, QH and Zhai, L and Wu, X and Du, SX and Li, XD},
title = {Resveratrol synergizes with cisplatin to suppress osteosarcoma U2-OS cells via up-regulating Cx43 and inducing ROS-dependent apoptosis.},
journal = {Discover oncology},
volume = {16},
number = {1},
pages = {2218},
pmid = {41422364},
issn = {2730-6011},
support = {JCYJ20190812171411416//Science and Technology Research and Development Foundation of Shenzhen/ ; JCYJ20210324131405016//Science and Technology Research and Development Foundation of Shenzhen/ ; JCYJ20230807142814031//Science and Technology Research and Development Foundation of Shenzhen/ ; A2018523//Medical Science and Technology Research Foundation of Guangdong Province/ ; },
abstract = {BACKGROUND: Resveratrol (Res), a plant-derived polyphenol, exerts synergistic effects when combined with various chemotherapeutic drugs, enhancing the antitumor activity of traditional chemotherapy. However, whether Res combined with cisplatin (CDDP) produces a synergistic inhibitory effect on osteosarcoma cell growth and its underlying mechanisms remain unclear.<br><br>METHODS: We investigated the responses of U2-OS cells to Res, CDDP, or their combination using Cell Counting Kit-8 (CCK-8) for proliferation, flow cytometry for apoptosis, wound healing assays for migration, and Transwell assays for invasion. The effects of the two drugs on Wnt/&#x3b2;-catenin signaling were analyzed via quantitative real-time PCR (qRT-PCR) and western blotting. Additionally, the relationship between Cx43 and Wnt/Wnt/&#x3b2;-catenin signaling was explored by knocking down Cx43 using lentiviral infection.<br><br>RESULTS: The combination of Res and CDDP exhibited greater cytotoxicity against osteosarcoma U2-OS cells than either drug alone, and this effect was synergistic as determined by the Chou-Talalay equation. Cx43 knockdown attenuated the strong antitumor effect of the Res&#x2009;+&#x2009;CDDP combination and restored Wnt/&#x3b2;-catenin signaling activity. Furthermore, the Res&#x2009;+&#x2009;CDDP combination generated more reactive oxygen species (ROS) than individual treatments, inducing ROS-dependent apoptosis, which was blocked by N-acetylcysteine (NAC).<br><br>CONCLUSIONS: Res combined with CDDP exerts a synergistic inhibitory effect on osteosarcoma by upregulating Cx43 and inducing ROS-dependent apoptosis. This study may provide a novel therapeutic strategy and potential clinical applications for osteosarcoma treatment.},
}
@article {pmid41421415,
year = {2026},
author = {Sun, R and Fan, H and Ma, Q and Li, X and Liu, J and Xu, C and Liu, C and Zhang, D and Ma, W},
title = {LL37-induced mitochondrial stress activates the mtDNA/cGAS/STING pathway to promote mast cell-mediated rosacea inflammation.},
journal = {Free radical biology &amp; medicine},
volume = {244},
number = {},
pages = {422-434},
doi = {10.1016/j.freeradbiomed.2025.12.026},
pmid = {41421415},
issn = {1873-4596},
mesh = {Animals ; *DNA, Mitochondrial/genetics/metabolism ; *Rosacea/pathology/genetics/metabolism/drug therapy/immunology ; *Mast Cells/metabolism/drug effects/pathology/immunology ; *Cathelicidins/pharmacology ; Mice ; *Mitochondria/metabolism/drug effects/pathology ; *Membrane Proteins/metabolism/genetics ; Signal Transduction ; *Nucleotidyltransferases/metabolism/genetics ; Humans ; Oxidative Stress ; Inflammation/pathology/genetics ; Cell Degranulation ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; },
abstract = {BACKGROUND: Rosacea is a chronic inflammatory skin disease characterized by persistent facial erythema and telangiectasia. The antimicrobial peptide LL37 is a key initiator in rosacea, with mast cells serving as critical inflammatory mediators. However, the precise mechanism underlying LL37-induced mast cell degranulation remains unclear.<br><br>METHODS: The rosacea RNA-seq dataset GSE65914 was downloaded from the Gene Expression Omnibus (GEO) database and subjected to transcriptome analysis. DCFH-DA staining was performed to detect oxidative stress. Mitochondrial function was evaluated using MitoSOX and JC-1 staining. Calcein AM/Co[2+] quencher staining was employed to assess mitochondrial permeability transition pore (mPTP) opening. Transmission electron microscopy was utilized to observe mitochondrial ultrastructure. Cytosolic mitochondrial DNA (mtDNA) was evaluated via immunofluorescence and qPCR. Western blotting and CUT&amp;RUN assays were conducted to detect activation of the cGAS/STING/NF-&#x3ba;B axis. Mast cell degranulation was assessed using ELISA. N-acetylcysteine (NAC) was administered to scavenge reactive oxygen species (ROS). Cyclosporin A (CsA) was used to inhibit mPTP opening. SP23 was applied for chemical degradation of STING. A LL37-induced rosacea-like dermatitis mouse model was established and topically treated with applied CsA/SP23 cream.<br><br>RESULTS: Transcriptomic profiling reveals significant enrichment of the cGAS/STING signaling pathway in rosacea lesions. LL37 induces oxidative stress-driven mitochondrial damage in mast cells, resulting in the leakage of mtDNA. Cytosolic mtDNA activates the cGAS/STING/NF-&#x3ba;B signaling pathway, inducing mast cell degranulation. ROS scavenging, blockade of mPTP or targeted degradation of STING significantly reduced mast cell activation. Animal experiments demonstrated that topical administration of CsA or SP23 suppressed cGAS/STING/NF-&#x3ba;B signaling in dermal mast cells and alleviated rosacea-like dermatitis.<br><br>CONCLUSION: LL37 promotes mast cell-driven inflammation through mitochondrial stress and innate immune activation and suggest that targeting the mtDNA/cGAS/STING pathway may offer a promising therapeutic strategy for rosacea.},
}
@article {pmid41419903,
year = {2025},
author = {Tekdemir, A and Ekici, MA and Çelikten, B and Helvacıoğlu Kıvanç, B},
title = {Comparison of calcium hydroxide removal efficiency of ethylenediaminetetraacetic acid, phytic acid and N-acetylcysteine using sonic activation: a micro-CT study.},
journal = {BMC oral health},
volume = {26},
number = {1},
pages = {158},
pmid = {41419903},
issn = {1472-6831},
mesh = {Humans ; *Edetic Acid/chemistry ; *Calcium Hydroxide/chemistry ; X-Ray Microtomography/methods ; *Phytic Acid/chemistry ; *Acetylcysteine/chemistry ; *Root Canal Irrigants/chemistry ; *Dental Pulp Cavity/diagnostic imaging/chemistry ; Root Canal Preparation/methods/instrumentation ; *Chelating Agents/chemistry ; Bicuspid ; *Calcium Chelating Agents/chemistry ; },
abstract = {BACKGROUND: The aim of this study was to compare the efficacy of ethylenediaminetetraacetic acid (EDTA), phytic acid (IP6), and N-acetylcysteine (NAC) with sonic activation on the removal efficiency of calcium hydroxide (Ca(OH)2) from root canals with micro-computed tomography (micro-CT) analysis.<br><br>METHODS: Thirty-two extracted human mandibular first premolars were used in this study. The teeth were randomly divided into 4 groups based on the chelating agents to be used to remove Ca(OH)2 from the root canals (n=8). The root canals were prepared with the ProTaper rotary system up to X5. The specimens were scanned using micro-CT after preparation. Calcium hydroxide paste was delivered into root canals using a syringe system (SURE-Paste) combined with a lentulo spiral. All teeth were scanned using micro-CT to determine the filling volume. After 7 days, Ca(OH)2 was removed from the root canals. EDTA was used with syringe irrigation for the first group while, EDTA, IP6, and NAC were used with sonic activation at other groups, respectively, to remove Ca(OH)2. Teeth were scanned using micro-CT to calculate the volume and the percentage of Ca(OH)2 remnants. Data were analyzed statistically by one-way ANOVA and Duncan's tests (&#x3b1;=0.05).<br><br>RESULTS: None of the chelating agents and irrigation techniques completely removed Ca(OH)2. The percentage of the remnant volume of the Ca(OH)2 was significantly different between the groups (p&#x2009;<&#x2009;0.05). The EDTA with syringe irrigation group had higher Ca(OH)2 remnant volume values compared to other groups (p&#x2009;<&#x2009;0.05). The use of the EDTA, IP6, and NAC with sonic activation did not significantly affect the percentage of remaining Ca(OH)2 (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSIONS: The calcium hydroxide removal efficiencies of all three chelating agents were similar. IP6 and NAC can be used as alternatives to EDTA for Ca(OH)2 removal from the root canals with sonic activation.},
}
@article {pmid41418387,
year = {2026},
author = {Zhao, XY and Yan, M and Zheng, L and Gou, CL and Huang, Q and Li, LG and Yu, XR and Lu, JY and Hu, C and Zhang, SH and Kong, C and Leng, F and Li, TF},
title = {Curcumin-mediated photodynamic action disturbs TOM70-depedent MIC60 import to damage mitonchondria against breast cancer.},
journal = {Journal of photochemistry and photobiology. B, Biology},
volume = {274},
number = {},
pages = {113339},
doi = {10.1016/j.jphotobiol.2025.113339},
pmid = {41418387},
issn = {1873-2682},
mesh = {*Curcumin/chemistry/pharmacology/therapeutic use ; Animals ; Humans ; *Breast Neoplasms/pathology/drug therapy/metabolism ; Female ; *Photochemotherapy ; Mice ; Cell Line, Tumor ; Apoptosis/drug effects ; Molecular Docking Simulation ; *Mitochondria/metabolism/drug effects ; *Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Precursor Protein Import Complex Proteins ; Cell Proliferation/drug effects ; Mice, Inbred BALB C ; Cell Survival/drug effects ; *Photosensitizing Agents/chemistry/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; },
abstract = {The regulation of mitochondrial membrane proteins is of crucial significance for breast cancer therapy. TOM70, which located in mitochondria outer membrane, could import MIC family molecules to preserve mitochondrial homeostasis. However, there are few agents targeting TOM70. Therein, the effects of curcumin and it's mediated photodynamic therapy (PDT) on the TOM70 and mitochondrial function for breast cancer treatment were investigated. The 4 T1 and MDA-MB-231 cells were utilized as the breast cancer cells. The 4 T1 cell-bearing mice were constructed as the breast cancer animal model. The anti-cancer efficacy was validated using the CCK-8, Annexin-V/PI staining, colony formation. The associated molecules were detected by Western blots (WB), RT-qPCR, and Immunohistochemistry (IHC). The target was verified by molecular docking, CETSA, and DARTS. The mitochondrial proteins and DNA were extracted for the MIC60 and mtDNA damage detection. Curcumin treatment showed poor efficacy in the breast cancer model, as characterized by cell viability, apoptosis, proliferation of breast cancer cells, and the growth of tumor grafts in mice. However, curcumin-mediated PDT inhibited breast cancer in vitro and in vivo. Further exploration identified curcumin bond to TOM70, which is highly expressed in breast cancer, thereby activating it. But curcumin-induced PDT inactivated TOM70 through generated reactive oxygen species (ROS), which in turn interfered with the binding of MIC60 and its translocation into mitochondria. Curcumin-triggered PDT led to severe mitochondrial damage compared with the curcumin treatment, which could be blocked by the N-Acetylcysteine (NAC). Additional TOM70 rescue dampened curcumin PDT-mediated mitochondrial damage and anti-breast cancer efficacy. To summarize, the present research identifies curcumin-induced PDT inactivated TOM70, thereby attenuating MIC60 import, leading to mitochondrial damage against breast cancer. We propose a novel approach to tumor treatment through the regulation of mitochondrial membrane proteins using the phytomedicine-driven PDT.},
}
@article {pmid41415424,
year = {2025},
author = {Rukh, S and Meechan, DW and Roberts, A and Siggins, C and Erwin, ZD and Maynard, TM and LaMantia, AS},
title = {Distinct cellular and transcriptional mechanisms mediate an antioxidant therapeutic response in 22q11-deleted upper layer cortical projection neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41415424},
issn = {2692-8205},
support = {R01 HD042182/HD/NICHD NIH HHS/United States ; R21 MH126294/MH/NIMH NIH HHS/United States ; },
abstract = {We characterized cellular and molecular mechanisms underlying the therapeutic response in vitro and in vivo to the antioxidant N-acetyl cysteine (NAC), which in the LgDel 22q11.2 Deletion Syndrome mouse model restores growth and connectivity of upper layer cortical projection neurons (Layer 2/3 PNs) and improves cognitive performance. NAC treatment of primary cultured LgDel L 2/3 PNs does not restore these neurons to a wild type (WT) state. Rather than returning to the bimodal dendrite and axon size distribution seen in WT, LgDel L 2/3 PN dendrite and axon growth in vitro increases unimodally in response to NAC. In parallel, altered expression of 22q11-deleted genes and presumed downstream targets are unchanged. Instead, novel antioxidant defense and neuronal growth genes are differentially expressed: some generally NAC-regulated, others responsive only in the context of 22q11 deletion. Apparently, NAC ameliorates L 2/3 PN developmental pathology without restoring WT cell states or typical expression of mutant genes or their downstream targets. NAC also elicits differential expression of antioxidant defense genes in 22q11-deleted L 2/3 PNs-but not L 5/6 counterparts-in the developing postnatal LgDel mouse cortex, rather than modulating 22q11 genes or downstream targets. These NAC-dependent, L 2/3 PN-selective in vivo cellular and transcriptional changes differ substantially from those in primary culture. Thus, despite some in vitro and in vivo parallels, the NAC therapeutic response that diminishes oxidative stress-related L 2/3 PN circuit and behavioral pathology due to 22q11 deletion has a unique in vivo signature.},
}
@article {pmid41415037,
year = {2025},
author = {Qi, J and Yin, Z and Peng, Y and Zhang, F and Li, Y and Xia, X and Jia, X},
title = {Evaluation of antioxidant co-therapy for polymyxin B-associated nephrotoxicity and mortality: a real-World retrospective cohort study.},
journal = {Journal of pharmaceutical policy and practice},
volume = {18},
number = {1},
pages = {2568673},
pmid = {41415037},
issn = {2052-3211},
abstract = {BACKGROUND: Polymyxin B is increasingly used to treat infections caused by multidrug-resistant gram-negative bacteria; however, its widespread clinical use is hindered by the high incidence of nephrotoxicity. Antioxidants, such as vitamin C, N-acetylcysteine (NAC), and methionine, have demonstrated renoprotective effects in preclinical models, although clinical evidence remains limited. This study aimed to investigate the potential protective effects of these antioxidants against polymyxin B-associated acute kidney injury (AKI) in real-world clinical practice.<br><br>METHODS: This retrospective cohort study included adult in patients who received intravenous polymyxin B for&#x2009;&#x2265;&#x2009;3 days between August 2018 and August 2020. The patients were classified into an antioxidant group (co-administered vitamin C, NAC, or methionine for&#x2009;&#x2265;&#x2009;3 days) or a control group. Propensity score weighting was applied to balance the baseline covariates. The primary outcome was the incidence of polymyxin B-associated AKI and the secondary outcome was discharge mortality.<br><br>RESULTS: A total of 321 patients were included, with 77 and 244 patients in the antioxidant and control groups, respectively. After propensity score adjustment, there were no statistically significant differences in AKI incidence (26.9% vs. 19.2%, P&#x2009;=&#x2009;0.352) or discharge mortality (7.7% vs. 15.4%, P&#x2009;=&#x2009;0.220) between the groups. Subgroup analyses of individual antioxidants also showed no significant differences in AKI or mortality, except for a lower unadjusted mortality in the methionine group (0% vs. 13.9%, P&#x2009;=&#x2009;0.042), which lost significance after adjustment.<br><br>CONCLUSION: This exploratory study did not provide conclusive evidence that vitamin C, NAC, or methionine reduced the risk of polymyxin B-associated AKI. The potential association between antioxidant use and reduced mortality warrants further investigation. Large-scale prospective studies are required to confirm the clinical utility of antioxidant cotherapy in patients receiving polymyxin B.},
}
@article {pmid41412528,
year = {2026},
author = {Wu, Z and Kuang, Z and Liang, L and Liu, J and Wang, G and Zou, F},
title = {TGF-β/LAMB3 axis drives ROS-dependent renal fibrosis under hypoxic conditions.},
journal = {Free radical biology &amp; medicine},
volume = {244},
number = {},
pages = {395-409},
doi = {10.1016/j.freeradbiomed.2025.12.024},
pmid = {41412528},
issn = {1873-4596},
mesh = {Animals ; *Reactive Oxygen Species/metabolism ; Fibrosis/pathology/metabolism ; Mice ; *Transforming Growth Factor beta/metabolism/genetics ; Epithelial-Mesenchymal Transition ; Signal Transduction ; Humans ; Acetylcysteine/pharmacology ; *Kidney Diseases/pathology/metabolism/genetics ; *Kidney/pathology/metabolism ; *Hypoxia/metabolism ; Myofibroblasts/metabolism/pathology ; Phosphatidylinositol 3-Kinases/metabolism/genetics ; Fibroblasts/metabolism/pathology ; Epithelial Cells/metabolism/pathology ; Cell Hypoxia ; },
abstract = {Hypoxia is a well-established driver of renal fibrosis, but the underlying mechanisms remain unclear. In this study, we demonstrate that hypoxia-induced excessive reactive oxygen species (ROS) drive renal fibrosis, while the antioxidant N-acetylcysteine (NAC) ameliorates this pathological process. Hypoxia-induced ROS overproduction in renal tubular epithelial cells acts as the central regulator driving concurrent partial epithelial-mesenchymal transition (pEMT) and TGF-β secretion. Integrated ATAC-seq and RNA-seq analysis demonstrates that TGF-β treatment induces LAMB3 upregulation in fibroblasts through enhanced chromatin accessibility at its promoter region. Mouse model of hypoxic renal fibrosis shows marked upregulation of both TGF-β and LAMB3, implicating their involvement in fibrogenesis under hypoxic conditions. Kidney-targeted knockdown of LAMB3 significantly ameliorates hypoxia-induced renal fibrosis. TGF-β secreted by hypoxic renal tubular epithelial cells activates canonical Smad signaling in fibroblasts, which in turn upregulates LAMB3 to initiate PI3K/AKT-dependent myofibroblast differentiation. Pharmacological ROS scavenging by NAC potently disrupts this TGF-β/LAMB3 axis, improving kidney fibrosis under hypoxic conditions. Our findings reveal that TGF-β/LAMB3 axis drives ROS-dependent renal fibrosis under hypoxic conditions, identifying LAMB3 and ROS as potential therapeutic targets for fibrotic kidney diseases.},
}
@article {pmid41412471,
year = {2026},
author = {Chang, YC and Lin, WH and Ko, HH and Lo, YC and Chang, HS and Lin, HC and Chen, YF},
title = {Formononetin protects against oxaliplatin-induced peripheral neurotoxicity via Nrf2/HO-1 antioxidant pathway without impairing anticancer efficacy.},
journal = {Neurotoxicology},
volume = {112},
number = {},
pages = {103368},
doi = {10.1016/j.neuro.2025.103368},
pmid = {41412471},
issn = {1872-9711},
mesh = {*Oxaliplatin/toxicity ; *Isoflavones/pharmacology ; Animals ; *NF-E2-Related Factor 2/metabolism ; *Heme Oxygenase-1/metabolism ; *Neuroprotective Agents/pharmacology ; *Antineoplastic Agents/toxicity ; *Peripheral Nervous System Diseases/chemically induced/prevention &amp; control/metabolism ; Ganglia, Spinal/drug effects/metabolism ; Humans ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Paclitaxel/toxicity ; Mice ; Rats ; Neurons/drug effects/metabolism ; },
abstract = {Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intolerable adverse effect of oxaliplatin and paclitaxel. The intolerance to CIPN symptoms often leads to poor compliance and treatment discontinuation, jeopardizing survival outcomes. However, no Food and Drug Administration (FDA)-approved interventions exist for preventing or treating CIPN. A major challenge has been that neuroprotective candidates often diminish the effectiveness of chemotherapy, limiting their translational development. Here, we aimed to identify neuroprotective agents that maintain anticancer activity. Using ND7/23 dorsal root ganglion neurons treated with oxaliplatin and paclitaxel, we screened our compound library and identified formononetin, a natural isoflavone, as a promising candidate. Formononetin significantly protected ND7/23 DRG neurons against oxaliplatin-induced neurotoxicity by reducing oxidative stress and apoptosis via activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway and modulating protein expressions of pro-apoptotic B-cell lymphoma 2-associated X (Bax) and anti-apoptotic B-cell lymphoma 2 (BCL-2). Formononetin showed limited protection against paclitaxel-induced structural neurite damage. Importantly, unlike the ROS scavenger N-acetylcysteine (NAC), which decreased the anticancer effectiveness of both oxaliplatin and paclitaxel, formononetin maintained their anticancer effects in colorectal cancer HT29 cells and cervical cancer SiHa cells. Taken together, formononetin holds potential as a neuroprotectant to prevent oxaliplatin-induced neurotoxicity without compromising anticancer efficacy.},
}
@article {pmid41401723,
year = {2026},
author = {Lin, CH and Lane, HY},
title = {Sodium benzoate treatment linked to increased glutathione levels and improved positive and negative symptoms, global function, and quality of life in patients with clozapine-resistant schizophrenia: secondary analysis of a randomized clinical trial.},
journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology},
volume = {103},
number = {},
pages = {112733},
doi = {10.1016/j.euroneuro.2025.11.010},
pmid = {41401723},
issn = {1873-7862},
mesh = {Humans ; *Sodium Benzoate/therapeutic use ; *Glutathione/blood ; Male ; Female ; *Quality of Life/psychology ; Adult ; *Clozapine/therapeutic use ; Double-Blind Method ; Middle Aged ; *Antipsychotic Agents/therapeutic use ; *Schizophrenia, Treatment-Resistant/drug therapy/blood/psychology ; Treatment Outcome ; *Schizophrenia/drug therapy/blood ; },
abstract = {Oxidative stress is implicated in schizophrenia. Glutathione (GSH), a crucial endogenous antioxidant, is usually reduced in individuals with schizophrenia. GSH and its precursor, N-acetyl cysteine, have demonstrated potential as adjunctive treatment for schizophrenia; however, their effectiveness appears inconsistent, possibly because of their limited ability to penetrate the blood-brain barrier (BBB). Administration of sodium benzoate, capable of crossing BBB, enhanced GSH capacity and antipsychotic-like activity in animals. Further, adjunctive benzoate therapy improved clinical and functional outcomes in patients with schizophrenia, including clozapine-resistant schizophrenia (CRS). Whether sodium benzoate can also boost GSH to exert its therapeutic efficacy for schizophrenia deserves elucidation. This secondary analysis used data from a double-blind trial, in which 60 patients with CRS were randomized to receive addon treatment of sodium benzoate (n = 40) or placebo (n = 20) for 6 weeks. Clinical and functional assessments were conducted bi-weekly. Plasma levels of GSH were assayed at baseline and endpoint. As a result, six-week treatment of sodium benzoate was linked to increased GSH levels than placebo. Among the 40 benzoate receivers, the changes in GSH levels were correlated with the improvements in positive symptoms, negative symptoms, quality of life, and global function. In comparison, among placebo recipients, GSH changes were not associated with any changes in clinical or functional variables. The findings suggest that benzoate treatment may be related with elevation in GSH levels in CRS patients and improvement in functional outcomes as well as positive and negative symptoms. Longer-term studies in other populations are necessary in the future.},
}
@article {pmid41399893,
year = {2025},
author = {Aly, S and Ali, M and Sayed, A and Hamadneh, BN and Yousef, M and Khalil, M and Rizk, A and El-Messery, TM and Kamel, RM and Mohammed, BM and Abdelkarim, DO and Younis, M},
title = {Enhanced color and antioxidant properties of sunflower protein concentrates extracted under alkaline conditions using anti-greening reagents.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70389},
pmid = {41399893},
issn = {1097-0010},
abstract = {BACKGROUND: Sunflower protein concentrates (SPCs) are valuable plant-derived ingredients. However, their application is limited by greening during alkaline extraction, caused by chlorogenic acid (CGA) oxidation. This study systematically developed and characterized SPCs extracted under alkaline conditions with two anti-greening reagents, N-acetylcysteine (NAC) and ascorbic acid (ASC), each applied at 12 mg g[-1] meal. The findings provide novel insights into how these reagents modulate the amino acid composition, structural conformation, and antioxidant potential, and improve color in SPCs obtained from completely hulled (SPC-CH) and unhulled (SPC-UH) sunflower seeds.<br><br>RESULTS: The addition of ASC during extraction increased the total phenolic content to 130.51 g kg[-1] CGA in SPC-CH and 119.08 g kg[-1] CGA in SPC-UH. The antioxidant capacity, measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, reached 1084.38&#x2009;mmol kg[-1] Trolox equivalent (TE) in ASC-treated SPC-CH, compared with 891.08 and 937.58&#x2009;mmol kg[-1] TE in the distilled water (DW) and NAC treatments. Both ASC and NAC inhibited greening, producing SPCs with a more acceptable yellowish color. Structural analysis showed only minor alterations in protein secondary structure across all extraction methods, indicating that protein integrity was maintained. Thermal stability and amino acid composition evaluations further supported the suitability of these SPCs for food applications.<br><br>CONCLUSION: The use of ASC and NAC as anti-greening reagents improved the color and antioxidant potential of sunflower protein concentrates while maintaining structural stability. This approach enables the sustainable production of high-quality SPCs, suitable for functional food formulations. &#xa9; 2025 Society of Chemical Industry.},
}
@article {pmid41389180,
year = {2025},
author = {Naik, S and Boopathy, R and Das, T and Mishra, M},
title = {Unravelling the Mechanism of N-Acetylcysteine in Alleviating Smoke-Induced Hypoxia-Driven Ocular Defects in Drosophila melanogaster.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {291},
pmid = {41389180},
issn = {1559-1182},
mesh = {Animals ; *Drosophila melanogaster/drug effects ; *Acetylcysteine/pharmacology/therapeutic use ; *Hypoxia/complications/drug therapy ; *Smoke/adverse effects ; *Eye/drug effects/pathology ; Drosophila Proteins/metabolism/genetics ; Particulate Matter ; },
abstract = {Smoke that includes particulate matter (PM), carbon monoxide (CO), sulfur dioxide (SO2), and nitrogen dioxide (NO2) has a substantial negative impact on human health. PM, which can vary from tiny dust to coarse particles, enters the respiratory system and reduces the amount of oxygen taken in by the lungs, leading to hypoxia. Drosophila was employed as the model organism to study the effects of smoke-induced hypoxia on eye development and to evaluate N-Acetylcysteine (NAC) as a potential protective agent. In this study, Drosophila eggs were exposed to 0.1 g of coconut husk smoke . Furthermore, different size fractions of particulate matter (PM) (10, 2.5, and 1.0 µm) and concentrations of different gases were monitored to correlate the inference of PM and gases on the tracheal terminal tube. To determine whether CO and PM (10, 2.5, and 1 µm) contribute to hypoxia, quantitative PCR analysis of sima and tango was performed, revealing a significant upregulation of sima expression. Impairment of the tracheal terminal branches results in reduced oxygen delivery to tissues, which affects the development of photoreceptor cells. Biochemical estimation disclosed the presence of reactive oxygen species, which led to cellular injury and DNA damage. The marked downregulation of NinaE (Rh1), Rh3, and Rh6 causes internal defect in the eye. Treatment with NAC restored all these abnormalities to normal levels. This research provides insight into how smoke-induced hypoxia disrupts eye development, while NAC shows potential as an effective therapeutic agent in counteracting its harmful effects.},
}
@article {pmid41385627,
year = {2025},
author = {Li, Y and Yu, T and Wang, Z and Wang, J and Tang, Y and Zhang, Y and Li, H and Zhou, H and Yin, P and Yao, S},
title = {A fluorescent probe for concurrent detection of cysteine, homocysteine, and superoxide anion.},
journal = {Science advances},
volume = {11},
number = {50},
pages = {eadx6659},
pmid = {41385627},
issn = {2375-2548},
mesh = {*Cysteine/analysis/metabolism ; *Superoxides/analysis/metabolism ; *Homocysteine/analysis/metabolism ; Animals ; *Fluorescent Dyes/chemistry ; Zebrafish ; Humans ; Oxidation-Reduction ; Oxidative Stress ; Mice ; },
abstract = {Redox imbalance is a key factor in the pathogenesis of diseases such as epilepsy and liver injury. Superoxide anion (O2[•-]), cysteine (Cys), and homocysteine (Hcy) play central roles in maintaining redox homeostasis, and their dysregulation drives oxidative stress and disease progression. Here, we report a multifunctional fluorescent probe, BPC, capable of simultaneously and selectively detecting Cys, Hcy, and O2[•-] in complex biological environments. BPC shows high sensitivity, selectivity, and biocompatibility, enabling real-time visualization of redox fluctuations in living cells and zebrafish with minimal cytotoxicity. In pentylenetetrazole (PTZ)- and acetaminophen (APAP)-induced models of epilepsy and liver injury, BPC revealed notable alterations in Cys, Hcy, and O2[•-] levels, providing mechanistic insights into redox dysregulation. Moreover, BPC successfully tracked redox restoration following N-acetylcysteine (NAC) treatment. These findings establish BPC as a versatile tool for redox biology and highlight its promise for diagnostic and therapeutic applications.},
}
@article {pmid41383104,
year = {2025},
author = {Kim, HB and Kim, YJ and Lim, HM and Suh, SW and Lee, JH and Lee, CJ and Woo, RS},
title = {N-acetylcysteine Restores Impaired Dentate Gyrus Neurogenesis in a Neonatal Maternal Separation Rat Model.},
journal = {Experimental neurobiology},
volume = {34},
number = {6},
pages = {277-288},
pmid = {41383104},
issn = {1226-2560},
abstract = {Early-life stress (ELS) is a major contributor to neurodevelopmental vulnerability, particularly within the dentate gyrus (DG), where oxidative burden and microglial activation disrupt adult neurogenesis. Here, we examined whether N-acetylcysteine (NAC), a cysteine prodrug and glutathione precursor, could counteract impaired neurogenesis induced by neonatal maternal separation (NMS). Adolescent NAC administration restored the number of Ki67[+] proliferating progenitors and DCX[+] immature neurons in the DG of NMS rats, accompanied by reduced reactive oxygen species, suppressed iNOS induction, and attenuated microglial activation. NAC also normalized EAAC1 expression, indicating enhanced neuronal antioxidant capacity. Notably, NAC rescued diminished neurogenesis in EAAC1 knockout mice, demonstrating its efficacy under both stress-induced and transporter-deficient redox imbalance. These findings identify NAC as a potent modulator of hippocampal neuroplasticity, acting through the restoration of redox and inflammatory homeostasis, and support its potential as an early therapeutic strategy to mitigate long-lasting neurodevelopmental consequences of ELS.},
}
@article {pmid41381010,
year = {2026},
author = {Xu, R and Liang, XW and Cai, QH and Cai, YW and Sun, N and Li, YP and Shi, ZJ and Hu, B and He, XH and Zha, QB and Ouyang, DY},
title = {Hyperthermia induces reductive stress in murine macrophages.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1872},
number = {3},
pages = {168133},
doi = {10.1016/j.bbadis.2025.168133},
pmid = {41381010},
issn = {1879-260X},
mesh = {Animals ; Mice ; *Macrophages/metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Thioredoxins/metabolism ; Apoptosis ; Mitochondria/metabolism/pathology ; Oxidation-Reduction ; *Hyperthermia/metabolism/pathology ; *Heat-Shock Response ; RAW 264.7 Cells ; DNA Damage ; },
abstract = {Hyperthermia induces heat stress (HS) and injuries in various human organs, or even leads to mortality, yet the underlying mechanism is incompletely uncovered. Our study revealed that HS in macrophages induced concurrent activation of pyroptotic, apoptotic, and necroptotic pathways, and the formation of PANoptosome-like complexes. However, these processes proceeded independently of ROS, as the ROS scavengers N-acetyl cysteine and mito-TEMPO failed to prevent the cell death (PANoptosis) despite effectively suppressing oxidative stress. Instead, HS caused reductive stress marked by NADPH accumulation and thioredoxin (Trx) system dysfunction. Trx1 aggregation impaired redox regulation, leading to aberrant disulfide bonding in mitochondrial proteins (e.g., Drp1, Bcl-2). The Trx reductase exogenous substrate DTNB partially rescued cell viability by restoring redox balance, confirming Trx failure as a key driver of cytotoxicity. Notably, such reductive stress was accompanied by DNA damage and mitochondrial injury during HS. Pharmacologic intervention revealed that pan-caspase inhibition by IDN-6556 abrogated the reductive stress and its consequences (ROS production, DNA damage, and mitochondrial injury), and suppressed the pyroptotic/apoptotic signaling and lytic cell death. However, the caspase inhibition alone triggered compensatory receptor-interaction protein 3 (RIPK3) activation, necessitating dual inhibition with GSK'872 (RIPK3 inhibitor) to fully block PANoptotic cell death. In vivo validation showed protection of the IDN-6556/GSK'872 combination against HS-induced injury on the intestines through reduced DNA damage and PANoptosis suppression. Our study reveals that reductive stress-mediated Trx dysfunction, not oxidative stress, underlies HS-induced PANoptosis. Dual targeting of caspases and RIPK3 provides a novel therapeutic avenue against heat shock-associated diseases.},
}
@article {pmid41380831,
year = {2026},
author = {Etemadi, Y and Akakpo, JY and Fields, TA and Ramachandran, A and Jaeschke, H},
title = {Differential effects on acetaminophen-induced nephrotoxicity and liver injury following modulation of glutathione resynthesis.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {208},
number = {},
pages = {115896},
pmid = {41380831},
issn = {1873-6351},
support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Acetaminophen/toxicity ; Male ; *Glutathione/biosynthesis/metabolism ; Mice, Inbred C57BL ; *Chemical and Drug Induced Liver Injury/metabolism ; *Acute Kidney Injury/chemically induced/metabolism ; Mice ; *Kidney/drug effects/metabolism/pathology ; Liver/drug effects/metabolism ; Alanine Transaminase/blood/metabolism ; Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; Blood Urea Nitrogen ; Hepatitis A Virus Cellular Receptor 1/metabolism ; },
abstract = {Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), with acute kidney injury (AKI) increasing morbidity and mortality. N-acetylcysteine (NAC) prevents APAP-induced liver damage, but not AKI, highlighting the need to address differential inter-organ responses to APAP toxicity. We investigated the relationship between hepatic glutathione (GSH) depletion, liver injury, and subsequent kidney damage following APAP overdose. Male C57BL/6J mice received either moderate (300 mg/kg) or severe (600 mg/kg) overdoses of APAP, with or without buthionine sulfoximine (BSO, 50 mg/kg) to deplete GSH, or NAC (500 mg/kg) to replenish GSH. A moderate APAP overdose elevated liver injury markers (alanine aminotransferase, ALT) without significantly affecting blood urea nitrogen (BUN) levels, though kidney injury molecule-1 (KIM-1) expression increased. A severe overdose significantly increased ALT activities, and BUN and creatine levels, together with marked upregulation of renal KIM-1 and histological evidence of cortical damage. BSO exacerbated APAP-induced kidney but not liver injury, where GSH remained depleted at 24 h. In contrast, NAC protected against APAP hepatotoxicity but not AKI. Thus, these findings demonstrate critical organ-specific responses to APAP toxicity and underscore the need for targeted therapeutic strategies specifically addressing APAP-induced kidney injury.},
}
@article {pmid41378547,
year = {2024},
author = {Kotze, C and Swanepoel, J and Kruger, EC and Decloedt, E},
title = {The management and clinical outcome of paracetamol poisoning in South African adults: A single-centre retrospective review.},
journal = {South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde},
volume = {114},
number = {12},
pages = {e1986},
doi = {10.7196/SAMJ.2024.v114i12.1986},
pmid = {41378547},
issn = {2078-5135},
mesh = {Humans ; *Acetaminophen/poisoning ; Female ; Retrospective Studies ; South Africa/epidemiology ; Adult ; Male ; *Chemical and Drug Induced Liver Injury/mortality/etiology/therapy/epidemiology ; *Drug Overdose/mortality ; *Analgesics, Non-Narcotic/poisoning ; Young Adult ; Acetylcysteine/therapeutic use ; Antidotes/therapeutic use ; Treatment Outcome ; },
abstract = {BACKGROUND: Paracetamol is a commonly prescribed drug, and often implicated in pharmaceutical overdoses. Paracetamol-induced hepatotoxicity is a common cause of acute liver failure in many high-income countries, but little is known about the factors associated with severity of liver injury and poor clinical outcomes among those treated in sub-Saharan African settings.<br><br>OBJECTIVE: To describe the characteristics of patients presenting with paracetamol poisoning, and to identify factors associated with severity of liver injury and poor outcomes in adults with biochemical evidence of paracetamol-induced liver damage treated at a South African (SA) tertiary hospital.<br><br>METHODS: A retrospective medical record review was conducted of all adult patients (&#x2265;18 years old) admitted between August 2013 and August 2018 to a tertiary referral centre in Cape Town, SA, with paracetamol poisoning and biochemical evidence of liver impairment. Demographics, clinical and laboratory data were obtained. Management practices and clinical outcomes were assessed.<br><br>RESULTS: The records of 91 patients were included in the analysis. The median (interquartile range (IQR)) age was 29 (23 - 39) years, and 63% were female. The majority of paracetamol poisonings followed an intentional overdose (91%). Acute single ingestions were the most common (81%) type of toxic ingestion, compared with staggered overdose and repeated supratherapeutic ingestion, and the median (IQR) number of tablets ingested was 22 (20 - 39). Two-thirds of patients developed mild liver injury and 12% developed acute kidney injury. The overall mortality rate was 12%. Mortality was lower in those who received intravenous N-acetylcysteine (NAC) before serum paracetamol concentrations were known compared with those who only received NAC after concentrations were known (8.8% v. 36%, p=0.03). A significant proportion of deaths occurred in those with accidental overdose compared with those with intentional overdosing (57% v. 7.2%; p=0.004). People living with HIV (p=0.04), a history of chronic alcoholism (p=0.04), chronic liver disease (p=0.01) and severity of acute kidney stage (p<0.001) were all associated with increased mortality.<br><br>CONCLUSION: A high case fatality rate was observed in the studied population. Early identification of at-risk individuals and prompt initiation of NAC can reduce poor outcomes. Larger multicentre studies are needed to identify independent predictors of paracetamol-induced hepatoxicity and mortality in Africa.},
}
@article {pmid41377542,
year = {2025},
author = {Thoppil, J and Farrar, JD and Sharma, D and Kirby, S and Mobley, A and Courtney, DM},
title = {Reactive oxygen species elevations in human immune cell subsets during sepsis are mitigated by norepinephrine and N-acetylcysteine.},
journal = {World journal of critical care medicine},
volume = {14},
number = {4},
pages = {108638},
pmid = {41377542},
issn = {2220-3141},
abstract = {BACKGROUND: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Peripheral blood mononuclear cells (PBMCs) are critical mediators of the immune response and may exhibit redox imbalance during sepsis. Reactive oxygen species (ROS) are known to influence immune cell signaling, and excessive ROS accumulation may contribute to sepsis-associated immune alterations.<br><br>AIM: To assess intracellular ROS levels in PBMC subsets from septic patients and determine whether norepinephrine (NE) or N-acetylcysteine (NAC) modulate ROS levels following inflammatory stimulation in vitro.<br><br>METHODS: PBMCs were isolated from Department of Emergency patients meeting SEP-1/SEP-2 sepsis criteria and from healthy controls without signs of infection. Intracellular ROS levels were measured using a total ROS detection assay and analyzed by flow cytometry. PBMCs were also stimulated in vitro with lipopolysaccharide (LPS) or hydrogen peroxide (H2O2), with or without co-treatment with NE or NAC.<br><br>RESULTS: ROS levels were significantly elevated in CD3+ and CD14+ cells from septic patients compared to controls. In vitro stimulation of control PBMCs with LPS or H2O2 increased ROS in CD3+ and CD14+ cells, which was attenuated by co-treatment with NE or NAC.<br><br>CONCLUSION: ROS levels are elevated in specific PBMC subsets in sepsis, particularly CD3+ T cells and CD14+ monocytes. NE and NAC reduced ROS accumulation in vitro, supporting their potential role as redox modulators. These findings warrant further mechanistic investigation into immune redox regulation in sepsis.},
}
@article {pmid41373660,
year = {2025},
author = {Izquierdo-Bermejo, S and Chioua, M and Hadjipavlou-Litina, D and López-Muñoz, F and Marco-Contelles, J and Oset-Gasque, MJ},
title = {Neuroprotective and Antioxidant Properties of Different Novel Steroid-Derived Nitrones and Oximes on Cerebral Ischemia In Vitro.},
journal = {International journal of molecular sciences},
volume = {26},
number = {23},
pages = {},
pmid = {41373660},
issn = {1422-0067},
support = {UCJC-NENs, UCJC-CHONICEN,UCJC- HDACi-ICTUS//Universidad Camilo Jos&#xe9; Cela (UCJC)/ ; SAF2015-65586-R//Spanish Ministry of Economy and Competitiveness/ ; },
mesh = {*Oximes/pharmacology/chemistry ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Nitrogen Oxides/pharmacology/chemistry ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; *Brain Ischemia/drug therapy/metabolism/pathology ; Animals ; *Steroids/chemistry/pharmacology ; Cell Survival/drug effects ; Humans ; Rats ; },
abstract = {Despite the substantial global impact of ischemic stroke, current therapeutic options remain limited and only partially effective. To advance neuroprotective strategies that could improve the safety and efficacy of existing treatments while preserving brain tissue, we synthesized and evaluated seven new nitrones (MC3, MC5, MC7) and oximes (MC1, MC2, MC4, MC6) derived from different neuroactive steroids-ethisterone (MC1-3), mifepristone (MC4-5) and stanolone (MC6-7)-in an in vitro model of cerebral ischemia. Overall, these derivatives exhibited neuroprotective and antioxidant effects superior to those of the reference compounds cholesteronitrone ChN2, α-tert-butyl nitrone (PBN) and N-acetylcysteine (NAC). Notably, nitrones showed greater neuroprotective, anti-necrotic, and antioxidant potency than their corresponding oximes, regardless of the degree of molecular conjugation. Among them, the stanolone-derived nitrone MC7, which lacks conjugated double bonds, displayed the most balanced and robust profile, consistently enhancing cell viability, reducing necrotic cell death, and suppressing superoxide anion production. Consequently, MC7 has been selected as a promising lead compound for further in vivo studies of cerebral ischemia.},
}
@article {pmid41373526,
year = {2025},
author = {Pachhapure, S and Shin, YM and Kim, DG and Choi, DR and Yun, JI and Kim, JH and Jang, BC},
title = {The Mitigating Effect and Mechanism of Polydeoxyribonucleotide Against Zoledronic Acid-Induced Growth Suppression of Human Gingival Fibroblasts.},
journal = {International journal of molecular sciences},
volume = {26},
number = {23},
pages = {},
pmid = {41373526},
issn = {1422-0067},
support = {B20220018//This work was supported by a grant (No. B20220018) from Zerone Cellvane Inc./ ; },
mesh = {Humans ; *Zoledronic Acid/pharmacology/adverse effects ; *Gingiva/cytology/drug effects/metabolism ; *Polydeoxyribonucleotides/pharmacology ; *Fibroblasts/drug effects/metabolism/cytology ; Cell Proliferation/drug effects ; STAT3 Transcription Factor/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/metabolism ; },
abstract = {Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is widely used to treat osteoporosis and bone metastases. However, its clinical application is limited by adverse effects, notably bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is associated with cytotoxicity in oral mucosal cells. Polydeoxyribonucleotide (PDRN), a salmon sperm-derived DNA polymer with regenerative and anti-inflammatory properties, has shown therapeutic potential in tissue repair; however, its ability to mitigate ZA-induced cytotoxicity remains poorly understood. Here, we investigated the molecular mechanisms of ZA-induced toxicity in HGF-1 cells, a human gingival fibroblast line, and evaluated the protective effects of PDRN. ZA treatment (50 µM, 48 h) significantly inhibited HGF-1 cell growth, accompanied by reduced phosphorylation of protein kinase B (PKB) and signal transducer and activator of transcription 3 (STAT-3), along with increased phosphorylation of TANK-binding kinase 1 (TBK1). TBK1 silencing restored cell growth under ZA exposure, whereas silencing PKB or STAT-3 further suppressed cell growth even without ZA. Co-treatment with PDRN (100 µg/mL) effectively prevented and reversed ZA-induced HGF-1 cytotoxicity. Mechanistically, PDRN inhibited ZA-induced TBK1 phosphorylation and partially restored PKB phosphorylation, though it did not reverse the reduction in p-STAT-3. Additionally, ZA significantly elevated intracellular reactive oxygen species (ROS) levels at 8 h, which were attenuated by PDRN. The antioxidant N-acetylcysteine (NAC) similarly reduced ZA-induced ROS and p-TBK1 levels and improved cell growth, although it had limited effects on p-PKB at 8 h. Importantly, delayed PDRN treatment following ZA exposure reversed ZA-induced cell growth inhibition and TBK1 activation in a dose- and time-dependent manner. In summary, these findings demonstrate that ZA suppresses HGF-1 cell growth through ROS production, TBK1 activation, and inhibition of PKB and STAT-3, whereas PDRN counteracts these effects primarily by suppressing TBK1 activation and oxidative stress.},
}
@article {pmid41371424,
year = {2026},
author = {Liu, W and Liu, Y and Shi, J and Li, J and Li, G and Quan, J and Zhao, W},
title = {Prepuberty exposure to polystyrene nanoplastics induces cardiac inflammation through calcium overload-mediated ROS/JAK1/STAT3 signaling cascade.},
journal = {Free radical biology &amp; medicine},
volume = {244},
number = {},
pages = {133-146},
doi = {10.1016/j.freeradbiomed.2025.12.006},
pmid = {41371424},
issn = {1873-4596},
mesh = {*STAT3 Transcription Factor/metabolism/genetics ; Animals ; Reactive Oxygen Species/metabolism ; *Janus Kinase 1/metabolism/genetics ; Signal Transduction/drug effects ; *Nanoparticles/toxicity/chemistry ; *Calcium/metabolism ; Mice ; Female ; *Polystyrenes/toxicity ; Pregnancy ; Oxidative Stress/drug effects ; Male ; Humans ; Myocytes, Cardiac/drug effects/metabolism/pathology ; Cell Line ; Inflammation/chemically induced/pathology ; },
abstract = {Polystyrene nanoparticles (PS-NPs) pose a significant threat to human health. In the present study, we aimed to investigate the toxicological effects of low-dose of PS-NPs on cardiac development and function following prepubertal exposure. Postpartum dams and their offspring were exposed to PS-NPs at concentrations of 0, 50 mg/L, and 100 mg/L via their daily drinking water, commencing from gestational day 1 and continuing until postnatal day (PND) 35. The results demonstrated that PS-NPs induced cardiac developmental toxicity in offspring. Proteomic analysis indicated that PS-NP exposure led to differentially expressed proteins, which were mainly enriched in JAK/STAT3 signaling pathway, inflammatory response pathway and antioxidant response signaling pathway. We subsequently found that exposure to PS-NPs in HL-1 cells increased the levels of reactive oxygen species (ROS), IL-6, IL-17, and TNF-α, as well as upregulated the expression of pJAK1 and pSTAT3. Treatment of HL-1 cells with N-Acetylcysteine (NAC) normalized the activity of the JAK1/STAT3 pathway and the levels of inflammatory cytokines. Furthermore, either inhibition of JAK1 with upadacitinib or knockdown of STAT3 in PS-NP-exposed HL-1 cells led to proinflammatory cytokine levels comparable to those in control cells. Given the well-established link between oxidative stress and mitochondrial calcium dysregulation, we demonstrated that PS-NP exposure impaired mitochondrial function by promoting calcium influx, which is mediated by the increased formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). This process facilitated calcium transfer through the IP3R3-GRP75-VDAC1 complex. Notably, pharmacological inhibition of calcium flux attenuated PS-NP-induced mitochondrial dysfunction, oxidative stress, and inflammatory responses in HL-1 cardiomyocytes. Collectively, our findings indicate that prepubertal PS-NP exposure triggers cardiac inflammation, which is likely mediated by MAM-dependent mitochondrial calcium overload and subsequent activation of the ROS/JAK1/STAT3 signaling axis.},
}
@article {pmid41360758,
year = {2025},
author = {Ma, X and Si, F and Ma, J and Feng, C and Wang, Y and Wang, L and Yu, J},
title = {Endoplasmic Reticulum Stress: A Novel Target for the Prevention and Treatment of Hypertension and Its Related Diseases.},
journal = {Journal of cellular and molecular medicine},
volume = {29},
number = {23},
pages = {e70977},
pmid = {41360758},
issn = {1582-4934},
support = {81960086//National Natural Science Foundation of China/ ; 82160089//National Natural Science Foundation of China/ ; 82460086//National Natural Science Foundation of China/ ; CY2021-MS-A13//Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital/ ; YJS-BD-24//Special Fund Project for Doctoral Training of the Lanzhou University Second Hospital/ ; PR0124002//International science and technology cooperation base/ ; },
mesh = {Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Hypertension/prevention &amp; control/drug therapy/metabolism/pathology ; Animals ; Oxidative Stress/drug effects ; Taurochenodeoxycholic Acid/therapeutic use/pharmacology ; Renin-Angiotensin System/drug effects ; Antihypertensive Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Molecular Targeted Therapy ; Phenylbutyrates/therapeutic use/pharmacology ; },
abstract = {Endoplasmic reticulum stress (ERS) emerges as a critical pathophysiological nexus in hypertension and related cardiovascular diseases. Chronic ERS activation via the IRE1α-XBP1, ATF6, and PERK pathways drives vascular endothelial dysfunction (reduced NO bioavailability, increased ET-1), renin-angiotensin system (RAS) hyperactivation, sympathetic overactivation, and vascular smooth muscle cell (VSMC) maladaptive proliferation/apoptosis, collectively promoting hypertension progression and end-organ damage. Pharmacological targeting of ERS demonstrates therapeutic promise: chemical chaperones 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA) stabilise proteostasis, reduce oxidative stress, and inhibit apoptosis; antioxidants N-acetylcysteine (NAC) and melatonin attenuate ERS-oxidative stress crosstalk. Notably, conventional antihypertensives-ACE inhibitors and angiotensin receptor blockers (ARBs)-exert ancillary benefits by suppressing ERS beyond their primary RAS blockade. Preclinical evidence supports the efficacy of these strategies in reversing hypertensive pathophysiology. Future research must prioritise isoform-selective ERS modulator development, validation in human trials, biomarker discovery, and elucidating ERS roles in therapy-induced hypertension. Targeting ERS represents a transformative mechanotherapeutic paradigm for precision hypertension management.},
}
@article {pmid41360103,
year = {2025},
author = {Yang, CW and Chen, CY and Yen, CH and Shu, CW and Lee, HY and Chang, HW},
title = {Threo-2,3-bis-(4-hydroxy-3-methoxyphenyl)-3-methoxypropanol (THMP) Inhibits Bladder Cancer Cell Proliferation via Oxidative Stress-dependent Apoptosis and DNA Damage.},
journal = {Planta medica},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2752-9897},
pmid = {41360103},
issn = {1439-0221},
support = {KMUH-111-1R55//Kaohsiung Medical University Hospital/ ; KMUH-112-2R57//Kaohsiung Medical University Hospital/ ; KMUH-113-3R49//Kaohsiung Medical University Hospital/ ; MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology/ ; NSTC 113-2324-B-037-027//National Science and Technology Council/ ; TB114009//Kaohsiung Medical University/ ; TC114A04//Kaohsiung Medical University/ ; NSYSU-KMU-114-P15//National Sun Yat-sen University-KMU Joint Research Project/ ; KMU-TC114A04//Kaohsiung Medical University Research Center/ ; },
abstract = {Many lignans exhibit antiproliferative effects against cancer cells, but it is rarely reported for threo-2,3-bis-(4-hydroxy-3-methoxyphenyl)-3-methoxypropanol (THMP), an edible red-pepper-derived lignan. This study evaluates the antiproliferative effects and mechanism of THMP against bladder cancer cells (BFTC905 and T24) regarding ATP content and flow cytometry assays in parallel with the presence and absence of N-acetylcysteine (NAC), an oxidative stress inhibitor. THMP suppressed bladder cancer cell viability in the ATP assay, which was reverted by NAC. Regarding flow cytometry, THMP triggered subG1 arrest and enhanced annexin V-affinity intensity. This apoptotic response was further supported by the finding that THMP upregulated the activation of caspases 3, 8, and 9, which is apoptotic signaling. Moreover, oxidative stress was induced by THMP regarding the upregulation of reactive oxygen species (ROS) and mitochondrial superoxide and the exhaustion of glutathione and mitochondrial membrane potential. Regarding γH2AX and 8-hydroxy-2-deoxyguanosine detection, THMP was confirmed to have DNA damage ability. These mechanisms were alleviated by NAC. Overall, THMP is the first report demonstrating the antiproliferative effect against bladder cancer cells and clarifying its oxidative stress-dependent mechanisms.},
}
@article {pmid41358602,
year = {2026},
author = {Wang, H and Wang, H and Yang, Y and Wang, T and Wang, C and Wu, D and Zheng, C and Wei, W},
title = {Berberine Suppresses Pathogenic Fungus Aspergillus fumigatus Hyphal Growth via Mitochondrial Fragmentation-Induced ROS Elevation and Hog1-MAPK Activation.},
journal = {ACS infectious diseases},
volume = {12},
number = {1},
pages = {190-201},
doi = {10.1021/acsinfecdis.5c00749},
pmid = {41358602},
issn = {2373-8227},
mesh = {*Aspergillus fumigatus/drug effects/growth &amp; development ; *Reactive Oxygen Species/metabolism ; *Berberine/pharmacology ; Animals ; *Mitochondria/drug effects/metabolism ; *Mitogen-Activated Protein Kinases/metabolism ; Mice ; *Antifungal Agents/pharmacology ; *Hyphae/drug effects/growth &amp; development ; Aspergillosis/drug therapy/microbiology ; Fungal Proteins/metabolism ; Disease Models, Animal ; MAP Kinase Signaling System/drug effects ; Signal Transduction/drug effects ; },
abstract = {Berberine (BER), a natural isoquinoline alkaloid, exhibits broad-spectrum antifungal activity, yet its mechanism against Aspergillus fumigatus─a leading cause of invasive fungal infections─remains poorly understood. Here, we aim to unveil the mechanism of BER against the pathogenicity of A. fumigatus through mitochondrial dynamics and related pathways. In vitro assays revealed that berberine treatment triggered mitochondrial fragmentation, resulting in reactive oxygen species (ROS) overaccumulation. Subsequent proteomic analyses identified Hog1-MAPK as the central signaling hub activated by ROS stress. Upon activation, Hog1 localizes to the nucleus. ROS scavenging (N-acetylcysteine (NAC) treatment) abolished BER's antifungal effects, confirming the ROS-Hog1-cell cycle axis. Crucially, in a murine invasive aspergillosis model, BER reduced the fungal burden in lungs and improved survival rates. Thus, we demonstrate that berberine suppresses A. fumigatus growth by disrupting mitochondrial dynamics, elevating reactive ROS, and activating the Hog1-MAPK signaling cascade, ultimately inducing cell cycle arrest. Our findings unveil a previously unrecognized mechanism linking mitochondrial morphology dysregulation to cell cycle control in fungi and establish BER as a promising therapeutic agent targeting mitochondrial-ROS-Hog1 signaling in A. fumigatus infections.},
}
@article {pmid41353446,
year = {2025},
author = {Kusuma, B and Rawat, S and Saha, O and Nimesh, S and Sadhu, S and Awasthi, A and Maiti, TK and Banerjee, A},
title = {Depletion of myeloid cells in AG129 mice reduces the infection-mediated oxidative stress and restrains dengue virus-induced thymic atrophy.},
journal = {Cell communication and signaling : CCS},
volume = {24},
number = {1},
pages = {20},
pmid = {41353446},
issn = {1478-811X},
support = {CRG/2023/003638//Science and Engineering Research Board/ ; },
mesh = {Animals ; *Oxidative Stress ; Atrophy ; *Thymus Gland/pathology/virology ; *Myeloid Cells/metabolism/pathology ; Mice ; Reactive Oxygen Species/metabolism ; *Dengue Virus/physiology ; *Dengue/pathology/virology/immunology ; Thymocytes ; },
abstract = {BACKGROUND: Infection-associated thymic atrophy is common and results in T-cell imbalance and immune dysfunction. Severe dengue, caused by infection with the dengue virus (DV), is associated with perturbation of T cell functions. However, it is unclear whether perturbation of T cell functions is linked to changes in thymic function during dengue infection.<br><br>METHODS: Herein, we employed a dengue virus serotype 2 (DV-2)-infected mouse model and Neonatal Thymic Organ Culture (NTOC) to study the impact of DV-2 infection on thymic function. Further, the contribution of infiltrating immune cells, especially myeloid cells, and reactive oxygen species (ROS) in the thymus on DV-2-induced thymic atrophy was studied by depleting Gr-1&#x2009;+&#x2009;myeloid cells and quenching ROS in mice.<br><br>RESULTS: We have demonstrated that DV-2 infection caused a massive thymic atrophy, dominated by a loss of CD4[+] CD8[+] double-positive (DP) thymocytes, reduction in na&#xef;ve T cells in blood and spleen, a significant increase in the infiltration of myeloid cells, and a reactive oxygen species (ROS) burst in the thymus. Using Neonatal Thymic Organ Culture (NTOC), we confirmed that DV-2 infection alone cannot induce thymic atrophy. Further, we documented that depletion of Gr-1&#x2009;+&#x2009;myeloid cells, or quenching of ROS using N-acetylcysteine (NAC) during DV-2 infection, partially protected thymic architecture. This protection of thymus function is also reflected in the thymic interstitial fluid proteome profile, where myeloid cells depletion or NAC treatment in DV-2-infected mice confirmed the reversal of protein expression associated with oxidative stress and neutrophil degranulation pathways within the thymus. Further, managing oxidative stress also influenced cytokine production by T cells in the spleen of infected mice.<br><br>CONCLUSIONS: Thus, our study confirms that thymic atrophy does not depend on viremia level but on the interaction between immune cells and the virus, highlighting the contribution of infiltrating myeloid cells and, thus, ROS in DV-2-associated thymic atrophy.},
}
@article {pmid41352626,
year = {2026},
author = {Chen, X and Wang, S and Ding, B and Nie, Y and Liu, F and Zhang, X and Yu, B and Li, X and Dou, J and Sun, W and Zhou, X},
title = {Dibutyl phthalate (DBP) induces cervical injury and promotes malignant transformation of cervical epithelial cells.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {208},
number = {},
pages = {115885},
doi = {10.1016/j.fct.2025.115885},
pmid = {41352626},
issn = {1873-6351},
mesh = {Female ; Humans ; *Dibutyl Phthalate/toxicity ; Animals ; *Cell Transformation, Neoplastic/drug effects/chemically induced ; Mice ; *Epithelial Cells/drug effects/pathology ; *Uterine Cervical Neoplasms/chemically induced/pathology/metabolism ; *Cervix Uteri/drug effects/pathology ; Oxidative Stress/drug effects ; Adult ; Middle Aged ; Apoptosis/drug effects ; },
abstract = {Dibutyl phthalate (DBP), a widespread phthalate with reproductive toxicity and potential carcinogenicity, its cervical effects remain unclear. This study explored DBP's cervical toxicity and mechanisms via epidemiological analysis, network toxicology, and in vivo/in vitro models. Urinary 6 phthalate metabolites in 104 cervical cancer (CC) patients and 104 controls (detected by UPLC-MS/MS) showed elevated levels of MBP, MEHP, MEOHP, MEHHP, MECPP, and ΣDEHP in CC patients; MBP had the strongest CC risk association (adjusted OR = 2.54, P < 0.001). Network toxicology identified 9 core targets of DBP (e.g., CASP3, MAPK8/14, ESR1) and key pathways involved (TNF, MAPK, apoptosis, oxidative stress, etc.). Short-term DBP exposure (mice: 10-50 mg/kg/day; HcerEpic cells: 100-400 μM) induced cervical injury/oxidative stress, suppressed NRF2, and activated MAPK/NF-κB; N-acetylcysteine (NAC) supplementation mitigated damages. Long-term exposure to environmentally relevant DBP concentrations (10[-7] M) promoted HcerEpic cell malignant transformation (e.g., enhanced proliferation, migration, invasion, epithelial-mesenchymal transition) via activation of the TGF-β/Smad2/3 and MAPK pathways, with in vivo tumorigenicity validated in nude mice. In conclusion, our findings not only elucidate the molecular mechanisms underlying DBP-induced cervical injury and malignant transformation, but also provide theoretical evidence for evaluating the health risks of phthalates (PAEs) and guiding prevention strategies for environmental pollutant-related female reproductive malignancies.},
}
@article {pmid41349802,
year = {2026},
author = {Jiang, Y and Chen, C and Huang, D and Qian, P and Zhu, S},
title = {Interactive effects of H2O2 and NO on mitochondrial function and oxidative mtDNA damage in cold-stored peach fruit.},
journal = {Plant science : an international journal of experimental plant biology},
volume = {364},
number = {},
pages = {112923},
doi = {10.1016/j.plantsci.2025.112923},
pmid = {41349802},
issn = {1873-2259},
mesh = {*Hydrogen Peroxide/metabolism/pharmacology ; *Nitric Oxide/metabolism/pharmacology ; *DNA, Mitochondrial/metabolism/drug effects ; *Mitochondria/drug effects/metabolism/physiology ; *DNA Damage ; *Prunus persica/metabolism/drug effects/genetics/physiology ; Fruit/metabolism/drug effects ; Reactive Oxygen Species/metabolism ; Cold Temperature ; Oxidative Stress ; Antioxidants/metabolism ; },
abstract = {Hydrogen peroxide (H2O2) and nitric oxide (NO), as bioactive species, play critical regulatory roles in plants and correlate with each other under physiological and stressful conditions. The protective effect of NO has been demonstrated through the enhancement of the antioxidative system and the alleviation of oxidative mitochondrial DNA (mtDNA) damage in mitochondria under cold stress. To investigate the effect of H2O2 on mitochondrial function and mtDNA damage in cold-stored peaches and elucidate the interactive effects of H2O2 and NO, sodium nitroprusside (SNP, an NO donor) -pretreated peaches were further treated with H2O2 and the scavenger of reactive oxygen species (N-acetyl cysteine, NAC). Treatment with H2O2 significantly increased endogenous ROS content, raised levels of 8-hydroxyguanosine (8-OHdG) and apurinic/apyrimidinic (AP) sites, and decreased the activities of key enzymes in the BER pathway and superoxide dismutase (SOD), thereby escalating mtDNA damage. Meanwhile, H2O2 negatively regulated mitochondrial function by enlarging the openness of mitochondrial permeability transition pore, aggravating the consumption of oxygen, and reducing the respiratory control ratio of mitochondria and membrane potential. In contrast, NAC, working in conjunction with NO, substantially up-regulated gene expression of the BER pathway. It indicated that H2O2 treatment counteracted the NO-induced protection of mitochondria in cold-stored peaches. This study provides new insight for understanding the crosstalk of different signal molecules in plants.},
}
@article {pmid41341490,
year = {2025},
author = {Hossain, KR and Alghalayini, A and Turkewitz, DR and Valenzuela, SM},
title = {CLIC1 and CLIC4 demonstrate cell protective antioxidant activity against UV exposure.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1674374},
pmid = {41341490},
issn = {2296-634X},
abstract = {BACKGROUND: Redox homeostasis is critical for maintaining healthy biological systems. Under physiological conditions, the human antioxidant defence system relies on enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Recent studies have shown that members of the Chloride Intracellular Ion Channel (CLIC) protein family, particularly CLIC1 and CLIC4, also exhibit antioxidant and cytoprotective activities. Overexpression of these proteins confers cellular protection, whereas their knockdown increases susceptibility to oxidative stress.<br><br>METHODS: This in vitro study investigated the antioxidant and cellular protective effects of CLIC1 and CLIC4 against UV-induced damage in human skin cells. Comparative analyses were performed using known endogenous antioxidant proteins, glutaredoxin (Grx) and Glutathione S-transferase-Omega (GST-&#x3a9;), as well as the antioxidant drug N-acetylcysteine (NAC). Recombinant purified CLIC proteins (rCLIC1 and rCLIC4) were added exogenously to skin cells, while CLIC knockdown models were used to assess loss-of-function effects.<br><br>RESULTS AND DISCUSSION: Exogenous addition of rCLIC1 and rCLIC4 provided significant cellular protection against UV-induced oxidative damage, reducing reactive oxygen species (ROS) production. In contrast, knockdown of CLIC1 or CLIC4 increased cellular vulnerability to oxidative stress. The protective and antioxidant activities of rCLIC1 and rCLIC4 were comparable to those of Grx, GST-&#x3a9;, and NAC. These findings highlight the potent antioxidant and cytoprotective roles of CLIC1 and CLIC4 in maintaining cellular redox balance. The ability of exogenously added recombinant CLIC proteins to mitigate oxidative and UV-induced damage suggests potential therapeutic applications for this protein family in oxidative stress-related conditions.},
}
@article {pmid41340591,
year = {2026},
author = {Demirtas, N and Mazlumoglu, BS and Celep, NA and Cadirci, E and Halici, Z and Palabiyik-Yucelik, SS},
title = {Epigallocatechin-3-Gallate Provides Hepatoprotection Through Endoplasmic Reticulum Stress/TXNIP/NLRP3 Axis in Paracetamol-Induced Acute Liver Injury.},
journal = {Basic &amp; clinical pharmacology &amp; toxicology},
volume = {138},
number = {1},
pages = {e70155},
doi = {10.1111/bcpt.70155},
pmid = {41340591},
issn = {1742-7843},
mesh = {Animals ; *Catechin/analogs &amp; derivatives/pharmacology ; *Endoplasmic Reticulum Stress/drug effects ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/pathology/drug therapy/metabolism/etiology ; *Acetaminophen/toxicity ; Male ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; *Antioxidants/pharmacology ; Liver/drug effects/pathology/metabolism ; Signal Transduction/drug effects ; Inflammasomes/metabolism/drug effects ; Disease Models, Animal ; Rats, Wistar ; },
abstract = {Epigallocatechin-3-gallate (EGCG) is a polyphenolic compound with strong antioxidant properties and is abundantly found in green tea. We investigated how EGCG affects the liver injury of high-dose paracetamol in this study. In our study, 56 rats were divided into seven groups (n = 8): healthy control, EGCG (100 mg/kg), paracetamol (2 g/kg), paracetamol + EGCG 25 (2 g/kg + 25 mg/kg), paracetamol + EGCG 50 (2 g/kg + 50 mg/kg), paracetamol + EGCG 100 (2 g/kg + 100 mg/kg) and paracetamol + N-acetyl cysteine (NAC, 2 g/kg + 140 mg/kg). Our findings suggest that high-dose paracetamol induces liver injury through endoplasmic reticulum (ER) stress and that EGCG alleviates liver injury by attenuating ER stress-induced inflammasome signalling.},
}
@article {pmid41340222,
year = {2026},
author = {Shi, Q and Wu, M and Zhong, J and Chen, C and Huang, Z and Peng, J and Yang, D and Zan, X and Wang, Z},
title = {Procyanidin Capsules Combat ALF by Restoring Mitochondrial Homeostasis and Inhibiting Necroptosis via the PGAM5/DRP1/PINK1 Pathway.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {13},
number = {7},
pages = {e08742},
pmid = {41340222},
issn = {2198-3844},
support = {G2023003//Natural Science Foundation of Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province/ ; Y202457244//General Research Project of Zhejiang Provincial Education Department/ ; },
mesh = {Animals ; Mice ; *Proanthocyanidins/pharmacology ; *Necroptosis/drug effects ; Dynamins/metabolism ; *Catechin/pharmacology ; Homeostasis/drug effects ; *Mitochondria/drug effects/metabolism ; *Liver Failure, Acute/drug therapy/metabolism ; Protein Kinases/metabolism/drug effects ; *Biflavonoids/pharmacology ; Male ; Rabbits ; Disease Models, Animal ; Mitochondrial Proteins/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Liver/drug effects/metabolism ; Mice, Inbred C57BL ; Phosphoprotein Phosphatases ; },
abstract = {Acute liver failure (ALF) is a life-threatening, multifactorial condition characterized by rapid progression, extensive hepatocellular necrosis, and high mortality rates. Current therapeutic options, including artificial liver support systems (ALSS) and liver transplantation, are limited by high costs, donor shortages, and insufficient efficacy. Mitochondrial dysfunction and necrotic cell death play central roles in both acute and chronic liver injury; however, their contribution to ALF remains poorly understood. In this study, self-assembled procyanidin capsules (PC-Ca) are developed with sustained antioxidant and anti-inflammatory properties that selectively accumulate in the liver of an ALF model. These findings demonstrate that PC-Ca significantly improves survival rates and more effectively mitigates liver injury, inflammation, and necrosis in thioacetamide (TAA)-induced ALF in mice and rabbits than the standard clinical agent, N-acetylcysteine (NAC). This protective effect is mediated through enhanced oxidative stress defense via activation of the KEAP1-NRF2 axis and inhibition of necroptosis via the RIPK1/RIPK3/MLKL pathway. In addition, PC-Ca preserves mitochondrial morphology and function via the PGAM5/DRP1/PINK1 pathway, offering hepatoprotection. These findings suggest that PC-Ca represents a promising therapeutic strategy for ALF, with the modulation of mitochondrial homeostasis offering valuable insights for the development of next-generation pharmacological interventions.},
}
@article {pmid41339973,
year = {2026},
author = {Shokoohi, M and Nasr Esfahani, MH and Khaki, AA and Ghazi Soltani, G and Alihemmati, A and Mohammadzadeh Boukani, L},
title = {N-acetylcysteine Improved Expression of FSHR, LHCGR, Catsper-1, Catsper-2, and SF-1 Genes in Testis of Rats with Varicocele.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {33},
number = {1},
pages = {150-160},
pmid = {41339973},
issn = {1933-7205},
mesh = {Male ; Animals ; *Varicocele/metabolism/drug therapy/genetics/pathology ; *Acetylcysteine/pharmacology/therapeutic use ; *Testis/metabolism/drug effects/pathology ; Rats, Wistar ; Rats ; Testosterone/blood ; *Receptors, FSH/genetics/metabolism ; *Receptors, LH/genetics/metabolism ; *Steroidogenic Factor 1/genetics/metabolism ; Sperm Motility/drug effects ; Spermatozoa/drug effects/metabolism ; },
abstract = {Varicocele, a condition of insufficient oxygen supply to testicular tissue leading to hypoxia, is a major factor contributing to male infertility. This study investigated the potential protective effects of N-acetylcysteine (NAC), a potent antioxidant, on sperm characteristics and hormonal receptor expression in a rat model of varicocele-induced testicular injury. Thirty-two adults male Wistar rats were randomly assigned to four groups: Sham, varicocele, varicocele with NAC treatment (varicocele + NAC), and NAC treatment only (NAC). Serum testosterone, LH, and FSH levels were measured, and sperm characteristics, testicular histology, and expression of some genes involved in sperm motility (Catsper-1 and Catsper-2), germ cell development (FSHR), and steroidogenesis (SF-1 and LHCGR) were evaluated in each group. Results revealed that varicocele significantly decreased serum testosterone levels, while simultaneously decreasing sperm quality, germ cell count, and expression of all the mentioned genes (P < 0.05). Also, the level of LH and FSH was significantly increased (P < 0.05). Notably, NAC treatment significantly improved sperm quality and protected testicular tissue against varicocele, suggesting its potential as a therapeutic agent for male infertility. This study demonstrates that NAC may offer a promising strategy for mitigating testicular damage induced by Varicocele.},
}
@article {pmid41339444,
year = {2025},
author = {Da, X and Guo, Q and Lu, Y and Huang, J and Mo, J and Lu, L and Fan, M and Zhao, X and Guo, T and Qi, Z and Haoshang, and Lu, H},
title = {Bile metabolite palmitic acid augments the migration of gallbladder cancer cells through the ROS/NF-кB signaling pathway.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {1262},
pmid = {41339444},
issn = {2045-2322},
support = {2023-YBSF-549//Shaanxi key research and development program Project/ ; },
mesh = {Humans ; *Palmitic Acid/metabolism/pharmacology ; *NF-kappa B/metabolism ; *Reactive Oxygen Species/metabolism ; *Cell Movement/drug effects ; *Gallbladder Neoplasms/metabolism/pathology ; *Signal Transduction/drug effects ; Cell Line, Tumor ; *Bile/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; },
abstract = {Bile reflux, resulting from pancreaticobiliary reflux (PBR), not only alters the chemical of bile but also constitutes a significant risk factor for the occurrence and development of gallbladder cancer. In previous studies, the authors identified a marked elevation of palmitic acid (PA) levels in the bile of patients with PBR. This study seeks to elucidate the mechanisms of promoting the migration of gallbladder cancer cells, with the objective of contributing novel strategies and theoretical foundations for the treatment of gallbladder cancer. We performed a cytotoxicity screening on the NOZ and GBC-SD human gallbladder cancer cell line using varying concentrations of palmitic acid. These following methodologies were employed to investigate the mechanism of PA in NOZ and GBC-SD cells. Intracellular lipid droplet accumulation was assessed using Oil red O staining, while cell migration capability was evaluated through the Transwell migration assay. Reactive oxygen species (ROS) levels were quantified using the superoxide anion fluorescent probe, Dihydroethidium (DHE), in conjunction with a ROS detection kit. The expression levels of relevant genes and proteins were analyzed using Western blot (WB), quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence (IF) techniques. In NOZ and GBC-SD cells, it was observed that palmitic acid facilitates the accumulation of intracellular lipid droplets and diminishes cellular activity while augmenting the cells' migratory capacity. Furthermore, elevated concentrations of PA have been shown to increase ROS levels in NOZ and GBC-SD cells. This elevation also activates the Nuclear factor-kappa B (NF-κB) and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Antioxidant Response Element (ARE) signaling pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) to NOZ and GBC-SD cells treated with high concentrations of PA effectively inhibits the enhancement of cell migration and epithelial-mesenchymal transition (EMT) induced by PA. PA promotes EMT in human gallbladder cancer cells by overproducing ROS and activating the NF-κB and NRF2/ARE signaling pathways, thereby facilitating increased migration.},
}
@article {pmid41333762,
year = {2025},
author = {Prabu, OG and Islami, NN and Mellenia, J and Nugroho, P and Rajabto, W and Shatri, H},
title = {N-Acetylcysteine Role in Maintaining Renal Function in Cancer Patients with Cisplatin-Based Chemotherapy.},
journal = {International journal of nephrology and renovascular disease},
volume = {18},
number = {},
pages = {337-348},
pmid = {41333762},
issn = {1178-7058},
abstract = {BACKGROUND: Cisplatin is a cornerstone chemotherapeutic agent used widely to treat various solid malignancies. Despite its efficacy, the usage of cisplatin is limited by its dose-dependent nephrotoxicity causing cisplatin-induced acute kidney injury (AKI) in up to 45% of treated patients. Current preventive strategies are limited to supportive measurement resulting in questionable clinical outcomes. N-acetylcysteine (NAC), a thiol-containing compound with antioxidant and anti-inflammatory properties, is already known for its safety.<br><br>PURPOSE: This review aims to explore the mechanisms of cisplatin-induced AKI, the role of NAC in its prevention, and the current evidence.<br><br>METHODS: A narrative review has been conducted of several literature, including preclinical and clinical studies evaluating NAC's efficacy in preventing cisplatin-induced AKI.<br><br>RESULTS: Cisplatin has cytotoxic effect via DNA structures disruption, leading to impairment of cell repair mechanism, triggering apoptosis that works effectively against cancer cells. However, cisplatin also accumulates in renal proximal tubular epithelial cells, disrupting DNA structures, increasing reactive oxygen species (ROS), inducing mitochondrial dysfunction and inflammation, all leading to apoptosis. NAC can counteract these mechanisms by scavenging ROS directly via its thiol group and indirectly by replenishing glutathione. Preclinical studies have demonstrated consistent NAC nephroprotective effects. However, findings from clinical studies remain inconsistent due to limited sample sizes, varied dosing regimens, and differences in administration routes, making comparison between studies difficult to conduct.<br><br>CONCLUSION: NAC exhibits strong nephroprotective properties through antioxidant, anti-inflammatory, and cytoprotective mechanisms as consistently shown in preclinical studies. Despite the limited current clinical evidence supporting these findings, NAC remains a promising agent for cisplatin-induced AKI prevention. Future research should focus on large-scale, well-designed, standardized clinical trials with optimized dosing strategies to validate NAC's efficacy and establish its clinical role.},
}
@article {pmid41333684,
year = {2025},
author = {Freitas, &#xcd;S and Guimarães, FS and Gomes, FV},
title = {Protective Effects of N-Acetylcysteine Against Schizophrenia-Related Behavioral and Parvalbumin Interneuron Deficits Induced by Adolescent Stress.},
journal = {Schizophrenia bulletin open},
volume = {6},
number = {1},
pages = {sgaf029},
pmid = {41333684},
issn = {2632-7899},
abstract = {BACKGROUND AND HYPOTHESIS: Adolescent stress has been linked to an increased risk of developing psychiatric disorders, including schizophrenia. Previous findings from our group suggest that adolescent stress causes redox imbalance and functional impairments in parvalbumin (PV) interneurons and their associated perineuronal nets (PNNs) in the ventral hippocampus (vHip). These changes are associated with behavioral abnormalities, vHip hyperactivity, and dopamine system overdrive, mirroring observations in people with schizophrenia. Thus, we hypothesized that the antioxidant N-acetylcysteine (NAC) could mitigate schizophrenia-related alterations induced by adolescent stress in adult rats.<br><br>STUDY DESIGN: Male Sprague-Dawley rats were subjected to a combination of daily footshock and restraint stress during adolescence [postnatal days (PD) 31-40]. NAC (900&#xa0;mg/L) was administered through the drinking water either during (PD31-40) or after the adolescent stress (PD51-60). In adulthood (PD63), rats underwent behavioral tests to assess anxiety-like behaviors, social interaction, and cognition. From PD70, in vivo recordings of dopamine neurons in the ventral tegmental area (VTA) and immunostaining of PV, PNNs, and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-Oxo-dG) in the vHip were performed.<br><br>STUDY RESULTS: Adolescent stress causes, in adulthood, anxiety-like responses, deficits in sociability and cognitive function, increased VTA dopamine neuron population activity, reduced PV[+] cells in the vHip, including those surrounded by PNNs, and enhanced expression of 8-Oxo-dG, particularly in PV[+] cells. NAC treatment, whether administered during or after adolescent stress, significantly attenuated these alterations.<br><br>CONCLUSIONS: NAC effectively mitigates schizophrenia-related changes induced by adolescent stress and may serve as a pharmacological intervention for prevention and treatment strategies.},
}
@article {pmid41332654,
year = {2025},
author = {Feng, J and Carreño, M and Jung, H and Naidu, SD and Diaz, NA and Ang, AD and Kulkarni, B and Kisielewski, D and Suzuki, T and Yamamoto, M and Hayes, JD and Honda, T and Leon-Ruiz, B and Eggler, AL and Vitturi, DA and Dinkova-Kostova, AT},
title = {The electrophilic metabolite of kynurenine, kynurenine-CKA, targets C151 in Keap1 to derepress Nrf2.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41332654},
issn = {2692-8205},
support = {R01 AI178864/AI/NIAID NIH HHS/United States ; R35 GM152083/GM/NIGMS NIH HHS/United States ; T32 AI007051/AI/NIAID NIH HHS/United States ; },
abstract = {The Kelch-like ECH-associated protein 1 / Nuclear factor-erythroid 2 p45-related factor 2 (Keap1/Nrf2) system responds to a wide array of structurally diverse small molecules, of both exogenous and endogenous origin, by inducing a robust cytoprotective program that allows adaptation during oxidative, metabolic and inflammatory stress. Here, we report that exposure to the tryptophan metabolite kynurenine and its electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA) leads to an increase in the abundance of transcription factor Nrf2 and induction of Nrf2-target genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), in murine and human cells. Additionally, both kynurenine and Kyn-CKA activate the aryl hydrocarbon receptor (AhR). Using cellular thermal shift assays, we found that Kyn-CKA increases the thermal stability of Keap1-mCherry fusion protein, but not free mCherry, indicating target engagement of Keap1, the principal repressor of Nrf2. The use of purified recombinant BTB domain of Keap1 and its C151S mutant counterpart revealed that Kyn-CKA reacts with wild-type, but not C151S mutant, Keap1-BTB, and at a much faster rate than with the small molecule thiol N-acetyl cysteine, demonstrating Kyn-CKA is targeted to react with C151 by the surrounding protein environment. In close agreement, Kyn-CKA increased the abundance of Nrf2 and expression of NQO1 in mouse embryonic fibroblast (MEF) cells expressing wild-type Keap1, but its inducer potency was greatly diminished in C151S-Keap1 mutant MEFs. Experiments in WT, AhR-knockout, and Nrf2- knockout primary murine bone marrow-derived macrophages showed that Nrf2 is required for the acute anti-inflammatory activity of Kyn-CKA, whereas AhR is dispensable. Together, these findings demonstrate that Kyn-CKA targets C151 in Keap1 to derepress Nrf2 and reveal that Nrf2, but not AhR, is a main contributor to the anti-inflammatory activity of Kyn-CKA in macrophages.},
}
@article {pmid41332367,
year = {2025},
author = {Meng, Q and Chen, B and Zhang, C and Jia, L and Yao, X and Liu, G},
title = {1,25-Dihydroxyvitamin D3 mitigates high glucose-induced oxidative stress, inflammation, and extracellular matrix accumulation in glomerular mesangial cells via the ROS/TXNIP/NLRP3 pathway.},
journal = {Histology and histopathology},
volume = {},
number = {},
pages = {25021},
doi = {10.14670/HH-25-021},
pmid = {41332367},
issn = {1699-5848},
support = {2024ZD047//Bingtuan Science and Technology Program/ ; },
abstract = {BACKGROUND: 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is a physiologically active form of vitamin D. Our study investigated the renoprotective functions of 1,25(OH)2D3 in diabetic nephropathy (DN) progression and its underlying mechanism targeting the ROS/TXNIP/NLRP3 inflammasome pathway.<br><br>METHODS: DN was induced in Wistar rats via high-fat diet (4 weeks) and streptozotocin injection (30 mg/kg, i.p.); hyperglycemic rats were randomized into DN and DN + 1,25(OH)2D3 (16 &#x3bc;g/kg, 12 weeks) groups. Rat mesangial HBZY-1 cells were maintained under normal glucose (5.5 mM), high glucose (25 mM), high glucose plus 1,25(OH)2D3 (1-50 nM), or high glucose plus N-acetylcysteine (NAC, 10 mM). Cell viability was assessed by the CCK-8 assay. Oxidative stress parameters (ROS via DCFH-DA fluorescence, MDA content, SOD activity) and pyroptosis markers (LDH release, PI/Hoechst 33342 nuclear staining) were quantified. Renal histopathology was performed using PAS and Masson trichrome staining. Biochemical analyses included serum creatinine, urea nitrogen, and 24-h urinary protein quantification. Molecular profiling encompassed ELISA (IL-1&#x3b2;, IL-6, TNF-&#x3b1;, IL-18, fibronectin, collagen IV), RT-qPCR (NOX2, NOX4, NLRP3, ASC), western blotting (TXNIP, NLRP3, ASC, caspase-1, IL-1&#x3b2;, IL-18, collagen IV, fibronectin, laminin), and TXNIP immunofluorescence.<br><br>RESULTS: 1,25(OH)2D3 significantly attenuated high glucose-induced pathological alterations in HBZY-1 cells, including ROS overproduction, TXNIP upregulation, NLRP3 inflammasome activation, oxidative stress, inflammation, extracellular matrix (ECM) deposition, and pyroptotic cell death. Consistently, 1,25(OH)2D3 suppressed ROS/TXNIP/NLRP3/caspase-1 signaling, ameliorated renal dysfunction, and mitigated histopathological damage in DN rats.<br><br>CONCLUSION: 1,25(OH)2D3 confers renoprotection in DN by inhibiting the ROS/TXNIP/NLRP3 inflammasome axis, thereby suppressing oxidative stress, inflammatory cytokine production, ECM accumulation, and pyroptotic cell death in glomerular mesangial cells and renal tissues.},
}
@article {pmid41326062,
year = {2026},
author = {Li, XY and Liu, YJ and Meng, XH and Gong, C and Yang, JL and Qiang, Y and Wang, J and Hou, XD},
title = {Ginsenoside Rk1 inhibits postharvest fruit anthracnose by disrupting reactive oxygen species (ROS) homeostasis and activating the autophagic mechanism in Colletotrichum gloeosporioides.},
journal = {Pesticide biochemistry and physiology},
volume = {216},
number = {Pt 1},
pages = {106727},
doi = {10.1016/j.pestbp.2025.106727},
pmid = {41326062},
issn = {1095-9939},
mesh = {*Colletotrichum/drug effects/metabolism ; *Reactive Oxygen Species/metabolism ; *Autophagy/drug effects ; Homeostasis/drug effects ; Fruit/microbiology ; *Plant Diseases/microbiology/prevention &amp; control ; *Ginsenosides/pharmacology ; Fungal Proteins/metabolism ; },
abstract = {Anthracnose is a highly contagious and destructive plant disease caused by Colletotrichum gloeosporioides. The objective of this study was to investigate the antifungal activity and mechanism of ginsenoside Rk1 (GRk1) against C. gloeosporioides. In vitro experiments demonstrated that GRk1 exhibited substantial antifungal activity, with EC50 values of 64.58 mg L[-1], surpassing the plant-derived pesticide d-limonene. Additionally, GRk1 could effectively suppress the dissemination of anthracnose spots in postharvest fruit. By observing the microstructure of C. gloeosporioides, it was observed that the mycelium structure underwent notable changes, and autophagosomes engulfed the organelles in the experimental groups. Fluorescent staining revealed specific signals in mycelial autophagosomes, and Western Blot analysis confirmed the upregulation of the autophagy-related protein Atg8. These findings indicate that GRk1 may activate the autophagy process by promoting Atg8 expression. Proteomic analysis revealed that the expression of Sec20 and Mpv17 proteins was significantly downregulated, whose dysregulated expression is associated with the crosstalk between SNAREs and peroxisomes during vesicle trafficking and metabolic processes. Assessment of catalase (CAT) activity, hydrogen peroxide (H2O2) content, and superoxide anion (O2[-]) levels further demonstrated that GRk1 could disrupt intracellular reactive oxygen species (ROS) homeostasis in mycelia. Moreover, the introduction of the ROS scavenger N-acetylcysteine (NAC) markedly inhibited autophagy, indicating that GRk1 promotes autophagy by inducing oxidative stress. Collectively, GRk1 inhibits pathogens via the ROS-autophagy axis. These findings suggested that GRk1 holds potential as a promising alternative to fungicides for the biological control of anthracnose.},
}
@article {pmid41324913,
year = {2026},
author = {Tao, S and Tao, H and Liu, Y and Wang, S and Li, M and Wang, J and Lu, G and Zhang, L and Gu, H},
title = {Intragastric administration of Vitamin C and N-acetylcysteine mitigates computed tomography radiation-induced biological damage in rats.},
journal = {International journal of radiation biology},
volume = {102},
number = {2},
pages = {145-152},
doi = {10.1080/09553002.2025.2591790},
pmid = {41324913},
issn = {1362-3095},
mesh = {Animals ; *Ascorbic Acid/administration &amp; dosage/pharmacology ; Male ; *Acetylcysteine/administration &amp; dosage/pharmacology ; Rats, Sprague-Dawley ; Rats ; *Tomography, X-Ray Computed/adverse effects ; *Radiation-Protective Agents/administration &amp; dosage ; *DNA Damage/drug effects ; Antioxidants/administration &amp; dosage ; Administration, Oral ; },
abstract = {PURPOSE: To assess the protective effects of intragastric Vitamin C and N-acetylcysteine (NAC) against DNA damage from CT scan radiation in rats.<br><br>MATERIALS AND METHODS: The male Sprague Dawley rats (n&#x2009;=&#x2009;8 per group) were allocated into four distinct groups: control (no CT radiation), IR (CT radiation only), Vitamin C (200&#x2009;mg/kg with CT radiation), and NAC (200&#x2009;mg/kg with CT radiation). Antioxidants were administered intragastrically 3&#x2009;hours before scanning. Non-control groups underwent CT radiation at 120 kVp and 110&#x2009;mA for 3 scans. Surface absorbed dose was measured with thermoluminescent dosimeter chips. Serum total antioxidant capacity (TAC) was measured pre- and post-scanning. &#x3b3;-H2AX foci in peripheral blood lymphocytes were assessed at baseline, 1&#x2009;hour, and 24&#x2009;hours post-scan. Bone marrow smears were prepared 24&#x2009;hours post-scan, stained with Giemsa, and micronucleus (MN) frequency in polychromatic erythrocytes was evaluated.<br><br>RESULTS: TAC levels increased by 68.2% in the Vitamin C group and 152.3% in the NAC group compared to the IR group. &#x3b3;-H2AX foci rates decreased by 10.3% in the Vitamin C group and 14.3% in the NAC group compared to the IR group. MN frequency decreased by 28.6% in the Vitamin C group and 34.9% in the NAC group compared to the IR group. No significant difference was found between Vitamin C and NAC.<br><br>CONCLUSION: Oral Vitamin C and NAC significantly mitigate radiation exposure from CT imaging in rats. Both antioxidants effectively reduce &#x3b3;-H2AX foci and micronucleus formation, offering substantial protection against radiation-induced DNA damage.},
}
@article {pmid41318115,
year = {2025},
author = {Mongkon, I and Kariya, R and Pearngam, P and Settha, N and Saisuwan, K and Boonnate, P and Sittithumcharee, G and Vaeteewoottacharn, K and Saeeng, R and Okada, S},
title = {Andrographolide Induces ROS-dependent Apoptosis and Suppresses STAT3 Phosphorylation in Primary Effusion Lymphoma Cells.},
journal = {Anticancer research},
volume = {45},
number = {12},
pages = {5299-5311},
doi = {10.21873/anticanres.17869},
pmid = {41318115},
issn = {1791-7530},
mesh = {*Diterpenes/pharmacology ; *Reactive Oxygen Species/metabolism ; *STAT3 Transcription Factor/metabolism ; *Apoptosis/drug effects ; Animals ; Humans ; *Lymphoma, Primary Effusion/drug therapy/metabolism/pathology ; Phosphorylation/drug effects ; Mice ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Caspases/metabolism ; },
abstract = {BACKGROUND/AIM: Primary effusion lymphoma (PEL) is a rare and aggressive form of non-Hodgkin lymphoma (NHL) with poor prognosis due to resistance to conventional chemotherapy. Andrographolide (AG), a diterpenoid lactone extracted from Andrographis paniculata, has shown anti-tumor activity in several malignancies, but its effects on PEL are unknown.<br><br>MATERIALS AND METHODS: PEL cell viability was assessed by MTT assay. Apoptosis was evaluated via Annexin V/PI staining and caspase activation. ROS generation was measured by DCFH-DA staining. Protein expression changes were analyzed by Western blotting. To determine the roles of ROS and caspases, cells were co-treated with a reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) or the pan-caspase inhibitor Q-VD-OPh. AG's in vivo effects were tested in a xenograft mouse model.<br><br>RESULTS: AG inhibited PEL cell proliferation in a dose- and time-dependent manner. Apoptosis was mediated via ROS production and caspase activation. STAT3 phosphorylation was suppressed in a ROS-dependent manner. In vivo, AG (500 mg/kg/day, oral gavage) significantly reduced tumor burden without observable toxicity.<br><br>CONCLUSION: AG exerts anti-tumor effects against PEL by inducing ROS-dependent apoptosis and suppressing STAT3 signaling. These findings suggest that AG may serve as a promising therapeutic agent for PEL.},
}
@article {pmid41314277,
year = {2026},
author = {Kim, NY and Gowda, SV and Harsha, KB and Kumar, DCV and Mohan, CD and Shivakumara, CS and Rangappa, KS and Ahn, KS},
title = {Multimodal cell death induced by indirubin-3'-oxime through inhibition of Akt/mTOR axis in lung cancer cells.},
journal = {Chemico-biological interactions},
volume = {423},
number = {},
pages = {111851},
doi = {10.1016/j.cbi.2025.111851},
pmid = {41314277},
issn = {1872-7786},
mesh = {Humans ; *Oximes/pharmacology/chemistry ; Lung Neoplasms/pathology/metabolism/drug therapy ; *Indoles/pharmacology/chemistry ; *TOR Serine-Threonine Kinases/metabolism/antagonists &amp; inhibitors ; *Proto-Oncogene Proteins c-akt/metabolism/antagonists &amp; inhibitors ; Cell Line, Tumor ; Apoptosis/drug effects ; Autophagy/drug effects ; Reactive Oxygen Species/metabolism ; Endoplasmic Reticulum Stress/drug effects ; *Signal Transduction/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Exportin 1 Protein ; Receptors, Cytoplasmic and Nuclear/metabolism ; Karyopherins/metabolism ; Cell Survival/drug effects ; Cell Death/drug effects ; *Antineoplastic Agents/pharmacology/chemistry ; },
abstract = {Lung cancer is a major type of malignancy that has contributed to a high mortality rate for many years. Discovering new small molecules with strong cytotoxic effects on lung cancer is crucial for developing new therapies. In this study, we describe the synthesis of a novel triazole-indirubin-3'-oxime derivative (designated as CRM1) and examine its ability to induce distinct forms of cell death, as well as elucidate the cytotoxicity-associated molecular mechanisms in lung cancer cells. CRM1 selectively reduced cell viability in lung cancer cell lines (A549, PC9, and H1299) without significantly affecting the viability of normal lung cells (HEL299). Mechanistic investigations have demonstrated that CRM1 induces paraptosis through the downregulation of Alix and the upregulation of ATF4 and CHOP. This process is associated with disruption of mitochondrial membrane potential, induction of endoplasmic reticulum stress, and accumulation of reactive oxygen species (ROS). CRM1 was observed to induce apoptosis, as indicated by DNA fragmentation, an increase in Sub-G1 cell population, as well as elevated caspase-3 cleavage and Bax expression. CRM1 also promoted autophagy, as evidenced by increased expression of Atg7, phosphorylated Beclin-1, and LC3-II, as well as enhanced autophagosome formation. Pharmacological inhibition studies confirmed the independent induction of apoptosis, paraptosis, and autophagy. Pre-exposure of cancer cells to N-acetyl cysteine abrogated CRM1-induced cytotoxicity. Mechanistic studies demonstrated that CRM1 suppresses the activation of Akt, mTOR, and p70S6K, while the overexpression of Akt counteracts the CRM1-driven cytotoxic effects. CRM1 also synergistically potentiated the cytotoxic efficacy of paclitaxel by co-targeting multiple cell death processes. Collectively, these results suggest CRM1 as a promising cytotoxic candidate with a multimodal mechanism of action in lung cancer cells.},
}
@article {pmid41312470,
year = {2025},
author = {Lin, IC and Tsai, WW and Wu, VC and Pan, HC and Chuang, MH and Chen, JY},
title = {Saline and N-acetylcysteine-based strategies and other approaches to prevent the risk of CA-AKI: a meta-analysis.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1608626},
pmid = {41312470},
issn = {2296-858X},
abstract = {BACKGROUND: While hydration is currently the most evidence-supported strategy for preventing contrast-associated acute kidney injury (CA-AKI) in patients undergoing cardiovascular angiography, the potential benefits of combining a saline and N-acetylcysteine (NAC) based strategy with additional pharmacologic interventions remain uncertain.<br><br>METHODS: We conducted a search for randomized controlled trials (RCTs) in PubMed, Embase, and the Cochrane library from the inception to 26th January 2024. RCTs involving adults undergoing cardiovascular angiography were analyzed, comparing the effects of saline and NAC-based strategies combined with additional agents compared to saline. The primary outcome was the risk of CA-AKI. The comparative effectiveness was visually represented through a network diagram and forest plot, with the treatments ranked by P-score in a league table.<br><br>RESULTS: We included 72 trials with 14,671 patients, 1,843 AKI events, comparing 12 different interventions based on hydration and NAC. The incidence of CA-AKI was 11.74% in the hydration with oral NAC group versus 15.49% in the hydration with saline alone group (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.62-0.97). Compared to individuals with saline alone, the incidence of CA-AKI in the hydration with intravenous NAC group was 10.62% (OR 0.71, 95% CI 0.52-0.99); In hydration with oral NAC and statin group, the incidence of CA-AKI was 8.28% (OR 0.47, 95% CI 0.29-0.77).<br><br>CONCLUSION: This network meta-analysis highlights that the combination of hydration with oral or intravenous NAC is more effective than hydration alone in preventing CA-AKI. Additionally, hydration with oral NAC and a statin significantly outperforms hydration with oral NAC alone in preventing CA-AKI.<br><br>CRD42024502497.},
}
@article {pmid41312188,
year = {2025},
author = {Benedetti, F and Santus, P},
title = {N-acetylcysteine in paediatrics: a review of efficacy, safety and dosing strategies in respiratory care.},
journal = {Drugs in context},
volume = {14},
number = {},
pages = {},
pmid = {41312188},
issn = {1745-1981},
abstract = {N-acetylcysteine (NAC) is widely used for its mucolytic, antioxidant, anti-inflammatory and synergistic antibacterial properties in the treatment of respiratory diseases. NAC and other mucolytics and mucoactive medications are frequently employed in the adult population and in paediatric settings to improve mucus clearance in conditions such as cystic fibrosis, bronchiolitis, pneumonia, and both chronic and acute bronchitis, with varying degrees of success. This narrative review evaluates the efficacy and safety of NAC in paediatric acute and chronic respiratory diseases, synthesizing data from clinical trials, observational studies and real-world evidence, with a particular focus on optimizing dosing based on patient-specific characteristics. Numerous studies indicate that oral NAC doses of 20 mg/kg/day for acute conditions and 200 mg three times daily for chronic conditions are generally effective and well tolerated in children. However, most participants in these studies were older than 9 years, resulting in a lack of literature-based evidence for the optimal dosing in younger children over 2 years of age. Given the significant weight variations within this age group, weight-based dosing is recommended to ensure appropriate drug exposure and optimize treatment benefits. Weight-based dosing adjustments and patient monitoring may help optimize treatment outcomes and reinforce the overall positive safety and tolerability profile in paediatric settings. NAC is a valuable therapeutic agent for paediatric respiratory diseases, particularly in older children. In younger patients, weight-adjusted dosing and careful monitoring for potential adverse effects may help maximize efficacy and maintain its favourable tolerability profile.},
}
@article {pmid41304539,
year = {2025},
author = {Zhang, Y and Xiao, Z and Mao, P and Yang, F and Ma, Y and Xian, B and Fu, M and Li, G},
title = {Effects of Decabromodiphenyl Ether (BDE209) Exposure on Toxicity and Oxidative Stress of Beas-2B Cells.},
journal = {Toxics},
volume = {13},
number = {11},
pages = {},
pmid = {41304539},
issn = {2305-6304},
support = {42207498//National Natural Science Foundation of China/ ; GKLECHRC-03//Open Fund Project of Guangdong Provincial Key Laboratory of Environmental Catalysis and Health Risk Control/ ; Guike Neng 2101Z017//Guangxi Key Laboratory of environmental pollution control theory and technology/ ; Guike Neng 2101Z014//Guangxi Key Laboratory of environmental pollution control theory and technology/ ; },
abstract = {Decabromodiphenyl ether (BDE209) has been widely used because of its excellent flame-retardant properties and ability. On the one hand, many studies have shown that the presence of BDE209 can potentially threaten human health and the environment. The production and processing of products containing BDE209 is prohibited except for special applications in China. On the other hand, the study of BDE209 on respiratory cells is not yet fully understood. Consequently, this study aims to investigate the mechanisms of toxic damage and oxidative stress induced by BDE209 exposure in lung epithelial Beas-2B cells. The proliferation of Beas-2B cells under BDE209 exposure was first analyzed by using a real-time label-free cell analyzer (RTCA). Then the cells' morphological changes were observed using laser confocal microscopy. Subsequently, the effects of BDE209 exposure alone, combined exposure to N-acetylcysteine (NAC) and BDE209, on reactive oxygen species (ROS) levels and antioxidant defense-related factors in Beas-2B cells were analyzed separately. The results show that BDE209 exposure induces the proliferation of Beas-2B cells with a dose-dependent increase in inhibition. Microscopic observation of Beas-2B cells reveals significant damage and death. The levels of ROS are significantly increased (p < 0.01), the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) are increased, the contents of catalase (CAT) are decreased, and the activities of glutathione peroxidase (GPX) are first decreased and then increased. However, under the co-exposure of NAC and BDE209, ROS levels are significantly reduced (p < 0.01), MDA contents decrease, and SOD activities increase. In summary, BDE209 exposure leads to inhibition of Beas-2B cell proliferation, cellular morphology damage, increased ROS levels, and disturbances in antioxidant defense-related factors. The cells showed toxic damage and oxidative stress. In contrast, NAC can suppress ROS levels, enhance SOD activity, and inhibit GPX activity, thereby alleviating BDE209-induced cellular damage.},
}
@article {pmid41303345,
year = {2025},
author = {Mulè, S and Ferrari, S and Galla, R and Uberti, F},
title = {Neuroprotective Pathway Modulation by a Novel Coriandrum sativum, N-Acetylcysteine and Glutathione-Based Formulation: Insights from In Vitro 3D Models.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
pmid = {41303345},
issn = {1422-0067},
mesh = {*Acetylcysteine/pharmacology/chemistry ; *Glutathione/pharmacology/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; *Coriandrum/chemistry ; *Plant Extracts/pharmacology/chemistry ; Blood-Brain Barrier/drug effects/metabolism ; Humans ; Oxidative Stress/drug effects ; Animals ; Cell Survival/drug effects ; Palmitic Acids/pharmacology ; },
abstract = {Pain remains a major clinical challenge due to its complex physiopathology and limited treatment options. In this context, several supplements based on palmitoylethanolamide (PEA) and alpha-lipoic acid (ALA) are known for their neuroprotective properties. ALA-based supplements have shown potential, but concerns about adverse effects persist. This study examines the formulations of two commercial products based on ALA and PEA, IperALA[®] and IperALA[®] Forte, in which ALA and vitamin D3 are replaced with Coriandrum sativum extract (C. sativum e.s.), N-acetylcysteine (NAC) and glutathione (GSH), assessing improvement of neuroprotective, anti-inflammatory and analgesic properties of the new formulation. Intestinal, blood-brain barrier (BBB), and central nervous system (CNS) models were sequentially stimulated with the test compounds. Both formulations were assessed for cytotoxicity, barrier integrity, permeability, oxidative stress, inflammation, and neuroprotection-related biomarkers. IperALA[®] Forte demonstrated superior performance compared to IperALA[®] and individual agents. It enhanced cell viability, preserved intestinal and BBB integrity, and improved compound permeability. Notably, it reduced ROS and pro-inflammatory cytokines (TNFα, IL-1), while increasing analgesic markers (CB2R, GABA) in the central system. The replacement of ALA and vitamin D3 with C. sativum, NAC, and GSH in IperALA[®] Forte significantly improved the neuroprotective, antioxidant, and anti-inflammatory profile of the supplement. These results indicate a possible connection between the observed neuroprotective properties and the pathways involved in nociception and pain regulation, stating the hypothetical potential relevance of this approach for the treatment of pain-related conditions.},
}
@article {pmid41300501,
year = {2025},
author = {Aremu, TD and Blanco Ayala, T and Meza-Sosa, KF and Ramírez Ortega, D and González Esquivel, DF and Vázquez Cervantes, GI and Flores, I and González Alfonso, WL and Custodio Ramírez, V and Salazar, A and Pineda, B and Pérez de la Cruz, G and Gómez Manzo, S and Roldan Roldan, G and Carrillo Mora, P and Pérez de la Cruz, V},
title = {N-Acetylcysteine Prevents Skeletal Muscle Cisplatin-Induced Atrophy by Inducing Myogenic microRNAs and Maintaining the Redox Balance.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
pmid = {41300501},
issn = {2076-3921},
support = {IA101224//UNAM-PAPIIT/ ; IN207025//DGAPA-UNAM/ ; },
abstract = {Cisplatin (CIS) is a widely used chemotherapeutic agent known for its efficacy; however, it induces several adverse effects, most notably cachexia, which is characterized by progressive loss of skeletal muscle mass, weakness, and reduced body weight. N-acetylcysteine (NAC) a compound with antioxidants properties, has been shown to mitigate CIS-induced neurotoxicity in experimental models. This study aimed to investigate the myoprotective effects of NAC during CIS treatment and explore the redox and molecular mechanisms involved in this response. For this, female Wistar rats were divided into four experimental groups: Control, NAC (300 mg/day/8 days), CIS (3 mg/kg i.p for 5 days), and NAC + CIS (NAC for 8 days, with CIS administered from day 4 onward). After treatment, muscle strength, redox status, mitochondrial biogenesis, expression of myogenic microRNAs and morphological changes were evaluated. CIS treatment caused muscle atrophy, decreased GSH/GSSG ratio, impaired cellular function, increased lipid peroxidation and altered antioxidant enzymes activity. These effects were mitigated by NAC coadministration. CIS also reduced the mtDNA/nDNA ratio; however, NAC treatment tended to increase TFAM and PGC-1α expression levels. Furthermore, CIS suppressed the expression of muscular miR-1-3p, miR-133a-3p and miR-206-3p, while NAC restored their levels when co-administered with CIS. These findings suggest that NAC may serve as a promising adjuvant therapeutic strategy to counteract CIS-induced myotoxicity through redox regulation and modulation of molecular pathways related to muscle integrity and regeneration.},
}
@article {pmid41300472,
year = {2025},
author = {Zhao, P and Yan, H and Wang, R and Zhao, J and Zheng, X and Li, D and Guo, X and Ji, F and Long, C and Shen, L and Wei, G and Wu, S},
title = {Parthenolide Restores Testosterone Biosynthesis After Nanoplastic Exposure by Blocking ROS-Driven NF-κB Nuclear Translocation.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
pmid = {41300472},
issn = {2076-3921},
support = {CSTB2024NSCQ-LZX0054//the Project of Sponsored by Natural Science Foundation of Chongqing/ ; },
abstract = {Nanoplastics are pervasive contaminants that adversely affect male reproductive function, yet the molecular basis of polystyrene nanoplastic (PS-NP) toxicity in immature testes and effective preventive strategies remain unclear. Here, male mice (postnatal days 22-35, PND 22-35) and TM3 Leydig cells were exposed to graded PS-NPs, followed by transcriptomic profiling to identify differentially expressed genes (DEGs). Candidate therapeutics were prioritized using Connectivity Map (CMap) analysis and molecular docking, and protein interactions were examined by co-immunoprecipitation (Co-IP). PS-NPs accumulated in immature testes, eliciting excessive reactive oxygen species (ROS) and activation of NF-κB. These events coincided with the downregulation of steroidogenic enzymes (CYP11A1 and StAR) and disruption of testicular microarchitecture. In TM3 cells, PS-NPs suppressed testosterone synthesis in a concentration-dependent manner; this effect was fully reversed by pretreatment with N-acetylcysteine (NAC) or Bay 11-7082. Co-IP demonstrated p65-steroidogenic factor-1 (SF-1) binding consistent with formation of a transcriptional repressor complex targeting steroidogenic genes. CMap and docking analyses nominated parthenolide (PTL) as a candidate inhibitor of NF-κB nuclear translocation (predicted binding affinity, -6.585 kcal/mol), and PTL mitigated PS-NP-induced impairment of testosterone synthesis in vitro. Collectively, these data indicate that PS-NPs disrupt testosterone biosynthesis in immature testes through the ROS/NF-κB/p65-SF-1 axis, while PTL emerges as a candidate small molecule to counter nanoplastic-associated reproductive toxicity. These findings underscore translational relevance and support future evaluation under chronic low-dose exposure conditions, including in vivo validation of PTL efficacy, pharmacokinetics, and safety.},
}
@article {pmid41300463,
year = {2025},
author = {Han, M and Zhao, M and Bai, F and Wang, M and Zhang, B and Shi, J and Liu, Z},
title = {Reactive Oxygen Species (ROS) Drive Osteocyte Dysfunction in Diabetic Osteoporosis by Impairing Autophagy and Triggering Apoptosis.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
pmid = {41300463},
issn = {2076-3921},
support = {32071246//National Natural Science Foundation of China/ ; 23YXYJ0127//Research Program of Science and Technology in Xi'an City/ ; xzy022023079//Basic Scientific Research Funds of Xi 'an Jiaotong University/ ; },
abstract = {This study investigates the mechanisms underlying osteocyte injury in a high glucose (HG) environment and explores potential therapeutic targets and diagnostic markers for diabetic osteoporosis, a common complication of type 2 diabetes mellitus (T2DM). Hyperglycemia induces oxidative stress through the reactive oxygen species (ROS) production, which impair osteocytes and accelerate bone loss. To examine these effects, MLO-Y4 cells and primary mouse osteocytes were cultured under normal glucose and HG conditions, with additional treatments using N-acetylcysteine (NAC, ROS scavenger) and rapamycin (autophagy promoter and mTOR inhibitor). Cell viability, ROS levels, and the autophagy and apoptosis markers expression (Beclin1, LC3, p62, Bax, Bcl2, cytochrome C, and caspase3) were assessed using CCK8/ATP level assay, flow cytometry, Western blot, qRT-PCR, immunofluorescence, and TUNEL staining. The results showed that HG inhibits cell proliferation, induces insulin resistance, generates ROS, alters antioxidant enzymes, and promotes oxidative stress, leading to mTOR activation, subsequent autophagy inhibition, and osteocyte apoptosis. NAC mitigated these effects, while rapamycin prevented HG-induced apoptosis by inhibiting mTOR activation and promoting autophagy. This suggests that ROS-induced mTOR activation impairs autophagy and hinders the clearance of damaged osteocytes, triggering apoptosis. This research provides foundational evidence and novel insights into diabetic osteoporosis pathogenesis and potential therapies.},
}
@article {pmid41295319,
year = {2025},
author = {Yu, MS and Chiu, CY and Lo, FS and Lin, WC and Wu, LJ and Yen, CY and Yu, MC},
title = {Dynamics of Urine Metabolomics and Tubular Inflammatory Cytokines in Type 1 Diabetes Across Disease Durations.},
journal = {Metabolites},
volume = {15},
number = {11},
pages = {},
pmid = {41295319},
issn = {2218-1989},
support = {CMRPG3F2261, CMRPG3F2262, CMRPG3F2263//Linkou Chang Gung Memorial Hospital/ ; },
abstract = {Background/Objectives: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by sustained inflammation, leading to diabetic kidney disease (DKD). This study investigated urinary tubular injury biomarkers and metabolomic profiles in relation to albuminuria and renal function across varying durations of T1D. Methods: A cross-sectional analysis was conducted in 247 youth-onset T1D patients categorized by disease duration: short ≤ 5 years (T1D-S, n = 62), medium 6-10 years (T1D-M, n = 67), and long > 10 years (T1D-L, n = 118). Urinary cytokines (MCP-1, KIM-1, NGAL) were measured by ELISA. Metabolomic profiling was performed using [1]H-NMR spectroscopy. Results: Urinary MCP-1/Cr, KIM-1/Cr, and NGAL/Cr levels were significantly elevated in T1D patients compared with non-diabetic controls, but did not correlate with disease duration. Metabolomic profiling identified distinct urinary signatures across T1D duration. Specifically, N-acetylcysteine (NAC) and N-delta-acetylornithine (NAO) increased progressively, while N-acetylaspartate (NAA) and pyruvic acid decreased with longer disease duration. These four metabolites remained statistically significant after both based on Mann-Whitney tests with false discovery rate (FDR) correction (q < 0.05) and application of a conservative alpha threshold (p < 0.01), suggesting potential disruptions in amino acid and carbohydrate metabolism. Conclusions: Urinary biomarkers (MCP-1/Cr, NGAL/Cr, and KIM-1/Cr) are sensitive indicators of subclinical kidney dysfunction in T1D patients, often preceding albuminuria. Alterations in amino acid-related metabolites (NAC, NAA, and NAO) and pyruvate highlight possible metabolic disturbances associated with T1D duration and oxidative stress. However, given the cross-sectional design, longitudinal studies are needed to confirm causality and clarify their predictive value in DKD progression.},
}
@article {pmid41282901,
year = {2025},
author = {Kong, X and Ibukun, F and Khan, MJ and Hafiz, G and Wehling, D and Dreger, K and Singh, M and Birch, D and Jaffe, G and Naufal, F and Traboulsi, EI and Duncan, J and Hufnagel, R and Carroll, J and Lu, Y and Matsui, R and Moulton, LH and Hawkins, B and Campochiaro, PA and , },
title = {Protocol for NAC Attack, a phase-3, multicenter randomized, parallel, double masked, placebo controlled trial evaluating the efficacy and safety of oral N-acetylcysteine (NAC) in patients with retinitis pigmentosa.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.05.25339486},
pmid = {41282901},
support = {UG1 EY033292/EY/NEI NIH HHS/United States ; },
abstract = {BACKGROUND: Retinitis pigmentosa (RP) is the most common inherited retinal disease. Genetic mutations of many genes have been linked to RP. The mutations cause rod photoreceptor degeneration while sparing cone photoreceptors. However, loss of rod photoreceptors results in oxidative stress leading to cone photoreceptors degeneration, causing constriction of visual fields. In animal models of RP, treatments that reduce oxidative stress, including N-acetylcysteine (NAC), promote cone survival and maintenance of function.<br><br>METHODS: NAC Attack, funded by the US National Institutes of Health, is a multicenter, randomized, double-masked, parallel and placebo-controlled clinical trial testing whether oral NAC can delay disease progression in RP. A total of about 483 RP patients aged 18-65 are recruited from 31 sites in America and Europe, and randomized 2:1 to take NAC 1800 mg bid or placebo for 45 months. Eligible eyes have best-corrected visual acuity (BCVA) of 20/63 or better and the ellipsoid zone (EZ) width on the horizontal fovea optical coherence tomography (OCT) scan between 1500 &#xb5;m and 8000 &#xb5;m. The primary outcome is the cumulative loss of EZ, calculated as the area above the curve using EZ width measured every 9 months over 45 months. Secondary outcomes are change in mean macular sensitivity (MMS) measured by microperimetry and change in BCVA best-corrected visual acuity (BCVA) from baseline to M45. The long-term safety and tolerability of oral NAC 1800 mg bid will be assessed based upon the incidence and severity of ocular and systemic adverse events.<br><br>DISCUSSION: Data from NAC Attack will provide clinical evidence (or lack of) on the role of oxidative stress in human RP. Findings from NAC Attack have the potential to change clinical management of a blinding disease and will lead to a better understanding of basic mechanisms in RP. Moreover, data from NAC Attack will advance our knowledge on safety and drug interaction of NAC, informing studies in other medical areas where NAC is of interest for its potential in treating many medical conditions. Therefore, the trial is of high public health, clinical, and scientific significances.<br><br>TRIAL REGISTRATION: The ClinicalTrials.gov ID for NAC Attack is NCT05537220 .},
}
@article {pmid41282011,
year = {2025},
author = {Yu, C and Zhang, M and Xia, W},
title = {Asymmetric dimethylarginine mediates oxidative stress and atrial remodeling in HL-1 cells.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1696845},
pmid = {41282011},
issn = {2296-858X},
abstract = {INTRODUCTION: Atrial fibrillation (AF) is a common cardiac arrhythmia, and endothelial dysfunction and oxidative stress (OS) are key mechanisms promoting atrial remodeling. Asymmetric dimethylarginine (ADMA) inhibits nitric oxide synthase (NOS) but its role in AF-related atrial remodeling remains unclear.<br><br>METHODS: Mouse atrial myocyte HL-1 cells were treated with ADMA, H2O2, N-acetylcysteine (NAC), or their combinations. Cell viability, reactive oxygen species (ROS) levels, and TGF-&#x3b2;1 expression were detected using CCK-8, flow cytometry, fluorescence microscopy, and Western blot. A clinical cohort study included 60 AF patients and 30 controls to measure serum ADMA, TGF-&#x3b2;1, and NO levels.<br><br>RESULTS: ADMA (30 &#x3bc;M) significantly increased ROS generation and upregulated p47phox and TGF-&#x3b2;1 expression in HL-1 cells, which was reversed by NAC. AF patients had higher serum ADMA and TGF-&#x3b2;1 levels and lower NO levels than controls (P<0.01).<br><br>DISCUSSION: ADMA may induce TGF-&#x3b2;1 expression by enhancing NOX-ROS levels, leading to myocardial oxidative damage and atrial remodeling, which provides new insights into AF pathophysiology.},
}
@article {pmid41281764,
year = {2025},
author = {Hu, P and Fu, S and Li, B and Zhu, X and Tu, B and Han, C and Wang, J and Xu, W and Liu, X and Zhu, S and Wang, C and Deng, Z and Deng, Y and Xin, S and Song, J and Liu, J and Cui, K},
title = {N-Homocysteinylation of HMGB1/2 Promotes Corpus Cavernosum Endothelial Senescence in Erectile Dysfunction.},
journal = {International journal of biological sciences},
volume = {21},
number = {15},
pages = {6723-6744},
pmid = {41281764},
issn = {1449-2288},
mesh = {Male ; Humans ; *Homocysteine/metabolism/analogs &amp; derivatives ; *Erectile Dysfunction/metabolism ; *HMGB1 Protein/metabolism ; Cellular Senescence/physiology ; Hyperhomocysteinemia/metabolism ; Middle Aged ; Endothelial Cells/metabolism ; *Penis/metabolism ; Animals ; },
abstract = {Homocysteine (Hcy) is an age-related risk factor for erectile dysfunction (ED), with enhanced vascular toxicity in middle-aged and elderly individuals. However, folate-based Hcy-lowering therapies have shown limited efficacy, necessitating a reevaluation of its age-dependent pathogenic mechanism. Here, we demonstrate that senescent endothelial cells exhibit heightened responsiveness of methionyl-tRNA synthetase 1 (MARS1) to Hcy, promoting the production of homocysteine thiolactone (HTL) and widespread N-homocysteinylation (K-Hcy) of proteins. K-Hcy, rather than acetylation, drives cytoplasmic translocation and extracellular release of high mobility group box proteins 1 and 2 (HMGB1/2), amplifying the senescence-associated secretory phenotype (SASP). Competitive inhibition of MARS1 with N-acetylcysteine (NAC) attenuates endothelial senescence and improves erectile function in middle-aged individuals with hyperhomocysteinemia by reducing HTL, rather than Hcy itself, while synergizing with tadalafil. Collectively, our findings highlight the pivotal role of the age-dependent MARS1-HTL axis in the pathogenesis of homocysteine-induced ED, offering a promising therapeutic strategy for ED in the aging population.},
}
@article {pmid41276507,
year = {2025},
author = {Liu, X and Hu, W and Sun, J and Wu, B},
title = {Fructose intake driven glycolysis-ROS-EGFR axis specifically promotes the generation and pathogenicity of Th17 cells.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {11115},
pmid = {41276507},
issn = {2041-1723},
support = {32170886//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32470939//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {*Th17 Cells/immunology/metabolism/drug effects ; *Fructose/metabolism/adverse effects ; Animals ; *Reactive Oxygen Species/metabolism ; *Glycolysis/drug effects ; Encephalomyelitis, Autoimmune, Experimental/immunology/metabolism/pathology/chemically induced ; Mice ; *ErbB Receptors/metabolism/genetics ; STAT3 Transcription Factor/metabolism ; Mice, Inbred C57BL ; Colitis/immunology/chemically induced/metabolism/pathology ; Cell Differentiation/drug effects ; Female ; Interleukin-23/metabolism ; Interleukin-6/metabolism ; Signal Transduction ; Interleukin-1beta/metabolism ; Acetylcysteine/pharmacology ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; },
abstract = {Th17 cells are quite heterogeneous. Treating Th17-related inflammatory disorders requires understanding the functionally diverse subtypes in the context of tissue homeostasis, which is shaped by nutrient availability among other factors. Here, we show that increased consumption of fructose exacerbates colitis and experimental autoimmune encephalomyelitis (EAE), via pathogenic Th17 cells. Fructose selectively enhances the differentiation and function of this pathogenic subtype of Th17 cells, which are induced by a combination of IL1β, IL-6 and IL-23 (pTh17). In contrast, TGFβ1and IL-6-induced homeostatic, non-pathogenic Th17 cells remain unaffected. Notably, fructose enhances metabolic activity in pTh17 cells, leading to increased ROS production and subsequently promoting pathogenic-Th17 cell differentiation. N-acetyl cysteine (NAC), a ROS scavenger, specifically impaired pathogenic-Th17 cell immunity and mitigated high-fructose regulated colitis and EAE disease. Mechanistically, ROS accumulation results in elevated EGFR expression and phosphorylation, which leads to increased nuclear translocation. Nuclear EGFR binds to STAT3, enhancing its transcriptional activity at the CNS6 and CNS9 regions of Rorc. In summary, our work describes here a mechanism through which high fructose intake specifically exacerbates pathogenic Th17-cell-related pathologies and provides potential therapeutic targets for pTh17-mediated diseases.},
}
@article {pmid41274519,
year = {2026},
author = {Burke, G and Ebrahimi, F and Fehrenbach, G and Buckley, C and Murphy, E and Devine, D and Major, I},
title = {Controlled-release hybrid hydrogels delivering synergistic N-acetyl cysteine, ibuprofen, and progesterone combinations for enhanced peripheral nerve regeneration.},
journal = {International journal of pharmaceutics},
volume = {687},
number = {},
pages = {126423},
doi = {10.1016/j.ijpharm.2025.126423},
pmid = {41274519},
issn = {1873-3476},
mesh = {*Acetylcysteine/administration &amp; dosage/pharmacology/chemistry ; Animals ; *Hydrogels/chemistry/administration &amp; dosage ; *Ibuprofen/administration &amp; dosage/chemistry/pharmacology ; Rats ; Delayed-Action Preparations/chemistry/administration &amp; dosage ; *Nerve Regeneration/drug effects ; Cell Proliferation/drug effects ; *Progesterone/administration &amp; dosage/chemistry/pharmacology ; Schwann Cells/drug effects ; PC12 Cells ; Cell Survival/drug effects ; Drug Synergism ; Drug Liberation ; Polyethylene Glycols/chemistry ; Drug Combinations ; },
abstract = {Peripheral nerve injuries (PNI) remain a major clinical challenge, particularly for defects exceeding 3 cm. Autografts are the current gold standard for small gaps, but their use is limited by donor site morbidity, infection risk, and poor outcomes in larger defects. Synthetic grafts and allografts have achieved only modest clinical success, underscoring the need for therapeutic systems that actively support regeneration. This study investigated three FDA-approved drugs - N-acetyl cysteine (NAC), ibuprofen (Ibu), and progesterone (Prog) - for their synergistic potential to enhance Schwann cell (SC) and PC-12 cell proliferation as a strategy for peripheral nerve repair. High-throughput screening using Alamar Blue assays assessed viability and proliferation at 24, 48, and 72 h across dual- and triple-drug combinations. The optimised formulation of 75 µM NAC, 16.25 µM Ibu, and 30 µM Prog significantly increased proliferation compared with untreated controls without inducing cytotoxicity. A validated high-performance liquid chromatography (HPLC) method was developed to quantify simultaneous release of all three drugs from polyethylene glycol dimethacrylate-dipentaerythritol hexa(3-mercaptopropionate) (PEGDMA-DiPETMP) hydrogels. Controlled, sequential release was achieved, with complete elution of NAC within 24 h, Ibu within 72 h, and Prog over 21 days. These timelines correspond to the early antioxidative, anti-inflammatory, and neurotrophic phases of peripheral nerve repair. Although proliferation assays were conducted using directly applied drug combinations, the established release behaviour provides a mechanistic rationale for future validation of hydrogel-mediated delivery. The synergistic combination of NAC, Ibu, and Prog delivered from PEGDMA-DiPETMP hybrid hydrogels provides a reproducible and temporally coordinated release platform that promotes cellular proliferation and supports peripheral nerve regeneration.},
}
@article {pmid41274204,
year = {2025},
author = {Zhu, Y and Wu, J and Zhao, S and Yang, J and Huang, M and Liu, N and Yang, B and Che, Z and Ju, J},
title = {Environmentally relevant concentrations of polystyrene nanoplastics induce Parkinson's-like neurotoxicity in C. elegans via oxidative stress.},
journal = {Environment international},
volume = {206},
number = {},
pages = {109926},
doi = {10.1016/j.envint.2025.109926},
pmid = {41274204},
issn = {1873-6750},
mesh = {Animals ; *Caenorhabditis elegans/physiology/drug effects ; *Oxidative Stress/drug effects ; *Polystyrenes/toxicity ; Parkinson Disease ; Reactive Oxygen Species/metabolism ; Caenorhabditis elegans Proteins/metabolism/genetics ; *Microplastics/toxicity ; *Nanoparticles/toxicity ; Dopaminergic Neurons/drug effects ; },
abstract = {This study reveals that environmentally relevant polystyrene nanoplastics (PS-NPs) induces Parkinson's disease (PD)-like pathology in Caenorhabditis elegans (C. elegans) through oxidative stress. Wild-type and transgenic strains were exposed to PS-NPs at concentrations of 0.1-100 μg/L to assess behavioral toxicity, neuronal damage, and molecular mechanisms. Locomotor deficits (reduction in body bends and head thrashes) and disrupted PD-associated behaviors (impairment of food-induced basal slowing response; increased swimming paralysis rate) were observed at all concentrations, while developmental parameters remained unaffected. Although some behavioral endpoints didn't exhibit a strictly monotonic dose-response, Jonckheere-Terpstra trend analyses confirmed significant overall trends for multiple key parameters, underscoring the pervasive impact of PS-NP exposure. Selective degeneration of dopaminergic neurons and exacerbated α-synuclein aggregation confirmed neuropathological specificity. Transcriptomic analysis linked these phenotypes to oxidative stress, showing elevated reactive oxygen species (ROS) and upregulation of antioxidant enzymes (SOD-3, GST-4), alongside paradoxical suppression of the redox regulator skn-1. Genetic validation using trx-1 mutants prevented PS-NP-induced paralysis, whereas trx-4 deficiencies exacerbated toxicity, highlighting their distinct roles in redox defense. Co-treatment with N-acetylcysteine (NAC) attenuated PS-NP-induced paralysis, lowering the rate from 51.33 % to 29.47 %, though rescue failure in trx-4 mutants indicated mechanistic complexity and the indispensable role of endogenous defense systems. Critically, neurotoxicity occurred even at 0.1 μg/L PS-NPs, a level relevant to environmental contamination. These findings establish PS-NPs as potent inducers of PD-like neurodegeneration via complex oxidative stress cascades, validated by genetic and antioxidant interventions at environmentally realistic exposure levels, and highlight the urgency of monitoring nanoplastic pollution and developing antioxidant-based interventions.},
}
@article {pmid41270839,
year = {2026},
author = {Gunes, M and Öcal, GK and Kılıclı, B and Ozturk, AM and Armagan, G and Karavana, SY},
title = {N-acetylcysteine loaded electrospun core/shell nanofibers: a promising system for ferroptosis in spinal cord injury.},
journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V},
volume = {218},
number = {},
pages = {114938},
doi = {10.1016/j.ejpb.2025.114938},
pmid = {41270839},
issn = {1873-3441},
mesh = {Animals ; *Spinal Cord Injuries/drug therapy ; *Acetylcysteine/administration &amp; dosage/pharmacology/chemistry ; *Nanofibers/chemistry ; Rats ; *Ferroptosis/drug effects ; Polyesters/chemistry ; Antioxidants/administration &amp; dosage ; Rats, Sprague-Dawley ; Oxidative Stress/drug effects ; Drug Delivery Systems/methods ; Poloxamer/chemistry ; Neuroprotective Agents/administration &amp; dosage/pharmacology ; Cell Survival/drug effects ; Disease Models, Animal ; Male ; Delayed-Action Preparations ; Drug Liberation ; },
abstract = {Spinal cord injury (SCI) induces a cascade of secondary damage mechanisms, including oxidative stress, inflammation, and cell death, which severely impair neuronal recovery. In this study, N-acetylcysteine (NAC), a thiol-based antioxidant with limited CNS bioavailability, was encapsulated in polycaprolactone (PCL) nanofibers using emulsion electrospinning. This approach allows localized and sustained drug delivery. Span 80 and Poloxamer 407 were used as surfactants to stabilize the emulsion and increase the hydrophilicity of the fibers. The resulting core/shell nanofibers (NAC-CSN) exhibited uniform morphology, improved wettability, and favorable mechanical properties, while supporting cell viability and migration in vitro. Sustained NAC release over several days was achieved, indicating diffusion-controlled delivery. In a rat model of SCI, NAC-CSN treatment attenuated oxidative and ferroptotic damage and promoted early neuroregeneration, which enabled measurable locomotor recovery. These findings suggest that NAC-CSN scaffolds offer an effective neuroprotective strategy against secondary SCI damage and, by enabling localized antioxidant delivery at the lesion site, represent a clinically applicable platform for future tissue engineering and translational therapies.},
}
@article {pmid41268347,
year = {2025},
author = {Chen, Q and Xiao, Z and Ying, X and Yang, Y and Chen, J and Wu, Z and Zeng, W and Miao, C and Nan, Y and Huang, Q and Ai, K},
title = {Molybdenum-bridged endo-exogenous antioxidant synergy reverses acute kidney injury via mitochondrial homeostasis reconstruction.},
journal = {Bioactive materials},
volume = {54},
number = {},
pages = {777-796},
pmid = {41268347},
issn = {2452-199X},
abstract = {Acute kidney injury (AKI) progression is driven by mitochondrial redox collapse in proximal tubular epithelial cells (PTECs), where reactive oxygen species (ROS) surge and molybdenum (Mo) metabolic dysregulation create an "oxidative storm-defense collapse" cycle. Conventional antioxidant therapies fail to halt AKI chronicity due to their inability to restore Mo-dependent detoxification enzymes (e.g., Mo-containing Amidoxime Reducing Component, mARC). To address this dual pathology, we developed N-acetylcysteine (NAC)-modified molybdenum disulfide quantum dots (NMDs) that implement an endo-exogenous antioxidant collaborative strategy, synergizing exogenous ROS elimination with endogenous Mo enzyme restoration. NMDs achieve triple-tiered targeting: 1) Organ-selective accumulation leveraging NMDs' hydrophilicity and ultrasmall size; 2) Cell-specific internalization through Organic Anion Transporter 1 (OAT1)-mediated active uptake into PTECs; 3) Mitochondrial precision delivery guided by NAC's intrinsic mitochondrial affinity. Within pathological microenvironments, NMDs exhibit multidimensional therapeutic superiority: exposed Mo(Ⅳ) directly quenches mitochondrial ROS via electron transfer (external clearance), while released Mo ions reactivate mARC and NAC supplies glutathione precursors, synergistically rebuilding endogenous antioxidant defenses (internal reinforcement). In vivo validation demonstrated NMDs' superior therapeutic efficacy, outperforming clinical antioxidant NAC. This work pioneers a "scavenging-fortification" strategy through Mo-centric metabolic regulation and nanotechnology integration, validating Mo-based materials' therapeutic potential and establishing a paradigm for mitochondrial-targeted AKI treatment.},
}
@article {pmid41267214,
year = {2025},
author = {Minchenberg, SB and Ribera, MO and Hionides Gutierrez, A and Datta, A and Brezani, V and Santos, B and Hong, SM and Kulkarni, S and Nagesh, PT and Szabo, G},
title = {Unraveling the gastrointestinal tract's response to alcohol binges: Neutrophil recruitment, neutrophil extracellular traps, and intestinal injury.},
journal = {Alcohol, clinical &amp; experimental research},
volume = {49},
number = {12},
pages = {2707-2720},
doi = {10.1111/acer.70196},
pmid = {41267214},
issn = {2993-7175},
support = {R01 AA017729/AA/NIAAA NIH HHS/United States ; R01AA011576/NH/NIH HHS/United States ; R56AA017729/NH/NIH HHS/United States ; },
mesh = {Animals ; *Extracellular Traps/drug effects/metabolism ; *Binge Drinking/pathology/metabolism/immunology ; Mice ; Female ; Mice, Inbred C57BL ; *Neutrophil Infiltration/drug effects/physiology ; *Ethanol ; *Gastrointestinal Tract/drug effects/pathology ; Reactive Oxygen Species/metabolism ; },
abstract = {BACKGROUND: Excessive alcohol consumption results in gastrointestinal (GI) tract dysfunction, including disruption of the intestinal barrier and exposure of the liver to microbes and gut-derived pathogen-associated molecular patterns (PAMPs). The upper GI tract is exposed to the highest amount of alcohol, but little is known about alcohol's impact on GI inflammation. This study aimed to evaluate the initial effects of alcohol binges on GI inflammation.<br><br>METHODS: A murine model of binge drinking was established with daily oral gavages of alcohol (3.5&#x2009;g/kg) for 3&#x2009;days in C57BL/6J female mice. The proximal small intestine (PSI), distal small intestine (DSI), and colon were evaluated for inflammation at 3 and 24&#x2009;h after the last binge. To determine whether reactive oxygen species (ROS) contribute to intestinal inflammation, a subset of mice were given 500&#x2009;mg/kg N-acetyl-cysteine (NAC) with alcohol via gavage. To assess the role of neutrophil extracellular traps (NETs), mice were treated 1&#x2009;h before the alcohol binges with 5&#x2009;mg/kg of DNase, a nonspecific inhibitor of NETs.<br><br>RESULTS: Alcohol binges induced a PSI enteropathy with neutrophil recruitment, activation, NETs, and increased serum endotoxin without significant changes in PSI pro-inflammatory cytokines. Neutrophil recruitment and serum endotoxin normalized 24&#x2009;h after the last binge with persistent PSI villous blunting. While alcohol generated ROS, administration of the antioxidant, NAC, failed to prevent the PSI enteropathy, neutrophil activation, or increased serum endotoxin. DNase treatment improved the PSI enteropathy and reduced serum endotoxin, neutrophil recruitment, and neutrophil activation. We found robust upregulation of Gal-3 and CXCL10 in the PSI after alcohol binges is associated with neutrophil recruitment and activation.<br><br>CONCLUSION: Alcohol binges result in a PSI enteropathy, transient infiltration of neutrophils, and NETs that are independent of ROS production. Treatment with DNase, a nonspecific inhibitor of NETs, mitigates alcohol-induced PSI enteropathy, neutrophil recruitment and bacterial translocation.},
}
@article {pmid41260340,
year = {2026},
author = {Zmuda, AJ and Toensing, AJ and Wissbroecker, KB and Niehaus, TD},
title = {Bacillus subtilis encodes three N-acetylcysteine deacetylase enzymes that can catalyze the final step in S-(2-succino)cysteine breakdown.},
journal = {The Journal of biological chemistry},
volume = {302},
number = {1},
pages = {110954},
pmid = {41260340},
issn = {1083-351X},
support = {R35 GM154803/GM/NIGMS NIH HHS/United States ; },
mesh = {*Bacillus subtilis/enzymology/genetics/growth &amp; development ; *Acetylcysteine/metabolism/analogs &amp; derivatives ; *Cysteine/metabolism/analogs &amp; derivatives ; *Bacterial Proteins/metabolism/genetics/chemistry ; *Amidohydrolases/metabolism/genetics/chemistry ; Acetylation ; },
abstract = {Succination occurs when the TCA cycle intermediate fumarate reacts with cellular thiols, such as cysteine, yielding the damaged metabolite S-(2-succino)cysteine (2SC). Increased fumarate levels result in global succination of thiol-containing macromolecules and metabolites, which has been implicated in many human diseases. 2SC is a chemically stable molecule; however, enzymatic breakdown pathways have been identified in prokaryotes that involve N-acetylation of 2SC followed by a breakdown step that results in the release of the succino-moiety and N-acetylcysteine (NAC). NAC must be metabolized to cysteine to be assimilated, but enzymes catalyzing NAC deacetylation had hitherto not been thoroughly characterized. Here, we describe three enzymes in Bacillus subtilis, ScmP, YhaA, and YtnL, that all possess high NAC deacetylase activity in vitro. All three enzymes are metal-dependent hydrolases that are most active with cobalt and show remarkable specificity to NAC compared to structurally related acetylated small molecules. Growth assays demonstrated that these genes are functionally redundant in B. subtilis, and growth on NAC is only severely compromised when all three genes are knocked out of the genome. Together, our biochemical and genetic studies complete the functional characterization of the three-step 2SC degradation pathway in B. subtilis.},
}
@article {pmid41248871,
year = {2025},
author = {Wang, L and Wang, C and Ding, H and Feng, S and Wang, X and Wu, J and Liu, D},
title = {Soybean glycinin and β-conglycinin disrupted mitochondria-endoplasmic reticulum interactions in porcine intestinal epithelial cells via oxidative stress cascades.},
journal = {Developmental and comparative immunology},
volume = {173},
number = {},
pages = {105523},
doi = {10.1016/j.dci.2025.105523},
pmid = {41248871},
issn = {1879-0089},
mesh = {Animals ; Oxidative Stress/drug effects ; *Soybean Proteins/metabolism/immunology ; Swine ; *Mitochondria/metabolism/drug effects ; *Antigens, Plant/immunology/metabolism ; *Globulins/immunology/metabolism ; *Seed Storage Proteins/metabolism/immunology ; *Epithelial Cells/metabolism ; *Endoplasmic Reticulum/metabolism/drug effects ; *Glycine max/immunology ; Cell Line ; Reactive Oxygen Species/metabolism ; *Intestinal Mucosa/metabolism ; Calcium/metabolism ; Membrane Potential, Mitochondrial ; },
abstract = {Soybean glycinin (11S) and β-conglycinin (7S) are major contributors to allergic diarrhea and intestinal barrier damage in young animals. This study investigated the molecular mechanisms underlying the 7S- and 11S-induced dysfunction of mitochondrial and endoplasmic reticulum (ER) interactions in porcine intestinal epithelial (IPEC-J2) cells via the oxidative stress pathway. The results showed that 7S- and 11S-induced oxidative stress, as evidenced by the following findings: reduced manganese superoxide dismutase (Mn-SOD) activity and elevated 8-Hydroxy-2'-deoxyguanosine (8-OHdG) levels, with excessive reactive oxygen species (ROS) accumulation and elevated Ca[2+] levels; decreased mitochondrial membrane potential (MMP), damaged mitochondria-associated endoplasmic reticulum membranes (MAM) structure; up-regulated the protein expression of glucose-regulated protein 75 (GRP75) and mitochondrial Rho-GTPase 1 (Miro1), while inositol 1,4,5 -trisphosphate receptor (IP3R), voltage-dependent anion channel 1 (VDAC1), mitofusin2 (MFN2) and phosphofurin acidic cluster sorting protein 2 (PACS2) were down-regulated. N-acetylcysteine (NAC)pre-treatment alleviated ROS accumulation and mitigated Ca[2+] overload and MAM dysfunction, thereby ameliorating IPEC-J2 cell injury. In conclusion, 7S- and 11S-induced ROS burst to disrupt mitochondria-ER interaction homeostasis, leading to MAM structural damage and calcium dysregulation in IPEC-J2 cells, NAC effectively mitigated this process by scavenging ROS. These findings elucidate the critical involvement of subcellular organelle interaction disorders in food allergy pathogenesis and provide novel insights for targeted intervention strategies.},
}
@article {pmid41245027,
year = {2025},
author = {Kamal, S and Akhavan, S and Warolin, J and Baig, A},
title = {A case of lactobezoar: Outpatient management in a neonate.},
journal = {JPGN reports},
volume = {6},
number = {4},
pages = {427-429},
pmid = {41245027},
issn = {2691-171X},
abstract = {A lactobezoar is a conglomerate of undigested and partially digested milk components and is the most common form of bezoar in infants. Described treatments include hospitalization for intravenous fluids and cessation of feeds, endoscopy with administration of N-acetyl cysteine, and surgical or endoscopic removal. We report a case of a 5-month-old infant with a history of prematurity of 28 weeks, with poor feeding and emesis, found to have a gastric lactobezoar on imaging without signs of obstruction that was managed without surgical intervention. This case presentation describes the successful treatment of a patient with 100% whey formula for the treatment of lactobezoar, avoiding invasive treatment and hospitalization.},
}
@article {pmid41243318,
year = {2025},
author = {Ikegaki, Y and Terachi, A and Yamao, S and Nagano, T and Iwasaki, T and Kamada, S},
title = {Epsin 3 Promotes Cellular Senescence Through Reactive Oxygen Species-Mediated Induction of DNA Damage.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {30},
number = {6},
pages = {e70067},
doi = {10.1111/gtc.70067},
pmid = {41243318},
issn = {1365-2443},
support = {25640063//Japan Society for the Promotion of Science/ ; 17K15595//Japan Society for the Promotion of Science/ ; 20K07591//Japan Society for the Promotion of Science/ ; 20K15791//Japan Society for the Promotion of Science/ ; 21K05308//Japan Society for the Promotion of Science/ ; 24K10360//Japan Society for the Promotion of Science/ ; JPMJSP2148//Japan Science and Technology Agency/ ; //Uehara Memorial Foundation/ ; //Japan Science Society/ ; #4067//Hyogo Science and Technology Association/ ; },
mesh = {*Reactive Oxygen Species/metabolism ; *Cellular Senescence/genetics ; *DNA Damage ; Humans ; rac1 GTP-Binding Protein/metabolism/antagonists &amp; inhibitors ; Oxidative Stress ; Acetylcysteine/pharmacology ; },
abstract = {Cellular senescence is caused by various stresses, including DNA damage, oxidative stress, oncogene activation, and telomere shortening. However, the detailed molecular mechanisms of cellular senescence have yet to be elucidated. Recently, using comparative transcriptomics and quantitative PCR, we identified several genes that are specifically upregulated in senescent cells in a p53-dependent manner, including Epsin 3 (EPN3). However, the functional relevance of EPN3 to senescence has not yet been defined. Here, we performed functional analyses to investigate the relationship between EPN3 and the senescence program. We found that EPN3 knockdown suppressed senescent phenotypes induced by DNA damage. Furthermore, ectopic expression of EPN3 induced senescence accompanied by increased reactive oxygen species (ROS) and accumulation of DNA damage. Furthermore, EPN3-induced DNA damage was suppressed by genetic and pharmacological inhibition of Rac1. Finally, treatment with ROS scavengers, N-acetyl-l-cysteine (NAC) and l-Ascorbic Acid (LAA), prevented EPN3-induced DNA damage, and a Rac1 inhibitor reduced ROS levels in EPN3-expressing stable clones. These results indicate that EPN3 induces DNA damage and promotes senescence via Rac1 activity and ROS generation.},
}
@article {pmid41242433,
year = {2025},
author = {Shiozawa, A and Kajiwara, C and Ishii, Y and Tateda, K},
title = {N-acetylcysteine is associated with restoration of autophagy-related signaling and reduced intracellular Mycobacterium avium in alveolar type 1 epithelial cells.},
journal = {Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy},
volume = {31},
number = {12},
pages = {102864},
doi = {10.1016/j.jiac.2025.102864},
pmid = {41242433},
issn = {1437-7780},
mesh = {*Autophagy/drug effects ; *Acetylcysteine/pharmacology ; Animals ; Mice ; *Alveolar Epithelial Cells/microbiology/drug effects ; Signal Transduction/drug effects ; *Mycobacterium avium/drug effects ; Humans ; Microtubule-Associated Proteins/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Cell Line ; *Mycobacterium avium-intracellulare Infection/drug therapy/microbiology/immunology ; },
abstract = {PURPOSE: In patients with pulmonary Mycobacterium avium complex disease, the barrier function of the airway epithelium is reduced. In this study, we focused on the host defense responses of alveolar epithelial cells to M. avium.<br><br>METHODS AND RESULTS: Clinical isolates of M. avium were used to infect murine alveolar type 1 epithelial cells (AT1s). Administration of N-acetylcysteine suppressed bacterial growth in the infected cells. Expression of the autophagosome marker microtubule-associated protein 1 light chain 3 was decreased in M. avium-infected cells and appeared to be restored by N-acetylcysteine administration. M. avium infection negatively affected the autophagic pathway, specifically mTORC1 signaling and its upstream factor, SLC37A4, which was partially restored by N-acetylcysteine administration. Autophagy inhibition by bafilomycin attenuated the NAC-associated reduction in bacterial load, suggesting involvement of autophagy-related pathways.<br><br>CONCLUSIONS: Our results suggest that M. avium infection is associated with suppressed autophagy-related responses in AT1s. NAC may function as an immunomodulatory agent by modulating autophagy-associated pathways and reducing intracellular bacterial burden.},
}
@article {pmid41242411,
year = {2026},
author = {Dai, J and Du, Y and Wang, Y and Yang, G},
title = {N-acetylcysteine suppresses proteasome pathway activation and muscular damage induced by microplastics and chromium nanoparticles.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {388},
number = {},
pages = {127387},
doi = {10.1016/j.envpol.2025.127387},
pmid = {41242411},
issn = {1873-6424},
mesh = {*Acetylcysteine/pharmacology ; *Chromium/toxicity ; Zebrafish ; Animals ; *Microplastics/toxicity ; *Proteasome Endopeptidase Complex/metabolism ; Humans ; Reactive Oxygen Species/metabolism ; *Metal Nanoparticles/toxicity ; Nanoparticles/toxicity ; },
abstract = {Under global plastic proliferation, microplastics (MPs) have become significant environmental pollutants. Annually, over one million patients undergo orthopedic surgeries involving chromium alloy implants, which release chromium nanoparticles (Cr NPs) during long-term intraosseous residence. These particles migrate to adjacent muscle tissues, potentially inducing adverse effects. This study aimed to investigate the combined impact of Cr NPs and MPs co-exposure on muscle systems and underlying mechanisms. Human tissue analysis confirmed concurrent Cr NPs and MPs accumulation in peri-implant regions. In vitro experiments showed elevated reactive oxygen species (ROS) levels and pro-inflammatory cytokine expression in C2C12 cells exposed to Cr NPs/MPs individually or combined, with synergistic enhancement under co-exposure conditions. Zebrafish models exhibited spinal deformities, reduced motility, and histopathological muscle damage following pollutant exposure. Mechanistic studies revealed proteasome pathway activation as a key mediator, evidenced by PSMD2 overexpression, Notably, N-acetylcysteine (NAC) pretreatment ameliorated co-exposure-induced muscle injury, reduced ROS accumulation, and inhibited proteasome activation. This research provides new perspectives on Cr NP/MP synergistic toxicity and identifies NAC as a potential therapeutic strategy against pollution-related muscle damage.},
}
@article {pmid41242401,
year = {2026},
author = {Mohammadpour-Asl, S and Shirpoor, A and Alipour, S and Naderi, R},
title = {Nandrolone decanoate induces liver damage via TGF-β/Smad3/miR-29 and regulation of FAT/CD36, PTP1B, HNF4A expression in male rats: Rescue effect of N-acetylcysteine.},
journal = {The Journal of steroid biochemistry and molecular biology},
volume = {256},
number = {},
pages = {106902},
doi = {10.1016/j.jsbmb.2025.106902},
pmid = {41242401},
issn = {1879-1220},
mesh = {Animals ; Male ; Rats, Wistar ; *Nandrolone Decanoate ; *Acetylcysteine/pharmacology ; Rats ; MicroRNAs/metabolism/genetics ; Smad3 Protein/metabolism/genetics ; *Liver/drug effects/metabolism/pathology ; *Anabolic Agents/adverse effects/toxicity ; *Chemical and Drug Induced Liver Injury/metabolism/drug therapy/pathology ; Transforming Growth Factor beta/metabolism ; *Nandrolone/analogs &amp; derivatives ; Gene Expression Regulation/drug effects ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; },
abstract = {Anabolic-androgenic steroid (AAS) abuse is associated with damage to various organs, including the liver. However, the underlying molecular mechanisms remain unclear. This study was conducted to elucidate the effect of nandrolone decanoate on liver injury, both alone and in combination with N-acetylcysteine (NAC), and its related mechanisms. Twenty-four male Wistar rats were randomly subdivided into three groups: Control (Con), Nandrolone (10 mg/kg) (ND), and Nandrolone + NAC (ND+NAC: 150 mg/kg daily). After 6 weeks, nandrolone treatment led to increased levels of triglycerides, cholesterol, LDL, AST, ALT, and ALP, along with a decreased HDL level compared to the control group. ND administration also elevated the expression of PTP1B, HNF4A, and FAT/CD36 genes, as well as protein levels of MMP-2, MMP-9, TGF-β1, SMAD-3, and SREBP-1. miRNA-29b levels decreased in liver tissue following nandrolone exposure, as determined by RT-PCR. Moreover, histopathological examination showed increased fibrosis after ND treatment. Consumption of NAC along with ND partially ameliorated gene and protein expression alterations and fibrotic changes, and improved the undesirable lipid profile and liver enzyme levels compared to the ND group. These findings indicate that ND-induced liver abnormalities may be partly associated with lipid homeostasis changes mediated by overexpression of the aforementioned genes and proteins. They also demonstrate that these effects can be reduced by using NAC as an antioxidant and anti-inflammatory agent.},
}
@article {pmid41241719,
year = {2025},
author = {El Far, MS and Kassem, MA and Edward, EA and Evans, BA and Baker, DJ and Zakaria, AS},
title = {Genomic insights into ST85 and ST158 belonging to recently emerged global clones of multidrug-resistant Acinetobacter baumannii isolates from Egypt: in vitro assessment of repurposed drug-antibiotic combinations.},
journal = {Annals of clinical microbiology and antimicrobials},
volume = {24},
number = {1},
pages = {63},
pmid = {41241719},
issn = {1476-0711},
mesh = {*Acinetobacter baumannii/genetics/drug effects/isolation &amp; purification/classification ; Egypt/epidemiology ; *Drug Resistance, Multiple, Bacterial/genetics ; *Anti-Bacterial Agents/pharmacology ; Humans ; *Acinetobacter Infections/microbiology/epidemiology/drug therapy ; Microbial Sensitivity Tests ; beta-Lactamases/genetics/metabolism ; Phylogeny ; Multilocus Sequence Typing ; Whole Genome Sequencing ; Genome, Bacterial ; Bacterial Proteins/genetics/metabolism ; Drug Repositioning ; Genotype ; Virulence ; },
abstract = {BACKGROUND: The strikingly rapid increase in multidrug-resistant Acinetobacter baumannii (MDRAB) incidence rates represents a major challenge in healthcare settings. This is due to the limitation of the currently available treatment options to combat tenacious A. baumannii infections. MDRAB isolates belonging to recently emerged global clones GC9 and GC10 are on the rise, especially in the Middle East and Africa, which warrants a thorough investigation of these global clones.<br><br>METHODS: Thirteen A. baumannii isolates belonging to less well-studied global clones were selected from 46 isolates collected in Alexandria, Egypt, after determining their clone using MLST. Susceptibility to multiple antibiotic classes was determined by the Kirby-Bauer disk diffusion method. Testing of carbapenemase activity and selected virulence phenotypes was done. Whole genome sequencing, phylogenetic analysis, and molecular characterization of the resistance and virulence genotypes were performed. Checkerboard assay was employed for testing the combination of each of ciclopirox and N-acetylcysteine (NAC), as potential repurposed drugs, with each of meropenem and levofloxacin antibiotics against MDRAB isolates.<br><br>RESULTS: All the isolates displayed multidrug resistance and were carbapenemase-positive. One isolate showed strong biofilm formation, whereas 4 and 8 isolates were moderate and weak biofilm formers, respectively. Twelve out of thirteen isolates were positive twitchers. The isolates showed moderate phospholipase and strong protease activities. However, low phospholipase production was detected in one isolate. The genomic analysis revealed that 3 and 10 isolates belonged to ST85 (GC9) and ST158 (GC10), respectively. All 13 isolates harbored multiple resistance genes including oxa23 and carried an RP-T1 rep type plasmid. Phylogenetic analysis demonstrated that the isolates were clustered together forming subclades with others from Alexandria/Egypt. The AbGRI3-2 resistance island (RI) was detected in ST158 isolates carrying R3-T60 rep type and 9 antibiotic resistance genes. The combination of NAC with each of meropenem or levofloxacin showed a synergistic action against 3 and one isolate(s), respectively, using the checkerboard assay.<br><br>CONCLUSION: The current study provides an in-depth characterization of the collected MDRAB isolates from the global clones GC9 and GC10. The endemicity of these clones necessitates strategies to mitigate ongoing MDRAB outbreaks in countries like Egypt. Combination of NAC with meropenem or levofloxacin represents a promising treatment option against the newly emerged global clones that needs further in vivo testing.},
}
@article {pmid41240208,
year = {2025},
author = {Qi, X and Hu, Y and Yang, J and Jiang, M and Zhang, J and Du, Y and Hu, C},
title = {Selenium alleviates Staphylococcus aureus-induced mastitis by modulating mitochondrial dynamics and inhibiting the ROS/NLRP3/Pyroptosis pathway.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {82},
pmid = {41240208},
issn = {1573-4978},
mesh = {Animals ; *Selenium/pharmacology/metabolism ; *Pyroptosis/drug effects ; Female ; Reactive Oxygen Species/metabolism ; Staphylococcus aureus/drug effects/pathogenicity ; Cattle ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Mastitis, Bovine/drug therapy/microbiology/metabolism ; *Mitochondrial Dynamics/drug effects ; *Staphylococcal Infections/drug therapy ; Mitochondria/metabolism/drug effects ; Signal Transduction/drug effects ; *Mastitis/drug therapy/microbiology ; Membrane Potential, Mitochondrial/drug effects ; Disease Models, Animal ; },
abstract = {BACKGROUND: The pathogenesis of bovine mastitis involves inflammation and cell death, with pyroptosis being a key factor in its development. Currently, antibiotics remain the primary therapeutic option for bovine mastitis, however, the increasing prevalence of antibiotic resistance constitutes a major public health threat. Selenium (Se) has been reported to alleviate inflammation primarily through its antioxidant properties, but the mechanism by which Se regulates pyroptosis in bovine mastitis remains unclear.<br><br>METHODS AND RESULTS: In this study, an in vitro mastitis model was established by infecting MAC-T cells with inactivated Staphylococcus aureus (S. aureus) (MOI&#x2009;=&#x2009;10, 12&#xa0;h). The results revealed that the mitochondrial membrane potential of the MAC-T cells in the infection group decreased significantly. Moreover, the accumulation of Reactive oxygen species (ROS) was accompanied by the activation of NOD-like receptor family containing pyrin domain 3 (NLRP3), the expression of the pyroptosis-related genes gasdermin D amino terminal fragment (GSDMD-N), and cysteine &#x200b;&#x200b;aspartate specific protease 1 (cleaved-caspase 1). Pretreatment with Se, the NLRP3 inhibitor MCC950 and the antioxidant N-acetylcysteine &#x200b;&#x200b;(NAC) attenuated mitochondrial damage, ROS accumulation, and the inhibition of pyroptosis. An in vivo mastitis model was established in mice fed a high-selenium diet (containing 1.5&#xa0;mg/kg Se) and intramammarily injected with inactivated S. aureus (1&#x2009;&#xd7;&#x2009;10[8] CFU/mL). Histological analysis revealed intact alveolar structure and reduced inflammatory cell infiltration in mice fed the high-selenium diet. The expression of the inflammasome NLRP3 downregulated, and the expression of GSDMD-N, a direct executor of pyroptosis, upregulated.<br><br>CONCLUSION: Our in vitro and in vivo results confirmed that Se alleviate mitochondrial damage and pyroptosis by inhibiting the NLRP3 pathway, ultimately alleviating mastitis.},
}
@article {pmid41239787,
year = {2025},
author = {Li, J and Li, W and Xue, Y and Zhu, H and Zhang, D and Ren, Y and Wu, C and Liu, Y and Peng, L and Yang, Z and Li, H and Liu, C and Li, Z and Jin, Z and Huang, H},
title = {Oral Ingestion of Polystyrene Microplastics Aggravates Chronic Pancreatitis Through ROS Induced NF-κb/TGF-β Signaling Pathway and Alteration of Gut Microbiota.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {22},
pages = {e71223},
doi = {10.1096/fj.202501205RR},
pmid = {41239787},
issn = {1530-6860},
support = {82020108005//MOST | NSFC | Major International Joint Research Programme/ ; 82370655//MOST | National Natural Science Foundation of China (NSFC)/ ; 82370658//MOST | National Natural Science Foundation of China (NSFC)/ ; //Wuxi Taihu Lake Talent Plan, Supports for Leading Talents inMedical and Health Profession/ ; },
mesh = {*Eating ; Mouth/metabolism ; *Microplastics/metabolism/toxicity ; *Polystyrenes/metabolism/toxicity ; *Pancreatitis, Chronic/metabolism/microbiology/pathology ; Animals ; Mice ; Disease Models, Animal ; *Pancreas/drug effects/metabolism/pathology ; Fibrosis ; Reactive Oxygen Species/metabolism ; NF-kappa B ; Transforming Growth Factor alpha/metabolism ; Signal Transduction ; *Gastrointestinal Microbiome/drug effects ; *Disease Progression ; Pancreatic Stellate Cells/drug effects/metabolism ; Humans ; Cells, Cultured ; Male ; Mice, Inbred C57BL ; },
abstract = {Microplastics (MPs), as a kind of emerging pollutant, have attracted widespread attention. The effects of MPs of different diameter sizes on chronic pancreatitis and their underlying mechanisms remain to be explored. Therefore, we established a mouse chronic pancreatitis model exposed to two-diameter polystyrene particles (2 or 0.5 μm) for 6 weeks. We found that MPs exposure resulted in severe pancreatic fibrosis in mice, which was negatively correlated with particle size. In-depth mechanistic exploration revealed that after exposure to MPs, MPs can enter pancreatic stellate cells through the cell membrane, stimulate the activation of cellular ROS, further activate the NF-κB and TGF-β signaling pathways, and increase the levels of fibrotic proteins and collagen. The pancreatic fibrosis can be reversed by the ROS inhibitor N-acetyl cysteine (NAC). Meanwhile, oral intake of polystyrene particles in chronic pancreatic mice also affected the diversity of intestinal bacteria, downregulating the bacteria in the Bacteroidota phylum and upregulating the bacteria in the Verrucomicrobiota phylum, which could be another potential mechanism underlying the pathogenic effect of pancreatic fibrosis. Our findings reveal the adverse effects of MPs on chronic pancreatitis through inducing cellular ROS, activating pancreatic stellate cells and altering gut microbes.},
}
@article {pmid41234378,
year = {2025},
author = {Sadeghzadeh-Bazargan, A and Farahani, S and Goodarzi, A and Zeinali, R and Gheisari, M and Atefi, N and Ghassemi, M and Roohaninasab, M and Dehghani, A},
title = {The Effectiveness and Safety of Oral N-Acetylcysteine in Combination With Narrow-Band Ultraviolet B (NB-UVB) Phototherapy Compared With NB-UVB Phototherapy Alone in the Treatment of Vitiligo: A Pilot Study.},
journal = {Health science reports},
volume = {8},
number = {11},
pages = {e71467},
pmid = {41234378},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Vitiligo is an autoimmune skin disease, characterized by depigmented patches over skin. Numerous studies have been conducted to identify the most effective treatment for this condition. Based on high rate of oxidative stress in pathogenesis of vitiligo, antioxidant treatments like N-acetylcysteine (NAC) is suggested. This study aimed to evaluate the efficacy and safety of oral NAC in combination with narrow-band UVB (NB-UVB) phototherapy, comparing it to NB-UVB therapy alone in treating patients with generalized vitiligo.<br><br>METHODS: This single-blind, randomized controlled Phase 1 trial conducted over a period of 4 months, involving 16 participants. The patients were split into two, with one group receiving 600&#x2009;mg of oral NAC twice daily, alongside NB-UVB, while the control group received only phototherapy. The patients were reassessed after 2 and 4 months, with evaluations based on the Vitiligo Extent Tensity Index (VETI), overall patient satisfaction, treatment tolerability, and side effects.<br><br>RESULTS: Among the 16 patients, 68.8% were male, with an average age of 40.7&#x2009;&#xb1;&#x2009;9.9 years. Both treatment groups showed a significant reduction in VETI scores during the second and third assessments (p&#x2009;<&#x2009;0.05). However, the difference between the two groups was not statistically significant (p&#x2009;>&#x2009;0.05). Patient satisfaction was notably higher in the NAC&#x2009;+&#x2009;NB-UVB group during the second visit (p&#x2009;=&#x2009;0.01), and by the third visit, 75% of patients in the NAC&#x2009;+&#x2009;NB-UVB group reported excellent satisfaction, compared to 25% in the control group (p&#x2009;=&#x2009;0.07). Treatment tolerability was similar across both groups, though one patient in the NAC&#x2009;+&#x2009;NB-UVB group experienced dizziness, which was resolved after adjusting the dose.<br><br>CONCLUSION: Oral NAC appears to be a safe adjuvant therapy in the treatment of generalized vitiligo patients in combination with NB-UVB phototherapy.<br><br>TRIAL REGISTER NAME: "Evaluation of the efficacy of NB-UVB phototherapy with oral N- acetylcysteine compared with NB-UVB phototherapy alone in the treatment of vitiligo patients: a randomized controlled clinical trial".Clinical trial registration number: IRCT20210729052013N1.},
}
@article {pmid41230648,
year = {2025},
author = {Nair, AS and Thimmappa, PY and Jasti, DB and Rodrigues, JA and Gangadharan, G and Sivakumar, G and Nagareddy, PR and Shivashankar, KN and Umakanth, S and Joshi, MB},
title = {Biochemical Modifications of Homocysteine Drive Neutrophil Extracellular Trap Formation in Ischemic Stroke.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {22},
pages = {e71221},
doi = {10.1096/fj.202500844RR},
pmid = {41230648},
issn = {1530-6860},
support = {R01 HL137799/HL/NHLBI NIH HHS/United States ; EMR/2017/001680//DST | Science and Engineering Research Board (SERB)/ ; },
mesh = {*Extracellular Traps/metabolism ; Animals ; Mice ; *Ischemic Stroke/metabolism/pathology ; *Homocysteine/metabolism ; Male ; Humans ; *Neutrophils/metabolism ; Hyperhomocysteinemia/metabolism ; Mice, Inbred C57BL ; Female ; Platelet Activation ; },
abstract = {Excessive production of neutrophil extracellular traps (NETs) contributes to immunothrombosis activation in ischemic stroke pathogenesis. The metabolic and mechanistic regulators of NET formation in relation to platelet activation during ischemic stroke remain poorly understood. In the present study, using multiple animal and clinical models of stroke, we examined the role of homocysteine and its biochemical modifications on NET formation and concomitant neuronal damage, platelet aggregation, motor and gait functions. Phosphoproteomics analysis of neutrophils in response to homocysteine revealed an enrichment of kinases and phosphoproteins associated with thrombosis. Homocysteinylated albumin induced significant NET formation via Erk1/2, Akt, ATM, and PAD4-dependent pathways, independent of reactive oxygen species. Hyperhomocysteinemic mice fed a methionine-rich diet exhibited elevated NETs components (neutrophil elastase, citrullinated histones, cell-free DNA (cfDNA)), platelet activation, neuronal damage, and impaired motor, balance, and learning functions. UCCAO-induced ischemia exacerbated neuronal damage, motor dysfunction, and platelet activation in hyperhomocysteinemic mice, which were reversed by disrupting NETs with N-acetyl cysteine and DNase. In stroke patients, homocysteine, neutrophil elastase, and cfDNA levels were significantly elevated, independent of comorbidities (e.g., hypertension, type 2 diabetes), etiology (TOAST classification), or stroke severity. Additionally, stroke patients generated autoantibodies against homocysteinylated albumin, which positively correlated with neutrophil elastase levels. This study identifies homocysteine and its modifications as key metabolic regulators of NETosis in stroke, linking NETs formation to platelet activation and neuronal damage. These findings highlight potential therapeutic targets for mitigating stroke pathogenesis through the modulation of NETs.},
}
@article {pmid41229849,
year = {2025},
author = {Oscullo, G and Méndez, R and Olveira, C and Girón, R and García-Clemente, M and Máiz, L and Sibila, O and Golpe, R and Rodríguez-Hermosa, JL and Barreiro, E and Prados, C and Rodríguez-Lopez, J and de la Rosa, D and Martinez-García, M&#xc1;},
title = {What is the optimal dose of N-acetylcysteine in adult patients with bronchiectasis?-data from the RIBRON registry.},
journal = {Journal of thoracic disease},
volume = {17},
number = {10},
pages = {9003-9012},
pmid = {41229849},
issn = {2072-1439},
abstract = {BACKGROUND: Bronchiectasis is characterized by excessive respiratory secretions, the management of which is clinically significant. Among the available pharmacological treatments, mucolytics play a pivotal role. N-acetylcysteine (N-AC) is the most commonly used mucolytic; however, the optimal dosing regimen remains inadequately defined. The primary aim of the present study is to specifically evaluate the efficacy of 1,200 mg/day of N-AC compared to 600 mg/day in patients with bronchiectasis.<br><br>METHODS: This was a retrospective, longitudinal, observational, multi-center study conducted across 43 centers, involving a cohort of 2,461 adult patients diagnosed with bronchiectasis based on a stable clinical state receiving either 600 mg/day of N-AC (n=252) or 1,200 mg/day (n=116), and provided follow-up data were available for 2 years. Propensity score matching (PSM) was employed to balance baseline characteristics between groups. Final outcomes were further adjusted for additional clinically relevant variables. Intergroup differences in intra-group changes were analyzed using a Poisson test.<br><br>RESULTS: Following PSM, the 1,200 mg/day N-AC group (n=104) demonstrated a statistically significant, fully adjusted reduction in exacerbations (-48.6%, P=0.01), hospitalizations (-29.9%, P=0.038), and total exacerbation rates (-54.1%, P=0.002), compared to the 600 mg/day group (n=219). Furthermore, the proportion of patients with more than 20 cc/day of sputum volume and those with mucopurulent sputum decreased by 24.3% (P=0.001) and 8.5% (P=0.041), respectively, in the 1,200 mg/day group versus the 600 mg/day group. No statistically significant difference was observed in the rate of Pseudomonas aeruginosa isolation (-0.9%; P=0.35).<br><br>CONCLUSIONS: N-AC at a dose of 1,200 mg/day is more effective than 600 mg/day in reducing exacerbations, hospitalizations, and daily sputum volume in patients with bronchiectasis.},
}
@article {pmid41226610,
year = {2025},
author = {Kadlecsik, C and Bognár, G and Kenari, F and Pintér, Z and Ribeiro, JCO and Envall, MG and Carvalho-Silva, VH and Napolitano, HB and Perjési, P},
title = {(E)-2-Benzylidenecyclanones: Part XXI-Reaction of Cyclic Chalcone Analogs with Cellular Thiols: Comparison of Reactivity of (E)-2-Arylidene-1-Indanone with -1-Tetralone and -1-Benzosuberone Analogs in Thia-Michael Reactions.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
pmid = {41226610},
issn = {1422-0067},
support = {EFOP-3.6.1.-16-2016-00004//European Social Fund/ ; },
mesh = {Humans ; Animals ; Mice ; *Sulfhydryl Compounds/chemistry ; *Tetralones/chemistry ; Cell Line, Tumor ; *Chalcones/chemistry ; *Indans/chemistry/pharmacology ; Glutathione/chemistry/metabolism ; Antineoplastic Agents/pharmacology/chemistry ; },
abstract = {In vitro cytotoxicity of three (E)-3-(4'-X-benzylidene)-1-indanones (2a-c) displayed lower cytotoxicity towards murine P388 and L1210 leukemic cells as well as human Molt 4/C8 and CEM T-lymphocytes than the respective six- (3a-c) and seven-membered (4a-c) analogs. To study whether thiol reactivity-as a possible basis of their mechanism of action-correlates with the observed cytotoxicities, kinetics of the non-enzyme catalyzed reactions with reduced glutathione (GSH) and N-acetylcysteine (NAC) of 2a-c were investigated. Furthermore, it was also the aim of the work to compare the thiol reactivity of the open-chain chalcones (1) and their carbocyclic analogs (2-4) with different ring sizes (n = 5-7). The reactivity of the compounds and the stereochemical outcome of the reactions were evaluated using high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Molecular modeling calculations were performed to rationalize the high initial rate and low conversion of the 2a indanone in comparison with those of the carbocyclic analog tetralone (3a) and benzosuberone (4a). Thiol reactivity and cancer cell cytotoxicity showed a dependence on both the ring size and the nature of aromatic substituents.},
}
@article {pmid41226401,
year = {2025},
author = {Sasaninia, K and Era, IH and Newman, N and Melendez, J and Akif, W and Sharma, E and Nikjeh, O and Glassman, I and Jiménez, C and Sharma, N and Xu, A and Lambros, M and Zhou, M and Tiwari, R and Venketaraman, V},
title = {Additive Effects of N-Acetylcysteine and [R4W4] Combination Treatment on Mycobacterium avium.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
pmid = {41226401},
issn = {1422-0067},
mesh = {*Acetylcysteine/pharmacology ; *Mycobacterium avium/drug effects ; Humans ; *Anti-Bacterial Agents/pharmacology ; Microbial Sensitivity Tests ; Macrophages/microbiology/drug effects ; Drug Synergism ; *Peptides, Cyclic/pharmacology ; THP-1 Cells ; Drug Therapy, Combination ; Membrane Potentials/drug effects ; },
abstract = {Mycobacterium avium is an opportunistic pathogen and a leading contributor to nontuberculous mycobacterial infections in immunocompromised individuals. However, treatment duration, antibiotic toxicity, and resistance present challenges in the management of mycobacterium infections, prompting the need for novel treatment. N-acetylcysteine (NAC) has demonstrated potent antimycobacterial activity, while antimicrobial peptides such as the cyclic [R4W4] have shown additive effects when combined with first-line antibiotics. This study aimed to investigate the mechanism and efficacy of NAC and [R4W4] combination therapy against M. avium. A membrane depolarization assay was used to evaluate the effects of NAC and [R4W4] on M. avium cell membrane integrity. Antimycobacterial activity was assessed by treating cultures with varying concentrations of NAC, [R4W4], a combination, or a sham treatment. The same regimens were applied to M. avium-infected THP-1-derived macrophages to assess intracellular efficacy. NAC and [R4W4] each disrupted the M. avium membrane potential, with enhanced effects in combination. The combination treatment significantly reduced M. avium survival in both the culture and infected macrophages compared with NAC alone and untreated controls. [R4W4] and NAC also demonstrated potent antibacterial activity, while the lowest MIC and the combination of [R4W4] and NAC displayed additive effects, indicating an improved bacterial inhibition compared to individual treatments. These findings demonstrate the additive activity of NAC and [R4W4] against M. avium in vitro and suggest that combining antioxidant compounds with antimicrobial peptides may represent a promising strategy for treating mycobacterial infections.},
}
@article {pmid41223462,
year = {2026},
author = {Mumcu, T and Oncuoglu, S and Mumcu, A and Yılmaz, &#xdc; and Ertekin, K},
title = {Emission based sensing of N-acetyl cysteine via silver equipped anthraquinone derivatives.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {348},
number = {Pt 1},
pages = {127152},
doi = {10.1016/j.saa.2025.127152},
pmid = {41223462},
issn = {1873-3557},
abstract = {In this work we investigated emission-based response of silver complexes of two newly synthesized anthraquinone derivatives for N-acetylcysteine (NAC) and thioglycolic acid. The interaction of the probes, DHA-dibenzonitrile and DHA-dibutanenitrile with silver nanoparticles resulted in metal chelation and following quenching of the fluorescence. To determine whether the emission intensity of the complexes was re-stored again, thiol compounds; NAC and thioglycolic acid were used. The released dyes re-emitted light, allowing the system to exhibit an intensity-based turn-on type sensor behavior for the NAC and thioglycolic acid, respectively. The re-stored fluorescence was monitored as a strong emission based analytical signal at 560 nm. The complex stoichiometries were investigated using several approaches, including Job's plot, density functional theory (DFT) and FT-IR measurements. The findings relying on HOMO-LUMO and energy gap calculations highlight that Ag coordination and following acetylcysteine adduction significantly re-shape both local nucleophilic and electrophilic regions, modulating the global electronic structure and reactivity of anthraquinone derivatives. N-acetylcysteine exhibited an exceptional spectral response at pH 9.0 in a buffered solution exhibiting 13.6 and 14.4-fold enhancement in the emission intensity, respectively. The reported linear responses for a concentration range of; 1.0 × 10[-5] M -1.0 × 10[-2] M, can easily be adopted to determination of the NAC levels in drugs, in vitro studies or in serum samples. Limit of detection (LOD) and limit of quantification (LOQ) values of the DHA-dibutanenitrile derivative for the NAC molecule were found to be 1.28 × 10[-6] and 1.21 × 10[-5] mol × L[-1], respectively. Similarly, the DHA-dibenzonitrile exhibited 1.11 × 10[-6] and 1.28 × 10[-5] mol × L[-1] of LOD and LOQ values, respectively.},
}
@article {pmid41220916,
year = {2025},
author = {Pinho, SA and Barosa, C and Deus, CM and Jones, JG and Oliveira, PJ and Cunha-Oliveira, T},
title = {Metabolic priming alters the morphology and metabolism of human dermal fibroblasts.},
journal = {EXCLI journal},
volume = {24},
number = {},
pages = {1419-1437},
pmid = {41220916},
issn = {1611-2156},
abstract = {The metabolic environment provided by the culture medium plays a critical role in shaping cellular function and mitochondrial activity in vitro. In this study, we investigated the effects of metabolic priming on the metabolism and morphology of Normal Human Dermal Fibroblasts (NHDFs) by manipulating glucose availability in the culture medium. Our strategy involved transitioning NHDFs from traditional high-glucose medium (HGm) to either a medium with physiological glucose levels (LGm) or a glucose-free, galactose-containing medium (OXm). Prior to cellular characterization, we confirmed the absence of glucose in the culture media and fetal bovine serum using [1]H nuclear magnetic resonance (NMR) spectroscopy. Given previous observations of elevated reactive species under glucose-free conditions, we explored the cellular adaptations associated with a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS). Cells cultured in OXm exhibited increased metabolic activity, elevated protein content, and substantial metabolic remodeling. Morphological analysis revealed enlargement of the cell body, cytoplasm, mitochondria, and nuclei, indicative of extensive structural adaptation. Notably, oxygen consumption rate (OCR) nearly doubled within 24 h of exposure to OXm, reflecting a rapid mitochondrial response to metabolic stress. The presence of the antioxidant N-acetyl cysteine (NAC) attenuated this increase, suggesting that redox signaling plays a key role in mitochondrial bioenergetic adaptation. These findings underscore the complex interplay between metabolic context, oxidative stress, and cellular morphology, and highlight the importance of appropriate normalization strategies in metabolic studies. See also the graphical abstract(Fig. 1).},
}
@article {pmid41215814,
year = {2025},
author = {Lang, SH and Salgado, AC and Snyder, MT and Rawls-Castillo, B and Williams, A and Gijavanekar, C and Elsea, SH and Wang, X and Tessier, MEM and Soler-Alfonso, C and Scaglia, F},
title = {Biochemical and clinical response to a sulfur-restricted diet in ethylmalonic encephalopathy.},
journal = {Molecular genetics and metabolism reports},
volume = {45},
number = {},
pages = {101270},
pmid = {41215814},
issn = {2214-4269},
abstract = {INTRODUCTION: Ethylmalonic encephalopathy (EE) is an often-severe inborn error of metabolism caused by biallelic variants in the ETHE1 gene leading to impaired detoxification of hydrogen sulfide (H2S). H2S is produced both exogenously by anerobic intestinal bacteria as well as by the endogenous catabolism of the sulfur-containing amino acids methionine and cysteine. Existing therapies including metronidazole, N-acetylcysteine (NAC), and orthotopic liver transplantation (OLT) have been pursued with the objective of reducing or detoxifying exogenously produced H2S. However, strategies to reduce endogenously produced H2S using a methionine and cysteine restricted diet are an understudied therapeutic avenue.<br><br>METHODS: We performed an open-label, single-arm study to evaluate the effects of dietary intervention with a methionine and cysteine restricted diet (20-30&#xa0;mg/kg/day) on biochemical parameters and overall clinical trajectory in three patients with molecularly confirmed ethylmalonic encephalopathy (two with attenuated phenotypes, one classically affected). All three patients were receiving a combination of medical therapy with metronidazole and NAC and were status-post OLT at the time of diet initiation. Plasma butyrylcarnitine (C4) levels were measured at diagnosis, serially following initiation of medical therapy and OLT, and at regular follow-up visits in a metabolic clinic after diet initiation. Additionally, we obtained untargeted metabolomics studies and directly evaluated ethylmalonate, butyrylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, 2-methylbutyrylcarnitine, glutarylcarnitine, and methylsuccinate levels in the pre- OLT/medical therapy, post- OLT/medical therapy, and post- sulfur-restricted diet states.<br><br>RESULTS: We observed a 20-38&#xa0;% reduction in plasma C4 levels in all three patients following OLT and combination medical therapy with NAC and metronidazole. An 8-10&#xa0;% reduction in C4 was observed following the introduction of dietary therapy in the two patients with attenuated phenotypes and an 82&#xa0;% increase in C4 was seen in the patient with the classical phenotype. The metabolic profile as assessed by untargeted metabolomics analysis was largely unchanged in the pre-OLT/medical therapy, post-OLT/medical therapy, and post-diet states.<br><br>CONCLUSIONS: The modest biochemical response to a sulfur-restricted diet observed in our cohort likely reflects the relatively minor contribution of endogenous sulfur-containing amino acid catabolism to overall H2S production. Further work is needed to study the impact of dietary intervention on the natural history of EE including diet only trials in the animal model as well as in the pre-OLT period in human participants.},
}
@article {pmid41212275,
year = {2025},
author = {Raza, W and Meena, A and Luqman, S},
title = {Antitumor effects of diosmetin in Ehrlich ascites carcinoma mouse model: insights into ROS-mediated mechanisms.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41212275},
issn = {1432-1912},
support = {HCP-007//Central Institute of Medicinal and Aromatic Plants/ ; },
abstract = {Cancer remains one of the leading global health challenges, highlighting the continuous need for innovative therapeutic approaches. In this context, medicinal plants have been recognized as potential candidates for developing bioactive compounds, including flavonoids, which have demonstrated good anticancer properties. Diosmetin, a flavonoid aglycone predominantly found in citrus fruits, has shown potent anticancer properties due to its ability to induce cell cycle arrest, induce apoptosis, and inhibit tumor progression. This study evaluates the anticancer potential of diosmetin across various cancer cell lines such as prostate, skin, liver, lung, and in a murine Ehrlich ascites carcinoma (EAC) model. The cytotoxic effects of diosmetin were assessed by using three independent assays like SRB, MTT, and NRU. Diosmetin exhibited potent antiproliferative effects, with the lung and hepatic cancer cell lines showing the highest sensitivity. Furthermore, in the EAC mouse model, diosmetin significantly reduced tumor growth and promoted cell death. Mechanistic investigations revealed that diosmetin increases reactive oxygen species (ROS) generation in tumor cells. This is further confirmed by co-treatment with N-acetyl cysteine (NAC), a ROS inhibitor. Additionally, diosmetin demonstrated favorable pharmacokinetic and drug-likeness properties, including high gastrointestinal absorption and non-toxicity towards human erythrocytes. These findings suggest that diosmetin holds considerable promise as a potential anticancer agent, warranting further investigation for its therapeutic development.},
}
@article {pmid41211476,
year = {2025},
author = {Fesharaki-Zadeh, A and Belliveau, T and Pietrzak, RH and Arnsten, A},
title = {A novel multimodal pharmacologic approach using guanfacine, N-acetylcysteine, and donepezil in severe TBI: a case series.},
journal = {Frontiers in rehabilitation sciences},
volume = {6},
number = {},
pages = {1648002},
pmid = {41211476},
issn = {2673-6861},
abstract = {Traumatic brain injury (TBI) remains a leading cause of long-term morbidity and disability worldwide. Individuals with moderate to severe TBI often experience persistent neurocognitive deficits, including short-term memory loss, executive dysfunction, and slowed cognitive processing for which there are currently no FDA-approved treatments. This case series investigates the synergistic use of guanfacine, N-acetylcysteine (NAC), and donepezil (GND) administered alongside ongoing cognitive rehabilitation, with treatment effects evaluated through pre- and post-intervention Montreal Cognitive Assessment (MoCA) scores. The guanfacine/NAC combination has previously been reported to improve working memory and executive function in individuals with mild TBI, suggesting its potential applicability to more severe TBI cases. Guanfacine, an alpha-2A agonist approved for ADHD, enhances prefrontal cortical function; Donepezil, a cholinesterase inhibitor, is widely used to treat cognitive symptoms in mild cognitive impairment and early dementia; and NAC, a potent antioxidant and glutamate modulator, has demonstrated neuroprotective effects across a range of clinical contexts, including TBI. Each of these agents has a well-established safety profile. The encouraging outcomes observed in this case series underscore the potential of the GND regimen as a multimodal pharmacologic approach to target the complex neurochemical disruptions following TBI. These preliminary findings warrant further investigation in larger, placebo-controlled trials in order to more rigorously assess the safety, efficacy, and translational potential of this intervention for mitigating chronic cognitive sequelae in individuals with moderate to severe TBI.},
}
@article {pmid41210458,
year = {2025},
author = {Abdullah, WHAABW and Mohamad, MIBK and Baharuddin, MNAB},
title = {Beyond the dose: unmasking 'therapeutic' paracetamol toxicity in a chronic alcohol user with severe acidosis-a case report.},
journal = {AME case reports},
volume = {9},
number = {},
pages = {114},
pmid = {41210458},
issn = {2523-1995},
abstract = {BACKGROUND: Paracetamol (PCM), widely used for its analgesic and antipyretic properties, is generally considered safe at recommended doses. However, its metabolism can be significantly altered in chronic alcohol users due to enzyme induction and glutathione (GSH) depletion. While some clinicians maintain that "therapeutic" doses remain harmless in alcoholics, others argue there is no safe threshold. This case report bridges these opposing views by highlighting an atypical presentation of PCM-induced toxicity in a chronic alcoholic. It adds to existing literature by illustrating how severe lactic acidosis may overshadow more typical hepatic symptoms, thereby delaying diagnosis and treatment.<br><br>CASE DESCRIPTION: A 53-year-old male with a 20-year history of alcohol use presented to the emergency department (ED) with sudden-onset dyspnea and profound metabolic acidosis. Initially misdiagnosed as mesenteric ischemia, subsequent investigations revealed strikingly elevated aminotransferases, coagulopathy, and a PCM level above the normal therapeutic range-despite the patient's claim of following standard dosing. Intravenous N-acetylcysteine (NAC) was started, but the patient deteriorated rapidly and succumbed on day 2. Autopsy or long-term follow-up data were unavailable due to the acute course and lack of liver transplantation options. Although previous guidelines have debated whether PCM dosing must be reduced in chronic alcoholics, this case underscores the potential dangers, even within seemingly acceptable intake levels.<br><br>CONCLUSIONS: Clinicians must maintain a high index of suspicion for PCM toxicity in chronic alcoholics, recognising that atypical presentations-such as isolated lactic acidosis and respiratory distress-can conceal the true aetiology. This case reinforces the need for routine PCM-level checks in unexplained acute liver failure, prompt NAC administration, and a balanced perspective regarding "therapeutic" dosing in alcoholics. The findings underscore the call for more nuanced guidelines and further research to determine appropriate dose thresholds and monitoring strategies for alcohol-dependent individuals. By harmonising these divergent clinical stances, patient safety can be enhanced through tailored, vigilant practice.},
}
@article {pmid41208834,
year = {2025},
author = {Yaqubi, S and Seyedalipour, B and Karimian, M},
title = {Modulation of lncRNAs and oxidative stress related genes by N-acetylcysteine and S-methylcysteine in rotenone-induced Parkinson's disease.},
journal = {Biochemistry and biophysics reports},
volume = {44},
number = {},
pages = {102328},
pmid = {41208834},
issn = {2405-5808},
abstract = {Oxidative stress and changes in lncRNA expression are key factors in the pathophysiology of Parkinson's disease. This study investigated the protective effects of N-acetylcysteine and S-methylcysteine on the expression of long non-coding RNAs and oxidative stress-related genes in the brain, as well as the activity of antioxidant enzymes in the brain and serum of mice with rotenone-induced Parkinson's disease. In this experimental study, 56 male BALB/c mice were utilized and treated continuously for 10 days. Gene expression of superoxide dismutase, glutathione peroxidase, catalase, Nrf2, Ho-1, and long non-coding RNAs Malat1, Neat1, and Gas5 in the brain was analyzed using real-time PCR. Biochemical assays measured antioxidant enzyme activities, malondialdehyde levels, and total antioxidant capacity in brain tissue and serum. A bioinformatics approach, including molecular docking and the construction of a gene interaction network, was also performed. Our data showed decreased expression of antioxidant genes and Nrf2 and Ho-1 regulatory factors in the Parkinson's group, which were significantly restored by N-acetylcysteine and S-methylcysteine treatments. Long non-coding RNAs were elevated in the Parkinson's disease model and reduced by interventions. Antioxidant enzyme activity and oxidative stress markers were significantly improved by N-acetylcysteine, S-methylcysteine, and their combination. Molecular docking suggested stable interactions of these compounds with antioxidant enzymes. The interaction network highlights Nrf2 as a central regulator of antioxidant genes, modulated by specific lncRNAs. Findings support the neuroprotective role of N-acetylcysteine, S-methylcysteine through activation of the Nrf2/Ho-1 pathway, modulation of long non-coding RNAs, and oxidative stress improvement in Parkinson's disease.},
}
@article {pmid41208439,
year = {2026},
author = {Wang, H and Zhang, Y and Zhao, L and Wang, C and He, C and Duan, C},
title = {NADH Mimic-Decorated Coordination Capsules for Biomimetic Capture of NO and Electrocatalytic Reduction to NH3.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {65},
number = {6},
pages = {e19123},
doi = {10.1002/anie.202519123},
pmid = {41208439},
issn = {1521-3773},
support = {22171034//National Natural Science Foundation of China/ ; 2024YFA1510301//National Key Research and Development Program of China/ ; DUT22LAB606//Fundamental Research Funds for the Central Universities/ ; },
mesh = {*NAD/chemistry ; Catalysis ; Oxidation-Reduction ; *Ammonia/chemistry ; *Biomimetic Materials/chemistry ; *Nitric Oxide/chemistry ; Electrochemical Techniques ; Biomimetics ; *Coordination Complexes/chemistry ; },
abstract = {Sustainable conversion of NO offers a promising technology for artificial nitrogen cycle, but faces challenges in integrating electrocatalysis with NO capture. Herein, a biomimetic NO capture-activation-conversion strategy was firstly formulated by encapsulating N-acetylcysteine (NAC) within a nicotinamide adenine dinucleotide (NADH) mimic-containing coordination capsule, enabling efficiently NH3 electrosynthesis. The installed NADH mimics onto the capsule interacted with the highly reactive NO-adduct generated from NAC within the microenvironment akin to the pocket of enzyme, facilitating intramolecular hydride transfer of the substrate-involving clathrate, accompanied by the formation of oxidated NAD[+] mimics. Subsequently, the cobalt-based coordination capsule consecutively reserved e[-] from cathode while donating 2e[-] to the NAD[+] mimic simultaneously for active cofactor recovered and recycle. This coordination capsule-mediated biomimetic system exhibited enzymatic kinetics following the Michaelis-Menten mechanism in the electrochemical NO reduction and realized almost 100% Faraday efficiency at potentials below -0.2 VRHE with a substantial NH3 yield rate of 121.6 µmol·h[-1]·cm[-2] at -0.3 VRHE, ranking among the optimal electrocatalytic NO performance ever achieved, offering an attractive avenue toward renewable electricity-driven nitrogen fixation exploiting bioinspired artificial catalyst.},
}
@article {pmid41207540,
year = {2026},
author = {Kamimura, N and Iuchi, K and Igarashi, T and Ohsawa, I and Nito, C and Usuda, J and Ohta, S},
title = {Molecular hydrogen mitigates acetaminophen-induced liver injury and enhances the effects of N-acetylcysteine in diabetic mice.},
journal = {The Journal of nutritional biochemistry},
volume = {149},
number = {},
pages = {110176},
doi = {10.1016/j.jnutbio.2025.110176},
pmid = {41207540},
issn = {1873-4847},
mesh = {Animals ; *Acetaminophen/toxicity/adverse effects ; *Acetylcysteine/pharmacology/therapeutic use ; *Hydrogen/pharmacology/therapeutic use ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/drug therapy/metabolism/pathology ; Mice ; Oxidative Stress/drug effects ; Fibroblast Growth Factors/metabolism/genetics ; Male ; *Diabetes Mellitus, Experimental/complications ; Liver/drug effects/metabolism/pathology ; Mice, Transgenic ; JNK Mitogen-Activated Protein Kinases/metabolism ; bcl-2-Associated X Protein/metabolism ; Alanine Transaminase/blood ; Aspartate Aminotransferases/blood ; Mice, Inbred C57BL ; },
abstract = {Acetaminophen (APAP) overdose induces severe liver injury, especially in diabetic patients. N-acetylcysteine (NAC) is commonly used as an approved antidote for APAP toxicity; however, its narrow therapeutic window limits its clinical utility. This study investigated the protective effects of molecular hydrogen (H2) against APAP-induced hepatotoxicity in diabetic mice. Diabetic db/db mice were provided with hydrogen-dissolved water (H2-water) for two weeks prior to APAP administration. Consumption of H2-water significantly attenuated APAP-induced liver injury, as evidenced by improved histological findings and decreased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Using transgenic mice expressing redox-sensitive green fluorescent protein, H2 was shown to reduce both cytosolic and mitochondrial oxidative stress caused by APAP overdose. We observed that H2 modulated c-Jun N-terminal kinase (JNK) activation, inhibited mitochondrial translocation of Bax, and suppressed the release of mitochondrial endonucleases. Additionally, H2 enhanced the expression of the hepatoprotective hormone fibroblast growth factor 21 (FGF21). These findings suggest that H2 protects against APAP-induced liver injury in diabetic mice by attenuating oxidative stress and upregulating FGF21 expression. Although NAC acts as an antioxidant, H2 was more effective in reducing mitochondrial oxidative stress. Importantly, co-treatment with H2 and NAC provided greater protection against APAP-induced hepatotoxicity than NAC alone. This synergistic effect may result from differences in the mechanisms by which NAC and H2 influence FGF21 expression and mitochondrial oxidative stress. The combination of H2 and NAC may offer an improved therapeutic strategy for treating APAP-induced liver injury in diabetic patients.},
}
@article {pmid41206153,
year = {2025},
author = {Nasr, A},
title = {Retraction notice to .ÇÿEffect of N-acetyl-cysteine after ovarian drilling in clomiphene citrate-resistant PCOS women: a pilot study.ÇÖ.},
journal = {Reproductive biomedicine online},
volume = {51},
number = {5},
pages = {105286},
doi = {10.1016/j.rbmo.2025.105286},
pmid = {41206153},
issn = {1472-6491},
}
@article {pmid41205773,
year = {2026},
author = {Wang, Y and Zhang, X and Yang, W and Liu, X and Xie, S and Zhang, L and Xiao, X and Xie, F and Zhu, J and Lin, H and Liu, X and Xiong, L},
title = {Caveolin-1 drives ferroptosis in MDSCs via PKA-DRP1-mediated ER‒mitochondria crosstalk to shape breast cancer immunosuppression.},
journal = {Free radical biology &amp; medicine},
volume = {242},
number = {},
pages = {601-613},
doi = {10.1016/j.freeradbiomed.2025.11.001},
pmid = {41205773},
issn = {1873-4596},
mesh = {Animals ; *Ferroptosis/genetics ; Female ; Mice ; *Myeloid-Derived Suppressor Cells/immunology/metabolism/pathology ; *Mitochondria/metabolism/immunology ; *Caveolin 1/genetics/metabolism/immunology ; *Breast Neoplasms/immunology/pathology/genetics/metabolism ; *Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; Tumor Microenvironment/immunology ; Endoplasmic Reticulum Stress ; Reactive Oxygen Species/metabolism ; Humans ; Endoplasmic Reticulum Chaperone BiP ; Cell Line, Tumor ; Signal Transduction ; Endoplasmic Reticulum/metabolism ; Mice, Inbred BALB C ; },
abstract = {BACKGROUND: Caveolin-1 (Cav-1) has been implicated in breast cancer progression and tumor-microenvironment remodeling. We investigated whether and how tumor-derived Cav-1 regulates myeloid-derived suppressor cell (MDSC) fate and function to shape the immunosuppressive tumor immune microenvironment (TIME).<br><br>METHODS: Using murine 4T1 breast cancer models and complementary cell culture systems, Cav-1 was manipulated by overexpression and CRISPR/Cas9 knockout. MDSCs were isolated from tumors or bone marrow and analyzed by flow cytometry, Western blotting, immunofluorescence, transmission electron microscopy and ELISA. Ferroptosis is modulated pharmacologically (RSL3, ferrostatin-1), and reactive oxygen species (ROS) are inhibited by N-acetylcysteine. ER stress (ERS), endoplasmic reticulum-mitochondrial contacts and PKA-DRP1 signaling were investigated via biochemical assays, immunoprecipitation and transcriptome/bioinformatic analyses. Statistical comparisons were performed via Student's t-test and ANOVA.<br><br>RESULTS: High Cav-1 expression is correlated with immune checkpoint markers; enhanced recruitment of MDSCs with an immunosuppressive phenotype; and increased secretion of IL-6, IL-10 and CXCL1. Cav-1 promoted ER stress (increased p-PERK, IRE1&#x3b1;, and GRP78), strengthened ER-mitochondrial contacts and upregulated MAM proteins (GRP75, IP3R, and VDAC1) via PKA-dependent DRP1 phosphorylation. These changes increased intracellular ROS, iron accumulation and lipid peroxidation; downregulated SLC7A11 and GPX4; and increased HMOX1 and oxidized phosphatidylcholine (OxPC) release, which is consistent with ferroptosis in MDSCs. Ferroptosis or ROS inhibition (ferrostatin-1, NAC) attenuated OxPC release, restored T-cell proliferation and function in coculture and limited tumor growth in vivo.<br><br>CONCLUSIONS: Tumor-derived Cav-1 promotes ROS-dependent ferroptosis in MDSCs via PKA-DRP1-mediated ER-mitochondrial crosstalk, causing the release of oxidized phosphatidylcholines that suppress T-cell function and promote an immunosuppressive TME. Targeting this axis may improve the response of breast cancer patients to immunotherapy.},
}
@article {pmid41202965,
year = {2025},
author = {Kuttikrishnan, S and Mariyam, Z and Ahmad, F and Suleman, M and Habeeba, U and Panicker, AJ and Prabhu, KS and Merhi, M and Dermime, S and Al Shabeeb Akil, AS and Bhat, AA and Ansari, AW and Uddin, S},
title = {Selective induction of apoptosis in T-cell acute lymphoblastic leukemia by pristimerin through dual PI3K/AKT pathway inhibition and ROS generation.},
journal = {European journal of pharmacology},
volume = {1008},
number = {},
pages = {178329},
doi = {10.1016/j.ejphar.2025.178329},
pmid = {41202965},
issn = {1879-0712},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism/antagonists &amp; inhibitors ; *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology/metabolism/drug therapy ; *Triterpenes/pharmacology/metabolism ; Pentacyclic Triterpenes ; *Signal Transduction/drug effects ; *Phosphatidylinositol 3-Kinases/metabolism ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Molecular Docking Simulation ; *Phosphoinositide-3 Kinase Inhibitors ; Jurkat Cells ; *Antineoplastic Agents/pharmacology ; Glutathione/metabolism ; },
abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by the aberrant activation of survival pathways, particularly the PI3K/AKT axis. Pristimerin (Prist), a naturally occurring quinonemethide triterpenoid, has recently gained attention for its anti-cancer potential. In this study, we demonstrate that Prist effectively inhibits the proliferation of T-ALL cell lines (Jurkat and Molt 4) by inducing G0/G1 cell cycle arrest and triggering intrinsic and extrinsic caspase-dependent apoptosis. Prist significantly increases reactive oxygen species (ROS) levels and depletes glutathione (GSH), leading to mitochondrial dysfunction and cytochrome c release. Notably, ROS scavenging with N-acetylcysteine (NAC) abrogated Prist-induced apoptosis, highlighting ROS as a critical mediator of its cytotoxicity. Network pharmacology and molecular docking revealed AKT as a key target of Prist, with strong binding affinity confirmed through docking analysis. Prist downregulated phosphorylated AKT and inhibitor of apoptosis proteins (XIAP, cIAP1/2), supporting its pro-apoptotic mechanism. Importantly, Prist inhibited the proliferation and AKT phosphorylation in activated primary human T cells but spared resting T cells, indicating selective cytotoxicity. These findings establish Prist as a promising therapeutic candidate for T-ALL through the selective targeting of PI3K/AKT-driven survival signaling.},
}
@article {pmid41200300,
year = {2025},
author = {Tareq, HM and Mashi, SK},
title = {Investigation of augmentin-induced hepatobiliary damage and its modulation by N-acetylcysteine in male rats.},
journal = {Open veterinary journal},
volume = {15},
number = {9},
pages = {4276-4285},
pmid = {41200300},
issn = {2218-6050},
mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use/administration &amp; dosage ; Male ; Rats ; *Chemical and Drug Induced Liver Injury/drug therapy ; Oxidative Stress/drug effects ; *Anti-Bacterial Agents/adverse effects ; *Antioxidants/pharmacology ; Liver/drug effects/pathology ; Tumor Necrosis Factor-alpha/blood ; Rats, Sprague-Dawley ; Malondialdehyde/blood ; },
abstract = {BACKGROUND: Augmentin is a common antibiotic used to treat infections. However, it may cause liver damage. Toxicity often involves oxidative stress and inflammation. N-acetylcysteine (NAC) is known for its antioxidant and anti-inflammatory effects and may help protect the liver.<br><br>AIM: This study aimed to assess whether NAC could reduce Augmentin-induced liver and bile duct injury.<br><br>METHODS: Forty adult male rats were divided into four groups (T1, T2, T3, and T4). Group 1 was the control group. Group 2 received Augmentin (30 mg/kg/day). Group 3 received 150 mg/kg/day NAC. Group 4 received both NAC and Augmentin. Treatments lasted for 35 days. Serum levels of tumor necrosis factor-alpha (TNF-&#x3b1;), malondialdehyde (MDA), glutathione (GSH), and CYP7A1 were measured. Histopathology was also performed.<br><br>RESULTS: Augmentin alone caused a significant (p < 0.05) increase in TNF-&#x3b1; (13.82 &#xb1; 0.31), MDA (407.25 &#xb1; 10.65), and CYP7A1 (7.69 &#xb1; 0.48). GSH dropped to (9.10 &#xb1; 0.43). Liver tissues showed inflammation, sinusoidal venostasis, and bile duct damage. NAC-treated rats had significantly (p < 0.05) lower TNF-&#x3b1; (4.88-4.97), MDA (253.05-258.15), and CYP7A1 (4.30-4.38). GSH levels significantly (p < 0.05) increased to (15.58-17.02). Histology improved with NAC. Livers exhibited fewer cell injuries and a more normal architecture.<br><br>CONCLUSION: NAC reduced the oxidative stress and inflammation caused by Augmentin. It also protected the liver structure. These findings suggest that NAC is a useful supplement for preventing drug-induced liver injury.},
}
@article {pmid41197729,
year = {2025},
author = {Wang, Y and Hekimi, S},
title = {Elevated cellular accumulation of endogenous and exogenous CoQ by altered intracellular trafficking.},
journal = {The Journal of biological chemistry},
volume = {301},
number = {12},
pages = {110878},
pmid = {41197729},
issn = {1083-351X},
mesh = {Animals ; Mice ; *Ubiquinone/metabolism/analogs &amp; derivatives ; RAW 264.7 Cells ; Iron/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Mitochondria/metabolism ; Macrophages/metabolism/cytology ; Biological Transport ; Oxidation-Reduction ; Paraquat/pharmacology ; },
abstract = {Coenzyme Q (CoQ) is produced in the inner membrane of mitochondria, from where it is transported to other cellular membranes. Cellular CoQ levels drop when its synthesis is interrupted, indicating that it can be degraded or eliminated in some way by currently still uncharacterized mechanisms. Low cellular iron availability has been found to lower CoQ levels, at least in part by inhibiting the action of the CoQ biosynthetic enzyme COQ7. These findings prompted us to test the effect of elevated intracellular iron content on CoQ levels. In the mouse macrophage cell line RAW264.7, we found that supplementation with ferrous ions (Fe[2+]) boosts CoQ levels rapidly and reversibly. Iron loading also increases the cellular accumulation of exogenous CoQ10 provided in the media. N-acetyl cysteine significantly attenuates the elevation of CoQ levels by iron, suggesting that the effect of iron is mediated by a redox mechanism, although overall cellular reactive oxygen species (ROS) levels were not affected. Treating RAW264.7 cells with the ROS-generator paraquat also dramatically increases CoQ, further pointing to a redox mechanism. No effect on the abundance of several COQ proteins was observed after iron or paraquat treatment, indicating that their effect on CoQ levels is unlikely to arise from altered mitochondrial CoQ synthesis. In contrast, we observed that targeting lysosome function also affects CoQ levels, suggesting that the effects we observe relate to degradation and/or recycling. Our study suggests that targeting these mechanisms could allow for new therapeutic options to boost cellular CoQ levels in patients.},
}
@article {pmid41195615,
year = {2025},
author = {Hou, WS and Luo, YH and Wu, N and Tang, YJ and Liu, YZ and Zhang, YL and Jin, CH},
title = {Madecassoside Induces Apoptosis and Inhibits Migration by Regulating ROS-Mediated Signaling Pathways in MDA-MB-231 Breast Cancer Cells.},
journal = {Chemical biology &amp; drug design},
volume = {106},
number = {5},
pages = {e70197},
doi = {10.1111/cbdd.70197},
pmid = {41195615},
issn = {1747-0285},
support = {GZ20220039//the Heilongjiang Province Key Research and Development Plan Guidance Project/ ; 82060118//Foundation for Innovative Research Groups of the National Natural Science Foundation of China/ ; 2020GSP16//the Central Government Supports Local College Reform and Development Fund Talent Training Project/ ; },
mesh = {Female ; Humans ; *Apoptosis/drug effects ; *Breast Neoplasms/metabolism/pathology/drug therapy ; Cell Line, Tumor ; *Cell Movement/drug effects ; G2 Phase Cell Cycle Checkpoints/drug effects ; NF-kappa B/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; *Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; STAT3 Transcription Factor/metabolism ; *Triterpenes/pharmacology/chemistry ; },
abstract = {Madecassoside (MC) is an anti-inflammatory and antibacterial active substance extracted from the traditional Chinese medicine Centella asiatica. Based on network pharmacology and experimental validation, this study assessed MC's anti-breast cancer (BC) actions and related molecular pathways. CCK-8, Trypan Blue, and Hoechst33342/PI assays showed that MC significantly reduced BC cell activity, but it had little inhibitory effects on normal cells. Network pharmacology analysis predicted 40 intersection targets between MC and BC, 291 GO-related biological processes, and 105 KEGG signaling pathways. The anti-breast cancer activity of MC is closely related to reactive oxygen species (ROS), AKT and MAPK signaling pathways. Through Annexin V-FITC/PI, flow cytometry, transwell, wound healing and western blotting experiments, it was found that MC induced mitochondria-dependent apoptosis, G2/M phase arrest and inhibited cell migration of MDA-MB-231 cells through MAPK/STAT3/NF-κB signaling pathway, PI3K/AKT signaling pathway and AKT/GSK-3β/β-catenin signaling pathway, respectively. The induction and blocking effects were inhibited by the addition of ROS scavenger N-acetyl cysteine (NAC). Molecular docking showed that MC had significant binding ability with STAT3, CASP3, BCL2 and JUN targets in BC. In summary, MC induced apoptosis, cell cycle arrest, and migration inhibition via ROS-mediated MAPK/STAT3/NF-κB, PI3K/AKT, and AKT/GSK-3β/β-catenin signaling pathways in MDA-MB-231 cells.},
}
@article {pmid41195221,
year = {2025},
author = {Mansouri, S and Farshid, AA and Tamaddonfard, E},
title = {Effects of histidine and N-acetylcysteine on acute kidney injury induced by doxorubicin in rats: roles of anti-oxidative, anti-inflammatory and anti-apoptotic mechanisms.},
journal = {Veterinary research forum : an international quarterly journal},
volume = {16},
number = {9},
pages = {507-514},
pmid = {41195221},
issn = {2008-8140},
abstract = {Doxorubicin (DOX), as a potent anti-cancer agent, exerts side effects in vital organs. Various chemical compounds with tissue protective properties are used to prevent the side effects of DOX. This study was planned to investigate the effects of histidine (HIS) and N-acetylcysteine (NAC) on DOX-induced acute kidney injury. The possible mechanisms were followed by determining the histopathological changes of the kidney along with the biochemical alterations of the blood and kidney tissue. Forty-eight rats were divided into eight groups of six animals each to receive normal saline and DOX after alone and combined treatments with HIS and NAC. The DOX at a single dose of 15.00 mg kg[-1] was intraperitoneally injected on day one. The separate and combined intraperitoneally injections of HIS and NAC at a similar dose of 100 mg kg[-1] were began 30 min after DOX administration and continued for seven consecutive days. The DOX increased kidney weight and caused congestion, hemorrhages and degeneration in kidney tissue. It also increased serum urea and creatinine concentrations and kidney tissue levels of malondialdehyde, tumor necrosis factor-alpha and caspase-3, and decreased superoxide dismutase activity in this tissue. Separate and combined treatments with HIS and NAC improved all the above-mentioned effects of DOX. The restoring effects of the combined treatment were more prominent than the effect of amino acids alone. It was concluded that anti-oxidative, anti-inflammatory and anti-apoptotic mechanisms might be related to the tissue protective effects of HIS and NAC against DOX-induced acute renal injury.},
}
@article {pmid41193727,
year = {2025},
author = {Shah, F and Jain, N and Muthu, V and Muthu, S and Wahid, JBA and Shah, M and Nagaraj, K},
title = {Efficacy of Bacopa monnieri in Mitigating Lead-Induced Blood Toxicity in Swiss Albino Mice Compared to Synthetic Antioxidants.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {41193727},
issn = {1559-0720},
support = {RGP 2/252/45//Deanship of Scientific Research, King Khalid University/ ; },
abstract = {The major objective of the current study is to investigate the protective and therapeutic potential of Bacopa monnieri extract and synthetic antioxidants (N-acetyl cysteine, ascorbic acid, tocopheryl acetate, and thiamine mixture) against lead-induced hematological toxicity in Swiss albino mice. HPLC analysis of the ethanolic extract of Bacopa monnieri (B. monnieri) revealed a rich profile of bioactive compounds, including flavonoids like apigenin and luteolin, bacosides, and bacopasaponins. In vivo experiments demonstrated dose-dependent statistically significant (p < 0.001) hematological alterations in lead-exposed groups, showing reductions in hemoglobin (Hb), red blood cell (RBC) count, platelet count, hematocrit, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), alongside an increase in white blood cell (WBC) count as compared to the control, indicating severe hematotoxic effects of lead. In synergistic study groups, co-administration of lead acetate with synthetic antioxidants or B. monnieri extract conferred protection against lead-induced toxicity by mitigating alterations in hematological parameters of Hb, RBC, WBC, and platelet count, with a more pronounced effect of B. monnieri than synthetic antioxidants. Curative study groups further demonstrated restoration of hematological parameters near the control group baseline, highlighting the superior efficacy of B. monnieri in reversing lead-induced toxicity. In conclusion, the findings of the study imply that the herbal antioxidant B. monnieri has better potential to be an effective ameliorative therapeutic agent against lead-induced hematological toxicity as compared to synthetic antioxidants, which may be attributed to the presence of plentiful phytochemicals in its extract that can be employed effectively for the development of plant-based therapies for the eradication of lead poisoning in endemic regions.},
}
@article {pmid41188701,
year = {2025},
author = {Hormati, A and Mousavi, A and Shojaei, S and Moghtadaei, A and Bordbar, S and Alemi, H and Kasaeian, A and Sepanlou, S},
title = {Efficacy of N-Acetylcysteine in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: a systematic review and meta-analysis.},
journal = {BMC gastroenterology},
volume = {25},
number = {1},
pages = {783},
pmid = {41188701},
issn = {1471-230X},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Pancreatitis/prevention &amp; control/etiology/epidemiology ; *Cholangiopancreatography, Endoscopic Retrograde/adverse effects ; Randomized Controlled Trials as Topic ; Incidence ; },
abstract = {BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a widely utilized procedure for diagnosing and treating biliary and pancreatic disorders. However, it carries a risk of post-ERCP pancreatitis (PEP). N-Acetylcysteine (NAC) has been proposed as a potential prophylactic agent due to its antioxidant properties, yet its efficacy remains debated. This systematic review and meta-analysis aimed to evaluate the effectiveness of NAC in preventing PEP in patients undergoing ERCP.<br><br>METHOD: We conducted a comprehensive literature search across multiple databases, including PubMed, Scopus, Web of Science, and EMBASE, for randomized controlled trials (RCTs) on humans published from January 2000 to end of August 2024. The primary outcome was the incidence of PEP in the group who received the NAC compared to the group receiving routine medication. Study selection and data extraction was performed according to PRISMA guidelines. Quality assessment was accomplished using risk of bias (RoB2) tool for RCTs.<br><br>RESULTS: A total of four RCTs involving 773 patients were included in the final analysis. The meta-analysis demonstrated a non-significant lower incidence of post-ERCP pancreatitis in the NAC group compared to controls (Risk Ratio: 0.66; 95% Confidence Interval: 0.38-1.16). Sensitivity analyses indicated low robustness of these results, with moderate heterogeneity observed among studies (I[2]&#x2009;=&#x2009;55.89%). Egger test did not provide evidence of publication bias. The trim-and-fill correction suggested one potentially missing study on the left side of the funnel plot. Imputation for this potentially missing study yielded an effect size of RR: 0.57; 95% CI: 0.32-0.99), which was statistically significant this time. The results were additionally statistically non-significant stratified by severity of the PEP.<br><br>CONCLUSION: While NAC shows promise in reducing the incidence of PEP, the current evidence does not support its routine use as a prophylactic agent. Further research is warranted to clarify its role and optimize preventive strategies for PEP.},
}
@article {pmid41184618,
year = {2026},
author = {Zhang, YM and Lu, H and Xiao, BJ and Xu, CC and Zhou, FF and Li, T and Zhan, ZJ and Lu, JJ},
title = {Sino-C, a novel sinomenine derivative, induces cell death by disrupting cholesterol homeostasis in colorectal cancer cells.},
journal = {Acta pharmacologica Sinica},
volume = {47},
number = {3},
pages = {750-761},
pmid = {41184618},
issn = {1745-7254},
mesh = {*Cholesterol/metabolism ; Humans ; *Colorectal Neoplasms/drug therapy/metabolism/pathology ; *Morphinans/pharmacology/therapeutic use/chemistry ; Homeostasis/drug effects ; Animals ; Endoplasmic Reticulum Stress/drug effects ; Cell Death/drug effects ; *Antineoplastic Agents/pharmacology/therapeutic use/chemistry ; Cell Line, Tumor ; Mice, Nude ; Mice, Inbred BALB C ; Mice ; },
abstract = {Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, necessitating the discovery of novel therapeutic agents. Sinomenine (Sin), a natural product derived from traditional Chinese medicine, has been extensively modified to enhance its therapeutic potential. Here, we synthesized Sino-C, a novel Sin derivative, and evaluated its anti-CRC activity. Sino-C exhibited significant anticancer effects both in vitro and in vivo. Mechanistically, Sino-C upregulated cholesterol homeostasis-related genes and increased intracellular cholesterol levels in CRC cells. Cholesterol depletion with methyl-β-cyclodextrin (MβCD) alleviated Sino-C-induced cholesterol accumulation, reduced cell death, and reversed cleaved PARP expression, indicating cholesterol imbalance as a critical mediator of Sino-C's activity. Furthermore, Sino-C-induced cholesterol imbalance promoted lipid peroxidation and endoplasmic reticulum (ER) stress, contributing to cell death. The antioxidant vitamin E (Ve), N-acetylcysteine (NAC), or PERK inhibitor GSK2656157 could reverse these effects of Sino-C. Clinical correlation analysis further revealed that high expression of Sino-C-upregulated cholesterol homeostasis genes was linked to better survival outcomes in CRC cohorts. In conclusion, this study highlights the therapeutic potential of Sino-C in CRC. In vitro mechanistic findings suggest that Sino-C exerts its anticancer effects through modulation of cholesterol metabolism, positioning natural product derivatives as valuable candidates for further development.},
}
@article {pmid41184380,
year = {2025},
author = {Kim, JE and Wang, SH and Kang, TC},
title = {PARP1-TRPM2-PKC cascade distinctly regulates reactive astrogliosis and clasmatodendrosis through NF-κB and AKT pathways in the hippocampus of chronic epilepsy rats.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38371},
pmid = {41184380},
issn = {2045-2322},
support = {HRFN-202410-002//Hallym University/ ; },
mesh = {Animals ; *TRPM Cation Channels/metabolism/genetics ; Rats ; *Hippocampus/metabolism/pathology ; *Proto-Oncogene Proteins c-akt/metabolism ; *NF-kappa B/metabolism ; *Poly (ADP-Ribose) Polymerase-1/metabolism ; Signal Transduction ; *Epilepsy/metabolism/pathology ; Astrocytes/metabolism/pathology ; *Gliosis/metabolism/pathology ; Male ; Rats, Sprague-Dawley ; Chronic Disease ; Disease Models, Animal ; },
abstract = {The epileptic hippocampi of rodent models show reactive astrogliosis and autophagic astroglial death (clasmatodendrosis) in the CA1 region, which contributes to spontaneous seizures. Oxidative stress upregulates transient receptor potential melastatin 2 (TRPM2, a non-selective Ca[2+] permeable cation channel) in astrocytes. However, the roles of TRPM2 in reactive astrogliosis and clasmatodendrosis in the epileptic hippocampus are largely unknown. In the present study, we found that TRPM2 was upregulated in astrocytes within the CA1 region of chronic epilepsy rats. N-acetylcysteine (NAC, an antioxidant) and PJ34, a poly-(ADP-ribose) polymerase-1 (PARP1) inhibitor, downregulated TRPM2 expression in reactive astrocytes and attenuated clasmatodendritic degeneration in this region, accompanied by reduced nuclear factor-κB (NF-κB) p65 serine (S) 311 phosphorylation. Both NAC and PJ34 increased pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1, a phosphatase for AKT) expression concomitant with reduced AKT S473 phosphorylation and microtubule-associated protein 1 A/1B-light chain 3 (LC3)-II/LC-I ratio. However, TRPM2 knockdown deteriorated clasmatodendritic degeneration and elevated AKT S473 phosphorylation and LC3-II/LC-I ratio without altering PHLPP1 expression. Bisindolylmaleimide (BIM, a protein kinase C inhibitor) exacerbated clasmatodendrosis accompanied by reduced p65 S311 phosphorylation and elevated AKT S473 phosphorylation in reactive astrocytes without affecting TRPM2 expression. Therefore, our findings suggest that PARP1-TRPM2-PKC-NF-κB signaling pathway may inhibit clasmatodendrosis, but facilitate reactive astrogliosis. In addition, NAC and PJ34 may attenuate clasmatodendrosis by activating PHLPP1-AKT-mediated pathway.},
}
@article {pmid41181138,
year = {2025},
author = {Kang, LP and Xie, H and Huang, HJ and Xu, P and Xu, C and Huang, DH and Jiang, ZB},
title = {Pterostilbene inhibits non-small cell lung cancer progression by activating the STING pathway and enhancing antitumor immune response.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1622284},
pmid = {41181138},
issn = {1664-3224},
mesh = {Animals ; *Carcinoma, Non-Small-Cell Lung/drug therapy/immunology/pathology/metabolism ; Humans ; *Lung Neoplasms/drug therapy/immunology/pathology/metabolism ; Mice ; Signal Transduction/drug effects ; *Membrane Proteins/metabolism ; *Stilbenes/pharmacology ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Tumor Microenvironment/drug effects/immunology ; Xenograft Model Antitumor Assays ; Cell Survival/drug effects ; *Antineoplastic Agents/pharmacology ; Disease Progression ; A549 Cells ; STING Protein ; },
abstract = {INTRODUCTION: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, and current therapies often yield limited efficacy. This study investigated the antitumor potential and mechanisms of Pterostilbene (PTE), a natural stilbenoid with superior bioavailability.<br><br>METHODS: The antitumor effects of PTE were assessed in A549 and H358 NSCLC cell lines to determine its impact on cell viability, cell cycle, apoptosis, and reactive oxygen species (ROS) generation, using N-acetylcysteine (NAC) to confirm the role of ROS. Key molecular mechanisms were probed via Western blot, siRNA knockdown, and pharmacological inhibition (H-151). The in vivo efficacy of PTE and its effect on the tumor immune microenvironment were evaluated in H358 xenograft and immunocompetent LLC1 murine models.<br><br>RESULTS: PTE suppressed cell viability in a concentration- and time-dependent manner, inducing G2/M phase arrest and mitochondrial apoptosis driven by ROS. It triggered DNA damage and activated the STING pathway, leading to TBK1/IRF3 phosphorylation and the secretion of T-cell chemoattractants (CXCL10, CXCL9, CCL5). STING inhibition markedly attenuated PTE's effects. In vivo, PTE suppressed tumor growth and remodeled the tumor microenvironment by increasing granzyme B[+], TNF-&#x3b1;[+], and IFN-&#x3b3;[+] CD8[+] T cells while reducing myeloid-derived suppressor cells and regulatory T cells.<br><br>DISCUSSION: Our findings elucidate a dual mechanism whereby PTE directly kills NSCLC cells via ROS-mediated apoptosis and simultaneously reinvigorates antitumor immunity through STING pathway activation. This positions PTE as a promising candidate for combination immunotherapy in NSCLC.},
}
@article {pmid41178763,
year = {2025},
author = {Koprowska, K and Fischer-Durand, N and Michlewska, S and Gapińska, M and Grodzicka, M and Makal, A and Krzeszczakowska, J and Wrona-Piotrowicz, A and Lignières, L and Salmain, M and Rudolf, B},
title = {Metallocarbonyl bromomaleimide derivatives for thiol bioconjugation and disulfide bridging: spectroscopic and biological properties.},
journal = {Dalton transactions (Cambridge, England : 2003)},
volume = {54},
number = {45},
pages = {16864-16875},
doi = {10.1039/d5dt02375k},
pmid = {41178763},
issn = {1477-9234},
mesh = {*Sulfhydryl Compounds/chemistry ; *Disulfides/chemistry ; Humans ; *Maleimides/chemistry/pharmacology ; *Antineoplastic Agents/chemistry/pharmacology/chemical synthesis ; Animals ; Cattle ; *Organometallic Compounds/chemistry/pharmacology ; Molecular Structure ; },
abstract = {Mono- and dibromomaleimides have been introduced as useful reagents for the modification of cysteine residues, disulfide rebridging and peptide stapling. Herein, we investigate the reaction of the organometallic compounds CpFe(CO)2(η[1]-2-bromomaleimidato) and CpFe(CO)2(η[1]-2,3-dibromomaleimidato) and their organic analogs 2-bromomaleimide and 2,3-dibromomaleimide with the bioactive thiols N-acetyl cysteine methyl ester and 1-thio-β-D-glucose tetraacetate, along with the disulfide-containing protein bovine insulin. Substitution and/or addition products were isolated and characterized by NMR, IR and MS and the molecular structure of two reaction products was confirmed by X-ray diffraction. In the case of the organic derivatives, formation of the dithiomaleimide adducts was also assessed by the emission of fluorescence in the green region. Visible light irradiation of the metallocarbonyl dithiomaleimides resulted in the decomposition of the organometallic fragment and generation of fluorescent products. This feature greatly helped to delineate the transformations operated by the metallocarbonyl compounds within cancer cells and provided clues to their molecular mechanism of action.},
}
@article {pmid41174747,
year = {2025},
author = {Sharma, AR and Chatterjee, S and Lee, YH and Sharma, G and Kim, JG and Kim, JC and Lee, SS},
title = {Nano-size tantalum particles suppress the osteogenic activity of osteoblasts and stimulate osteoclasts.},
journal = {Journal of biological engineering},
volume = {19},
number = {1},
pages = {95},
pmid = {41174747},
issn = {1754-1611},
support = {NRF-2020R1C1C1008694//National Research Foundation of Korea/ ; NRF-2020R1I1A3074575//National Research Foundation of Korea/ ; 2022RIS-005//Ministry of Education/ ; },
abstract = {BACKGROUND: Tantalum (Ta) and its derivatives are inert, possess mechanical qualities such as corrosion resistance, and are biocompatible. They also offer structural support during surgical correction, such as bone grafts during surgery, in instances of dental or skeletal disabilities. However, various sizes of Ta particles could be expelled from the implant's surface due to mechanical stress and load-induced wear caused by micromotion between loose implant surfaces during usage. Therefore, the study examined the effects of nano (25 nm) and micro-sized Ta particles (10 μm and 40-50 μm) on osteoblasts and osteoclasts.<br><br>RESULTS: Osteoblasts efficiently phagocytosed 25&#xa0;nm sized Ta particles compared to micro-sized particles and triggered significant biological effects. Only 25&#xa0;nm Ta particles suppressed ALP activity, downregulated osteogenic regulators and markers, and inhibited collagen synthesis and mineralization. Moreover, 25&#xa0;nm sized Ta particles induced inflammatory responses in osteoblasts by increasing Cox-2 expression and activating the NFkB signaling pathway. Nano-sized Ta particles induced intracellular ROS generation in osteoblasts and osteoclasts. Compared to micro-sized Ta particles, 25&#xa0;nm sized Ta particles stimulated osteoclast formation, but ROS scavenging by N-acetyl cysteine (NAC) inhibited Ta particle-mediated osteoclastogenesis. Likewise, ALP activity of osteoblasts was partially restored after NAC treatment. 25&#xa0;nm Ta particles suppressed Axin-2 reporter activity and protein levels of pGSK3&#x3b2; and &#x3b2;-catenin stability, implicating suppressed WNT signaling in treated osteoblasts. Expression levels of several families of antagonists like DKK, sFRP, and SOST of the WNT signaling pathway were found elevated several-fold in 25&#xa0;nm-sized Ta particles treated osteoblasts, explaining suppressed WNT signaling pathway in exposed osteoblasts.<br><br>CONCLUSION: Ta supports osseointegration and biocompatibility, but micromotion-induced nanoscale wear particles may disrupt osteoprogenitor function and enhance osteoclast activity, risking implant loosening. Thus, vigilant post-operative monitoring for nano-sized Ta particles is advisable and critical in detecting early osteolysis and ensuring implant longevity.},
}
@article {pmid41172065,
year = {2025},
author = {Piazza, FRG and Schuch, JB and Ferreira, DNSDS and Gabiatti, MP and Kessler, FHP and von Diemen, L and Hansen, F},
title = {Serum 25-Hydroxyvitamin D Levels did not improve with N-Acetylcysteine administration nor with abstinence in Adults Treated for Alcohol Use Disorder: A Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.},
journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)},
volume = {},
number = {},
pages = {},
doi = {10.47626/1516-4446-2025-4304},
pmid = {41172065},
issn = {1809-452X},
support = {08129.011787/2015-95/Senad/Secretaria Nacional de Pol&#xed;ticas Sobre Drogas/Brazil ; 2015-0488/FIPE/HCPA/Fundo de Incentivo &#xe0; Pesquisa e Eventos/Hospital de Cl&#xed;nicas de Porto Alegre/Brazil ; 001/Capes/Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/Brazil ; },
abstract = {OBJECTIVE: N-acetylcysteine (NAC) is a medication known for its hepatoprotective properties and potential to reduce cravings and psychoactive substance use. Vitamin D is metabolized in the liver, and individuals with alcohol abuse often have lower levels. This study aims to evaluate the effect of NAC administration on vitamin D levels (25(OH)D) in adults with alcohol use disorder (AUD) undergoing treatment.<br><br>METHODS: This is a secondary analysis of a randomized, double-blind, placebo-controlled study with 47 male AUD patients who received either NAC (600mg twice daily, n=22) or placebo (n=25) for eight weeks. Blood samples were analyzed to assess 25(OH)D, liver and renal functions, and glutathione metabolism. The effects of time, intervention, and their interaction on 25(OH)D were evaluated using Generalized Estimating Equations.<br><br>RESULTS: At hospitalization, 45.0% of patients had 25(OH)D deficiency and 21.7% insufficiency. After eight weeks, 43.3% of patients had deficiency, and 40.0% had insufficiency. Intervention (NAC vs. placebo) (p = 0.130), study time (p = 0.429), and their interaction (p = 0.834) showed no significant effect on 25(OH)D levels.<br><br>CONCLUSION: There is a high prevalence of 25(OH)D deficiency and insufficiency in AUD patients. 25(OH)D levels did not improve spontaneously with abstinence, and NAC intervention did not significantly affect 25(OH)D concentrations.},
}
@article {pmid41168006,
year = {2025},
author = {Wang, D and Zhou, S and Tang, Y and Liang, Z and Yu, X and Huang, G and Huang, C and Wang, S and Liu, H},
title = {S-nitrosylation of paired-related homeobox 1 promotes cardiac remodeling following myocardial infarction.},
journal = {Redox biology},
volume = {87},
number = {},
pages = {103887},
pmid = {41168006},
issn = {2213-2317},
mesh = {Animals ; *Myocardial Infarction/metabolism/pathology/genetics ; Mice ; *Homeodomain Proteins/metabolism/genetics ; Humans ; *Ventricular Remodeling ; Nitric Oxide/metabolism ; Male ; Cell Differentiation ; Disease Models, Animal ; Fibrosis ; Myofibroblasts/metabolism ; },
abstract = {BACKGROUNDS: Cardiac remodeling, mediated by fibroblast-to-myofibroblast differentiation, is a key pathophysiologic step to determine the prognosis of patients following myocardial infarction (MI). Paired-related homeobox 1 (Prrx1) is a master transcription factor of fibroblasts for myofibroblastic lineage progression. Protein S-nitrosylation by nitric oxide (NO) is highly related to regulate cellular functions. This study is to investigate whether and how Prrx1 S-nitrosylation plays a key role in postischemic remodeling of heart.<br><br>METHODS: The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac fibrosis was assessed using Masson staining. Heart function was measured by echocardiography.<br><br>RESULTS: MI induced cardiac remodeling as cardiac fibrosis and heart dysfunction in mice, accompanied with increased Prrx1 transcriptional activity, but inhibited by N-acetyl-cysteine administration. In recombinant human protein, NO donors increased Prrx1 S-nitrosylation at cysteine 207 (C207). In human cardiac fibroblasts, oxygen-glucose deprivation or transforming growth factor beta upregulated NO productions, Prrx1 S-nitrosylation, Prrx1 transcriptional activity, Wnt5a gene expression, and fibroblast-to-myofibroblast differentiation, which were abolished by Prrx1-C207R mutant. In vivo, exogenous expression of Prrx1-C209R alleviated MI-induced cardiac fibrosis and promoted the recovery of heart functions in mice. Fibroblast-specific Prrx1 gene knockout prevented cardiac fibrosis and heart dysfunctions in mice fowling MI. In human patients with post-MI, Prrx1 S-nitrosylation was increased.<br><br>CONCLUSION: Upregulation of Prrx1 by S-nitrosylation increases Wnt5a gene expression to induce fibroblast-to-myofibroblast differentiation, which contributes to cardiac remodeling after MI. In perspective, targeting Prrx1 S-nitrosylation should be considered to improve the outcome of patients with MI.},
}
@article {pmid41165773,
year = {2025},
author = {Schuurman, M and Wilson, RB and Borradaile, N and Wang, R},
title = {The antioxidant, N-acetyl-L-cysteine, affects beta cell oxidative stress, insulin secretion, and intracellular signaling pathways in MIN6 cells.},
journal = {Cell and tissue research},
volume = {402},
number = {3},
pages = {267-281},
pmid = {41165773},
issn = {1432-0878},
support = {152944)/CAPMC/CIHR/Canada ; 152944)/CAPMC/CIHR/Canada ; },
mesh = {*Acetylcysteine/pharmacology ; *Oxidative Stress/drug effects ; *Insulin-Secreting Cells/drug effects/metabolism/cytology ; *Insulin/metabolism ; *Signal Transduction/drug effects ; *Antioxidants/pharmacology ; Insulin Secretion ; Animals ; Mice ; Cell Line ; Adenosine Triphosphate/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Glucose/pharmacology ; Phosphorylation/drug effects ; },
abstract = {There is intense public interest in the potential of antioxidant supplements as a preventative treatment for conditions associated with increased oxidative stress, such as type 2 diabetes mellitus. However, there is limited evidence regarding the effects of antioxidants on beta cells during physiological and pathological conditions. We examined the direct effects of N-acetyl-L-cysteine (NAC) supplementation on the MIN6 beta cell line under physiological and fatty acid stress conditions. MIN6 cells were cultured in growth medium with or without NAC (physiological conditions) or growth medium plus palmitate with or without NAC (fatty acid stress conditions). We observed that MIN6 cells receiving NAC, under physiological or fatty acid stress conditions, displayed significantly reduced cellular ATP content and oxidative stress without changes to markers of cell proliferation or apoptosis. Regardless of the treatment conditions, NAC lowered basal insulin release with no change to cellular insulin content, yet improved high glucose-stimulated insulin secretion (GSIS) was only observed under physiological conditions. Importantly, phosphorylated AKT was significantly reduced with NAC supplementation under physiological and fatty acid stress conditions, which was inversely proportional to ERK1/2[Thr202/Tyr204] phosphorylation during fatty acid stress. Our findings provided evidence that NAC directly impacts ATP production and insulin signaling pathways in MIN6 cells. This study highlights the importance of investigating ROS balance in pancreatic beta cells under physiological and pathological conditions to determine if antioxidant therapies can improve functionality without interfering with essential signaling processes.},
}
@article {pmid41158731,
year = {2025},
author = {Solga, I and Şahin, A and Yogathasan, V and Hofer, L and Celik, FG and El Rai, A and Hosen, MR and Wischmann, P and Becher, S and Polzin, A and Gerdes, N and Jung, C and Kelm, M and Chennupati, R},
title = {Acute blood loss anemia aggravates endothelial dysfunction after acute myocardial infarction.},
journal = {Frontiers in cardiovascular medicine},
volume = {12},
number = {},
pages = {1635293},
pmid = {41158731},
issn = {2297-055X},
abstract = {BACKGROUND: Anemia is frequently observed in patients with acute myocardial infarction (AMI) and is known to be associated with poor prognosis. We recently demonstrated that acute blood loss anemia is associated with a compensatory increase in endothelial nitric oxide (NO)-dependent flow-mediated dilation (FMD) responses. However, the effects of acute anemia on systemic endothelial function after AMI remain unclear. In this study, we evaluated systemic endothelial function following AMI in an established murine model of acute blood loss anemia. We hypothesize that acute anemia aggravates systemic endothelial dysfunction (ED) after AMI.<br><br>METHODS AND RESULTS: Acute anemia was induced in male C57BL/6J mice by repeated blood withdrawal for three consecutive days. Separate groups of anemic and non-anemic mice underwent AMI via left anterior descending artery (LAD) ligation (45&#x2005;min), followed by reperfusion. Endothelial function was assessed using both in vivo and in vitro methods 24&#x2005;h post-AMI. Impaired FMD (in vivo) and endothelium-dependent relaxation (EDR) responses were observed in the aorta, femoral, and saphenous arteries of AA mice compared to their respective control groups 24&#x2005;h post-AMI. Analysis of oxidative products of NO in plasma revealed reduced nitrite and nitrate levels in acute anemia compared to controls 24&#x2005;h post-AMI. Immunohistochemistry of aortic tissues from both anemic groups showed increased reactive oxygen species (ROS) product 4-Hydroxynonenal (4-HNE). Co-incubation of RBCs from anemic mice or anemic acute coronary syndrome (ACS) patients with aortic rings from wild-type mice demonstrated attenuated EDR responses. Supplementation with the ROS scavenger N-acetyl cysteine (NAC) for four weeks improved both in vivo and ex vivo EDR in acute anemic mice 24&#x2005;h post-AMI.<br><br>CONCLUSION: After AMI, acute anemia is associated with ROS-mediated severe endothelial dysfunction, which is partly mediated by RBCs. Antioxidant supplementation with NAC is a potential therapeutic option to reverse the severe ED in anemia following AMI.},
}
@article {pmid41156848,
year = {2025},
author = {Huang, J and Di, Y and Song, Q and Cheng, Z and Wu, H and Wu, M and He, M and Zhang, G and Wang, F and Tong, L},
title = {ROS-Mediated Necroptosis Promotes Coxsackievirus B3 Replication and Myocardial Injury.},
journal = {Microorganisms},
volume = {13},
number = {10},
pages = {},
pmid = {41156848},
issn = {2076-2607},
support = {2022J01311//Natural Science Foundation of Fujian Province/ ; 81860354//National Natural Science Foundation of China/ ; 605-50Y18058//High-Level Talent Innovation and Entrepreneurship Program of Huaqiao University/ ; 2024QZC002YR//QuanZhou High Level Talent Innovation and Entrepreneurship Project/ ; },
abstract = {Coxsackievirus B3 (CVB3) is a primary causative agent of viral myocarditis (VMC), which can lead to both acute and chronic cardiac inflammation accompanied by progressive heart failure and arrhythmias. Although CVB3 has been implicated in various forms of programmed cell death, whether it triggers necroptosis and the underlying mechanisms remains unclear. This study aimed to investigate the role and mechanism of CVB3-induced necroptosis and its effect on viral replication. Using both in vitro and in vivo models, we demonstrated that CVB3 infection significantly upregulates the expression of key necroptotic markers RIP1 and RIP3 in HeLa cells and mouse myocardial tissues. This upregulation was accompanied by elevated intracellular reactive oxygen species (ROS) levels and suppression of the Nrf2/HO-1 antioxidant pathway. Intervention with the necroptosis inhibitor Necrostatin-1 (Nec-1) or the ROS scavenger N-acetylcysteine (NAC) markedly attenuated cell death, suppressed viral replication, and ameliorated myocardial injury and inflammatory responses in infected mice. Mechanistically, CVB3 inhibits the Nrf2/HO-1 pathway, thereby inducing substantial ROS accumulation that promotes necroptosis. This effect can be reversed by NAC treatment. Our study reveals a novel mechanism through which CVB3 induces ROS-dependent necroptosis via the suppression of the Nrf2/HO-1 pathway, providing new insights into the pathogenesis of viral myocarditis and suggesting potential therapeutic strategies.},
}
@article {pmid41154783,
year = {2025},
author = {Moyano, P and Flores, A and Sanjuan, J and Plaza, JC and Guerra-Menéndez, L and Abascal, L and Mateo, O and Del Pino, J},
title = {Cholinergic Transmission Dysregulation and Neurodegeneration Induced by Thyroid Signaling Disruption Following Butylparaben Single and Repeated Treatment.},
journal = {Biology},
volume = {14},
number = {10},
pages = {},
pmid = {41154783},
issn = {2079-7737},
support = {172C126PMA//Fundaci&#xf3;n Alborada/Luunt Medicina Amabiental/Catedra Extraordinaria de Patologia y Medioambiente/ ; },
abstract = {Butylparaben (BP), a widely used preservative, was implicated in cognitive impairment, though its neurotoxic mechanisms remain elusive. Basal forebrain cholinergic neurons (BFCN) are selectively lost in dementias, contributing to cognitive decline. To explore different mechanisms related with BFCN loss, we employed BF SN56 cholinergic wild-type or silenced cells for Tau, amyloid-beta precursor protein (βApp), acetylcholinesterase (AChE), or glycogen synthase kinase-3 beta (GSK3β) genes, exposing them to BP (0.1-80 µM) for 1 or 14 days alongside triiodothyronine (T3; 15 nM), N-acetylcysteine (NAC; 1 mM), or recombinant heat shock protein 70 (rHSP70; 30 µM). BP disrupted cholinergic transmission by AChE inhibition and provoked cell death through thyroid hormones (THs) pathway disruption, Aβ/p-Tau protein accumulation, AChE-S overexpression, and oxidative stress (OS). Aβ/p-Tau accumulation was correlated with HSP70 downregulation, OS exacerbation, and GSK3β hyperactivation (for p-Tau). BP-induced OS was mediated by reactive oxygen species (ROS) overproduction and nuclear factor erythroid 2-related factor 2 (NRF2) pathway disruption. All observed effects were contingent upon TH signaling impairment. These findings uncover novel mechanistic links between BP exposure and BFCN neurodegeneration, providing a framework for therapeutic strategies.},
}
@article {pmid41154722,
year = {2025},
author = {Gopal, T and John Kathiravan, AD and Kabanov, AV and Casey, CA and Saraswathi, V},
title = {The Pathophysiology of Alcohol-Associated Liver Disease: Focusing on Superoxide Dismutase 1 as a Therapeutic Target.},
journal = {Biology},
volume = {14},
number = {10},
pages = {},
pmid = {41154722},
issn = {2079-7737},
support = {I01 CX002084/CX/CSRD VA/United States ; R01 AA030793/AA/NIAAA NIH HHS/United States ; 1R01AA030793-24/NH/NIH HHS/United States ; 1P50AA030407-24/NH/NIH HHS/United States ; },
abstract = {Alcohol-associated liver disease (ALD) is a major health problem of global importance, caused by chronic alcohol consumption, leading to the accumulation of reactive oxygen species (ROS) and subsequent oxidative stress-a central mechanism in liver injury. Superoxide dismutase 1 (SOD1), a Cu-Zn containing antioxidant enzyme, plays a crucial role in attenuating ALD-induced oxidative stress triggered by ethanol metabolism. However, alcohol exposure, whether chronic, acute or binge, differentially affects SOD1 levels, either diminishing its expression or temporarily compensating for alcohol-induced oxidative damage. Regardless, overexpression of SOD1 reverses early stages of ethanol-induced liver inflammation and injury in animal models, highlighting the protective role of SOD1. Current therapies, including alcohol abstinence, corticosteroids, and pentoxifylline, have limited long-term efficacy. Antioxidant-based treatments, such as N-acetylcysteine (NAC) and S-adenosyl-L-methionine (SAM), have demonstrated moderate benefits. While combination therapies like NAC with prednisolone yield more promising outcomes, these benefits are often limited in duration. The use of natural compounds including nutraceuticals and probiotics provide liver protection by enhancing antioxidant defenses, reducing inflammation, and mitigating alcohol-induced liver damage. In particular, these compounds upregulate antioxidant enzymes like SOD1. Recent research suggests that enhancing the activity of SOD1, particularly through nanoformulated SOD1 (NanoSOD1), which had direct effect on the oxidative stress at the cellular level, could offer a promising therapeutic option for ALD. NanoSOD1 aims to improve the bioavailability and stability of SOD1, offering a targeted approach to reduce oxidative stress and protect against liver damage. The effectiveness of NanoSOD1 to improve antioxidant defenses suggests a valuable therapeutic arsenal in ALD treatment. Taken together, given the limited treatment options for ALD, increasing SOD1 activity is essential for managing the progression of the disease.},
}
@article {pmid41154576,
year = {2025},
author = {Hsu, FT and Kuo, YY and Chao, CY},
title = {High-Frequency, Low-Intensity Pulsed Electric Field and N-Acetylcysteine Synergistically Protect SH-SY5Y Cells Against Hydrogen Peroxide-Induced Cell Damage In Vitro.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
pmid = {41154576},
issn = {2076-3921},
support = {NSTC 113-2112-M-002-024//National Science and Technology Council/ ; NSTC 112-2112-M-002-033//National Science and Technology Council/ ; MOST 110-2112-M-002-004//Ministry of Science and Technology/ ; },
abstract = {Oxidative stress plays an important role in the progression of neurodegenerative diseases (NDDs), and N-acetylcysteine (NAC) has gained attention as a potential agent due to its antioxidant capabilities. This study investigated the synergistic neuroprotective effects of combining NAC with non-contact, high-frequency, low-intensity pulsed electric field (H-LIPEF) stimulation on SH-SY5Y human neuronal cells subjected to hydrogen peroxide (H2O2)-induced oxidative damage. It was found that after SH-SY5Y cells were pretreated with NAC and exposed to H-LIPEF stimulation, the oxidative stress of cells was reduced in the subsequent treatment with H2O2. The results showed that the combined NAC and H-LIPEF treatment significantly improved cell viability and more effectively reduced mitochondrial apoptosis. Mechanistic analyses revealed that the combination substantially decreased levels of superoxide and intracellular H2O2, which was associated with enhanced activation of the phosphorylated Akt (p-Akt)/nuclear factor erythroid 2-related factor 2 (Nrf2)/superoxide dismutase type 2 (SOD2) signaling pathway. Furthermore, the treatment reduced the accumulation of 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dG) accumulation and elevated MutT homolog 1 (MTH1) expression, indicating a protective effect against oxidative DNA damage. These results suggest that H-LIPEF enhances the neuroprotective efficacy of low-dose NAC, highlighting the potential of this combination approach as a new therapeutic strategy for the treatment of NDDs.},
}
@article {pmid41154550,
year = {2025},
author = {Peralta-Buendía, K and Cuevas-López, B and García-Arroyo, FE and Díaz-Rojas, M and León-Contreras, JC and Silva-Palacios, A and Gonzaga, G and Tapia, E and Saavedra, E and Hernández-Pando, R and Pedraza-Chaverri, J and Sánchez-Lozada, LG and Aparicio-Trejo, OE},
title = {Early Administration of N-Acetylcysteine Provides Renal and Cardiac Mitochondrial and Redox Protection, Preventing the Development of Cardio-Renal Syndrome Type IV Induced by 5/6NX.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
pmid = {41154550},
issn = {2076-3921},
support = {IN202725//Programa de Apoyo a Proyectos de Investigaci&#xf3;n e Innovaci&#xf3;n Tecnol&#xf3;gica (PAPIIT)/ ; 21-1252//Fondos de Gasto Directo Autorizados a la Subdirecci&#xf3;n de Investigaci&#xf3;n B&#xe1;sica del Instituto Nacional de Cardiolog&#xed;a Ignacio Ch&#xe1;vez/ ; CBF2023-2024-190//Consejo Nacional de Humanidades, Ciencia y Tecnolog&#xed;a (CONAHCyT)/ ; },
abstract = {Chronic kidney disease (CKD) cardiac impairment is manifested as cardio-renal syndrome type 4 (CRS-IV). The kidneys and heart are highly dependent on mitochondria; thus, bioenergetics and redox and biogenesis alterations are critical in CKD and heart damage. Most previous studies have focused on the advanced stage of CRS-IV, but mitochondrial impairment onset in the early stages and its pathological pathways are poorly understood. In this work, we characterized mitochondrial bioenergetics, biogenesis and redox impairment in both tissues in the early stages after CKD and analyzed their relationship with CRS-IV in a CKD model with 5/6 nephrectomy (NX). We found the first cardiac mitochondrial alterations 10 days after surgery, together with an increase in plasma cardio-renal connectors, derived from renal mitochondrial damage. Oxidative phosphorylation capacity decreased and uncoupling led to oxidative stress, inflammation, cardiac hypertrophy and ejection fraction reduction, triggering CRS-IV. N-acetylcysteine (NAC) administration prevented mitochondrial alterations in both organs and heart damage. Interestingly, the protective effects of NAC correlated with SIRT1/3-PGC-1α pathway overactivation. These results suggest that mitochondrial biogenesis induction and redox regulation protection in the early stages after renal damage serve as a strategy to prevent bioenergetic alterations in the kidneys and heart, preventing inflammation and CRS-IV development.},
}
@article {pmid41154544,
year = {2025},
author = {Zhao, B and Fan, L and Liu, M and Wu, H and Zhang, Y and Shen, Q and Kang, J},
title = {Androgen-Induced Lactic Acid Accumulation Contributes to the Apoptosis of Ovarian Granulosa Cells in Polycystic Ovary Syndrome Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
pmid = {41154544},
issn = {2076-3921},
support = {82171634//the National Natural Science Foundation of China/ ; 31971068//the National Natural Science Foundation of China/ ; 7242085//Beijing Natural Science Foundation/ ; },
abstract = {BACKGROUND: Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. The apoptosis of granulosa cells (GCs) is strongly associated with the impaired follicular development in PCOS. The underlying mechanisms, however, remain incompletely elucidated. A significant increase in circulating lactic acid, an anaerobic respiration product, has been detected in PCOS patients. Yet, alterations in local ovarian lactic acid levels and their impact on GCs remain unknown.<br><br>METHODS: PCOS mouse models were established via 20-day daily subcutaneous dehydroepiandrosterone (DHEA) injections. In vitro experiments utilized DHEA-treated KGN cells to mimic hyperandrogenic conditions. Circulating, ovarian, and cellular lactic acid concentrations were quantified. Intracellular and extracellular pH values were measured using BCECF-AM fluorescent probe and a blood gas analyzer, respectively. Apoptosis was assessed through both flow cytometry and TUNEL assay. The antioxidant N-acetylcysteine (NAC) was used to investigate its effects on lactic acid levels and the subsequent GC apoptosis.<br><br>RESULTS: High androgen levels caused mitochondrial damage, promoted anaerobic glycolysis and led to lactic acid accumulation, inducing decreased intracellular pH and thus apoptosis of GCs. The antioxidant NAC effectively alleviated oxidative stress, mitigated mitochondrial damage, and decreased lactic acid levels and apoptosis in KGN cells. In PCOS mice, NAC improved ovarian morphology, but it did not affect the estrous cycle of the mice.<br><br>CONCLUSIONS: Hyperandrogenemia-induced mitochondrial dysfunction caused the accumulation of lactic acid and thus apoptosis of ovarian GCs in PCOS mice. NAC enhanced mitochondrial function, consequently decreasing lactic acid concentrations. These findings suggest novel therapeutic targets for PCOS.},
}
@article {pmid41153879,
year = {2025},
author = {Arena, R and Manuguerra, S and Gonzalez, MM and Petrosillo, E and Lanzoni, D and Poulain, C and Debeaufort, F and Giromini, C and Francesca, N and Messina, CM and Santulli, A},
title = {Valorization of Blue Crab (Callinectes sapidus) By-Products into Antioxidant Protein Hydrolysates for Nutraceutical Applications.},
journal = {Animals : an open access journal from MDPI},
volume = {15},
number = {20},
pages = {},
pmid = {41153879},
issn = {2076-2615},
support = {Project Code (CUP): G53D23003940006, Grant Assignment No. 1048//Project CELLtoFOOD, Italian Ministry of University and Research (MUR) funded by the European Union/ ; grant code CN_00000033, CUP B73C22000790001//NextGenerationEU. NBFC-National Biodiversity Future Center-Node 6 Biodiversity and human wellbeing/ ; },
abstract = {The Atlantic blue crab (Callinectes sapidus) is an opportunistic invasive species in the Mediterranean that is negatively affecting biodiversity, fisheries, and tourism. In Italy, it is appreciated for its good meat quality, but the processing yield is low (21.87 ± 2.38%), generating a significant amount of by-products (72.45 ± 4.08%), which are underutilized. Valorizing this biomass is in line with circular economy principles and can improve both environmental and economic sustainability. This study aimed to valorize Atlantic blue crab by-products (BCBP), producing protein hydrolysates and assessing their in vitro bioactivities, in order to plan applications in animal food and related sectors. BCBP hydrolysates were obtained by enzymatic hydrolysis using Alcalase and Protamex enzymes. The treatment with Alcalase resulted in a higher degree of hydrolysis (DH = 23% in 205 min) compared to Protamex (DH = 14% in 175 min). Antioxidant activity of the hydrolisates was evaluated through DPPH, ABTS, reducing power and FRAP assays, as well as in vitro test in fibroblasts (HS-68). At 10 mg/mL, hydrolysates from both enzymes exhibited the maximum radical scavenging activity in DPPH and ABTS assays. In HS-68 cells, 0.5 mg/mL hydrolysates protected against H2O2-induced oxidative stress, showing a cell viability comparable to cells treated with 0.5 mM N-acetyl cysteine (NAC), as an antioxidant. Statistical analyses were performed using one-way ANOVA followed by Student-Newman-Keuls (SNK) or Games-Howell post hoc tests, with significance set at p < 0.05. Overall, both enzymes efficiently hydrolyzed BCBP proteins, generating hydrolysates with significant antioxidant activity and cytoprotective effects. These results demonstrate the potential to produce high-quality bioactive compounds from BCBPs, suitable for food, nutraceutical, and health applications. Scaling up this valorization process represents a viable strategy to improve sustainability and add economic value to the management of this invasive species, turning a problem in a resource.},
}
@article {pmid41151839,
year = {2025},
author = {El Nsouli, D and Chung, C and Wilkins, H and Alqeisi, T and Maqsood, M and Sandhu, R and Bate-Jones, PE and Johnson, GD and Jameel, A},
title = {Quality improvement project to enhance adherence to RCEM standards for patients with paracetamol overdose.},
journal = {BMJ open quality},
volume = {14},
number = {4},
pages = {},
pmid = {41151839},
issn = {2399-6641},
mesh = {Humans ; *Acetaminophen/adverse effects/therapeutic use/poisoning ; *Quality Improvement ; *Drug Overdose/drug therapy ; Female ; Male ; Acetylcysteine/therapeutic use ; Emergency Service, Hospital/organization &amp; administration/statistics &amp; numerical data ; Adult ; Middle Aged ; *Guideline Adherence/statistics &amp; numerical data/standards ; Analgesics, Non-Narcotic ; Scotland ; },
abstract = {BACKGROUND: Delayed or inconsistent administration of N-acetylcysteine (NAC) for paracetamol overdose in the emergency department (ED) poses a risk to patient safety, with current Royal College of Emergency Medicine (RCEM) standards often not being met. The traditional 21-hour NAC regimen is associated with adverse drug reactions, medication errors and prolonged admissions. The Scottish and Newcastle Acetylcysteine Protocol (SNAP) was introduced as a simpler alternative with comparable efficacy. This quality improvement project (QIP) aimed to improve compliance with RCEM standards by implementing targeted interventions while also reducing the length of inpatient stay and maintaining patient safety.<br><br>METHOD: This QIP was conducted at Royal Derby Hospital using a multidisciplinary, systematic approach based on Plan-Do-Study-Act cycles. Baseline data were collected from 100 randomly selected patients (November 2021-May 2022) and compared with outcomes during a 52-week intervention period (September 2023-August 2024). Interventions included educational sessions, quick reference materials and enhanced prescribing tools. Data were analysed for compliance with RCEM standards, adverse events (liver function derangement and anaphylactoid reactions) and system-level measures, such as length of inpatient stay and timing of paracetamol plasma levels.<br><br>RESULTS: A total of 214 patients were included. Compliance with RCEM standard 1 improved from 36% to 43%. No change was noted for standards 2 and 3. Median inpatient stay decreased from 35 hours to 30.5 hours. No significant differences were found in adverse events. Special cause variation was identified in paracetamol plasma level timing, attributed to early sampling in some cases.<br><br>CONCLUSION: This QIP addressed problems of delayed or inconsistent NAC administration in the ED by improving compliance with RCEM standard 1 and reducing inpatient stay while maintaining patient safety. Although standards 2 and 3 did not improve, the interventions proved cost-effective, feasible and scalable. Future work should focus on sustaining improvements and exploring patient-centred outcomes across diverse healthcare settings.},
}
@article {pmid41150214,
year = {2025},
author = {de-Luna-López, MC and Valdivia-Flores, AG and Quezada-Tristán, T and Ortiz-Martínez, R and Rangel-Muñoz, EJ and Hernández-Valdivia, E and Albarrán-Rodríguez, E and de Santiago-Díaz, E},
title = {Protective Effect of Ethoxyquin and N-acetylcysteine on Biochemical and Pathological Changes Induced by Chronic Exposure to Aflatoxins in Laying Hens.},
journal = {Toxins},
volume = {17},
number = {10},
pages = {},
pmid = {41150214},
issn = {2072-6651},
support = {PIP/SA 25-1//Autonomous University of Aguascalientes/ ; 227916/209250//CONAHCYT/ ; },
mesh = {Animals ; Chickens ; *Acetylcysteine/pharmacology/therapeutic use ; *Aflatoxins/toxicity ; Female ; Liver/drug effects/pathology/metabolism ; Kidney/drug effects/pathology/metabolism ; *Ethoxyquin/pharmacology ; *Antioxidants/pharmacology ; *Protective Agents/pharmacology ; Glutathione/metabolism ; Poultry Diseases/chemically induced/prevention &amp; control ; Glutathione Transferase/metabolism ; },
abstract = {Aflatoxins (AFs) represent a major threat to poultry health and food safety due to their hepatotoxic, immunosuppressive, and carcinogenic effects. This study evaluated the chemoprotective potential of ethoxyquin (EQ) and N-acetylcysteine (NAC) in laying hens (80.8 and 33.3 mg/kg BW/d) exposed to chronic dietary AFs contamination (0.0-1.5 mg/kg). A total of 360 Hy-Line W36 Leghorn hens were monitored over 72 weeks using biochemical and histopathological analyses of liver and kidney tissues. NAC significantly (p < 0.01) increased hepatic and renal levels of reduced glutathione (GSH) and stimulated glutathione S-transferases (GST) and gamma-glutamyl transferase (GGT) activity, enhancing detoxification. Both agents significantly (p < 0.05) reduced plasma ALT and AST levels, preserved total protein concentrations, and attenuated liver and kidney hypertrophy. EQ demonstrated antioxidant effects, stabilizing enzymatic responses and limiting tissue damage. Histopathological analysis revealed fewer structural alterations and cellular degeneration, especially in the NAC-treated group (p < 0.01). These results suggest that NAC and EQ activate endogenous detoxification mechanisms, both enzymatic and non-enzymatic, effectively mitigating chronic aflatoxin toxicity. Their dietary supplementation offers a safe and sustainable chemoprotection strategy to support poultry health and productivity, particularly in regions facing high mycotoxin exposure.},
}
@article {pmid41149623,
year = {2025},
author = {Radomska-Leśniewska, DM and Niderla-Bielińska, J and Kujawa, M and Jankowska-Steifer, E},
title = {Targeting Metabolic Dysregulation in Obesity and Metabolic Syndrome: The Emerging Role of N-Acetylcysteine.},
journal = {Metabolites},
volume = {15},
number = {10},
pages = {},
pmid = {41149623},
issn = {2218-1989},
abstract = {Obesity and metabolic syndrome (MetS), growing global health concerns, are closely linked to the development of insulin resistance, type 2 diabetes, steatotic liver disease, and cardiovascular diseases (CVDs). An increase in visceral adipose tissue, the main symptom of MetS, contributes to systemic metabolic dysfunction, resulting in disturbances in glucose and lipid metabolism, mitochondrial dysfunction, and redox imbalance, which creates a vicious cycle of inflammation and oxidative stress, accelerating comorbidities. N-acetylcysteine (NAC), a precursor to glutathione, with antioxidant and anti-inflammatory properties, is described as a potent metabolic modulator that restores metabolic homeostasis. NAC's ability to modulate oxidative stress and inflammation may be particularly valuable in preventing or mitigating cardiovascular complications of MetS. The aim of this narrative review is to summarize current evidence from cellular, animal, and human studies on NAC's impact on metabolic health. MetS affects nearly one-third of the global population; therefore, there is a pressing need for accessible therapeutic strategies. NAC appears to offer potential benefits as an adjunctive agent for individuals with metabolic disturbances, but further research is needed to confirm its efficacy and establish its role in clinical practice.},
}
@article {pmid41145378,
year = {2025},
author = {Gad, FA and Emam, MA and Abdelhameed, AA and Khalil, DM and Elgebaly, EA and Bakhuraysah, MM and Albattal, SB and Alotaibi, KS and Soliman, MM},
title = {N-acetyl cysteine and vitamin E attenuate acrylamide-induced hepatotoxicity via regulation of miRNA-34a and P53/Nrf2/SIRT 1 signaling pathways.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/01480545.2025.2574393},
pmid = {41145378},
issn = {1525-6014},
abstract = {The present study is aimed to evaluate the hepatoprotective role of N-acetyl cysteine (NAC) and vitamin E (VE), as potent antioxidants, against acrylamide (ACR)-induced hepatotoxicity via investigation of alterations in miRNA-34a, P53, Nrf2, and SIRT 1 hepatic expressions in addition to, changes in liver function tests, oxidative stress/antioxidant parameters, cytokines, histopathological analysis and immunohistochemical expressions of caspase 3. For this study, thirty-five male rats were randomly assigned into seven equal groups: group I (control), group II received ACR at dose 20 mg/kg b.wt., group III received NAC at dose 150 mg/kg b.wt., group IV received VE at a dose of 100 mg/kg b.wt., group V received NAC+ACR, group VI received VE+ACR and finally group VII received NAC+VE+ACR, for 28 days. ACR induced marked hepatic tissue damage as evident by severe alterations in hepatic biomarkers, in addition to histological and immunohistochemical pictures. This was accompanied by a significant elevation of hepatic MDA and apoptotic genes expressions, alteration in miRNA-34a and P53/Nrf2/SIRT1 pathway as well as cytokines. In contrast, marked depletion for antioxidant parameters was detected. These findings were confirmed with marked histological changes. Co-administration of NAC and VE significantly attenuated the hepatotoxic effects of ACR where liver parameters, oxidative status, genetic expressions, and liver histo-architecture were improved in comparison to ACR, NAC+ACR, and VE+ACR groups. NAC and/or VE had powerful antioxidants and could be used as an applicable hepatoprotective agent against oxidative damage mediated by ACR via regulation of miRNA-34a and P53/Nrf2/SIRT 1 signaling pathways.},
}
@article {pmid41139132,
year = {2026},
author = {Sonwani, A and Pathak, A and Jain, K},
title = {Development and characterization of multifunctional dendrimeric nanoconjugates for delivery of rutin: in vitro characterization for potential neuroprotective application.},
journal = {Nanomedicine (London, England)},
volume = {21},
number = {1},
pages = {1-14},
pmid = {41139132},
issn = {1748-6963},
mesh = {*Rutin/chemistry/administration &amp; dosage/pharmacology ; *Dendrimers/chemistry ; *Neuroprotective Agents/chemistry/administration &amp; dosage/pharmacology ; *Nanoconjugates/chemistry ; Humans ; Antioxidants/chemistry/pharmacology ; Animals ; Folic Acid/chemistry ; Drug Liberation ; Cell Survival/drug effects ; Particle Size ; Acetylcysteine/chemistry ; Drug Delivery Systems ; *Drug Carriers/chemistry ; },
abstract = {AIM: In the present research work, multifunctional dendrimeric nanoconjugates were developed, where poly(amidoamine) dendrimer generation 4.0 (G4.0) was conjugated with folic acid and N-acetyl cysteine simultaneously to deliver rutin for potential neuroprotective applications.<br><br>METHODS: G4.0 was functionalized with folic acid and N-acetyl cysteine by carbodiimide coupling chemistry, and the conjugation was confirmed using [1]H NMR and FTIR spectroscopy. Further, rutin was incorporated within the conjugate, and the rutin-loaded dendrimeric conjugate was evaluated for size, drug release, cytotoxicity, cellular uptake, and antioxidant activity.<br><br>RESULTS: The results of FTIR and [1]H NMR confirmed the conjugation of folic acid and N-acetyl cysteine over the dendrimeric surface. The particle size of NAC-FA-G4.0 was 163.4&#x2009;&#xb1;&#x2009;16.63&#x2009;nm, which was increased to 229.76&#x2009;&#xb1;&#x2009;14.05&#x2009;nm following the rutin incorporation. The in vitro drug release study showed an initial burst release of rutin, i.e. 44.27&#x2009;&#xb1;&#x2009;6.4% from dendrimeric conjugate within 4&#x2009;h, followed by sustained release up to 72&#x2009;h. The safety and biocompatibility of the developed nanoconjugate were confirmed by the hemolytic toxicity and cytotoxicity studies.<br><br>CONCLUSION: The developed rutin-loaded dendrimeric conjugate showed improved antioxidant activity and acetylcholinesterase inhibition, suggesting promising neuroprotection properties and hence may be further explored for the treatment of neurodegenerative diseases, including Alzheimer's disease.},
}
@article {pmid41138574,
year = {2025},
author = {Teng, C and Chen, JW and Shen, LS and Lin, Z and Lin, YS and He, WY and Yuan, ZH and Yang, ZX and Liu, YX and Lei, YB and Zhang, H and Chen, S and Chen, GQ},
title = {Arnicolide C induces ROS-mediated modulation of PI3K/Akt and MAPK pathways to suppress MYC in hepatocellular carcinoma.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {148},
number = {},
pages = {157423},
doi = {10.1016/j.phymed.2025.157423},
pmid = {41138574},
issn = {1618-095X},
mesh = {*Sesquiterpenes/chemistry/pharmacology ; Liver Neoplasms/drug therapy/metabolism/pathology ; Cell Proliferation/drug effects ; MAP Kinase Signaling System/drug effects ; Humans ; Animals ; Mice ; Mice, Nude ; Mice, Inbred BALB C ; *Lactones/pharmacology ; Xenograft Model Antitumor Assays ; Antineoplastic Agents, Phytogenic/pharmacology ; Cell Line, Tumor ; Reactive Oxygen Species/chemistry/metabolism ; },
abstract = {BACKGROUND: The urgent need for more effective therapies for hepatocellular carcinoma (HCC), an aggressive and lethal liver cancer, has prompted the search for novel compounds with distinct mechanisms of action. Targeting reactive oxygen species (ROS) has emerged as a promising anticancer strategy, particularly for natural products that modulate redox homeostasis. Arnicolide C (AC), a sesquiterpene lactone from Centipeda minima, has demonstrated potential anticancer activity, but its efficacy against HCC and the underlying mechanisms remain unclear.<br><br>METHODS: We assessed the effects of AC on HCC cell proliferation, apoptosis, and metastasis through a series of in vitro assays. Its antitumor efficacy was further validated in a xenograft mouse model. RNA-seq-based bioinformatics analysis was conducted to explore potential molecular targets and pathways. ROS generation by AC was evaluated using both chemical and cellular assays. The role of ROS in mediating AC's effects was investigated in vitro and in vivo using the ROS scavenger N-acetylcysteine (NAC).<br><br>RESULTS: AC markedly inhibited HCC cell proliferation, triggered apoptosis, and suppressed metastatic behaviors. Notably, AC reduced tumor growth without overt toxicity in vivo. Mechanistically, AC downregulated the oncogene MYC by modulating the PI3K/Akt and MAPK pathways. Importantly, AC induced ROS accumulation in HCC cells, and NAC abrogated its antitumor effects and reversed the suppression of MYC and related signaling pathways.<br><br>CONCLUSION: AC exerts potent anti-HCC activity via ROS-mediated modulation of PI3K/Akt and MAPK signaling, resulting in MYC downregulation. These findings support AC as a promising redox-targeting therapeutic agent for HCC.},
}
@article {pmid41138059,
year = {2026},
author = {Yin, X and Xia, R and Song, H and Zhang, Y and Guo, D and Gan, F},
title = {Pharmacokinetics and bioequivalence of two N-acetylcysteine tablets in healthy Chinese volunteers under fasting and fed conditions.},
journal = {Clinical pharmacology in drug development},
volume = {15},
number = {2},
pages = {e1619},
doi = {10.1002/cpdd.1619},
pmid = {41138059},
issn = {2160-7648},
support = {//Guangdong Tailai Runzhi Pharmaceutical Technology Co., Ltd/ ; },
mesh = {Humans ; Therapeutic Equivalency ; *Acetylcysteine/pharmacokinetics/administration &amp; dosage/adverse effects/blood ; Cross-Over Studies ; *Fasting/blood ; Male ; Adult ; Tablets ; Healthy Volunteers ; Young Adult ; Area Under Curve ; Female ; Asian People ; Tandem Mass Spectrometry ; Administration, Oral ; Chromatography, Liquid ; China ; East Asian People ; },
abstract = {N-acetylcysteine (NAC) is a derivative of cysteine with potent mucolytic and antioxidant properties. However, the pharmacokinetics of NAC tablets remain unclear in healthy Chinese subjects. This study aimed to assess the pharmacokinetics, bioequivalence, and safety of a domestically manufactured NAC tablet (600 mg) compared with the reference formulation in healthy Chinese volunteers under both fasting and fed conditions. A single-dose, randomized, open-label, two-formulation, crossover bioequivalence study was conducted, using a two-period, two-sequence design under fasting conditions and a four-period, fully replicated crossover design under fed conditions. Blood samples were collected at predetermined time points and analyzed using a validated liquid chromatography-tandem mass spectrometry method. The 90% confidence intervals for the geometric mean ratios (test/reference) of the maximum plasma concentration, the area under the concentration-time curve from time zero to the last measurable concentration, and from time zero to infinity were all within the accepted bioequivalence range of 80%-125%. Furthermore, both the test and reference formulations were well tolerated, and no serious adverse events were reported. These results demonstrate that the test and reference NAC tablets are bioequivalent and exhibit similar pharmacokinetic profiles and safety in healthy Chinese subjects under both fasting and fed conditions.},
}
@article {pmid41136359,
year = {2025},
author = {Pan, X and Su, Z and Huang, Z and Chen, Y and Li, X and Zheng, X},
title = {N-acetylcysteine (NAC) ameliorates ethanol-induced oxidative stress, neuroinflammation, and cognitive dysfunction in APP/PS1 mouse model.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {435},
pmid = {41136359},
issn = {2158-3188},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Ethanol/toxicity/adverse effects ; Mice ; *Oxidative Stress/drug effects ; Disease Models, Animal ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroinflammatory Diseases/chemically induced/drug therapy ; Mice, Transgenic ; Male ; Microglia/drug effects ; *Antioxidants/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; Disks Large Homolog 4 Protein/metabolism/drug effects ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder that predominantly affects the elderly, leading to a progressive decline in cognitive function. Accumulating evidence suggests that many environmental and dietary factors, especially chronic ethanol exposure, aggravate the risk of this disease. However, its precise influence on AD has not yet been clarified. Here, we show that ethanol exposure caused earlier and severer cognitive behavioral impairments, more beta amyloid (Aβ) depositions, microglia activation, decreased total antioxidant capacity (T-AOC). Moreover, inflammatory mediators, such as Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and Tumor necrosis factor-alpha (TNF-α) increased, while pivotal proteins involved in dendritic and synaptic development, such as Synaptophysin (SYP), postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) decreased in APP/PS1 mice. N-acetylcysteine (NAC), a well-known antioxidant, could attenuate cognitive behavioral impairments and neuroinflammatory damage by restoring inflammatory and neurodevelopmental mediators. In general, our study uncovered that chronic ethanol exposure may exacerbate AD progress at the pathological and molecular levels and NAC may act as a potential drug for the treatment of AD patients with chronic ethanol exposure.},
}
@article {pmid41135647,
year = {2025},
author = {Lei, Y and Forest, A and Daneault, C and Liu, Y and Pantopoulos, K and Tantiworawit, A and Phrommintikul, A and Chattipakorn, S and Chattipakorn, N and Rosiers, CD and Sweeney, G},
title = {Correlation of plasma lipidomic profiles with cardiometabolic disease in transfusion-dependent thalassemia patients with six-month N-acetylcysteine intervention: A prospective cohort study.},
journal = {Clinical biochemistry},
volume = {140},
number = {},
pages = {111030},
doi = {10.1016/j.clinbiochem.2025.111030},
pmid = {41135647},
issn = {1873-2933},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; Male ; Female ; *Lipidomics/methods ; Adult ; *Lipids/blood ; Prospective Studies ; *Thalassemia/blood/therapy ; *Blood Transfusion ; Oxidative Stress/drug effects ; Young Adult ; Adolescent ; *Cardiovascular Diseases/blood/etiology ; },
abstract = {OBJECTIVES: Oxidative stress, driven by iron imbalance from recurrent blood transfusions, is a major contributor to cardiometabolic complications in transfusion-dependent thalassemia (TDT). N-acetylcysteine (NAC), a glutathione precursor, is a well-known antioxidant with cardioprotective effects achieved by mitigating the impact of oxidative stress on cell metabolism. Current study aimed to evaluate the effect of a six-month NAC intervention by focusing on previously reported changes in the plasma lipidome in TDT patients. Design &amp; Methods A randomized cohort of 62 Thai TDT patients was divided into two groups: both received six months of cocktail therapy involving standardized blood transfusions and iron chelator therapy, with the intervention group additionally receiving 600 mg oral NAC daily and the control group receiving a placebo. Plasma lipidomic profiling was performed using mass spectrometry to assess 339 previously annotated lipid features significantly altered in TDT patients. Clinical parameters, including heart rate variability (HRV), were measured before and after the intervention.<br><br>RESULTS: NAC treatment significantly altered 152 plasma lipid features (P&#xa0;<&#xa0;0.03), 78 of which were also altered in the placebo group. Importantly, 29 lipid features (26 unique lipids) were restored toward healthy control levels following NAC treatment. Within this subset, circulating diacylglycerophosphocholines PC(14:0_20:4) and cholesteryl ester CE 18:3 positively correlated with HRV, a clinical marker markedly improved in NAC-treated patients.<br><br>CONCLUSIONS: Six-month oral NAC intervention modified the plasma lipidomic profile in TDT patients, partially restoring lipid species likely disrupted by chronic oxidative stress. The observed correlation between NAC-responsive lipids and improved HRV suggests a potential cardioprotective effect. These findings highlight the potential of NAC as an adjunctive therapy to mitigate cardiometabolic complications in TDT.},
}
@article {pmid41133840,
year = {2025},
author = {Asgharzadeh, N and Noori, A and Amini-Khoei, H and Yazdanpanahi, N and Korrani, MS},
title = {N-acetyl Cysteine Reduces Behavioral Disorders of the First and Second-generation Weaned Mice through the Modulation of TAC and the DNMT1 Gene Expression in the Hippocampus.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128372635250927103524},
pmid = {41133840},
issn = {1873-4286},
abstract = {INTRODUCTION: This research aimed to reveal the role of antioxidants and DNMT1 gene expression in behavioral disorders after exposure to stress.<br><br>METHODS: Forty-eight male and female mice (weight 25-35 grams) were used. Their pups (weight 18-22 grams) were divided into 6 groups (n=20), Control, Social isolation stress (SIS), and SIS + N-acetylcysteine (NAC) 150 mg/kg intraperitoneally for male and 3 similar groups for female subjects, eight mice from each group were used for the first-generation experiments and another for mating and producing the second generation. The second-generation pups were designated into 9 groups A to I. After conducting behavioral tests of the Morris water maze (MWM) and shuttle box, they were anesthetized, decapitated, and their brains were removed. The neuronal counts of CA1 and CA3 were performed. DNMT1 gene expression, total antioxidant capacity (TAC), and malondialdehyde (MDA) of the brain were measured.<br><br>RESULTS: Spatial memory, passive avoidance, and TAC decreased in the SIS groups. MDA and DNMT1 gene expression of the SIS groups increased (p<0.001). Dead neurons in the CA1 and CA3 regions increased in the SIS group (p<0.001).<br><br>DISCUSSION: According to the results of this study, N-acetylcysteine enhanced learning and memory while reducing neuronal death by decreasing oxidative stress. Additionally, it lowered the expression of the DNMT1 gene, which plays a crucial role in DNA methylation.<br><br>CONCLUSION: After studying the human population, N-acetylcysteine may be introduced as an adjunct therapy to help mitigate the effects of stress.},
}
@article {pmid41128676,
year = {2025},
author = {Dunbar, KY and Dali, G and DeMayo, MM and Logge, W and Hurzeler, T and Kelly, C and Watt, J and Squeglia, LM and Kirkland, AE and Haber, PS and Morley, KC},
title = {The Effect of N-Acetylcysteine (NAC) on Neurometabolites and Cognitive Function in Adults With Alcohol Use Disorder: A Preliminary Randomized Controlled Trial.},
journal = {Neuropsychopharmacology reports},
volume = {45},
number = {4},
pages = {e70066},
pmid = {41128676},
issn = {2574-173X},
support = {2021/GNT200985//National Health and Medical Research Council/ ; //University of Sydney/ ; },
mesh = {Humans ; *Acetylcysteine/pharmacology/administration &amp; dosage/therapeutic use ; Male ; Female ; Middle Aged ; Adult ; *Cognition/drug effects ; *Alcoholism/drug therapy/metabolism/diagnostic imaging/psychology ; Glutamic Acid/metabolism ; Glutathione/metabolism ; Aspartic Acid/metabolism/analogs &amp; derivatives ; Double-Blind Method ; *Gyrus Cinguli/metabolism/drug effects/diagnostic imaging ; Proton Magnetic Resonance Spectroscopy ; },
abstract = {BACKGROUND AND AIMS: Preclinical studies have demonstrated that N-acetylcysteine stabilizes levels of glutamate and glutathione and reduces alcohol-seeking behaviors, indicating it as a potential pharmacotherapy for the management of alcohol use disorder. In this preliminary study, we examined brain metabolite levels and cognitive functioning in individuals with alcohol use disorder enrolled in a randomized controlled trial of N-acetylcysteine versus placebo.<br><br>METHODS: In this preliminary trial, 23 participants (average age&#x2009;=&#x2009;49; 70% male) with moderate to severe alcohol use disorder (DSM-5) were randomized to receive 2400&#x2009;mg/day of N-acetylcysteine (N&#x2009;=&#x2009;9) or placebo (N&#x2009;=&#x2009;14). At baseline and follow-up (M&#x2009;=&#x2009;19&#x2009;days; SD&#x2009;=&#x2009;3.73&#x2009;days post-baseline), participants underwent proton magnetic resonance spectroscopy ([1]H-MRS) to assess levels of glutamate (Glu), glutathione (GSH) and total N-acetylaspartate (tNAA) in the anterior cingulate cortex (ACC) and completed the Stroop Color and Word Test (SCWT; a measure of distractor interference and cognitive control) and the Trail Making Test (TMT; a measure of set shifting ability).<br><br>RESULTS: There were no significant differences between the N-acetylcysteine or placebo groups in neurometabolite concentrations (GSH/Cr: p&#x2009;=&#x2009;0.75, CI; -0.12-0.09, tNAAG/Cr: p&#x2009;=&#x2009;0.797, CI; -0.10-0.13, Glu/Cr: p&#x2009;=&#x2009;0.60, CI; -0.19-0.32), or cognitive scores (Stroop: p&#x2009;=&#x2009;0.57, CI; -306.93-172.78, TMT: p&#x2009;=&#x2009;0.166, CI; -6.62-36.77).<br><br>CONCLUSION: These preliminary findings indicate that N-acetylcysteine may not alter brain neurometabolite levels within the ACC or show improvements in certain domains of cognitive functioning measured by the SCWT and TMT, specifically resistance to distractor interference and set-shifting ability respectively, in individuals with alcohol use disorder.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03879759.},
}
@article {pmid41127960,
year = {2025},
author = {Martínez-Gili, L and Fucho, R and Caballero, F and Núñez, S and Jaara, HS and Alarcón-Vila, C and Rico, N and Nagasawa, HT and García-Ruiz, C and Fernández-Checa, JC and Torres, S},
title = {l-Cysteine-Glutathione Mixed Disulfide, a Novel Bioavailable Sulfhydryl-Modified Glutathione Precursor, Protects against Early Liver Injury Induced by Short-Term Hypercholesterolemia.},
journal = {Chemical research in toxicology},
volume = {38},
number = {11},
pages = {1961-1976},
pmid = {41127960},
issn = {1520-5010},
support = {P01 CA281819/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Mice ; *Glutathione/metabolism/chemistry ; *Hypercholesterolemia/complications/drug therapy ; *Cysteine/chemistry/pharmacology/therapeutic use ; Male ; Mice, Inbred C57BL ; Liver/drug effects/metabolism/pathology ; *Glutathione Disulfide/chemistry/pharmacology/therapeutic use ; *Protective Agents/pharmacology/chemistry ; Oxidative Stress/drug effects ; },
abstract = {Oxidative stress contributes to the damage of biological molecules and is linked to the development of multiple diseases, including liver disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD). In mammals, reduced glutathione (GSH) is a pivotal antioxidant that regulates cellular responses to redox imbalances caused by reactive oxygen and nitrogen species. The presence of reduced GSH within mitochondria is especially crucial for preserving the organelle's routine performance by eliminating hydrogen peroxide generated under both physiological and pathological conditions. Cumulative evidence indicates that MASLD is associated with a diminished mitochondrial GSH (mGSH) pool, attributed to alterations in mitochondrial membrane fluidity due to cholesterol accumulation. Therefore, strategies aimed at boosting mGSH may offer therapeutic benefits against MASLD-associated liver injury. This study aims to investigate whether l-cysteine-glutathione disulfide (l-CySSG), a proposed GSH donor and precursor, can effectively restore total and mGSH in vitro and in vivo in mice fed cholesterol-enriched (HC) or methionine-choline-deficient (MCD) diets. Additionally, S-adenosylmethionine (SAM), a compound that serves as both a GSH precursor and a membrane fluidizer, along with N-acetylcysteine (NAC), a GSH precursor by providing cysteine, was used as the control molecules in the study. Our findings show that l-CySSG has great potential as a liver protector, especially due to its good oral bioavailability. Although it does not restore GSH levels in the mitochondria as efficiently as SAM does, l-CySSG can still offer protection against liver damage, possibly through mechanisms that are not yet fully understood. Overall, l-CySSG emerges as a promising alternative for treating conditions related to oxidative stress and mitochondrial dysfunction, paving the way for future research and therapeutic development.},
}
@article {pmid41126973,
year = {2025},
author = {Yudhawati, R and Husodo, S and Aini, FN},
title = {N-Acetylcysteine as a Potential Immunomodulator in Tuberculosis: Evidence of IL-2 Elevation in a Pilot Study.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {14381-14390},
pmid = {41126973},
issn = {1178-7031},
abstract = {PURPOSE: Aimed to investigate the potential of N-acetylcysteine (NAC) as an adjunctive immunomodulatory therapy to support the host immune response against Mycobacterium tuberculosis by enhancing interleukin-2 (IL-2) production.<br><br>PATIENTS AND METHODS: A quasi-experimental study was conducted on the effect of NAC administration on IL-2 levels in patients newly diagnosed with pulmonary tuberculosis at Universitas Airlangga Teaching Hospital, Indonesia. Participants who met the inclusion criteria were subsequently divided into two groups: treatment group (received 600 mg every 12&#xa0;hours of NAC therapy, n = 15) and control group (did not receive NAC therapy, n = 15). Enzyme-linked immunosorbent assay (ELISA) was used to analyze IL-2 levels in both groups, which were subsequently compared using statistical analysis.<br><br>RESULTS: Analysis of IL-2 levels before treatment with NAC revealed no significant difference between the treatment and control groups. The treatment group exhibited a significant increase in IL-2 levels after NAC administration (p=0.023). The median IL-2 level in the treatment group increased from 243.7 to 386.62 ng/L after two weeks of NAC administration, whereas in the control group, it decreased from 303.6 to 285.89 ng/L. The comparison test analysis of delta IL-2 levels also showed a significant difference between the treatment and control group (p = 0.025), with the median value of delta IL-2 levels in the treatment group being 147.0 ng/L and -24.7 ng/L in the control group.<br><br>CONCLUSION: This preliminary study demonstrated that IL-2 levels significantly increased with NAC supplementation, suggesting an enhanced immune response and its potential as an adjunct to standard tuberculosis therapy.},
}
@article {pmid41125047,
year = {2025},
author = {Zheng, Z and Lin, X and Ma, F and Shi, Q and Li, X and Wang, Y and Li, H and Ge, RS and Pan, P},
title = {Zearalenone impairs trophoblast function via ROS-mediated apoptosis and autophagy: A mechanistic insight into unexplained recurrent spontaneous abortion.},
journal = {Ecotoxicology and environmental safety},
volume = {305},
number = {},
pages = {119259},
doi = {10.1016/j.ecoenv.2025.119259},
pmid = {41125047},
issn = {1090-2414},
mesh = {Reactive Oxygen Species/metabolism ; *Zearalenone/metabolism/toxicity ; Humans ; Animals ; Rats ; *Mycotoxins/metabolism/toxicity ; Trophoblasts/drug effects/physiology ; Apoptosis/physiology ; Female ; Pregnancy ; Abortion, Spontaneous ; *Abortion, Habitual/chemically induced ; Chorionic Gonadotropin/metabolism ; Cell Line ; Cell Survival ; Membrane Potential, Mitochondrial/drug effects/physiology ; Antioxidants/metabolism ; Superoxide Dismutase/metabolism ; Catalase/metabolism ; Follicular Fluid/metabolism/microbiology ; Rats, Sprague-Dawley ; },
abstract = {The impact of zearalenone (ZEN) on miscarriage, especially unexplained recurrent spontaneous abortion (URSA), remains unclear. We collected follicular fluid from URSA patients and found significantly elevated ZEN levels. This study further investigated ZEN's cytotoxic effects on human (HTR-8) and primary rat trophoblast cells. In HTR-8 cells, ZEN exposure (0.05-50 μM) induced time-dose-dependent suppression of cell viability, with concomitant reductions in human chorionic gonadotrophin (hCG) levels. ZEN (0.05-50 μM) downregulated the expression of antioxidants (SOD1, SOD2, CAT1 and GPX1) and anti-apoptotic gene (BCL2), and upregulated apoptotic genes (P53 and CASP9). ZEN affected the expression of nutrient transporters, including CD36 (at ≥ 50 μM), LDLR (at ≥50 μM), and SLC38A2 (at ≥ 5 μM). Flow cytometry analysis demonstrated that ZEN, at concentrations of ≥ 10 μM, induced reactive oxygen species (ROS) production, reduced mitochondrial membrane potential (MMP), and promoted apoptosis in HTR-8 cells. These effects were attenuated by acetylcysteine (NAC). In primary rat trophoblast cells, ZEN at ≥ 50 μM similarly triggered ROS generation, decreased MMP, and enhanced apoptosis, which were partially reversed by NAC. Western blot analysis further revealed that ZEN at concentrations as low as 5 μM induced autophagy in HTR-8 cells, as evidenced by increased levels of BECLIN1, LC3B, and p62. Notably, the ZEN-induced upregulation of LC3B protein was attenuated by NAC. ZEN remarkably reduced the phosphorylation of AKT1, AKT2, ERK1/2, and mTOR. These findings suggest that ZEN may harm pregnancy health through ROS-mediated apoptosis and autophagy in trophoblast cells.},
}
@article {pmid41124265,
year = {2025},
author = {Li, N and Liu, Z and Chen, C and Jiang, H and Liu, Y and Ni, D},
title = {Activatable fluorescent ratiometric probes for early diagnosis and prognostic assessment of acute kidney injury.},
journal = {Science advances},
volume = {11},
number = {43},
pages = {eaea1654},
pmid = {41124265},
issn = {2375-2548},
mesh = {*Acute Kidney Injury/diagnosis/metabolism ; Animals ; Mice ; *Fluorescent Dyes/chemistry ; Early Diagnosis ; Prognosis ; Hydrogen Peroxide/metabolism ; Humans ; Hepatitis A Virus Cellular Receptor 1/metabolism ; Male ; Disease Models, Animal ; Kidney/metabolism ; },
abstract = {Early and accurate diagnosis of acute kidney injury (AKI) is crucial for clinical treatment. However, most existing fluorescent probes are prone to background interference and limited renal targeting. We developed a ratiometric nanoprobe (RP-SC) that synergistically responded to H2O2 and targeted kidney injury molecule-1 (KIM-1). In AKI kidneys, RP-SC was hydrolyzed and slowly released encapsulated Hcy-BOH and Cy-Dopa. The H2O2 level was semi-quantitatively analyzed by fluorescence ratio (FHcy-BOH/FCy-Dopa). RP-SC exhibited prominent renal fluorescence in AKI mice, making it possible to accurately diagnose AKI and dynamically monitor renal function for up to 60 hours. RP-SC could monitor the process of AKI in vivo and provide an earlier warning of AKI than traditional strategies, subsequently evaluating the recovery of renal function after N-acetyl cysteine (NAC) treatment. Our study confirmed the ability of RP-SC for longitudinal monitoring of renal function in vivo by dual-targeting capacity, providing an effective tool for accurate diagnosis of early AKI while tracking the dynamic process of AKI treatment.},
}
@article {pmid41114544,
year = {2025},
author = {Altowijri, MA and Abdelmageed, ME and El-Gamal, R and El-Agamy, DS},
title = {The protective effects of neferine against paracetamol-induced liver injury are associated with the activation of SIRT1/Nrf2/HO-1 signaling pathway and inhibition of NF-kappa B/TNF-alpha/iNOS/COX-II cascade.},
journal = {Drug and chemical toxicology},
volume = {48},
number = {6},
pages = {1394-1409},
doi = {10.1080/01480545.2025.2559844},
pmid = {41114544},
issn = {1525-6014},
mesh = {Animals ; *Acetaminophen/toxicity ; Sirtuin 1/metabolism ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/pathology/etiology/metabolism ; NF-E2-Related Factor 2/metabolism ; NF-kappa B/metabolism ; Signal Transduction/drug effects ; Mice ; Male ; Tumor Necrosis Factor-alpha/metabolism ; *Benzylisoquinolines/pharmacology ; Nitric Oxide Synthase Type II/metabolism ; Cyclooxygenase 2/metabolism ; Liver/drug effects/pathology ; Heme Oxygenase-1/metabolism ; Oxidative Stress/drug effects ; Membrane Proteins ; },
abstract = {Drug-induced hepatotoxicity is a significant public health issue that influences the development of novel pharmaceutical therapies and the retraction of numerous promising medications from the market. Therefore, the current study investigated the potential hepato-protective benefits of NEF against hepatotoxicity caused by paracetamol (APAP) in mice and assessed its underlying mechanisms. Mice were divided randomly into six groups; control (received normal saline), NEF control, APAP, N-acetylcysteine (NAC; served as a standard treatment) + APAP, NEF (10 mg/kg) + APAP, and NEF (20 mg/kg) + APAP. The serum and hepatic tissues were collected for different biochemical, genetic, and histological assessments. APAP induced profound hepatic damage that was evident through all biochemical, histological, and molecular assessments. NEF pretreatment opposed the elevation of liver injury biomarkers and attenuated hepatic histological disruption. At the molecular level, NEF increased the hepatic level and protein expression of SIRT-1. NEF increased the hepatic mRNA and protein expression of Nrf2 and HO-1. NEF also decreased hepatic level of oxidative stress biomarker, MDA and increased the hepatic levels of antioxidants: GSH, GR, GST, TAC, and SOD, NEF also counteracted the activation of NF-κB and inhibited the upregulation of different inflammatory cytokines as TNF-α and interleukins- (IL-1β and IL-6). Furthermore, NEF pretreatment decreased the hepatic level and mRNA expression of COX-II and iNOS. NEF ameliorated APAP-induced liver injury in mice where the higher dose of NEF (20 mg/kg) was more effective than the lower (10 mg/kg) compared to NAC. This effect is association with upregulation of SIRT-1/Nrf2/HO-1 and interruption of NF-κB/cytokines/iNOS/COX-II signaling cascades.},
}
@article {pmid41114213,
year = {2025},
author = {Liška, TJ and Janovec, L and Michalková, R and Potočňák, I and Samolova, E and Tvrdoňová, M and Bekešová, S and Gramblička, M and Kudličková, Z and Trizna, L and Sabolová, D and Mojžiš, J and Vilková, M},
title = {Conformational Dynamics, Isomerization, and Biological Activity of Acridine-Thiazolidinone Hybrids: A Combined Experimental and Theoretical Study.},
journal = {ACS omega},
volume = {10},
number = {40},
pages = {47007-47021},
pmid = {41114213},
issn = {2470-1343},
abstract = {A new series of acridin-4-yl-based thiazolidinone derivatives was synthesized and structurally characterized using NMR, IR, HRMS, and single-crystal X-ray diffraction. NMR analysis in solution revealed signal multiplicity suggestive of isomeric or conformational heterogeneity. To investigate this behavior, we employed GFN2-xTB, DFT (PBE0-D4 and revDSD-PBEP86-D4), and ab initio molecular dynamics simulations. Theoretical results indicated a preference for nonplanar conformers due to steric hindrance and internal rotations, in agreement with experimental NMR and crystallographic data. Conformational searches and NMR prediction further supported the predominance of E C1N2 Z N3C4 Z C7C8 and Z C1N2 E N3C4 Z C7C8 isomers in solutions. Biological evaluation revealed selective cytotoxicity of compound 4e against HeLa and A549 cell lines (IC50 = 14.75 and 17.75 μM, respectively). Mechanistic studies in HeLa cells demonstrated dose-dependent apoptosis induction, mitochondrial membrane hyperpolarization, cytochrome c release, S-phase cell cycle arrest, and elevated intracellular ROS. Co-treatment with the antioxidant N-acetylcysteine (NAC) significantly mitigated these effects, suggesting a ROS-mediated mitochondrial apoptotic pathway. This integrated experimental-theoretical study highlights the importance of conformational dynamics in modulating biological activity and provides valuable insights into the structure-activity relationship of acridine-thiazolidinone hybrids. The results support their potential as modular scaffolds for further development of anticancer agents.},
}
@article {pmid41113963,
year = {2025},
author = {Bai, LY and Chiu, CF and Wu, CY and Weng, JR},
title = {Hydrogen peroxide and cisplatin regulate the ROS/PKM2 pathway to affect the growth of cancer.},
journal = {American journal of cancer research},
volume = {15},
number = {9},
pages = {4082-4091},
pmid = {41113963},
issn = {2156-6976},
abstract = {Aberrant production of reactive oxygen species (ROS) cause DNA damage which led to the chronic diseases and cancer. During glycolysis, the enzyme pyruvate kinase M2 (PKM2) is responsible for energy metabolism and its overexpression can be found in various malignancies. To investigate the impact of PKM2 and ROS, hydrogen peroxide (H2O2) and cisplatin were used. This study showed that H2O2 and cisplatin induced ROS production and apoptosis in these four tumor cells: pancreatic cancer, oral cancer, gastric cancer, and hepatocellular carcinoma. In addition, H2O2- and cisplatin-increased apoptosis was partially reduced by pre-treatment with an antioxidant N-acetylcysteine (NAC) in SC-M1 gastric cancer and HSC-3 oral cancer cells. Interestingly, the levels of p-PKM2 in the nucleus were downregulated after treatment with H2O2 and cisplatin. This phenomenon was reversed with the combination of NAC. These findings provide PKM2 may be a potential target for anticancer therapy.},
}
@article {pmid41110517,
year = {2026},
author = {Hu, Y and Gong, Q and Jia, X and Zhu, Q and Zheng, C and Ali, T and Li, S and Liang, R and Feng, J},
title = {P2Y6 receptor blockade promotes depression-like symptoms through oxidative stress and impaired autophagy.},
journal = {Free radical biology &amp; medicine},
volume = {242},
number = {},
pages = {203-219},
doi = {10.1016/j.freeradbiomed.2025.10.268},
pmid = {41110517},
issn = {1873-4596},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Autophagy/drug effects ; Mice ; *Depression/metabolism/pathology/drug therapy/genetics/chemically induced ; Male ; Hippocampus/metabolism/drug effects/pathology ; Disease Models, Animal ; *Receptors, Purinergic P2/metabolism/genetics ; Mice, Inbred C57BL ; Signal Transduction ; Stress, Psychological ; },
abstract = {The P2Y6 receptor (P2Y6R) is implicated in neuroinflammation and synaptic plasticity, but its role in depression remains unclear. This study reveals a crucial role for the P2Y6 receptor (P2Y6R) in depression. Using a chronic restraint stress (CRS) mouse model, we found reduced hippocampal P2Y6R expression. Pharmacological inhibition of P2Y6R with MRS2578 (MRS) induced robust depressive-like behaviors in mice, including anhedonia and behavioral despair, accompanied by decreased hippocampal serotonin and norepinephrine. At the molecular level, MRS disrupted synaptic integrity, evidenced by reduced expression of key synaptic proteins (PSD95, synaptophysin, SNAP25, mature BDNF) and impaired associated signaling pathways. Our multi-omics analysis further showed that P2Y6R inhibition profoundly disrupted neuronal autophagic flux and metabolic homeostasis. The late-stage autophagy inhibitor chloroquine was more effective than the early-stage inhibitor 3-methyladenine in attenuating MRS-induced depressive symptoms and restoring synaptic protein expression. This suggests that lysosomal dysfunction is a key contributor to the pathology. We identified that MRS disrupts neuronal autophagy primarily through the P2Y6R-Oxidative stress axis, as evidenced by dysregulated antioxidant defences and increased oxidative damage markers, including protein carbonyls (PC), 3-nitrotyrosine (3-NT), and the lipid peroxidation product 4-hydroxynonenal (4-HNE). Crucially, antioxidant intervention with N-acetylcysteine (NAC) rescued MRS-induced depressive behaviors, synaptic deficits, and normalized oxidative stress and autophagy dynamics. Validation with P2Y6R agonists confirmed that the observed effects were specific to P2Y6R inhibition. These findings establish the P2Y6R-Oxidative stress-autophagy axis as a novel and promising therapeutic target for Major Depressive Disorder, offering new avenues for more effective treatments.},
}
@article {pmid41109361,
year = {2026},
author = {Chentunarayan Singh, N and Yadav, N and Sharma, RK and Gupta, P and Sarkar, J and Mitra, K},
title = {Oxidative stress-mediated DNA damage promotes selective degradation of nuclear components via noncanonical autophagy in triple-negative breast cancer cells.},
journal = {Free radical biology &amp; medicine},
volume = {242},
number = {},
pages = {37-53},
doi = {10.1016/j.freeradbiomed.2025.10.264},
pmid = {41109361},
issn = {1873-4596},
mesh = {Humans ; *Autophagy/drug effects ; *Oxidative Stress/drug effects ; *Triple Negative Breast Neoplasms/genetics/metabolism/pathology/drug therapy ; *DNA Damage/drug effects ; Female ; Autophagy-Related Protein 5/genetics/metabolism ; Cell Line, Tumor ; Beclin-1/genetics/metabolism ; Cell Nucleus/metabolism/drug effects ; Apoptosis/drug effects ; },
abstract = {SK (SK), a secondary plant metabolite from Lithospermum erythrorhizon, is an inducer of oxidative stress and a DNA Topoisomerase inhibitor with promising anticancer properties. However, the underlying mechanisms, especially the involvement of autophagy in cancer cell death, are poorly understood. Here, we report a novel mechanism of action that activates a noncanonical, Beclin1-independent but ATG5-dependent autophagy pathway triggered by oxidative stress in two distinct subtypes of triple-negative breast cancer (TNBC) cell lines: mesenchymal stem cell-like MDA-MB-231 and basal-like-1 MDA-MB-468. We observed that this noncanonical autophagy pathway specifically targets and degrades nuclear material by nucleophagy. Electron microscopy analysis of both cell lines revealed distinct nuclear alterations, including envelope-limited chromatin sheets (ELCS), nuclear buds, and micronuclei after SK treatment. Furthermore, numerous autophagosomes and lysosomes were found in close proximity to the nuclear membrane, suggesting the occurrence of nucleophagy. The localization of γ-H2AX in nuclear buds and micronuclei observed by confocal microscopy indicated cytosolic leakage of damaged DNA. Additionally, Western blot analysis confirmed the role of the cGAS-STING pathway, which is essential for detecting damaged DNA in the cytosol. Inner nuclear membrane protein Lamin B1 was found to interact with LC3II and was subsequently degraded through the nucleophagy pathway. Knockout of ATG5 using CRISPR-Cas9 reduced autophagy, while Beclin1 knockdown did not reduce LC3II conversion, indicating that the process follows a noncanonical autophagy pathway that is dependent on ATG5 and independent of Beclin1. SK induces oxidative stress, leading to mitochondrial depolarization and DNA damage accumulation, which subsequently triggers autophagy and ultimately causes apoptotic cell death. Treatment with the ROS scavenger N-acetylcysteine (NAC) reduced nuclear stress, mitochondrial dysfunction, autophagy, and cell death, emphasizing the role of oxidative stress in SK-induced cell death. MDA-MB-468 cells exhibited greater sensitivity to SK-induced nuclear stress and cell death compared to MDA-MB-231 cells. Taken together, we demonstrate that SK exerts its anticancer effects in TNBC cells through the generation of oxidative stress and noncanonical autophagy, thus highlighting SK's potential for targeted anticancer therapeutics.},
}
@article {pmid41099880,
year = {2025},
author = {Lee, MY and Tseng, WL and Yang, ZY and Chien, TM and Chiu, CC and Lo, YH and Chen, CY and Chang, HW},
title = {Ginger-derived 1-(4'-hydroxy-3'-methoxyphenyl)-5-methoxydecan-3-one (HMPM) induces apoptosis and DNA damage against triple-negative breast cancer cells in vitro.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {1036},
doi = {10.1007/s11033-025-11150-6},
pmid = {41099880},
issn = {1573-4978},
support = {ZYAFGH_A_114013//Zuoying Armed Forces General Hospital/ ; ZYAFGH_A_114013//Zuoying Armed Forces General Hospital/ ; ZYAFGH_A_114013//Zuoying Armed Forces General Hospital/ ; NSTC 114-2314-B-037-032//National Science and Technology Council/ ; NSTC 114-2320-B-037-015//National Science and Technology Council/ ; KMU-TB114009//Kaohsiung Medical University/ ; KMU-TC114A04//Kaohsiung Medical University Research Center/ ; },
mesh = {Humans ; *Triple Negative Breast Neoplasms/drug therapy/metabolism/genetics/pathology ; *Apoptosis/drug effects ; *DNA Damage/drug effects ; Cell Line, Tumor ; *Zingiber officinale/chemistry/metabolism ; Cell Proliferation/drug effects ; Oxidative Stress/drug effects ; Female ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; },
abstract = {BACKGROUND: Ginger contains many biocompounds, but the antiproliferative effects of its phenylalkanoids (such as 1-(4'-hydroxy-3'-methoxyphenyl)-5-methoxydecan-3-one (HMPM)) on cancer cells are rarely reported. This study aims to explore the antiproliferative effects and mechanisms of HMPM on triple-negative breast cancer (TNBC) cells.<br><br>METHODS: ATP-based viability, flow cytometry, and Western blotting were conducted to explore the anti-TNBC in vitro effects and mechanisms.<br><br>RESULTS: HMPM inhibits the proliferation of several breast cancer cell lines. Two TNBC cell lines (Hs578T and MDA-MB-231), showing the highest sensitivity to HMPM, exhibited oxidative stress-dependent antiproliferation, as validated by N-acetylcysteine (NAC). Regarding flow cytometry, HMPM changes cell cycle distribution; upregulates apoptosis (annexin V), reactive oxygen species, and mitochondrial oxidative stress; and downregulates mitochondrial membrane potential and glutathione to a greater extent in TNBC cells than in normal breast cells (H184B5F5/M10), attenuated by NAC. Regarding flow cytometry and Western blotting, HMPM notably triggers oxidative stress-mediated caspase 3 and 8 activation in TNBC cells compared to M10 cells. Finally, HMPM causes oxidative DNA damage, as indicated by &#x3b3;H2AX and 8-hydroxy-2-deoxyguanosine flow cytometry.<br><br>CONCLUSION: Taken together, the ginger-derived HMPM offers antiproliferative activity against TNBC cells via oxidative stress-dependent changes with limited cytotoxicity to normal cells.},
}
@article {pmid41098416,
year = {2025},
author = {Kuo, WT and Lai, IH},
title = {Medication, Nutrition, and Hygiene in COVID-19 Prevention and Treatment: A Comprehensive Narrative Review.},
journal = {Global challenges (Hoboken, NJ)},
volume = {9},
number = {10},
pages = {e00223},
pmid = {41098416},
issn = {2056-6646},
abstract = {Despite advances in Coronavirus Disease 2019 (COVID-19) prevention and treatment, emerging variants and persistent challenges continue to affect global health. Studies are retrieved from PubMed using title-based searches for COVID-19, SARS-CoV-2, and related therapies from 2020 to 2025, focusing on randomized controlled trials, systematic reviews, and clinical guidelines. This review explores treatments, nutrients, and adjuvant therapies that support the immune system in fighting COVID-19. It highlights the role of antiviral medications such as remdesivir, nirmatrelvir/ritonavir, and molnupiravir in reducing mortality and hospitalizations. Additionally, adjunctive therapies like corticosteroids, interleukin-6 (IL-6) inhibitors, Janus kinase (JAK) inhibitors, and N-acetylcysteine (NAC) are discussed for their potential to modulate inflammation. Nutritional support, including omega-3 fatty acids, vitamins D, C, and A, zinc, selenium, and probiotics, enhances immune function. Preventive measures, such as hygiene practices, wearing masks, and physical distancing, reduce transmission. An integrated approach that combines antiviral treatments with adjunctive therapies, prevention, and nutrition is crucial for improving outcomes.},
}
@article {pmid41085263,
year = {2025},
author = {Shi, M and Li, X and Fan, Z and Wang, Y and Li, C and Ning, Y and Ma, Y and Sun, M and Xia, X and Du, J and Zheng, JC},
title = {N-Acetylcysteine-Capped TLQP21-Containing Au Nanocages Alleviate Depression in Mice.},
journal = {ACS nano},
volume = {19},
number = {42},
pages = {37186-37205},
pmid = {41085263},
issn = {1936-086X},
mesh = {Animals ; *Acetylcysteine/chemistry/pharmacology ; Mice ; *Gold/chemistry ; Oxidative Stress/drug effects ; Male ; Mice, Inbred C57BL ; *Major Depressive Disorder/drug therapy ; *Metal Nanoparticles/chemistry ; Antioxidants/chemistry/pharmacology ; *Depression/drug therapy ; Microglia/drug effects ; },
abstract = {Major depressive disorder (MDD) is the most prevalent neuropsychiatric disorder globally. Promising therapies for MDD are urgently needed due to the limited effectiveness, delayed efficacy, and non-negligible side effects of current treatments. Oxidative stress and neuroinflammation have been recognized as key contributors to MDD. Here, we developed an antioxidant N-acetylcysteine (NAC)-capped Au nanocage (TNNC) that entrapped VGF-derived peptide TLQP21 with neuro-immunomodulatory effects. Once internalized by cells suffering from oxidative stress, NAC was consumed, and TLQP21 was released from TNNC. TNNC administration alleviated MDD-like behaviors of the chronic unpredictable mild stress (CUMS)-exposed mice and effectively relieved oxidative stress in the brains. Moreover, TLQP21 in TNNC inhibits the activation, excessive synaptic pruning, and inflammatory responses of microglia through targeting the complement C1q receptor (C1qR) and complement C3a receptor 1 (C3aR1). This work provides a bioinspired strategy to target multiple pathogenic factors in one nanoparticle for the intervention of MDD and other diseases.},
}
@article {pmid41083115,
year = {2026},
author = {Hu, H and Chen, J and Wang, X and Gong, M and Li, W and Liu, Y and Li, H and Huang, M and Liu, A and Liu, Z},
title = {Resveratrol attenuates trimethyltin chloride-induced cardiac defects via the ROS/Wnt/β-catenin pathway.},
journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP},
volume = {299},
number = {},
pages = {110373},
doi = {10.1016/j.cbpc.2025.110373},
pmid = {41083115},
issn = {1532-0456},
mesh = {Animals ; *Zebrafish/embryology ; *Resveratrol/pharmacology ; *Reactive Oxygen Species/metabolism ; *Wnt Signaling Pathway/drug effects ; *Trimethyltin Compounds/toxicity ; *Heart Defects, Congenital/chemically induced/metabolism/prevention &amp; control/drug therapy ; Apoptosis/drug effects ; *Heart/drug effects/embryology ; Embryo, Nonmammalian/drug effects/metabolism ; Antioxidants/pharmacology ; DNA Damage/drug effects ; },
abstract = {Trimethyltin chloride (TMT), a toxic byproduct of organotin manufacturing, is an emerging environmental contaminant linked to developmental cardiotoxicity. However, its pathogenic mechanism remains undefined. Here, using zebrafish embryos, we show that TMT exposure induced dose-dependent cardiac malformations, increasing pericardial area by 44.9 % and decreasing heart rate by 16.8 % at 5 μM (both P < 0.001), accompanied by excessive ROS (+48.5 %, P < 0.001) and mitochondrial ROS (+82.8 %, P < 0.001) generation. Co-treatment with resveratrol (RSV) or the ROS inhibitor N-acetylcysteine (NAC) reduced TMT-induced cardiac defects and suppressed ROS and mitochondrial ROS overproduction (all P < 0.05). RSV or NAC also mitigated DNA damage, mitochondrial injury, and apoptosis in the heart. Mechanistically, TMT inhibited the Wnt/β-catenin signaling pathway (-61.7 % β-catenin, P < 0.001), an effect attenuated by RSV or NAC. Inhibition of apoptosis with Ac-DEVD-CHO or activation of Wnt/β-catenin signaling with CHIR likewise alleviated TMT-induced cardiac malformations. These results indicate that TMT disrupts heart development through ROS-mediated suppression of Wnt/β-catenin signaling, leading to mitochondrial damage, DNA damage, and apoptosis. Furthermore, RSV, a dietary antioxidant, provides significant protection against TMT-induced cardiac developmental toxicity. This study identifies potential molecular targets for preventing and treating embryonic heart injury caused by environmental toxicants.},
}
@article {pmid41081839,
year = {2025},
author = {Prisciandaro, JJ and Jarnecke, AM and Joseph, JE and Gray, KM and Santa Ana, EJ and Back, SE},
title = {Effects of N-acetylcysteine treatment on frontal glutamate and GABA levels and associations with drinking quantity in people with co-occurring posttraumatic stress disorder and alcohol use disorder.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41081839},
issn = {1432-2072},
abstract = {RATIONALE: Though half of people with posttraumatic stress disorder (PTSD) develop alcohol use disorder (AUD), co-occurring PTSD and AUD (PTSD + AUD) is associated with more severe clinical outcomes relative to either alone and little remains known about the pathophysiology of PTSD + AUD. PTSD and AUD have each been associated with marked dysfunction in brain glutamate and GABA systems, making these systems promising targets for pharmacological intervention, including N-acetylcysteine (NAC), which restores extracellular glutamate concentrations via GLT-1 and System Xc-.<br><br>OBJECTIVES AND METHODS: Based on promising results from our pilot study of NAC, we recently completed a 12-week, randomized, double-blind, placebo-controlled clinical trial of NAC for PTSD&#x2009;+&#x2009;AUD. As part of this trial, we acquired proton MR spectroscopy ([1]H-MRS) data at pretreatment and&#x2009;~&#x2009;8-weeks posttreatment in a subsample of (n&#x2009;=&#x2009;44) participants to evaluate whether NAC significantly affects frontal glutamate levels (i.e., represented by Glx, glutamate&#x2009;+&#x2009;glutamine), with exploratory evaluation of GABA and glutathione levels, and whether NAC-related changes in neurometabolite levels correspond to decreased drinking and/or PTSD symptoms, in people with PTSD&#x2009;+&#x2009;AUD.<br><br>RESULTS: We found that NAC was associated with significantly higher frontal Glx (t&#x2009;=&#x2009;2.45, p&#x2009;=&#x2009;0.017), and significantly lower GABA (t&#x2009;=&#x2009;-2.82, p&#x2009;=&#x2009;0.007) but equivalent glutathione (t&#x2009;=&#x2009;-1.00, p&#x2009;=&#x2009;0.321), levels relative to placebo. Finally, lower NAC-related GABA, but not Glx or glutathione, levels were significantly associated with decreased drinks per drinking day (t&#x2009;=&#x2009;2.57, p&#x2009;=&#x2009;0.014), but not percent drinking days or PTSD symptoms (ps&#x2009;>&#x2009;0.10).<br><br>CONCLUSIONS: Though preliminary, these findings are consistent with the mechanistic hypothesis that NAC reduces drinking quantity through its effects on excitatory and inhibitory neurotransmission in people with PTSD&#x2009;+&#x2009;AUD.},
}
@article {pmid41073871,
year = {2026},
author = {Mandler, WK and Knepp, AK and Leonard, SS and McKinney, W and Keeley, S and Qian, Y},
title = {Characterization of engineered stone dust-induced reactive oxygen species generation and cytotoxicity in vitro.},
journal = {Journal of toxicology and environmental health. Part A},
volume = {89},
number = {7},
pages = {304-314},
doi = {10.1080/15287394.2025.2562482},
pmid = {41073871},
issn = {2381-3504},
mesh = {*Reactive Oxygen Species/metabolism ; *Dust/analysis ; Mice ; Animals ; RAW 264.7 Cells ; *Silicon Dioxide/toxicity ; Apoptosis/drug effects ; Cell Survival/drug effects ; Macrophages/drug effects ; *Construction Materials/toxicity ; },
abstract = {Engineered stone (ES) fabrication generates respirable dust containing crystalline silica (CS), linked to accelerated silicosis outbreaks. Mechanisms underlying this toxicity, particularly the role of particle aging, remain unclear. In the occupational setting, workers are exposed to engineered stone dust (ESD) upon generation by cutting and grinding ES; however, ESD-initiated toxicity is frequently studied in labs using aged particles. This study aimed to compare radical generation and in vitro cytotoxicity of fresh versus aged ESD. Three different respirable ES types (ES A: 60% CS; B: 20%; C: 0%), granite (30%), and Min-u-Sil 5 (MS5, 99.5%) were generated using an automated cutting system and analyzed either freshly stored under N2 at -80°C or after aging in air at room temperature for 2 weeks. RAW 264.7 macrophages were exposed to particles (10 µg/well, 100 µg/ml, 31.25 µg/cm[2], 24 hr), and viability, apoptosis, necrosis, and intracellular reactive oxygen species (ROS) were measured. Fresh ESD/granite exhibited significantly higher electron paramagnetic resonance (EPR) radical signals than aged counterparts and MS5. Fresh ES/granite reduced macrophage viability, while aged materials/MS5 did not. Apoptosis increased with all particles where fresh/aged difference occurred only in ES B. Necrosis rose markedly with fresh ES A. Intracellular ROS was elevated by some materials, but N-acetylcysteine (NAC) antioxidant failed to prevent cytotoxicity induced by fresh particles. In conclusion, freshly generated ESD displayed greater radical-generating capacity and distinct cytotoxic effects compared to aged ESD, influenced by factors beyond CS content. ROS-independent mechanisms appear crucial for acute cytotoxicity. These findings indicate particle aging as a critical factor in ESD toxicological assessment.},
}
@article {pmid41072831,
year = {2025},
author = {Hösch, NG and Reis, RAF and Novaes, RD and Nascimento, CGO and Ventura, RR and Ruginsk, SG and Amin-Naves, J},
title = {N-acetylcysteine prevents ethanol-induced neuropathic pain by downregulating nociceptive activation of supraspinal brain areas.},
journal = {Alcohol (Fayetteville, N.Y.)},
volume = {129},
number = {},
pages = {134-144},
doi = {10.1016/j.alcohol.2025.10.003},
pmid = {41072831},
issn = {1873-6823},
mesh = {Animals ; Male ; *Acetylcysteine/pharmacology/therapeutic use ; *Ethanol/toxicity ; Rats, Wistar ; Rats ; *Neuralgia/prevention &amp; control/chemically induced ; Down-Regulation/drug effects ; *Brain/drug effects/metabolism ; *Nociception/drug effects ; *Alcoholic Neuropathy/prevention &amp; control ; Hyperalgesia/prevention &amp; control/chemically induced ; },
abstract = {Considering the important clinical applications of N-acetylcysteine (NAC), the present study investigated the effects of NAC treatment on ethanol-induced neuropathic alterations. For this purpose, a total number of eighty-one male adult Wistar rats were used. Alcoholic neuropathy was induced by administration of 38 % (v/v) ethanol (10 g/kg/day, oral gavage) for 10 weeks. NAC solution (1.4 g/kg/day, oral gavage) was administered immediately after ethanol treatment, also for 10 weeks. The electronic von Frey, Randall Selitto and tail flick tests were used to characterize the nociceptive thresholds to mechanical and thermal stimulations. The Rota-rod test was used to evaluate motor coordination, whereas the open field test was employed to assess general locomotor activity. The present study also determined the integrity of the sciatic nerve and the number of c-Fos immunoreactive neurons in key brain structures. As expected, long-term exposure to ethanol reduced the thickness of myelin sheath in the peripheral nerve, as well as induced allodynia, mechanical and thermal hypernociception, as well as motor incoordination. Although ethanol treatment did not alter general locomotor activity, it increased the number of rearing events, indicating enhanced exploratory behavior. In the brain, chronic ethanol consumption was associated with higher levels of c-Fos expression in the dorsal raphe nucleus, parvocellular and magnocellular groups of the hypothalamic paraventricular nucleus, and also in the periaqueductal gray. Consistent with its protective effects, NAC treatment prevented the development of all ethanol-induced alterations, including at central level. Taken together, these results suggest that NAC consistently prevents ethanol-induced neuropathy.},
}
@article {pmid41071453,
year = {2025},
author = {Ma, G and Yin, G and Wu, X and Yang, Z},
title = {FAM72A Promotes Colorectal Cancer Progression by Regulating Reactive Oxygen Species and Inhibiting Cellular Pyroptosis.},
journal = {Digestive diseases and sciences},
volume = {},
number = {},
pages = {},
pmid = {41071453},
issn = {1573-2568},
abstract = {BACKGROUND AND AIMS: Colorectal cancer (CRC) is a common malignant tumor worldwide with a complex pathogenesis and an urgent need for new molecular targets. The aim of this study was to investigate the expression of FAM72A in CRC and its potential mechanism to affect cancer cell proliferation and invasion through regulating cellular pyroptosis.<br><br>METHODS: The expression of FAM72A in various cancers was analyzed by TIMER2.0 and GEPIA2 databases, and its relationship with the prognosis of CRC patients was evaluated. FAM72A was knocked down and overexpressed in CRC cell lines HCT116 and DLD1, respectively, and changes in cell proliferation and invasion ability were assessed by CCK-8, EdU, Transwell, and scratch assays. Meanwhile, the regulatory effects of FAM72A on cellular pyroptosis-associated proteins and inflammatory factors were detected by Western blotting and ELISA, and the role of ROS in FAM72A-regulated cellular pyroptosis and cancer cell behaviors was further explored by N-Acetylcysteine (NAC) intervention assay. Finally, the effect of FAM72A on tumor growth was verified by in vivo nude mouse experiments.<br><br>RESULTS: High levels of FAM72A expression were observed in CRC, linking it to poor prognosis in patients. Knockdown of FAM72A significantly inhibited the proliferation, migration, and invasion of CRC cells and activated cellular pyroptosis, accompanied by the upregulation of NLRP3, Caspase-1, and GSDMD expression and the increased secretion of IL-1&#x3b2; and IL-18. In contrast, overexpression of FAM72A inhibited cell pyroptosis and enhanced cancer cell proliferation and invasion. NAC intervention experiments demonstrated that ROS played a critical role in FAM72A-regulated cell pyroptosis and CRC progression. Furthermore, in vivo experiments showed that knockdown of FAM72A significantly inhibited the growth of subcutaneous transplanted tumors in nude mice.<br><br>CONCLUSION: FAM72A inhibits cellular pyroptosis by decreasing ROS levels, which in turn promotes the proliferation and invasion of CRC cells, and it is expected to be a potential therapeutic target for CRC.},
}
@article {pmid41067161,
year = {2025},
author = {Ogawa, H and Uchida, Y and Enjuto, LE},
title = {N-acetylcysteine inhalation improved sputum rheology in chronic productive cough: Clinical application in two cases.},
journal = {Respiratory investigation},
volume = {63},
number = {6},
pages = {1246-1249},
doi = {10.1016/j.resinv.2025.08.009},
pmid = {41067161},
issn = {2212-5353},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage ; *Sputum ; Aged ; Male ; *Cough/drug therapy ; *Rheology ; Female ; Administration, Inhalation ; Chronic Disease ; Pilot Projects ; Quality of Life ; Middle Aged ; Retrospective Studies ; Asthma/drug therapy/complications ; },
abstract = {This pilot study evaluated the effects of inhaled N-acetylcysteine (NAC) on sputum rheology in patients with chronic productive cough (CPC). Rheological measurements before and 30 min after inhalation were compared retrospectively in 16 outpatients receiving either NAC (n = 9) or bromhexine hydrochloride (BXH) (n = 7). NAC inhalation significantly reduced critical strain (γC), an indicator of sputum stringiness, from 2370 [1310-4390] % to 643 [389-700] % (median and interquartile range), with a significantly greater effect than BXH. This reduction was observed regardless of airway fungal colonization. In addition, two case reports, a 67-year-old man with bronchorrhea and a 79-year-old woman with refractory asthma, demonstrated improved quality-of-life scores evaluated with the Cough and Sputum Assessment Questionnaire (CASA-Q) and rheological improvement following 1-2 weeks of twice-daily NAC inhalation. These findings suggest that nebulized NAC may be a promising add-on therapy for refractory airway diseases characterized by high sputum stringiness (γC).},
}
@article {pmid41065101,
year = {2025},
author = {Kang, LP and Li, NN and Chen, PS and Chen, HH and Huang, DH and Jiang, ZB},
title = {Plumbagin Triggers STING Pathway Activation to Suppress Non-Small Cell Lung Cancer Progression.},
journal = {Chemical biology &amp; drug design},
volume = {106},
number = {4},
pages = {e70176},
doi = {10.1111/cbdd.70176},
pmid = {41065101},
issn = {1747-0285},
support = {2022A1515110790//Guangdong Basic and Applied Basic Research Foundation of China/ ; 2024A1515012478//Guangdong Basic and Applied Basic Research Foundation of China/ ; 20251345//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 20221361//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 20241285//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 2320004000290//Zhuhai Science and Technology Innovation Bureau/ ; 2420004000007//Zhuhai Science and Technology Innovation Bureau/ ; 2420004000006//Zhuhai Science and Technology Innovation Bureau/ ; 242//Zhuhai Science and Technology Innovation Bureau/ ; 202303//Zhuhai Hospital of Integrated Traditional Chinese &amp; Western Medicine/ ; B2025352//Medical Science and Technology Research Fund of Guangdong Province/ ; [2023] 108//Guangdong Province-Provincial Chinese Medicine construction special fund named Traditional Chinese Medicine Inheritance Studio construction project Guangdong Chinese Medicine Office Letter/ ; },
mesh = {*Naphthoquinones/pharmacology/chemistry ; Humans ; *Carcinoma, Non-Small-Cell Lung/pathology/drug therapy/metabolism ; *Lung Neoplasms/pathology/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; *Membrane Proteins/metabolism/antagonists &amp; inhibitors/genetics ; Apoptosis/drug effects ; Signal Transduction/drug effects ; Cell Proliferation/drug effects ; Cell Line, Tumor ; *Antineoplastic Agents, Phytogenic/pharmacology/chemistry ; Cell Survival/drug effects ; STING Protein ; },
abstract = {Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Plumbagin (PLBG), a naturally occurring active naphthoquinone derived from Chinese herbal plants, exhibits anti-cancer effects across multiple cancer types. However, the mechanisms underlying PLBG-induced anti-tumor activity in NSCLC remain incompletely understood. Our study demonstrated that PLBG significantly inhibited NSCLC cell proliferation and induced apoptosis by elevating intracellular and mitochondrial reactive oxygen species (ROS), leading to mitochondrial dysfunction. The ROS scavenger N-acetylcysteine (NAC) abrogated PLBG-induced apoptosis and restored cell viability. Notably, RNA sequencing analysis revealed that differentially expressed genes in PLBG-treated cells were enriched in the cytosolic DNA-sensing pathway and STING pathway. Mechanistically, PLBG treatment activated the STING pathway and upregulated key chemokines (CXCL10, CXCL9, CCL5) in NSCLC cells. Critically, STING inhibition by H151 attenuated PLBG-induced apoptosis, confirming the essential role of STING. These results suggest that PLBG exerts potent anti-NSCLC effects through ROS-mediated apoptosis, STING pathway activation, and chemokine induction, while concurrently inhibiting pro-survival signaling. These findings position PLBG as a promising therapeutic candidate for NSCLC treatment.},
}
@article {pmid41063445,
year = {2025},
author = {Kim, TW and Ko, SG},
title = {Jujuboside B Induces Ferroptosis and Overcomes Radioresistance Through the PPARγ-ATF3-Gpx4 Signaling Pathway in Non-Small Cell Lung Cancer.},
journal = {Phytotherapy research : PTR},
volume = {39},
number = {11},
pages = {5345-5364},
doi = {10.1002/ptr.70111},
pmid = {41063445},
issn = {1099-1573},
support = {2018R1D1A1B07048556//National Research Foundation of Korea/ ; 2020R1A5A2019413//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Ferroptosis/drug effects ; *Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism/radiotherapy ; *Saponins/pharmacology ; Signal Transduction/drug effects ; *Lung Neoplasms/drug therapy/metabolism/radiotherapy ; Cell Line, Tumor ; PPAR gamma/metabolism ; Activating Transcription Factor 3/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Endoplasmic Reticulum Stress/drug effects ; *Radiation Tolerance/drug effects ; TNF-Related Apoptosis-Inducing Ligand/pharmacology ; Animals ; Reactive Oxygen Species/metabolism ; },
abstract = {Jujuboside B (JJB) is a saponin extracted from the Ziziphus jujuba var. spinose and has been reported to have anticancer effects. However, the detailed mechanism of its anti-cancer effect in non-small cell lung cancer (NSCLC) remains unclear. New combination therapies may be able to overcome TRAIL resistance. In this study, we found that JJB regulates the activity of PPARγ and investigated whether the combination of JJB and TRAIL had synergistic anti-cancer effects against NSCLC cells. Experimental procedure: We assessed cell death induced by the combination of TRAIL and JJB in NSCLC cells using ATPlite Luminescence, LDH, and caspase activity assays. We also examined endoplasmic reticulum (ER) stress-mediated cell death using the intracellular calcium assay and western blot analysis. The combination of JJB and TRAIL significantly reduced cell viability and increased apoptotic cell death by binding CHOP to the DR4/5 promoter in NSCLC cells. JJB induced ferroptosis by increasing the expression of Nox4 and ATF3 and the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), as well as by reducing the expression of SLC7A11 and Gpx4 and the level of glutathione (GSH) through the activation of ER stress. Consistent with this, N-acetylcysteine (NAC) suppressed ER stress-mediated ferroptosis by reducing the expression of Nox4, ATF3, and cleaved caspase-3 and by increasing the expression of SLC7A11 and Gpx4 in JJB-treated NSCLC cells. In radioresistant NSCLC models, combined treatment with JJB and radiation induced ferroptosis and overcame radioresistance by regulating the epithelial-mesenchymal transition (EMT) phenomenon. Therefore, JJB could be a potential therapeutic strategy in NSCLC.},
}
@article {pmid41061823,
year = {2026},
author = {Tsai, HR and Chang, WC and Lee, YC},
title = {Oral Acetylcysteine and the Risk of Age-Related Macular Degeneration: A Retrospective Cohort Study.},
journal = {Ophthalmology},
volume = {133},
number = {2},
pages = {223-232},
doi = {10.1016/j.ophtha.2025.09.025},
pmid = {41061823},
issn = {1549-4713},
mesh = {Humans ; Retrospective Studies ; Male ; Female ; *Acetylcysteine/administration &amp; dosage ; Aged ; Taiwan/epidemiology ; Middle Aged ; Administration, Oral ; Risk Factors ; Aged, 80 and over ; *Macular Degeneration/epidemiology/prevention &amp; control ; Propensity Score ; Incidence ; Databases, Factual ; *Antioxidants/administration &amp; dosage ; *Wet Macular Degeneration/epidemiology/prevention &amp; control/diagnosis ; Follow-Up Studies ; Proportional Hazards Models ; },
abstract = {PURPOSE: N-acetylcysteine (NAC) functions as both a direct antioxidant agent and precursor for glutathione (GSH) synthesis, both of which are implicated in the pathogenesis of age-related macular degeneration (AMD). However, whether NAC use confers protective effects against AMD remains unclear. This study aimed to investigate potential associations between NAC use and the risks of AMD development in a large cohort of the Taiwanese population.<br><br>DESIGN: Retrospective cohort study.<br><br>PARTICIPANTS: The study included 22 498 NAC users and 138 607 non-NAC users between 2003 and 2017 before propensity score matching (PSM).<br><br>METHODS: This nationwide, population-based study leveraged data from the Taiwan National Health Insurance Research Database. Propensity score matching was applied to ensure comparability of baseline demographics and comorbidities between NAC users and nonusers. Stratified analyses by age and sex were conducted, and a cumulative defined daily dose was calculated to evaluate dose-response relationships among NAC users. Cox proportional hazards regression models were used post-PSM to estimate the hazard ratio (HR) for each outcome.<br><br>MAIN OUTCOME MEASURES: Outcome measures included the HR of overall, dry, and wet AMD.<br><br>RESULTS: After PSM, 5234 patients were included in each cohort: NAC users and non-NAC users. N-acetylcysteine users exhibited a significantly lower risk of AMD than nonusers did (HR, 0.19; 95% confidence interval [CI], 0.14-0.26; P < 0.001). This protective effect was observed for both dry AMD (HR, 0.19; 95% CI, 0.14-0.26) and wet AMD (HR, 0.31; 95% CI, 0.12-0.81). Stratified analyses demonstrated a reduced risk of AMD among NAC users, consistent across different age and sex groups. A dose-response relationship was identified, with higher cumulative doses of NAC associated with greater reductions in the risk of AMD and dry AMD. Sensitivity analyses for patients aged &#x2265;60 and &#x2265;70 years further supported the association between NAC use and reduced AMD risk, particularly for dry AMD.<br><br>CONCLUSIONS: Use of NAC was associated with a significantly reduced risk of AMD, especially dry AMD. These findings support the need for further investigation into the effectiveness of NAC as a preventive treatment for AMD.<br><br>FINANCIAL DISCLOSURES: The author(s) have no proprietary or commercial interest in any materials discussed in this article.},
}
@article {pmid41061299,
year = {2025},
author = {Park, A and Son, YG and Lee, KW and Kim, JY and Kim, KD},
title = {Rotenone-mediated mitochondrial ROS generation inhibits melanogenesis in B16F10 cells by inducing the ERK activation-MITF degradation pathway.},
journal = {Biochemical and biophysical research communications},
volume = {786},
number = {},
pages = {152762},
doi = {10.1016/j.bbrc.2025.152762},
pmid = {41061299},
issn = {1090-2104},
mesh = {*Rotenone/pharmacology ; *Melanins/biosynthesis/antagonists &amp; inhibitors ; Animals ; Mice ; *Reactive Oxygen Species/metabolism ; *Mitochondria/metabolism/drug effects ; *Microphthalmia-Associated Transcription Factor/metabolism ; Cell Line, Tumor ; Melanoma, Experimental/metabolism/pathology ; *MAP Kinase Signaling System/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Melanogenesis ; },
abstract = {Pachyrhizus erosus seeds have been reported to have various biological activities, including antifungal, antisecretory, insecticidal, antibacterial, and antispasmodic properties. In this study, we evaluated the hypopigmentation effects of the ethanol extract of Pachyrhizus erosus seeds (PESE), identified rotenone as a representative active metabolite, and proposed a mechanism for inhibiting α-MSH-mediated melanogenesis in B16F10 cells. PESE treatment effectively inhibited melanin synthesis in B16F10 cells stimulated with α-MSH or forskolin. Among the three major metabolites characterized from PESE, pachyrrhizine, neotenone, and rotenone, only rotenone exhibited a strong inhibitory effect on melanin synthesis at a concentration of 8 nM, with minimal cytotoxicity. Rotenone suppressed transcriptional expression of melanosomal genes, TRP-1 and TYR, in B16F10 cells stimulated by α-MSH, primarily due to a reduction in the protein level of microphthalmia-associated transcription factor (MITF). Rotenone, an inhibitor of mitochondrial electron transport chain complex I, induced mitochondrial reactive oxygen species (ROS) production, and the increased ROS activated ERK. Treatment with N-acetylcystein (NAC), a ROS scavenger, or PD98059, an ERK inhibitor, suppressed the decrease in MITF protein induced by rotenone, thereby eliminating the hypopigmentation effect of rotenone. These findings provide novel insights into the whitening activity mechanism of rotenone and suggest that mitochondrial damage may affect melanogenesis.},
}
@article {pmid41052996,
year = {2025},
author = {Szkudlarek, HJ and Singh Mann, R and Wieczerzak, K and Sarikahya, MH and Uzuneser, TC and De Felice, M and Rodríguez-Ruiz, M and Galindo, JP and Pusparajah, M and Whitehead, SN and Rushlow, WJ and Hardy, DB and Schmid, S and Yeung, KK and Laviolette, SR},
title = {The antioxidant N-acetylcysteine prevents cortical neuropathological phenotypes caused by adolescent Δ-9-tetrahydrocannabinol exposure in male rats.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {374},
pmid = {41052996},
issn = {2158-3188},
support = {MOP-123378//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Sant&#xe9; du Canada)/ ; },
mesh = {Animals ; *Dronabinol/toxicity/adverse effects ; *Acetylcysteine/pharmacology ; Male ; *Antioxidants/pharmacology ; Rats ; *Oxidative Stress/drug effects ; *Prefrontal Cortex/drug effects/pathology ; Rats, Sprague-Dawley ; Phenotype ; Disease Models, Animal ; },
abstract = {Clinical and pre-clinical evidence demonstrates that adolescent Δ-9-tetrahydrocannabinol (THC) exposure, the primary psychoactive component of cannabis, increases the risk of developing neuropsychiatric symptoms in later life. The medial prefrontal cortex (mPFC) serves as a pathophysiological nexus point underlying many cannabis-related pathophysiological outcomes. Nevertheless, the molecular mechanisms underlying these risk factors are poorly understood. THC increases oxidative stress, which is a well-established causal factor for increased neuropsychiatric risk, including schizophrenia. N-acetylcysteine (NAC) is an antioxidant glutathione precursor that normalizes glutamate and GABA activity in neuropathological states. We examined if NAC may prevent the pathophysiological impacts of THC using a rodent model of adolescent brain development and chronic THC exposure. We report that NAC treatment prevents cognitive, synaptic, neuronal and neurochemical deficits induced by adolescent THC. These findings highlight the critical role of THC-induced oxidative stress as a contributing factor to cannabinoid-mediated neuropsychiatric risk and identifies a novel antioxidant treatment candidate for the prevention and/or reversal of these pathophysiological outcomes.},
}
@article {pmid41049074,
year = {2025},
author = {Sun, X and Shen, L and Zheng, R and Tao, M and Chen, S},
title = {MRPL35 Attenuates Neonatal Parenteral Nutrition-Associated Cholestasis by Modulating the ROS/JNK/NF-κB Pathway.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {13489-13502},
pmid = {41049074},
issn = {1178-7031},
abstract = {OBJECTIVE: This study aimed to elucidate the role of the MRPL35/ROS/JNK/NF-κB signaling pathway in the pathogenesis of neonatal parenteral nutrition-associated cholestasis (PNAC) to identify underlying mechanisms and potential therapeutic targets.<br><br>METHODS: The study employed both human and animal models. Neonates receiving parenteral nutrition for at least 2&#xa0;weeks were divided into PNAC (n=10) and control groups (n=13). A PNAC model was established in male Sprague-Dawley rats (parenteral nutrition for 14 days, n=6/group), with interventions including adenovirus-mediated MRPL35 overexpression and N-acetylcysteine (NAC) treatment. Inflammatory markers, oxidative stress indicators, and signaling pathway activation were assessed using ELISA, immunohistochemistry, qRT-PCR, and Western blotting.<br><br>RESULTS: Clinically, neonates with PNAC exhibited elevated serum levels of AST, DBil, TBA, TNF-&#x3b1;, and IL-1&#x3b2;, along with reduced levels of anti-inflammatory cytokines (IL-4, IL-10), increased ROS, and higher apoptosis in peripheral blood mononuclear cells (PBMCs). MRPL35 expression was significantly downregulated and JNK and NF-&#x3ba;B pathways were activated. In the animal model, PNAC rats showed severe liver injury, elevated TNF-&#x3b1;, IL-1&#x3b2; and ROS in hepatocytes, and higher hepatocyte apoptosis; the expression of MRPL35 mRNA was significantly downregulated. Overexpression of MRPL35 reduced JNK/NF-&#x3ba;B activation, inflammatory cytokines, oxidative stress and liver injury, effects that were enhanced by co-treatment with N-acetylcysteine (NAC).<br><br>CONCLUSION: The MRPL35/ROS/JNK/NF-&#x3ba;B signaling pathway plays a critical role in the pathogenesis of PNAC. Targeting MRPL35 is expected to alleviate liver injury by blocking mitochondrial ROS signaling, offering a novel precision treatment model targeting the mitochondrial-inflammation axis for PNAC.},
}
@article {pmid41045636,
year = {2025},
author = {Sreevaram, HH and Kishore, A and Sivanesan, S and Prabhakaran, M and Karunakaran, B and Kasirajan, SP and Jyothi, AK and Maria Francis, Y},
title = {Comparative neuroprotective efficacy of N-acetylcysteine and naringin in lead-induced neurotoxicity: Restoration of BDNF, neurotransmitters, and cognitive function.},
journal = {Morphologie : bulletin de l'Association des anatomistes},
volume = {109},
number = {367},
pages = {101075},
doi = {10.1016/j.morpho.2025.101075},
pmid = {41045636},
issn = {1286-0115},
mesh = {Animals ; *Flavanones/pharmacology/therapeutic use ; *Brain-Derived Neurotrophic Factor/metabolism ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Acetylcysteine/pharmacology/therapeutic use ; Hippocampus/drug effects/pathology/metabolism ; Male ; *Cognition/drug effects ; Neurotransmitter Agents/metabolism ; Acetylcholine/metabolism ; Glutamic Acid/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/drug effects ; Rats, Wistar ; Organometallic Compounds/toxicity ; Lead/toxicity ; *Lead Poisoning, Nervous System/drug therapy ; Interleukin-6/metabolism ; },
abstract = {BACKGROUND: Exposure to lead acetate is reported to induce neurotoxicity associated with cognitive dysfunction, neurotransmitter dysfunction, oxidative stress, neuroinflammation, and neuronal damage in the hippocampus. Flavonoids and other natural compounds possessing antioxidant and neuroprotective properties can be of therapeutic interest. In the current study, naringin's protective property as a flavonoid was compared with that of N-acetylcysteine (NAC) against lead-induced neurotoxicity in rats.<br><br>METHODS: Adult rats were randomly distributed into control, lead acetate-treated, lead+NAC-treated, lead+low-dose naringin, and lead+high-dose naringin groups, each group containing 6 animals. The Novel Object Recognition (NOR) test was used for the evaluation of cognitive function. Biochemical analysis of hippocampal glutamate, acetylcholine, Brain-Derived Neurotrophic Factor (BDNF), Nuclear factor erythroid 2-related factor 2 (Nrf2), pro-inflammatory markers (IL-6, GFAP), and serum lead levels was done. Histopathological analysis of hippocampal sections by crystal violet staining was done.<br><br>RESULTS: Exposure to lead acetate-induced severe neurotoxicity in the guise of compromised recognition memory, reduced glutamate and acetylcholine content, reduced BDNF and Nrf2 expression, increased IL-6 and GFAP content, and severe hippocampal neuronal damage. NAC treatment effectively reversed cognitive function, neurotransmitter content, neurotrophic factors, and diminished neuroinflammation. Dose-dependent neuroprotection was afforded by naringin, where the high-dose group had better recovery in all the parameters than the low-dose group. Interestingly, high-dose naringin was similar to or even larger than that of NAC's neuroprotection, normalization of hippocampal histoarchitecture, enhancement of antioxidant defense, and decrease in pro-inflammatory markers and serum lead levels.<br><br>CONCLUSION: Lead acetate causes profound neurotoxicity on cognition, neurotransmission, oxidative stress, and inflammation. Naringin, especially at high doses, exhibits highly potent neuroprotective effects, such as NAC, preventing lead-induced cognitive dysfunction and hippocampal pathology by displaying antioxidant, anti-inflammatory, and neurotrophic effects. The results propose naringin as a potential natural drug candidate for preventing and/or treating lead-induced neurotoxicity.},
}
@article {pmid41044637,
year = {2025},
author = {Havaldar, AA},
title = {Successful management of paraquat poisoning: a case report.},
journal = {Journal of medical case reports},
volume = {19},
number = {1},
pages = {479},
pmid = {41044637},
issn = {1752-1947},
mesh = {Humans ; *Paraquat/poisoning ; Adult ; Male ; Female ; *Herbicides/poisoning ; *Immunosuppressive Agents/therapeutic use/administration &amp; dosage ; *Cyclophosphamide/therapeutic use/administration &amp; dosage ; Acetylcysteine/therapeutic use ; Treatment Outcome ; Renal Replacement Therapy/methods ; India ; },
abstract = {BACKGROUND: Paraquat is a herbicide used for weed control and is one of the lethal poisons associated with high mortality. Exposure to this compound could be accidental or as a deliberate self-harm. Clinical manifestations can range from mild symptoms initially to multiorgan failure. Owing to high case fatality (50-90%) and no specific antidote is available; different treatment regimens are proposed with variable success rates. Here, we present two patients with paraquat poisoning, their initial presentation, clinical progress, and successful management.<br><br>CASE PRESENTATION: Two young adults, one 29-year-old male and one 32-year-old female patient from South India, presented with gastrointestinal symptoms and worsening renal and Liver failure. Patients had already received gastric lavage at the local hospital and later transferred to our hospital. We initiated immunosuppressive therapy with cyclophosphamide at 15&#xa0;mg/kg/day for 3&#xa0;days and steroids. Both patients received renal replacement therapy and N-acetyl cysteine infusion. We observed improvement in clinical and biochemical parameters over a week. There were no respiratory symptoms throughout the hospitalization. At the time of discharge, both patients were off renal replacement therapy. On long-term follow-up after 2.5&#xa0;years, both patients had recovered well without any renal dysfunction.<br><br>CONCLUSION: This case report highlights the successful management of paraquat poisoning with high-dose cyclophosphamide with steroids. The timely initiation of immunosuppression prevented disease progression and facilitated prompt recovery.},
}
@article {pmid41038427,
year = {2025},
author = {Silva, SANM and Machado, FDS and Santos, LS and de Castro, MVL and Nogueira, ML and Soares, MBP and Rocha, SAS and Araújo, RM and Dias, RB and Bezerra, DP and Araújo, AJ and Marinho Filho, JDB},
title = {Cordiaquinone B induces cytotoxicity and oxidative stress-mediated apoptosis in human colorectal cancer cells invitro and invivo.},
journal = {Chemico-biological interactions},
volume = {421},
number = {},
pages = {111764},
doi = {10.1016/j.cbi.2025.111764},
pmid = {41038427},
issn = {1872-7786},
mesh = {Humans ; *Apoptosis/drug effects ; Animals ; *Colorectal Neoplasms/pathology/drug therapy/metabolism ; *Oxidative Stress/drug effects ; Mice, SCID ; Mice ; HCT116 Cells ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Cell Survival/drug effects ; *Quinones/pharmacology/chemistry ; Mitochondria/metabolism/drug effects ; },
abstract = {Cordiaquinones are natural molecules derived from the Varronia and Cordia genera with diverse biological potential. In this work, the effects of Cordiaquinone B were initially evaluated in a panel of cancer cell lines. Subsequently, it was first-hand investigated both in vitro and in vivo in human colorectal adenocarcinoma (HCT-116) cells. Experiments were conducted using two-dimensional (2D) and three-dimensional (3D) cell cultures and in the HCT-116 xenograft model in immunodeficient CB17-SCID mice. Cordiaquinone B inhibited the viability of both adherent and non-adherent cancer cell lines without inducing hemolysis in human erythrocytes. In Cordiaquinone B-treated HCT-116 cells, morphological changes and alterations in apoptosis-related protein levels were observed, indicating an apoptotic mechanism associated with mitochondrial oxidative stress. This was supported by an increased mitochondrial superoxide content and prevention of observed cytotoxic and apoptotic effects by N-acetylcysteine (NAC) pretreatment. In the 3D tumor model of HCT-116 spheroids, Cordiaquinone B treatment led to a spheroid size reduction. Additionally, in CB17-SCID mice, a dose of 3 mg/kg/day inhibited HCT-116 tumor growth by 42.6 % without causing severe organ toxicity or alterations in hematological parameters, except for mild to moderate hepatic and pulmonary alterations. These results demonstrate the efficacy of Cordiaquinone B and highlight its potential as a promising candidate for colorectal cancer therapy.},
}
@article {pmid41032464,
year = {2026},
author = {Li, H and Wei, X and Sun, H},
title = {Molecular Insights into Bismuth's New Applications against Antimicrobial Resistance and Coronaviruses.},
journal = {Accounts of chemical research},
volume = {59},
number = {1},
pages = {1-12},
doi = {10.1021/acs.accounts.5c00471},
pmid = {41032464},
issn = {1520-4898},
mesh = {*Bismuth/pharmacology/chemistry ; Humans ; *Anti-Bacterial Agents/pharmacology/chemistry ; Helicobacter pylori/drug effects ; *Antiviral Agents/pharmacology/chemistry ; Drug Resistance, Bacterial/drug effects ; SARS-CoV-2/drug effects ; Organometallic Compounds/pharmacology/chemistry ; Salicylates ; },
abstract = {ConspectusBismuth, a heavy metal distinguished by its low toxicity, compared to lead or mercury, has long been associated with medicine for the treatment of various conditions, notably as a key component in triple and quadruple therapies for eradicating Helicobacter pylori, including antibiotic-resistant strains. Compounds such as bismuth subsalicylate (BSS) and colloidal bismuth subcitrate (CBS) enhance the efficacy of antibiotics, e.g., metronidazole and tetracycline. Over the past two decades, the knowledge on the molecular mechanism of action of bismuth drugs has been significantly advanced, in particular with the aid of the metallomics/metalloproteomics, facilitating the discovery of novel therapeutic applications beyond H. pylori eradication.This Account describes how the molecular mechanism of action of bismuth drugs was unveiled at a system level by multiple-metalloproteomics approaches, which enable the comprehensive identification of bismuth-binding proteins with diverse affinities in bacteria. By integration with other techniques such as proteomics, bioinformatics and molecular biology, the sustained efficacy of bismuth drugs was attributable to their capacities to disrupt multiple biological pathways through binding and functional perturbation of key enzymes, in particular, those enzymes bearing CXnC (n = 2, 7), CXnH (n = 5, 6) and HXnH (n = 0-2, 8) motifs, in consistence with the thiophilic nature and high acidic property of bismuth.The generated knowledge on the mode of action of bismuth drugs lays a solid foundation for further exploration of their novel therapeutic applications. Our extensive studies have revealed that bismuth drugs and compounds hold great potential as versatile agents in combating antimicrobial resistance (AMR) crisis through co-therapies with clinically used antibiotics. This includes bismuth drugs as broad-spectrum inhibitors of metallo-β-lactamases (MBLs), enzymes responsible for resistance to β-lactam antibiotics, to fight against MBLs-positive bacterial infection together with β-lactams; bismuth drugs serve as adjuvants of Cefiderocol (Fetroja), the only clinically approved sideromycin, against infections caused by multidrug-resistant Pseudomonas aeruginosa and Burkholderia cepacia; bismuth drugs (and relevant compounds) in combination with clinically used antibiotics could combat Pseudomonas aeruginosa infections by disrupting iron homeostasis and functionally impairing Fe-S cluster-containing enzymes in multidrug-resistant Pseudomonas aeruginosa; newly developed bismuth compounds serve as novel metalloantibiotics to combat AMR. Moreover, the ability of bismuth to disrupt key zinc finger proteins for the transcription and replication in coronavirus rendered its new potential in treating coronavirus infections, particularly SARS-CoV-1 and SARS-CoV-2. Combining clinically used bismuth drugs with N-acetyl cysteine (NAC), a thiol-containing drug, increases bismuth uptake in blood plasma to therapeutic levels for SARS-CoV-2 without apparent toxicity. Bismuth drugs, therefore, hold great potential for the treatment of viral infections.We anticipate that our mechanism-guided discoveries of bismuth's new therapeutic applications are poised to inspire researchers in relevant fields to rationally design drugs (and metallodrugs) and repurpose FDA-approved drugs, ultimately leading to the development of new effective therapeutics for combating emerging infectious diseases, which will positively impact human health and well-being.},
}
@article {pmid41031098,
year = {2025},
author = {Leavy, OC and Goemans, AF and Hernandez-Beeftink, T and Stockwell, AD and Allen, RJ and Guillen-Guio, B and Adegunsoye, A and Booth, HL and Fahy, WA and Fingerlin, TE and Virk, HS and Hall, IP and Hart, SP and Hill, MR and Hirani, N and Kaminski, N and Ma, SF and McAnulty, RJ and Sheng, XR and Millar, AB and Molina-Molina, M and Navaratnam, V and Neighbors, M and Parfrey, H and Saini, G and Sayers, I and Strek, ME and Tobin, MD and Whyte, MKB and Zhang, Y and Maher, TM and Molyneaux, PL and Oldham, JM and Yaspan, BL and Flores, C and Martinez, F and Reynolds, CJ and Schwartz, DA and Noth, I and Jenkins, RG and Wain, LV},
title = {Sex-specific genetic effects on susceptibility to idiopathic pulmonary fibrosis.},
journal = {ERJ open research},
volume = {11},
number = {5},
pages = {},
pmid = {41031098},
issn = {2312-0541},
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood; differing environmental exposures due to historically sex-biased occupations and diagnostic bias are possible explanations. To date, over 20 independent genetic association signals have been reported for IPF susceptibility, but these have been discovered when combining males and females. The objectives of the present study were to assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF and to test for sex-specific associations with IPF susceptibility.<br><br>METHODS: We performed a genome-wide single nucleotide polymorphism (SNP)-by-sex interaction study meta-analysis of IPF risk in six independent case-control studies comprising 4561 cases (1280 females, 3281 males) and 22&#x2009;888 controls (8360 females, 14&#x2009;528 males) of European genetic ancestry. We used polygenic risk scores (PRSs) comprising common (minor allele frequency >1%) autosomal variants to assess differences in genetic risk prediction between males and females.<br><br>RESULTS: The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific association results. Three new independent genetic association signals were identified (p<1&#xd7;10[-6]).<br><br>CONCLUSIONS: The predictive accuracy of common autosomal SNP-based PRSs did not vary significantly between males and females. We prioritised three genetic variants whose effect on IPF risk may be modified by sex. These findings would not account for the differences in prevalence between males and females. Future studies should ensure adequate representation of both sexes.},
}
@article {pmid41030491,
year = {2025},
author = {Iguh, C and Bakhsh, I and Grujic, S},
title = {Acute Hepatitis in a Patient Treated With Ribociclib for Metastatic Breast Carcinoma.},
journal = {Journal of medical cases},
volume = {16},
number = {9},
pages = {372-380},
pmid = {41030491},
issn = {1923-4163},
abstract = {Ribociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, is widely used in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. Although hepatotoxicity is a recognized adverse effect, severe cases of ribociclib-induced liver injury with histologic confirmation of submassive hepatic necrosis remain rare. We describe a case of a postmenopausal woman with newly diagnosed stage IV HR+/HER2-negative invasive lobular carcinoma who developed acute hepatocellular injury 8 weeks after initiating ribociclib and anastrozole. The patient presented with fatigue, jaundice, and dark urine, and was found to have markedly elevated transaminases (alanine aminotransferase 1,825 U/L; aspartate aminotransferase 1,536 U/L) and hyperbilirubinemia. A thorough workup excluded viral, autoimmune, and obstructive hepatobiliary causes. Liver biopsy demonstrated confluent centrilobular necrosis without fibrosis or significant inflammation. Causality assessments yielded an R-factor of 20.73, a Roussel Uclaf Causality Assessment Method score of 10 (highly probable), and a Naranjo score of 7 (probable). Ribociclib was discontinued and intravenous N-acetylcysteine (NAC) initiated, leading to gradual normalization of liver enzymes. The patient was maintained on anastrozole alone, with no recurrence of liver injury and stable disease at 13-month follow-up. This case highlights the potential for ribociclib to induce severe hepatocellular injury with histologic evidence of submassive necrosis. Early recognition and structured causality assessment ensures patient safety. In patients with significant hepatotoxicity, discontinuation of ribociclib and non-rechallenge may be prudent. Furthermore, consideration of NAC in management is important in cases demonstrating persistent transaminitis despite ribociclib discontinuation.},
}
@article {pmid41025906,
year = {2025},
author = {Laxmanan, K and Shin, H and Jo, J and Bose, S and Ranganathan, P and Nam, SY and Kang, HW},
title = {Theranostic Polyaniline-Integrated N-Acetyl-l-Cysteine Hydrogel for Synergistic Photothermal Antibacterial Therapy and Enhanced Cell Migration.},
journal = {ACS applied bio materials},
volume = {8},
number = {10},
pages = {8751-8766},
doi = {10.1021/acsabm.5c00829},
pmid = {41025906},
issn = {2576-6422},
mesh = {*Anti-Bacterial Agents/pharmacology/chemistry/chemical synthesis ; *Hydrogels/chemistry/pharmacology ; Escherichia coli/drug effects ; Cell Movement/drug effects ; Staphylococcus aureus/drug effects ; *Aniline Compounds/chemistry/pharmacology ; *Acetylcysteine/chemistry/pharmacology ; Microbial Sensitivity Tests ; Humans ; *Biocompatible Materials/pharmacology/chemistry/chemical synthesis ; Photothermal Therapy ; Theranostic Nanomedicine ; Materials Testing ; Particle Size ; },
abstract = {Bacterial infections continue to pose a significant global health challenge, highlighting the urgent need for innovative therapeutic approaches that combine antibacterial efficacy with photothermal treatment modalities. In this study, we report a theranostic multifunctional hydrogel (APQ@NH), comprising Asiatic acid (AA)-doped polyaniline (PANi) loaded with quercetin (Q), and incorporated into an N-acetyl-l-cysteine (NAC)-based hydrogel matrix, for in vitro antibacterial and photothermal applications. The APQ@NH hydrogel exhibits excellent rheological stability and controlled, sustained drug release behavior, ensuring prolonged antibacterial activity. Upon near-infrared 808 nm laser irradiation, the APQ@NH hydrogel effectively generates localized hyperthermia, facilitating membrane disruption and enhancing the intracellular delivery of antibacterial agents. The photothermal conversion efficiency (PCE) of APQ@NH was calculated to be 21.7% under 808 nm laser irradiation, confirming its effective photothermal capability. This synergistic system exhibited potent antibacterial activity against both Escherichia coli (E.coli) and Staphylococcus aureus (S. aureus) , resulting in substantial bacterial eradication. Additionally, in vitro studies confirmed the hydrogel's ability to promote cell migration, further supporting its potential for wound healing applications.},
}
@article {pmid41023622,
year = {2025},
author = {Diako, K and Rahimi, S and Mirbagheri Saghaleksari, SA and Mousavi Eshkelani, SM and Keshavarz Taramsari, N and Beigi Harchegani, A and Mohsenifar, Z and Shahriarinour, M and Ranji, N},
title = {N-Acetylcysteine as an anti-oxidant and anti-inflammatory agent in decreasing histopathological damages and oxidative stress after mercury exposure in lung tissue of rats.},
journal = {BMC biotechnology},
volume = {25},
number = {1},
pages = {108},
doi = {10.1186/s12896-025-01041-w},
pmid = {41023622},
issn = {1472-6750},
abstract = {BACKGROUND: Mercury (Hg) is a naturally occurring heavy metal with high toxicitythat affects various organs. This study aimed to evaluate the protective effects of N-acetylcysteine (NAC) on the lung tissue of Wistar rats exposed to mercury.<br><br>METHODS: Rats were divided into five groups: H1 (control), H2 (single dose of Hg), H3 (continuous dose of Hg), H4 (single dose of Hg+ single dose of NAC), and H5 (continuous dose of Hg+ continuous dose of NAC). The expression levels of SOD1, NOS, TIMP1, Fibronectin1, HIF1, MPO, MMP2 and TIMP2 were analyzed using qRT-PCR.<br><br>RESULTS: Mercury levels in the blood and lung tissues significantly increased in the H2 and H3 groups compared to the H4 and H5 groups, respectively. Hg exposure in H3 group significantly (P&#x2009;<&#x2009;0.001) led to the upregulation of MPO (4.55-fold), HIF1(4.31-fold), MMP2 (4.20-fold), TIMP1(3.18-fold), TIMP2 (4.83-fold), NOS (3.52-fold), and FN1 (3.52-fold), along with the downregulation of SOD1 (0.51-fold) compare to control group (H1). In contrast, rats treated with NAC after Hg exposure in H5 group significantly (p&#x2009;<&#x2009;0.01&#x2013;0.001) showed downregulation of MPO (2.49-fold), HIF1(2.12-fold), MMP2 (1.94-fold), TIMP1(1.92-fold), TIMP2 (1.96-fold), NOS (2.00-fold), and FN1 (1.90-fold), and upregulation of SOD1 (0.76-fold) compare to H3 group. A significant reduction in mercury levels was also observed in the blood and lung tissue of rats treated with NAC compared to those exposed Hg alone.<br><br>CONCLUSION: NAC exerts a protective effect against mercury-induced cytotoxicity and genotoxicity in rat lungs by scavenging mercury and modulating the expression of oxidative stress-related genes.},
}
@article {pmid41020832,
year = {2025},
author = {Cherneva, DI and Kehayova, G and Dimitrova, S and Dragomanova, S},
title = {The Central Nervous System Modulatory Activities of N-Acetylcysteine: A Synthesis of Two Decades of Evidence.},
journal = {Current issues in molecular biology},
volume = {47},
number = {9},
pages = {},
pmid = {41020832},
issn = {1467-3045},
abstract = {N-acetylcysteine (NAC) has garnered increasing interest for its neurotherapeutic capabilities beyond its recognized functions as a mucolytic agent and an antidote for acetaminophen toxicity. This review consolidates findings from both preclinical and clinical studies to investigate NAC's diverse modulatory effects on the central nervous system (CNS). NAC primarily functions as an antioxidant by replenishing glutathione and mitigating oxidative stress; however, it produces glutathione-independent effects through the modulation of mitochondrial redox systems, ferroptosis, and the Nrf2-ARE signaling pathway. It plays a significant role in neuroinflammatory processes by inhibiting the production of cytokines, the expression of iNOS, and the activation of microglia. Furthermore, NAC affects various neurotransmitter systems-including glutamatergic, dopaminergic, GABAergic, serotonergic, cholinergic, and adrenergic pathways-by modulating synaptic transmission, receptor activity, and transporter functionality. It promotes neuroprotection through the enhancement of neurotrophic factors, the preservation of mitochondrial integrity, and the upregulation of survival signaling pathways. Recent evidence also emphasizes NAC's role in gene expression and the regulation of cortisol levels. The extensive range of NAC's neurobiological effects highlights its therapeutic potential in treating neurodegenerative and neuropsychiatric disorders. Nevertheless, the variability in clinical outcomes indicates a pressing need for more focused, mechanism-based research.},
}
@article {pmid41019354,
year = {2025},
author = {Aziz, ND and Azeez, DD and Mosa, AU and Al-Kareem, ZA and Majeed, SA and Ghafil, FA},
title = {Hepatoprotective potential of N-acetyl cysteine in rats with phenytoin induced liver injury.},
journal = {F1000Research},
volume = {14},
number = {},
pages = {593},
pmid = {41019354},
issn = {2046-1402},
mesh = {Animals ; *Phenytoin/adverse effects/toxicity ; *Acetylcysteine/pharmacology/therapeutic use ; Male ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/pathology/drug therapy/blood ; Rats, Wistar ; Rats ; *Liver/drug effects/pathology ; Anticonvulsants/toxicity ; Aspartate Aminotransferases/blood ; Alanine Transaminase/blood ; Bilirubin/blood ; *Protective Agents/pharmacology ; },
abstract = {BACKGROUND: Phenytoin is an anticonvulsant medication that is effective in treating various seizure disorders. It is mostly metabolized by the liver, which increases the risk of PHT-induced hepatotoxicity.<br><br>AIMS: This study aimed to assess the effectiveness of N-acetylcysteine (NAC) in protecting the liver from phenytoin-induced hepatotoxicity in rats.<br><br>MATERIALS AND METHODS: Four sets of five rats male Wistar albino rats (Rattus norvegicus) used for this study was based on their availability, well-established physiology, and long history of use in pharmacological and toxicological studies each were used for analysis. Each of the four groups received different treatments: the control group received normal saline, one group received 200 mg/kg/day of NAC, another group received 5 mg/kg/day of phenytoin, and the fourth group received 200 mg/kg/day of both phenytoin and NAC. The treatments were administered orally by gavage for 45 days. Biochemical indicators (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total serum bilirubin (TSB)) were measured in serum after the animals were anaesthetized and the experiment ended. Histological analysis was performed on liver specimens.<br><br>RESULTS: Our investigation showed that phenytoin significantly elevated liver enzymes and total serum bilirubin compared to the control and NAC groups. The concurrent administration of NAC and phenytoin led to a notable reduction in these biomarkers, excluding ALP levels. Moreover, the group that received NAC alone did not exhibit a significant increase in the levels of these biomarkers compared with the control group. The histopathological results were in agreement with the biochemical tests.<br><br>CONCLUSION: This study concluded that Concomitant administration of NAC and phenytoin lowered the risk of phenytoin-induced hepatotoxicity. Moreover, this study confirmed that NAC is relatively safe when administered for a relatively prolonged period.},
}
@article {pmid41018992,
year = {2025},
author = {Miller, TJ and Qiu, L and Nevin, A and Williams, R and Beachy, W},
title = {"Too Much of a Good Thing": Inadvertent Acetaminophen Overdose in a Low-Weight Elderly Patient.},
journal = {Clinical case reports},
volume = {13},
number = {10},
pages = {e71031},
pmid = {41018992},
issn = {2050-0904},
abstract = {Commonly used for its analgesic and anti-pyretic properties, acetaminophen ("Tylenol") is effective in managing generalized pain. Complications arise with supratherapeutic dosing of acetaminophen, especially in elderly and frail individuals with diminished glutathione production and reduced metabolic drug clearance potential. Limited cases outline this danger and offer alternative dosing considerations to avoid drug-induced liver injury from acetaminophen (DILI). We present a unique case of an 89-year-old woman without prior liver disease who developed acute liver failure (ALF) while taking recommended dosing of acetaminophen. Physical exam was revealing for generalized abdominal pain, lethargy, and vomiting without ascites, jaundice, or asterixis upon admission. She progressed to ALF with encephalopathy and worsening transaminitis along with evidence of synthetic liver failure. With an elevated acetaminophen level and no prior history of liver disease with Tylenol dosing of 30 mg/kg/dose, DILI due to acetaminophen toxicity was suspected. N-acetylcysteine (NAC) and albumin infusions were initiated with improvement in transaminitis and acute tubular necrosis (ATN). The patient was discharged after 12 days to a rehabilitation facility for strength recovery without long-term sequelae or transplant. While 4000 mg/day dosing regimen is generally safe, it can be dangerous for certain patients. Using the typical pediatric, weight-based regimen of 15 mg/kg as a framework, this patient represents a 66% higher dose than recommended. Considering her frailty and age, this case emphasizes the importance of patient-specific risk factors in acetaminophen dosing and prioritizing an individualized, weight-based approach to analgesic management.},
}
@article {pmid41016202,
year = {2025},
author = {Zhang, Y and Huang, C and Qiu, Y and Li, R and Liu, J and Du, Y and Li, D},
title = {Synergistic elimination of bacillus Calmette-Guérin biofilm and tissue restoration facilitated by ultrasound-mediated nanoparticles and antioxidants.},
journal = {International immunopharmacology},
volume = {166},
number = {},
pages = {115582},
doi = {10.1016/j.intimp.2025.115582},
pmid = {41016202},
issn = {1878-1705},
mesh = {*Biofilms/drug effects ; Animals ; *Nanoparticles/chemistry ; *Antioxidants/therapeutic use/pharmacology ; *Levofloxacin/administration &amp; dosage/pharmacology/therapeutic use ; Macrophages/drug effects/immunology ; Mice ; *Catalase/administration &amp; dosage/therapeutic use ; *Mycobacterium bovis/physiology/drug effects ; Polyethylene Glycols/chemistry ; *Tuberculosis/therapy/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; *Mycobacterium tuberculosis/physiology/drug effects ; Cytokines/metabolism ; Ultrasonic Waves ; *Ultrasonic Therapy/methods ; Female ; Humans ; },
abstract = {Biofilm formation in Mycobacterium tuberculosis (MTB) enhances antibiotic resistance by impeding drug penetration and evading host immunity. This poses a significant challenge to conventional drug therapies, highlighting the urgent need for novel treatment strategies to overcome MTB's biofilm-mediated resistance. This study introduces the development of low-intensity ultrasound-mediated levofloxacin (LEV) and catalase (CAT) -loaded PEG-PLGA nanoparticles (LEV@CAT-NPs) for antimicrobial sonodynamic therapy (aSDT), offering an innovative strategy to combat BCG biofilm infection, by utilizing BCG as a model for MTB. N-acetylcysteine (NAC) was supplemented during the latter stages of the treatment process of anti-infection therapy to facilitate the transformation of macrophages to the M2 phenotype and to promote tissue repair. Ultrasound-mediated LEV@CAT-NPs, along with the subsequent addition of NAC not only enhanced repair at the infection site but also led to a progressive resolution of the inflammatory response in tissues. The treatment regimen induced a shift in macrophage polarization towards the M2 phenotype and modulated cytokine expression, decreasing pro-inflammatory while increasing anti-inflammatory cytokines, which contributed to the restoration of redox balance in the infected tissues. This study proposes a novel therapeutic strategy that not only targets drug-resistant MTB but also promotes tissue repair, highlighting its dual role in infection management.},
}
@article {pmid41012520,
year = {2025},
author = {Josef, M and Abdellatif, MM and Abdelmonem, R and El-Nabarawi, MA and Teaima, M and Bedair, HM and Attia, A},
title = {Invasomes and Nanostructured Lipid Carriers for Targeted Delivery of Ceftazidime Combined with N-Acetylcysteine: A Novel Approach to Treat Pseudomonas aeruginosa-Induced Keratitis.},
journal = {Pharmaceutics},
volume = {17},
number = {9},
pages = {},
pmid = {41012520},
issn = {1999-4923},
abstract = {Objectives: This study was designed to optimize a ceftazidime (CTZ)-loaded nanocarrier that could efficiently permeate across corneal tissues. Moreover, N-acetylcysteine (NAC) was combined with an optimized CTZ-loaded formula to augment the antimicrobial activity and facilitate the efficient healing of Pseudomonas aeruginosa-induced keratitis. Methods: Different CTZ-loaded invasomes (INVs) and CTZ-loaded nanostructured lipid carriers (NLC) were fabricated and fully characterized via the determination of the entrapment efficiency (EE%), particle size (PS), surface charge, and percentage of CTZ release. Next, NAC was added to the optimized formulae from each nanocarrier, which were further assessed through ex vivo corneal permeation and in vitro antimicrobial activity studies. Finally, an in vivo evaluation of the optimal nanocarrier in the presence of NAC was performed. Results: Both nanocarriers showed nanoscale PS with sufficient surface charges. CTZ-loaded NLC formulae showed a higher EE% range with a sustained drug release profile. Both optimized formulae showed a spherical shape and excellent stability. Moreover, the antibacterial activity and biofilm inhibition assessments confirmed the synergistic effects of NAC when combined with different CTZ-loaded nanocarriers. However, the optimized CTZ-loaded INV formula achieved higher corneal permeation and deposition compared to the optimized CTZ-loaded NLC formula. Finally, the in vivo assessment confirmed the dominance of the optimized CTZ-loaded INV formula combined with NAC, where the microbiological, histopathological, and immunohistopathological examinations showed the rapid eradication of keratitis. Conclusions: Recent strategies for the incorporation of antibiotics into nanocarriers, combined with mucolytic agents, can offer a promising platform to boost the therapeutic efficiency of antibiotics and prevent antimicrobial resistance.},
}
@article {pmid41011426,
year = {2025},
author = {Shen, J and Li, Y and Miao, H},
title = {The PP2A Catalytic Subunit PPH21 Regulates Biofilm Formation and Drug Resistance of Candida albicans.},
journal = {Microorganisms},
volume = {13},
number = {9},
pages = {},
pmid = {41011426},
issn = {2076-2607},
abstract = {Candida albicans (C. albicans) biofilms exhibit enhanced resistance to conventional antifungal agents; however, the underlying pathogenic mechanisms warrant deeper exploration. Protein phosphatase 2A (PP2A), especially its catalytic activity, is crucial for maintaining physiological balance. This study focused on the role of the PP2A catalytic subunit coding gene PPH21 in biofilm formation and drug resistance of C. albicans. The mutant strain (pph21Δ/Δ) was generated and identified. The oxidative stress was detected by the reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). The autophagic activity was evaluated, and the autophagosomes were observed by transmission electron microscopy (TEM). The biofilm formation was measured by XTT reduction assay, crystal violet (CV) staining, and scanning electron microscopy (SEM). The susceptibility to antifungal agents was examined by XTT reduction assay and spot assay. Additionally, the antioxidant N-acetylcysteine (NAC) was applied to clarify the regulatory effect of C. albicans autophagy on oxidative stress. The pathogenicity of PPH21 in oral C. albicans infection was evaluated through in vivo experiments. We found that PPH21 deletion led to increased oxidative stress and autophagic activities, but it can be reversed by the application of NAC. Moreover, PPH21 deletion also impaired the biofilm formation ability and reduced resistance to antifungal agents. Our findings revealed that PPH21 is involved in both virulence and stress adaptation of C. albicans.},
}
@article {pmid41011382,
year = {2025},
author = {Jotic, A and Cirkovic, I and Bozic, D and Savic Vujovic, K and Milovanovic, J and Folic, M and Trivic, A and Cvorovic, L and Radivojevic, N},
title = {Antibiofilm Effects of N-Acetyl Cysteine on Staphylococcal Biofilm in Patients with Chronic Rhinosinusitis.},
journal = {Microorganisms},
volume = {13},
number = {9},
pages = {},
pmid = {41011382},
issn = {2076-2607},
support = {451-03-65/2024-03/200110//Ministry of Science, Technological Development and Innovation, the Republic of Serbia/ ; },
abstract = {Staphylococcal bacterial biofilm plays an important role in the pathogenesis and bacterial persistence of chronic rhinosinusitis. N-acetyl cysteine (NAC) has an inhibitory role in biofilm formation, suppressing adhesion and matrix production or favoring dispersal of preformed biofilm. The aim of this study was to examine the in vitro effect of NAC on Staphylococcal biofilm formation by bacterial strains isolated from tissue samples of patients with chronic rhinosinusitis with or without nasal polyps (CRSwNP and CRSsNP). Prospective study included 75 patients with CRS. The biofilm-forming capacity of isolated strains was detected by microtiter-plate method and the effects of sub-inhibitory (1/2x, 1/4x, and 1/8x minimal inhibitory concentration, MIC) and supra-inhibitory minimal concentrations (2x, 4x, and 8xMIC) of NAC on biofilm production were investigated. Staphylococcal bacterial strains were isolated in 54 (72%) patients, and the most frequently isolated species were Staphylococcus aureus (40.7%). Coagulase-negative Staphylococci species were weak producers of biofilm, while S. aureus was a strong biofilm producer. Concentration of 3.1 mg/mL (1/2 MIC) was sufficient to completely prevent biofilm formation in 77.8% of the isolates, where 49.6 mg/mL (8xMIC) led to the complete eradication of formed biofilm in 81.5% of the isolates. The subinhibitory and eradication effects were dose- and strain-dependent. There were no significant differences in MIC values between isolates from patients with CRSwNP and CRSsNP isolates. NAC proved to be effective in inhibiting biofilm formation and reducing formed biofilm by Staphylococcal isolates from patients with CRS. A comparable antibiofilm effect was exhibited in both phenotypes of CRS, indicating that NAC's antibiofilm activity was independent of the underlying clinical phenotype, and more targeted on biofilm matrix components.},
}
@article {pmid41005550,
year = {2025},
author = {Sawyer, TW and Song, Y},
title = {Protective effects of N-acetylcysteine and its amide derivative against toxic metals in vitro: Potential alternatives/adjuncts to traditional chelators.},
journal = {Environmental toxicology and pharmacology},
volume = {120},
number = {},
pages = {104825},
doi = {10.1016/j.etap.2025.104825},
pmid = {41005550},
issn = {1872-7077},
mesh = {*Acetylcysteine/pharmacology/analogs &amp; derivatives ; Animals ; *Chelating Agents/pharmacology ; CHO Cells ; Cricetulus ; *Metals, Heavy/toxicity ; Glutathione/metabolism ; Cell Survival/drug effects ; *Protective Agents/pharmacology ; Cricetinae ; },
abstract = {The protective efficacies of N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) against the toxicity of compounds containing arsenic, cadmium, cobalt, chromium and mercury, were compared to those of dimercaprol, dimercaptosuccinic acid, 2,3-dimercaptopropanesulphonate, D-penicillamine, and derivatives of ethylenediamine tetraacetic acid and diethylenetriaminepentaacetic in CHO-K1 cells. Both NAC and NACA were found to confer protection against these metals, with comparable or better efficacy than many of the test chelators. Results from studies using the glutathione synthesis inhibitor buthionine sulphoximine were consistent with NAC/NACA protection being mediated through both GSH up-regulation and chelation. Given NAC's activity against metal toxicity, widespread clinical use, parenteral or oral routes of administration, high clinical safety, low cost and ease of accessibility, it should be given consideration as a broad-spectrum protectant against toxic metal poisoning as a treatment or adjunct/combination treatment. Its more lipophilic derivative NACA, also warrants attention, especially in those cases where brain toxicity is a concern.},
}
@article {pmid41001250,
year = {2025},
author = {Rankin, TJ and Mayer, S and Laird, JG and Lobeck, B and Kalmanek, E and Drack, AV},
title = {N-Acetylcysteine Ameliorates Loss of the Electroretinogram b-wave in a Bardet-Biedl Syndrome Type 10 Mouse Model.},
journal = {Journal of experimental neurology},
volume = {6},
number = {1},
pages = {49-63},
pmid = {41001250},
issn = {2692-2819},
support = {P30 EY025580/EY/NEI NIH HHS/United States ; T32 GM145441/GM/NIGMS NIH HHS/United States ; },
abstract = {Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder characterized by retinal degeneration leading to blindness. This study investigates the therapeutic efficacy of N-Acetylcysteine (NAC), an oxygen free radical scavenger, in ameliorating retinal degeneration associated with BBS using a murine model of BBS10. BBS is caused by mutations in BBS genes, the protein products of which are involved in ciliary function; mutant or absent BBS10 protein disrupts the assembly of the BBSome protein complex, disturbing ciliary trafficking and leading to photoreceptor cell dysfunction and death. Photoreceptor function can be assessed using the electroretinogram (ERG), and anatomy can be assessed using optical coherence tomography (OCT) and histology to demonstrate progressive degeneration over time. This study utilizes Bbs10 [-/-] mice to assess the effect of NAC supplementation on retinal degeneration. Results reveal that NAC supplementation ameliorates the progressive degeneration of the retinal outer nuclear layer (ONL) on OCT and mitigates the loss-of-b-wave ERG phenotype observed in Bbs10 [-/-] mice. The ERG b-wave is generated by retinal bipolar cells after synapsing with photoreceptors which have been hyperpolarized by light exposure. Reducing the loss-of-b-wave phenotype may indicate improved synaptic function. Synaptic staining demonstrates a correlation between the absence of an electropositive b-wave and mislocalized presynaptic terminals, highlighting the significance of synaptic integrity for retinal function. These findings suggest NAC as a promising therapeutic intervention for managing BBS10-related retinal degeneration.},
}
@article {pmid40998099,
year = {2025},
author = {Lawless, SC and Kelley, C and Nikulina, E and Tahir, U and Kaur, A and Alarcon, JM and Bergold, PJ},
title = {Chronic functional deficits following a single closed head injury in mice are prevented by minocycline and N-acetyl cysteine.},
journal = {Molecular and cellular neurosciences},
volume = {135},
number = {},
pages = {104049},
doi = {10.1016/j.mcn.2025.104049},
pmid = {40998099},
issn = {1095-9327},
mesh = {Animals ; *Acetylcysteine/therapeutic use/pharmacology ; *Minocycline/therapeutic use/pharmacology ; Mice ; *Head Injuries, Closed/drug therapy/physiopathology/complications ; Male ; Mice, Inbred C57BL ; Corpus Callosum/drug effects/physiopathology ; Brain Injuries, Traumatic/physiopathology ; Action Potentials/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; },
abstract = {Traumatic brain injury (TBI) can produce chronic limb coordination and gait deficits that are associated with ongoing white matter damage. In rodent TBI models, chronic motor deficits may be obscured by aging or motor compensation. In addition, there are no treatments for TBI. The murine closed head injury (CHI) model produces diffuse, chronic white matter injury that may underlie chronic white matter dysfunction and motor deficits. Evoked compound action potentials (CAP) assess corpus callosum function from 3 to 180-days post injury (DPI). CHI acutely decreases total CAP amplitudes that recover by 90 DPI and increase further at 180 DPI. Total CAP amplitude changes are blocked by dosing of minocycline and N-acetylcysteine beginning 12 h post-injury (MN12). Injured or sham mice have similar times to traverse or number of foot faults on beam walk. DeepLabCut™ markerless limb tracking provides limb positions used to develop novel assays to assess beam walk and simple/complex wheel. Absition analysis integrates the duration and extent of foot faults during beam walk. Injured mice develop absition deficits at 90 DPI that worsen at 180 DPI suggesting a chronic and progressive decline. Chronic absition deficits are blocked by MN12 treatment. Speed typically assesses performance on simple/complex wheel. Novel limb coordination assays show that at 180 DPI, injured mice decrease coordination that significantly correlates with increased total CAP amplitude. MN12 alleviates chronic corpus callosum dysfunction and motor deficits suggesting a strong efficacy to treat TBI. DeepLabCut™ limb tracking reveals chronic deficits and motor compensation not seen with standard outcomes.},
}
@article {pmid40995338,
year = {2025},
author = {Semnic, I and Rački, V and Perković, O and Vuletić, V},
title = {Mercury exposure leading to functional vitamin B12 deficiency and subacute combined degeneration: a case report and literature review.},
journal = {Frontiers in toxicology},
volume = {7},
number = {},
pages = {1580275},
pmid = {40995338},
issn = {2673-3080},
abstract = {INTRODUCTION: The association between neurological symptomatology and heavy metal exposure has been reported in the literature. A few cases of extrapyramidal symptomatology and subacute combined degeneration have been described as manifestations of mercury intoxication. We highlight a case of a patient presenting with Parkinsonian features (tremor, rigidity, and bradykinesia), pyramidal deficits, dysarthria, paresthesia, mild cognitive decline, and emotional lability, with proven elevated mercury levels in blood and hair and elevated arsenic in urine.<br><br>CASE: A 60-year-old man, with history of mercury exposure while working at the Centre for Waste Management and Environmental Protection presented to a neurologist after 10&#xa0;months of persistent tremors, muscle spasms, paresthesia, and irritability, followed by the onset of bradykinesia, slurred speech, rigidity, insomnia, and subtle cognitive decline. Laboratory investigations revealed functional vitamin B12 and vitamin D deficiencies, while toxicological quantitative analysis showed elevated blood mercury levels (15.2&#xa0;&#x3bc;g/L) and hair root levels (3&#xa0;&#x3bc;g/g). MRI of the brain was normal, whereas MRI of the posterior cervical spine detected signs of myelopathy. Florodeoxyglucose (FDG) Positron Emission Tomography (PET) of the brain revealed bilateral temporal and parietal glucose hypometabolism, most pronounced in the left inferior parietal and left superior temporal regions. Single-Photon Emission Computed Tomography (SPECT) imaging of dopaminergic neurons in the striatum was negative, and the patient was unresponsive to levodopa. Multivitamin therapy (vitamins B, E, and D) with selenium, in combination with symptomatic therapy (benzodiazepines, muscle relaxants, and antidepressants) provided minimal relief, leading to the introduction of N-acetyl cysteine, which resulted in moderate improvement of symptoms. Physical and speech therapy were of great importance in this case.<br><br>DISCUSSION: This case is unique because it represents the development of therapy-resistant extrapyramidal symptoms over 3&#xa0;years of mercury exposure, likely leading to subacute combined degeneration due to functional vitamin B12 deficiency. Epidemiological data describe methylmercury poisoning, known as Minamata disease, which presents with -somatosensory deficits, ataxia, parkinsonism, dysarthria, and visual and hearing impairments.<br><br>CONCLUSION: Toxicological screening for heavy metals in blood and urine should be considered in patients presenting with unexplained, levodopa-resistant extrapyramidal symptoms, behavioral and sleep disturbances, cognitive decline, and other non-specific neurological signs.},
}
@article {pmid40993955,
year = {2025},
author = {Marazziti, D and Caruso, V and Cappellato, G and Chiarantini, I and Gurrieri, R and Perrone, P and Violi, M and Crivelli, NSB and Weiss, F and Perugi, G},
title = {The Emerging Role of N-Acetylcysteine in Psychiatry: A Narrative Review of Available Data.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673365458250901115725},
pmid = {40993955},
issn = {1875-533X},
abstract = {N-acetylcysteine (NAC), a cysteine derivative with a reactive thiol group, possesses antioxidant and anti-inflammatory properties. Its redox activity plays a central role in scavenging reactive oxygen and nitrogen species and modulating cellular signaling pathways. Recent research highlights its potential role in psychiatric disorders through the modulation of oxidative stress and inflammatory pathways. This narrative review examines the efficacy of NAC in treating psychiatric conditions, including mood disorders, schizophrenia, anxiety disorders, post-traumatic stress disorder (PTSD), obsessive- compulsive disorder (OCD), substance use disorders (SUDs), and neurodevelopmental disorders. A comprehensive search of PubMed, Scopus, Embase, PsycINFO, and Google Scholar databases was conducted for studies published between March 1, 2007, and December 30, 2024. The search utilized keywords related to NAC and psychiatric disorders. Data were critically analyzed to evaluate NAC's therapeutic potential. Preclinical studies demonstrate NAC's benefits in reducing oxidative stress, inflammation, and modulating neurotransmitter systems. Animal models of depression, schizophrenia, and OCD show symptom reduction through glutamatergic and antioxidant mechanisms. Clinical trials reveal NAC's efficacy as an adjunct in treating major depressive disorder, bipolar disorder, and schizophrenia, particularly for negative and cognitive symptoms. Evidence for anxiety disorders, PTSD, and OCD is limited but suggests anxiolytic and anti-obsessive effects. In SUDs, NAC shows promise in reducing cravings and substance- seeking behavior, while preliminary findings in autism suggest improvements in irritability and hyperactivity. NAC exhibits potential as an adjunctive treatment for various psychiatric disorders due to its safety profile, low cost, and broad mechanisms of action. However, clinical results are mixed, highlighting the need for larger, well-designed trials to confirm its efficacy and define optimal dosing strategies.},
}
@article {pmid40990566,
year = {2026},
author = {Morrow, LM and Barr, EA and Grossi, E and Pillai, VK and Kight, KA and Wright, EB and Turner, RP and Swatzyna, RJ},
title = {Identifying Neuroinflammation: The Diagnostic Potential of Spindling Excessive Beta in the EEG.},
journal = {Clinical EEG and neuroscience},
volume = {57},
number = {1},
pages = {42-52},
doi = {10.1177/15500594251376475},
pmid = {40990566},
issn = {2169-5202},
mesh = {Humans ; *Electroencephalography/methods ; Adult ; *Neuroinflammatory Diseases/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *COVID-19/physiopathology ; *Brain Injuries, Traumatic/physiopathology/diagnosis ; *Beta Rhythm/physiology ; *Brain/physiopathology ; },
abstract = {This manuscript examines the pivotal role of neuroinflammation in the central nervous system (CNS), particularly considering the impact of the COVID-19 pandemic. Neuroinflammation serves as a defense mechanism against various insults, including toxins, infections, and trauma. However, if left untreated, neuroinflammation can become chronic, leading to significant symptomatic and structural brain damage. Notably, neuroinflammation can mimic psychological disorders, complicating diagnosis and treatment. Current diagnostic methods for neuroinflammation-such as lumbar punctures, MRIs, brain biopsies, blood tests, and PET scans-are often hindered by inaccuracy, invasiveness, and cost. This study posits that electroencephalography (EEG), particularly identifying spindling excessive beta (SEB) activity, offers a promising, non-invasive, and cost-effective alternative for detecting neuroinflammation. This study investigates the relationship between SEB activity and neuroinflammation, focusing on traumatic brain injury (TBI). Through statistical analysis of EEG data from 1,233 psychiatric patients, we identified and compared two groups: 75 non-benzodiazepine-using adults without TBI and 79 non-benzodiazepine using adults with TBI exhibiting SEB activity. We identified a significant prevalence of SEB in individuals with refractory psychiatric conditions, underscoring the significance of this biomarker for neuroinflammation. Furthermore, we examine the therapeutic implications of reducing SEB through interventions such as guanfacine combined with N-Acetyl Cysteine (NAC), photobiomodulation, and hyperbaric oxygen therapy, all of which have demonstrated efficacy in mitigating neuroinflammation. These findings suggest that EEG could play a transformative role in the early detection and management of neuroinflammatory conditions, paving the way for more personalized and effective treatments for mental health disorders.},
}
@article {pmid40988585,
year = {2025},
author = {Mohammad, A and Ibrahim, M and Akram, M and Mohsin, H and Imran, MT and Khan Alizai, HN},
title = {N-acetylcysteine for Parkinson's disease: a translational systematic review of mechanistic and early clinical data.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2025.2563489},
pmid = {40988585},
issn = {1758-2032},
abstract = {BACKGROUND: Parkinson's disease (PD) involves progressive motor and non-motor decline, linked to oxidative stress and glutathione depletion. N-acetylcysteine (NAC), a glutathione precursor and antioxidant, is a potential disease-modifying therapy.<br><br>OBJECTIVE: To evaluate preclinical and clinical evidence on NAC in PD, focusing on motor and non-motor outcomes, dopaminergic function, and oxidative stress biomarkers.<br><br>METHODS: A PRISMA-compliant review of MEDLINE and Embase (May 2025) identified prospective studies in animal models or adults with PD. Outcomes included Unified Parkinson's Disease Rating Scale (UPDRS), dopamine transporter (DAT) imaging, glutathione levels, and safety.<br><br>RESULTS: Twelve studies met criteria. Preclinical models showed consistent neuroprotection. Intravenous NAC raised brain glutathione levels; high-dose oral NAC reached CSF. Two open-label trials (n&#x2009;=&#x2009;65), reported&#x2009;~&#x2009;13% improvement in UPDRS scores and 4-9% dopamine transporter signal increases over three months. No serious adverse events were attributed to NAC.<br><br>CONCLUSIONS: Larger randomized controlled trials are needed to test efficacy and disease-modifying potential.},
}
@article {pmid40987193,
year = {2025},
author = {Tang, J and Chen, B and Yu, F and Xu, L and Yu, M and Wang, C and Zhang, F and Zhang, L and Yang, Y and Hou, J and Li, X and Xu, W and Zhang, N},
title = {BPA exposure activated estrogen receptor α (ER-α) and ROS to induce pyroptosis in cochlear hair cells.},
journal = {Ecotoxicology and environmental safety},
volume = {304},
number = {},
pages = {119094},
doi = {10.1016/j.ecoenv.2025.119094},
pmid = {40987193},
issn = {1090-2414},
mesh = {Animals ; *Benzhydryl Compounds/toxicity ; *Pyroptosis/drug effects ; *Reactive Oxygen Species/metabolism ; *Phenols/toxicity ; Mice ; *Hair Cells, Auditory/drug effects/metabolism ; *Estrogen Receptor alpha/metabolism/genetics ; Cell Survival/drug effects ; *Environmental Pollutants/toxicity ; Bisphenol A Compounds ; },
abstract = {Increasing evidence links hearing loss to environmental pollutant exposure, with cochlear hair cell being a key target. Bisphenol A (BPA) has been suggested to cause ototoxicity, but its mechanism is not fully understood. In this study, cell viability was assessed by varying concentrations of BPA (0-150 μM) exposed to mouse cochlear hair cells (HEI-OC1), followed by RNA transcriptome sequencing to identify the possible molecular mechanisms. Results showed that BPA above 50 μM reduced cell viability in a dose-dependent manner. RNA sequencing identified 1764 differentially-expressed genes, comprised of 1152 up-regulated and 612 down-regulated genes. Notably, estrogen receptor-related genes were enriched, with a marked up-regulation of estrogen receptor α (ER-α) at both mRNA and protein levels. GO and KEGG analyses revealed the main pathway involvement for oxidative damage, lipid metabolism, protein phosphorylation, and DNA damage. STRING analyses constructed gene networks to identify functionally interacting genes correlated with pyroptotic pathways. BPA exposure induced pyroptosis-like morphological changes characterized by cell swelling, rounding, and membrane blebbing. Increased intracellular ROS and mitochondrial superoxide (MitoSOX) levels, reduced mitochondrial membrane potential (ΔΨm), and elevated intracellular calcium (Ca[2+]) levels were observed. Flow cytometry showed an increased proportion of apoptotic and necrotic cells. Pyroptosis-related genes, including caspase-3, caspase-8, caspase-9, and GSDME, were down-regulated, while IL-1β and IL-18 were up-regulated. Protein expressions of caspase-3, caspase-8, caspase-9, and GSDME were decreased, while cleaved caspase-3 and N-terminal GSDME (GSDME-NT) were increased. Furthermore, ROS inhibitor N-acetylcysteine (NAC) and the ER-α antagonist fulvestrant alleviated BPA-induced cell death, and suppressed the protein expressions of the pyroptotic pathway. These results demonstrate that BPA exposure induces ototoxicity possibly through activating ER-α and triggering mitochondrial ROS that contributes to pyroptosis.},
}
@article {pmid40977385,
year = {2025},
author = {Papke, V and Klimes-Dougan, B and Sahasrabudhe, SA and Mueller, BA and Park, YW and Öz, G and Eberly, LE and DiMaggio-Potter, ME and Kartha, RV and Cloyd, J and Coles, L and Cullen, KR},
title = {Examination of oxidative stress and glutamate as potential mechanisms of N-acetylcysteine in the treatment of non-suicidal self-injury in young people assigned female at birth: randomised trial.},
journal = {BJPsych open},
volume = {11},
number = {5},
pages = {e221},
pmid = {40977385},
issn = {2056-4724},
abstract = {BACKGROUND: Non-suicidal self-injury (NSSI) often emerges during adolescence and young adulthood. A prior open-label pilot study suggested that N-acetylcysteine (NAC) may reduce NSSI frequency in young individuals.<br><br>AIMS: This study investigated potential NSSI-related biological markers for NAC in young adults with a history of NSSI using a placebo-controlled, randomised clinical trial of two NAC dosage regimens.<br><br>METHOD: Forty-three individuals (assigned female at birth) aged 16-24 years and with a history of NSSI were randomly assigned to either low-dose NAC (3600 mg/day), high-dose NAC (5400 mg/day) or placebo treatment for 4 weeks. Participants underwent blood draws, magnetic resonance imaging with spectroscopy and clinical assessments before and after treatment. Primary outcomes included brain glutathione (GSH), blood reduced to oxidised GSH ratio and brain glutamate. Secondary outcomes included antioxidant protein levels, brain gamma-aminobutyric acid concentrations, functional connectivity (between amygdala and insula) and clinical outcomes. Pharmacokinetics, tolerability and correlations among measures were also explored.<br><br>RESULTS: For 39 participants who completed study assessments at follow-up, weekly NSSI and depression symptoms improved similarly across both treatment and placebo groups, with no significant group differences in primary or secondary outcomes at follow-up. Some significant correlations emerged.<br><br>CONCLUSIONS: The study did not support the proposed biological signatures of NAC in young adults with NSSI, although exploratory findings suggested potential biological correlates of clinical improvement. Further research is necessary to explore neurobiologically based treatments for young adults with NSSI.},
}
@article {pmid40975184,
year = {2026},
author = {An, Z and Hu, H and Wang, Q and Qiu, Y and Chu, J and Xia, Y and Li, S},
title = {Dietary Selenium deficiency activates the NLRP3 inflammasome to induce gallbladder pyroptosis by regulating glycolysis and histone lactylation through ROS/HIF-1α pathway.},
journal = {The Journal of nutritional biochemistry},
volume = {147},
number = {},
pages = {110118},
doi = {10.1016/j.jnutbio.2025.110118},
pmid = {40975184},
issn = {1873-4847},
mesh = {Animals ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; Glycolysis ; *Pyroptosis ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Inflammasomes/metabolism ; *Selenium/deficiency ; Reactive Oxygen Species/metabolism ; *Histones/metabolism ; Swine ; *Gallbladder/metabolism/pathology ; Signal Transduction ; Oxidative Stress ; Diet ; Humans ; },
abstract = {Selenium (Se) is an essential micronutrient, and inadequate intake can disrupt redox balance in digestive organs, promoting inflammation. Enhanced glycolysis leads to lactate accumulation, exacerbating the inflammatory response through inflammation-related pathways. Histone lysine lactylation plays a key role in epigenetic regulation. The effect of Se deficiency on the gallbladder remains unclear. To explore the mechanism of Se deficiency on gallbladder injury and the regulatory role of histone lactylation, we established Se-deficient swine models and in vitro cell models. Histopathological observation of the gallbladder found that Se deficiency led to inflammatory damage to the gallbladder. Metabolomics and proteomics results showed that Se deficiency led to significant enrichment of "glycolytic flux," "oxidative stress," and "hypoxia-inducible factor-1 α (HIF-1α) signaling pathway." Further studies have found that Se deficiency led to oxidative stress in gallbladder tissue, abnormal expression of HIF-1α factor, increased glycolysis levels, excessive lactate production, increased histone lactylation, and pyroptosis. HIF-1α knockdown suppressed Se deficiency-induced glycolysis and reduced lactate accumulation. In vitro studies using N-acetylcysteine (NAC), 2-deoxyglucose (2-DG), Oxamate and A-485 showed that Reactive oxygen species (ROS) regulated increased glycolysis through HIF-1α and increased H3K18 lactylation (H3K18la) levels through substrate-dependent modifications. Furthermore, H3K18la activated NLRP3 inflammasome, triggering pyroptosis and inflammatory cascades. In conclusion, the results of this study showed that dietary Se deficiency promotes glycolysis-dependent histone lactylation via the ROS/HIF-1α pathway, activating NLRP3 inflammasome, leading to pyroptosis and inflammation in gallbladder. These findings provide insights into targeted therapies for Se deficiency-related metabolic disorders and pathological changes in organs.},
}
@article {pmid40969002,
year = {2025},
author = {Wei, M and Xue, H and Gu, X and Zhang, K and Huang, Z and Lu, B and Ji, L},
title = {Chlorogenic acid promotes liver regeneration and repair after acetaminophen-induced liver injury via alleviating oxidative stress and enhancing fatty acid β-oxidation by activating Nrf2.},
journal = {Food &amp; function},
volume = {16},
number = {19},
pages = {7590-7606},
doi = {10.1039/d5fo01485a},
pmid = {40969002},
issn = {2042-650X},
mesh = {Animals ; *NF-E2-Related Factor 2/metabolism/genetics ; *Acetaminophen/adverse effects/toxicity ; *Oxidative Stress/drug effects ; *Liver Regeneration/drug effects ; Mice ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/genetics ; *Chlorogenic Acid/pharmacology/administration &amp; dosage ; Male ; Mice, Inbred C57BL ; Oxidation-Reduction ; Liver/drug effects/metabolism ; *Fatty Acids/metabolism ; Mice, Knockout ; PPAR alpha/metabolism/genetics ; Humans ; },
abstract = {Acetaminophen (ACM)-induced hepatotoxicity involves an acute injury phase followed by a recovery phase. Although N-acetylcysteine (NAC) is widely used clinically to mitigate ACM-caused hepatotoxicity during the initial injury phase, effective therapeutic strategies to promote liver regeneration (LR) during the recovery phase remain unavailable. Chlorogenic acid (CGA), abundantly present in dietary sources, has been shown to exert significant hepatoprotective effects. This study reported that CGA not only promoted LR in mice following ACM (300 mg kg[-1]) intoxication (p < 0.05) but also significantly elevated the survival rate of mice treated with a lethal dose (500 mg kg[-1]) of ACM, increasing survival from approximately 9% to 45%. Mechanistically, CGA alleviated oxidative liver damage by activating nuclear factor erythroid 2-related factor 2 (Nrf2) and facilitated energy supply for LR via enhancing fatty acid β-oxidation mediated by peroxisome proliferator-activated receptor α (PPARα). Genetic Nrf2 knockout (Nrf2[-/-]) and pharmacological inhibition of PPARα (using GW6471) confirmed the critical roles of both Nrf2 and PPARα in this process. Further analysis revealed that the CGA-induced Nrf2 activation upregulated the expression of peroxisome proliferator-activated receptor gamma, coactivator 1-alpha (PGC-1α), a key coactivator of PPARα. Collectively, CGA promoted LR following ACM intoxication by alleviating hepatic oxidative stress via activating Nrf2. Additionally, Nrf2 activation triggered the expression of PGC-1α, which further strengthened PPARα-mediated fatty acid β-oxidation, thereby supplying sufficient energy for CGA-promoted LR following ACM intoxication. These findings highlight CGA's hepatoprotective effects and suggest it as a promising dietary supplement for promoting LR following toxic injury.},
}
@article {pmid40961779,
year = {2025},
author = {Chen, S and Han, Q and Zhou, Z and Gao, M and Song, J and Zhang, B and Guo, Y and Lv, Z},
title = {Dietary N-acetylcysteine supplementation improves antioxidant capacity and production performance of breeder hens and offspring.},
journal = {Poultry science},
volume = {104},
number = {11},
pages = {105745},
pmid = {40961779},
issn = {1525-3171},
mesh = {Animals ; *Chickens/physiology/growth &amp; development ; *Acetylcysteine/administration &amp; dosage/metabolism ; Animal Feed/analysis ; Dietary Supplements/analysis ; Female ; Diet/veterinary ; *Antioxidants/metabolism ; Random Allocation ; Animal Nutritional Physiological Phenomena/drug effects ; *Reproduction/drug effects ; },
abstract = {This study investigated the effects of dietary N-acetylcysteine (NAC) supplementation on the antioxidant capacity and production performance of broiler breeder hens and their offspring. The breeder hens were randomly assigned to two groups: one received a corn-soybean meal-based control diet, while the other was supplemented with 1 g/kg NAC. Eggs from each group were randomly selected for incubation, and the offspring broilers were fed a basal diet. Dietary NAC treatment not only increased the albumen height and Haugh unit values of eggs but also improved fertilization rates (P < 0.05). Additionally, broiler chicks from the NAC-treated hens demonstrated higher eviscerated weight, full evisceration rate, and semi-eviscerated weight (P < 0.05). Dietary supplementation with NAC in breeder hens enhanced antioxidant capacity, as evidenced by increased total antioxidant capacity and catalase (CAT) activity in egg yolk, elevated CAT and glutathione peroxidase activities in breeder hen serum, and higher superoxide dismutase activity in chick serum. In particular, the NAC-treated group showed significantly higher glutathione levels and lower malondialdehyde levels throughout the transition from breeder hens to offspring (P < 0.05). Furthermore, maternal NAC treatment decreased the relative mRNA expression levels of pro-inflammatory cytokines interferon-γ, interleukin 18, and interleukin 6 in the ileum of the offspring broilers (P < 0.05). In conclusion, maternal dietary supplementation with NAC can continuously enhance the antioxidant capability and intestinal barrier function of chicken offspring, while also improving egg quality, growth performance and slaughter performance.},
}
@article {pmid40954254,
year = {2025},
author = {El-Alamin, MMA and Elkhalek, OA and Azab, MM},
title = {An environmental green factorial design/assisted spectrofluorimetric technique for quantitation of citicoline in pharmaceutical dosage form and wastewater.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {32547},
pmid = {40954254},
issn = {2045-2322},
mesh = {*Wastewater/chemistry/analysis ; Spectrometry, Fluorescence/methods ; Limit of Detection ; Reproducibility of Results ; *Water Pollutants, Chemical/analysis ; o-Phthalaldehyde/chemistry ; Pharmaceutical Preparations/chemistry ; Green Chemistry Technology/methods ; },
abstract = {A novel, sensitive, and straightforward spectrofluorimetric method was developed for the quantitative determination of citicoline in pharmaceutical formulations and wastewater. The technique depends on the efficient derivatisation of the primary amino group of citicoline with O-phthalaldehyde (OPA) and N-acetylcysteine (NAC) in borate buffer (pH 11), yielding a highly fluorescent derivative. The fluorescence intensity was measured at 425 nm with an excitation wavelength of 341 nm. Experimental parameters affecting the derivatisation reaction were thoroughly optimised. Under optimal conditions, the method exhibited a linear response over the concentration range of 50.0-300.0 ng/mL, with an excellent correlation coefficient (R[2] = 0.9942). The limits of detection (LOD) and quantification (LOQ) were 6.4 ng/mL and 19.5 ng/mL, respectively. The approach demonstrated high accuracy and precision, with per cent recovery values close to 100% and a relative standard deviation (RSD) of 0.512%, confirming its reliability. Validation was done in agreement with ICH Q2(R1) guidelines, and statistical comparison with previously reported approaches indicated no significant difference in performance. The sustainability of the method was studied using the analytical greenness tools confirms the method's eco-friendly profile. Collectively, these contributions advance drug bioavailability while promoting a more efficient and sustainable analytical framework.},
}
@article {pmid40950264,
year = {2025},
author = {Long, S and Qin, H and Guo, J and Liu, L},
title = {Therapeutic outcomes and inflammatory modulation of inhaled N-acetylcysteine bronchoalveolar lavage in severe pneumonia.},
journal = {American journal of translational research},
volume = {17},
number = {8},
pages = {6630-6638},
pmid = {40950264},
issn = {1943-8141},
abstract = {OBJECTIVE: To evaluate the therapeutic efficacy of inhaled N-acetylcysteine (NAC) bronchoalveolar lavage (iNAC-BAL) in severe pneumonia (SP) and explore its effects on inflammatory cytokines modulation.<br><br>METHODS: A total of 146 SP cases were assigned to two groups: the control group received bronchoalveolar lavage with isotonic saline (0.9% NaCl) alone, while the observation group received additional NAC aerosol inhalation. Clinical efficacy, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, intensive care unit (ICU) stay, duration of ventilator dependence, adverse reactions, symptom resolution times, respiratory mechanics, pulmonary function, inflammatory cytokines, and humoral immunity were assessed and compared between the two groups.<br><br>RESULTS: The observation group achieved better therapeutic effects (P=0.007), with significantly lower APACHE II scores, shorter ICU stays, reduced ventilator dependence, faster symptom resolution, and fewer adverse events (all P<0.05). Additionally, respiratory dynamics, lung function, inflammatory cytokines, and humoral immunity improved markedly in the observation group compared with the control group (all P<0.05).<br><br>CONCLUSION: iNAC-BAL demonstrates significant clinical efficacy and potent anti-inflammatory effects in the management of SP.},
}
@article {pmid40948959,
year = {2025},
author = {Bohn, MC and Oltmanns, H and Harting, H and Meißner, J},
title = {N-acetyl cysteine as an additive to bone cement against pathogens involved in periprosthetic joint infections.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {13},
number = {},
pages = {1595821},
pmid = {40948959},
issn = {2296-4185},
abstract = {Periprosthetic joint infections (PJIs) and septic loosening of implants are common complications following surgical replacement of destructive joints in both human and veterinary medicine. Increasing occurrence of multi-resistant bacteria and failure to manage periprosthetic joint infections make it necessary to identify new antibacterial substances for the treatment and prevention of these infections. N-acetyl cysteine (NAC), a derivative of the amino acid cysteine, has been chosen as a candidate substance due to its shown antibacterial activity. The aim of the study was to evaluate the suitability of NAC for the use together with polymethylmethacrylate bone cement in the context of PJIs. Antibacterial activity of pure NAC and NAC-containing bone cement against clinical isolates of Staphylococcus (S.) pseudintermedius was tested by determining minimal inhibitory concentrations, analyzing growth of bacteria on bone cement, and examining the influence on infection of human osteosarcoma (HOS) cells. Cytotoxicity of pure NAC and bone cement with NAC against HOS cells was analyzed with viability and proliferation assays, Live/Dead staining of cells on bone cement, measurement of Interleukin-6 (IL-6) release, and visualizing activation of p38 MAP kinase with Western blotting. NAC inhibited growth of Staphylococcus pseudintermedius at 2.5 mg/mL and reduced bacterial growth on bone cement but could not inhibit infection of cells at 1.5 mg/mL. The IC50 of pure NAC for viability was 3.6 mg/mL. Bone cement with NAC reduced viability and proliferation at some concentrations but did not provoke IL-6 release. Western blots indicated that p38 could be activated following treatment with NAC. Taken together, antibacterial effectiveness could be shown but cytocompatibility of NAC in bone cement was limited, so that NAC cannot currently be used as a bone cement additive. Further research is necessary to balance antibacterial activity and cytotoxicity.},
}
@article {pmid40947894,
year = {2025},
author = {Li, C and Zhang, Y and Pan, Y and Wu, H and Zhang, C and Wu, Y and Meng, R and Su, J},
title = {N-Acetylcysteine Promotes the Maturation of Sheep Oocytes and Embryo Development In Vitro.},
journal = {Reproduction in domestic animals = Zuchthygiene},
volume = {60},
number = {9},
pages = {e70084},
doi = {10.1111/rda.70084},
pmid = {40947894},
issn = {1439-0531},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *In Vitro Oocyte Maturation Techniques/veterinary ; *Oocytes/drug effects ; *Embryonic Development/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Female ; Glutathione/metabolism ; Embryo Culture Techniques/veterinary ; Sheep/embryology ; Antioxidants/pharmacology ; Blastocyst/drug effects ; Calcium/metabolism ; Fertilization in Vitro/veterinary ; },
abstract = {During the in vitro maturation process of oocytes, oxidative stress is commonly present, and excessive oxidative stress can affect oocyte maturation. Thus, adding antioxidants during maturation is an effective strategy for reducing oxidative stress. N-acetylcysteine (NAC), a derivative of cysteine, participates in glutathione (GSH) metabolism and stimulates glutathione synthesis. However, a clear understanding of the effect of NAC on sheep oocytes remains unknown. In this study, we investigated NAC's impact on the maturation of sheep oocytes, and the results revealed that the maturation rate, and subsequently the cleavage and blastocyst formation, were significantly enhanced by incubation with 1 mM NAC. The GSH and Ca[2+] levels increased, and the cortical granules were significantly elevated, whereas the reactive oxygen species levels were significantly reduced in the 1 mM NAC-treated group. Additionally, the number of inner cell masses was significantly increased. The findings of this study support the hypothesis that NAC increases oocyte maturation rate by protecting them from oxidative stress damage. These discoveries provide a new approach for improving the efficiency of in vitro production of sheep embryos.},
}
@article {pmid40945056,
year = {2025},
author = {Harvey, HJ and Szepe, KJ and Hendry, AC and Archer, DB and Avery, SV},
title = {Sorbic acid resistance and metabolism of Brettanomyces bruxellensis in the spoilage of low sugar soft drinks.},
journal = {International journal of food microbiology},
volume = {443},
number = {},
pages = {111439},
doi = {10.1016/j.ijfoodmicro.2025.111439},
pmid = {40945056},
issn = {1879-3460},
mesh = {*Sorbic Acid/pharmacology ; Fermentation ; *Brettanomyces/metabolism/drug effects/growth &amp; development ; *Carbonated Beverages/microbiology/analysis ; Food Microbiology ; *Food Preservatives/pharmacology ; Reactive Oxygen Species/metabolism ; Drug Resistance, Fungal ; },
abstract = {Brettanomyces bruxellensis is an emerging spoilage yeast of low-sugar ethanol fermentation processes and alcoholic beverages. As soft (non-alcoholic) drinks manufacturers transition towards low sugar formulations, this study investigated the ability of B. bruxellensis to grow in different soft-drink and preservative conditions. Multiple B. bruxellensis isolates grew comparably to the common spoilage yeast Z. bailii in a variety of soft drink formulations, including zero sugar lemonades, low-sugar fruit juices, and carbonated beverages. Growth assays with B. bruxellensis in laboratory minimal-medium supplemented with low (0.1 %) glucose were characterised by turbid biomass accumulation (a spoilage indicator) and resistance to the major food preservative sorbic acid (SA), known to cause oxidative stress and to inhibit respiration. Analysis of respiro-fermentative metabolism revealed that B. bruxellensis favoured respiration over fermentation regardless of glucose concentration, with oxygen limitation significantly reducing its growth. Cell-to-cell heterogeneity was used as a tool to test whether cellular levels of respiratory reactive oxygen species (ROS) influence the organism's SA resistance phenotype. At low glucose, sorted cell-subpopulations with high background ROS were more SA resistant than low ROS cells. Furthermore, the antioxidant N-acetyl cysteine (NAC) hyper-sensitized these cell subpopulations to SA. Therefore, one explanation for SA resistance despite the organism's primarily respiratory metabolism could be that respiratory ROS builds cells' resilience to (subsequent) SA-induced oxidative stress. The work shows that B. bruxellensis is capable of growth in zero- or low-sugar media and drinks formulations, and in the presence of relatively high sorbic acid levels.},
}
@article {pmid40944367,
year = {2025},
author = {Roussos, A and Kitopoulou, K and Borbolis, F and Ploumi, C and Gianniou, DD and Li, Z and He, H and Tsakiri, E and Borland, H and Kostakis, IK and Samiotaki, M and Trougakos, IP and Bohr, VA and Palikaras, K},
title = {Urolithin Α modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.},
journal = {Autophagy},
volume = {21},
number = {12},
pages = {3097-3122},
pmid = {40944367},
issn = {1554-8635},
support = {P40 OD010440/OD/NIH HHS/United States ; },
mesh = {*Mitophagy/drug effects ; Animals ; Caenorhabditis elegans/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; *Aging/drug effects/metabolism ; *Calcium/metabolism ; Endoplasmic Reticulum/metabolism/drug effects ; Lysosomes/metabolism/drug effects ; *Coumarins/pharmacology ; Humans ; Calcium Signaling/drug effects ; Mitochondrial Dynamics/drug effects ; Caenorhabditis elegans Proteins/metabolism ; },
abstract = {Mitochondrial dysfunction and impaired mitophagy are hallmarks of ageing and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, Urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analysis reveals that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In Caenorhabditis elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.Abbreviations: Ca[2+]: calcium ions; BJ: human foreskin fibroblasts; BNIP3: BCL2 interacting protein 3; BP: bipyridyl; CAMK2D: calcium/calmodulin dependent protein kinase II delta; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DEGs: differentially expressed genes; DEPs : differentially expressed peptides; DFP: deferiprone; DNM1L/DRP1: dynamin 1 like; EGTA: ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid; EMC: endoplasmic reticulum membrane protein complex; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-trifluoro-methoxyphenyl hydrazone; GO: gene ontology; GSVA: Gene Set Variation Analysis; HUVECs: human umbilical vein endothelial cells; IMM: inner mitochondrial membrane; ITPR/InsP3R: inositol 1,4,5-triphosphate receptor; MAM: mitochondria-associated ER membrane; MAPK: mitogen-activated protein kinase; MCU: mitochondrial calcium uniporter; MEFs: mouse embryonic fibroblasts; NAC : N-acetylcysteine; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; NMN: nicotinamide mononucleotide; NR: nicotinamide riboside; OMM: outer mitochondrial membrane; PCA: principal-component analysis; PPARGC1A/PGC1α: PPARG coactivator 1 alpha; PQ: paraquat; TMCO: transmembrane and coiled-coil domains 1; TMRE: tetramethylrhodamine ethyl ester perchlorate; UA: urolithin A; VDAC: voltage dependent anion channel.},
}
@article {pmid40943427,
year = {2025},
author = {Albahri, G and Badran, A and Hellany, H and Baydoun, S and Abdallah, R and Alame, M and Hijazi, A and Maresca, M and Baydoun, E},
title = {Mandragora autumnalis: Phytochemical Composition, Antioxidant and Anti-Cancerous Bioactivities on Triple-Negative Breast Cancer Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
pmid = {40943427},
issn = {1422-0067},
mesh = {Humans ; *Triple Negative Breast Neoplasms/drug therapy/metabolism/pathology ; *Antioxidants/pharmacology/chemistry ; Cell Line, Tumor ; *Plant Extracts/pharmacology/chemistry ; Female ; *Phytochemicals/pharmacology/chemistry ; Cell Proliferation/drug effects ; Cell Movement/drug effects ; Cell Survival/drug effects ; *Antineoplastic Agents, Phytogenic/pharmacology/chemistry ; Plant Leaves/chemistry ; Matrix Metalloproteinase 9/metabolism ; },
abstract = {Breast cancer is a common and chronic condition, and despite improvements in diagnosis, treatment, and prevention, the number of cases of breast cancer is rising annually. New therapeutic drugs that target specific checkpoints should be created to fight breast cancer. Mandragora autumnalis possesses substantial cultural value as a herb and is regarded as one of the most significant medicinal plants; however, little is known about its anticancerous biological activity and chemopreventive molecular pathways against the triple-negative breast cancer (MDA-MB-231) cell line. In this study, the antioxidant, anticancer, and underlying molecular mechanisms of the Mandragora autumnalis ethanolic leaves extract (MAE) were evaluated, and its phytochemical composition was determined. Results indicated that MAE diminished the viability of MDA-MB-231 cells in a concentration- and time-dependent manner. Although MAE exhibited 55% radical scavenging activity at higher concentrations in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, the attenuation of its cytotoxic effects in MDA-MB-231 cells with N-acetylcysteine (NAC) co-treatment suggests a potential role of oxidative stress. Additionally, MAE caused an increase in the tumor suppressor p53. Moreover, this extract caused a significant decrease in the expression of Ki-67 (a cellular proliferation marker), MMP-9 (matrix metalloproteinase-9, an enzyme involved in extracellular matrix degradation and metastasis), and STAT-3 (a transcription factor regulating cell growth and survival). Also, MAE altered cell cycle, cell migration, angiogenesis, invasion, aggregation, and adhesion to suppress cellular processes linked to metastasis. All of our research points to MAE's potential to function as an anticancer agent and opens up new possibilities for the development of innovative triple-negative breast cancer treatments.},
}
@article {pmid40939324,
year = {2025},
author = {Zhang, Y and Chen, J and Lin, W and Qin, Z and Zhou, D and Li, P and Xiong, W},
title = {Quantitative LC-MS/MS profiling of N-Acetylcysteine in chicken plasma: Method validation and pharmacokinetic characterization.},
journal = {Poultry science},
volume = {104},
number = {11},
pages = {105777},
pmid = {40939324},
issn = {1525-3171},
mesh = {Animals ; *Chickens/blood/metabolism ; *Acetylcysteine/pharmacokinetics/blood/administration &amp; dosage ; *Tandem Mass Spectrometry/veterinary/methods ; Chromatography, Liquid/veterinary/methods ; Administration, Oral ; Male ; Dose-Response Relationship, Drug ; Reproducibility of Results ; Liquid Chromatography-Mass Spectrometry ; },
abstract = {N-Acetylcysteine (NAC), an essential precursor in glutathione synthesis, exhibits broad therapeutic potential but remains pharmacokinetically (PK) poorly characterized in poultry. To address this gap, we developed and validated a novel LC-MS/MS method that incorporates an isotope-labeled internal standard (d[3]-NAC) and a surrogate matrix (5 mg/mL bovine serum albumin). This approach effectively overcame interference from endogenous thiols through one-step methanol protein precipitation followed by DTT reduction, with chromatographic separation on a C18 column using 0.1 % formic acid-acetonitrile gradient elution (0.3 mL/min). Method validation demonstrated excellent linearity (0.01-4 μg/mL, R[2] > 0.99), sensitivity (LOD: 0.005 μg/mL; LLOQ: 0.01 μg/mL), accuracy (84.9-114.77 %), and precision (RSD < 10.61 %). Pharmacokinetic studies in broilers revealed distinct profiles under intravenous (IV, 10 mg/kg) and oral administration (10, 20, 40 mg/kg): (1) IV injection achieved rapid high exposure (AUC0-t: 14.573 ± 2.2 h·μg/mL) with prolonged elimination (t1/2: 3.59 ± 2.59 h). (2) Oral dosing showed dose-proportional absorption (tmax: 0.65-0.81 h) but low bioavailability (F: 17.04-22.56 %), though higher doses accelerated absorption (t1/2 increased from 1.31 ± 0.19 h at 10 mg/kg to 3.40 ± 2.29 h at 40 mg/kg). These findings establish two clinical application paradigms: (1) IV administration is optimal for acute respiratory crises due to its immediate high plasma concentration. (2) Oral delivery suits chronic supplementation, with dose escalation enhancing absorption efficiency. The validated LC-MS/MS platform provides a robust solution for veterinary drug analysis in biologically complex matrices, while the PK insights directly inform rational NAC regimens in poultry respiratory disease management.},
}
@article {pmid40935016,
year = {2026},
author = {Zuo, H and Huang, L and Huang, M and Ma, X and Zheng, C and Holman, BWB and Zhang, Y and Luo, X and Mao, Y},
title = {Peroxiredoxin 6 (Prdx6) and oxidative stress in post-mortem beef tenderization: A proteomic perspective.},
journal = {Journal of proteomics},
volume = {322},
number = {},
pages = {105527},
doi = {10.1016/j.jprot.2025.105527},
pmid = {40935016},
issn = {1876-7737},
mesh = {Animals ; Cattle ; *Oxidative Stress ; *Peroxiredoxin VI/metabolism ; *Proteomics/methods ; *Red Meat/analysis ; Hydrogen Peroxide/pharmacology ; Glutathione Peroxidase/metabolism ; Muscle, Skeletal/metabolism ; },
abstract = {This research explored the role of peroxiredoxin 6 (Prdx6)-mediated non‑selenium glutathione peroxidase (NSGPx) activity in modulating the tenderization process of beef during post-mortem aging, extending up to 168 h. Shear force, NSGPx activity, differential protein abundance, heat shock proteins (HSP70, HSP27), and troponin-T levels were analyzed in beef longissimus lumborum muscles treated with hydrogen peroxide (H2O2), N-acetylcysteine (NAC), mercaptosuccinic acid (MA), or saline (Control). MA treatment inhibited NSGPx activity and accelerated tenderization compared to NAC. Proteomics revealed that proteins differentially abundant between 0 and 24 h post-mortem were linked to cytoskeleton, extracellular matrix, amino acid metabolism, and apoptosis pathways.MA upregulated HSP70 abundance, oxidative stress, and troponin-T breakdown. H2O2 upregulated HSP70 and HSP27 abundance only within 6-12 h post-mortem. These results demonstrate that oxidative stress treatments modulate protein dynamics during aging, offering insights into strategies to enhance beef tenderness. SIGNIFICANCE: This study highlights peroxiredoxin 6 (Prdx6) as a crucial regulatory element that affects oxidative stress-associated pathways involved in the meat tenderization process during post-mortem beef aging. We demonstrate that inhibiting Prdx6's on‑selenium glutathione peroxidase (NSGPx) enzymatic activity with mercaptosuccinic acid (MA) increases HSP70 abundance and accelerates troponin-T proteolysis through enhanced oxidative stress and calcium signaling pathways. Conversely, antioxidant N-acetylcysteine (NAC) delays tenderization by preserving cytoskeletal integrity. Our TMT-based proteomics further identifies 35 core proteins linking extracellular matrix remodeling, amino acid metabolism, and apoptosis to tenderness modulation. These findings provide the first mechanistic evidence that targeted manipulation of Prdx6 activity can optimize beef aging efficiency. For the meat industry, MA treatment offers a science-driven strategy to reduce tenderization time by >20 % within 24-72 h post-mortem, lowering processing costs while maintaining quality. This work also establishes HSP70 and troponin-T degradation as novel biomarkers for real-time monitoring of oxidative stress in meat processing systems.},
}
@article {pmid40931599,
year = {2025},
author = {Osman, AG and Avula, B and Khan, IA and Chittiboyina, AG},
title = {Unraveling Origins of N-Acetylcysteine (NAC): A Critical Review.},
journal = {Journal of dietary supplements},
volume = {22},
number = {6},
pages = {833-843},
doi = {10.1080/19390211.2025.2555015},
pmid = {40931599},
issn = {1939-022X},
mesh = {*Acetylcysteine/analysis/chemistry ; *Dietary Supplements/analysis ; Humans ; *Allium/chemistry ; *Plant Extracts/chemistry ; },
abstract = {The controversial status of N-acetylcysteine (NAC) as a dietary supplement ingredient has renewed interest in its origin. This opinion article critically examines the scientific literature to investigate whether NAC is a naturally occurring compound, with a particular focus on its potential presence in plants. The primary objective of this opinion is to determine the natural occurrence of NAC, specifically within herbal matter. The classification of NAC as a dietary ingredient falls outside the scope of this analysis. We will rigorously evaluate the methodologies implemented in establishing NAC's presence in plant or herbal sources, specifically in Allium species which are often touted to contain NAC. By analyzing the strengths and weaknesses of prior research, we aim to clarify the evidence supporting the origin of NAC.},
}
@article {pmid40921646,
year = {2025},
author = {Morley, K and Arunogiri, S and Connor, JP and Clark, PJ and Chatterton, ML and Baillie, A and Slade, T and Berk, M and Lubman, D and Haber, PS},
title = {N-acetyl cysteine for the treatment of alcohol use disorder: study protocol for a multi-site, double-blind randomised controlled trial (NAC-AUD study).},
journal = {BMJ open},
volume = {15},
number = {9},
pages = {e091631},
pmid = {40921646},
issn = {2044-6055},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Double-Blind Method ; *Alcoholism/drug therapy ; Randomized Controlled Trials as Topic ; Cost-Benefit Analysis ; Adult ; Male ; Treatment Outcome ; Multicenter Studies as Topic ; Female ; Alcohol Drinking ; Cognition/drug effects ; },
abstract = {INTRODUCTION: Current treatments for alcohol use disorders (AUD) have limited efficacy. A previous 28-day pilot trial of N-acetyl cysteine (NAC) vs placebo found NAC to be feasible and safe, with evidence of improvement on some measures of alcohol consumption. Thus, the primary aim of the NAC-AUD study is to examine the therapeutic and cost-effectiveness of NAC vs placebo in improving treatment outcomes for AUD. We will also examine the (i) effect of NAC vs placebo on mood, markers of liver injury, cognition and hangover symptoms; and (ii) predictors of any response.<br><br>METHODS AND ANALYSIS: This double-blind trial will randomise participants with AUD to a 12-week regimen of either NAC (2400&#x2009;mg/day) or placebo. All participants will receive medical management. The primary drinking outcome will be the number of heavy drinking days (HDDs) per week, validated by phosphatidylethanol (PEth). Secondary alcohol-related outcomes will include standard drinks per drinking day (SDDD) per week and absence of any HDDs. Other secondary outcomes will include markers of liver injury, depression, anxiety, craving, hangover symptoms, cognition and blood oxidative stress markers. We will also examine the cost-efficacy of NAC vs placebo.<br><br>ETHICS AND DISSEMINATION: Ethics approval for the study has been granted by The Sydney Local Health District Ethics Review Committee (X21-0342&amp; HREC2021/ETH11614). There are no restrictions on publication from the sponsor or other parties.<br><br>TRIAL REGISTRATION NUMBER: NCT05408247.},
}
@article {pmid40919813,
year = {2025},
author = {Ishii, K and Kurihara, Y and Yoshimura, M and Walenna, NF and Shimizu, A and Ozuru, R and Hiromatsu, K},
title = {FABP4-dependent fatty acid oxidation-fueled mitochondrial ROS induces the mobilization of cellular iron and facilitates Trypanosoma cruzi proliferation in murine adipocytes.},
journal = {mBio},
volume = {16},
number = {10},
pages = {e0218025},
pmid = {40919813},
issn = {2150-7511},
support = {22K08614//Japan Society for the Promotion of Science/ ; 23K07932//Japan Society for the Promotion of Science/ ; 24K11646//Japan Society for the Promotion of Science/ ; 24K10225//Japan Society for the Promotion of Science/ ; },
mesh = {Animals ; *Trypanosoma cruzi/growth &amp; development/physiology ; Mice ; *Fatty Acid-Binding Proteins/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; *Adipocytes/parasitology/metabolism ; Oxidation-Reduction ; *Fatty Acids/metabolism ; *Mitochondria/metabolism ; *Iron/metabolism ; 3T3-L1 Cells ; Chagas Disease/parasitology/metabolism ; Carnitine O-Palmitoyltransferase/metabolism/genetics ; },
abstract = {Fatty acid-binding protein 4 (FABP4) is a cytosolic lipid chaperone predominantly expressed in adipocytes. It has been shown that Trypanosoma cruzi targets adipose tissues and resides in adipocytes. However, how T. cruzi manipulates adipocytes to redirect nutrients for its benefit remains unknown. Here, we uncover the role of FABP4 in facilitating T. cruzi infection in murine 3T3-L1 adipocytes. We demonstrate that pharmacological or genetic inhibition of FABP4, carnitine palmitoyltransferase I (CPT-1), or fatty acid oxidation (FAO) abrogates the intracellular growth of T. cruzi in adipocytes. We also found that inhibiting FABP4, CPT-1, or FAO eliminates the infection-induced elevation of mitochondrial and cellular reactive oxygen species (ROS) in adipocytes. Furthermore, T. cruzi infection-induced elevation of ROS in adipocytes increased the cytosolic Fe[2+], which fueled T. cruzi proliferation. The treatment with antioxidants such as ROS scavenger N-acetyl cysteine (NAC) or mitochondrial ROS inhibitors MitoQ increased the expression level of mRNA for Ferroportin and Ferritin, leading to the decrease in cytosolic Fe[2+] and the intracellular growth inhibition of T. cruzi in adipocytes. The addition of ferrous sulfate reversed the FABP4 inhibitor or antioxidant-induced decrease in adipocyte parasite burden. Our results demonstrate that T. cruzi exploits host FABP4 to facilitate fatty acid oxidation and elevate cellular ROS, increasing the labile iron pool for the intracellular replication of T. cruzi in adipocytes. These results highlight the therapeutic possibility of host FABP4 as a drug target for T. cruzi infection.IMPORTANCEPersistent infection with a protozoan parasite, Trypanosoma cruzi, causes Chagas disease. While it has been appreciated that adipose tissues are one of the sites of persistent infection, the mechanism of how the parasite survives in adipocytes remains to be established. Our study highlights FABP4, a key regulator of metabolic dysfunction and inflammation, as a therapeutic host target controlling T. cruzi infection in adipocytes. We uncover the importance of FABP4 for T. cruzi replication in mouse adipocytes through engagement with lipid droplet degradation and trafficking of liberated free fatty acids to the host cell's mitochondria, which are utilized for fatty acid oxidation (FAO). T. cruzi infection-induced FAO fuels reactive oxygen species, and the subsequent iron mobilization accelerates parasite replication. These results shed light on the mechanisms of T. cruzi persistent infection in adipocytes, raising the possibility of host FABP4 as a drug target for T. cruzi infection.},
}
@article {pmid40917936,
year = {2025},
author = {Ma, Z and Xu, Q and Xu, X},
title = {The Pathophysiological Role of Mitochondrial Oxidative Stress in Rheumatic Diseases.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {12021-12044},
pmid = {40917936},
issn = {1178-7031},
abstract = {Mitochondria play a crucial role in reactive oxygen species (ROS)-dependent rheumatic diseases, including ankylosing spondylitis, osteoarthritis (OA), systemic lupus erythematosus (SLE) and scleroderma. Mitochondrial DNA (mtDNA), which encodes mitochondrial proteins, is more vulnerable to oxidants compared to nuclear DNA. When mtDNA gets damaged, it leads to mitochondrial dysfunction, such as electron transport chain impairment and loss of mitochondrial membrane potential. Moreover, the damaged mtDNA functions as a damage-associated molecular pattern (DAMP), triggering inflammatory and immune responses. In this review, ROS-related transcription factors and downstream cell signaling pathways are investigated. It also explains the mechanism of mitochondrial dysfunction and the clinical significance of major rheumatic diseases, as well as the clinical transformation status of key antioxidants, the risks/reasons for promoting mitochondrial ROS research in rheumatic diseases, and antioxidant therapy. We conclude that targeting oxidative stress with antioxidant agents,such as polyphenols, garlic, pomegranate, Coenzyme Q10, probiotic, α-lipoic acid, N-acetylcysteine (NAC), selenium, microalgae, fucoidan, resveratrol, quercetin, and curcumin should be considered as promising new strategies for treating rheumatic diseases lacking effective treatments.},
}
@article {pmid40901687,
year = {2025},
author = {Koonsiripaiboon, P and Ruamtawee, W and Simasingha, N and Tanasoontrarat, W and Claimon, T and Sethasine, S},
title = {Efficacy of N-acetylcysteine vs dexamethasone in preventing postembolization syndrome post-transarterial chemoembolization in hepatocellular carcinoma: A randomized controlled trial.},
journal = {World journal of gastroenterology},
volume = {31},
number = {31},
pages = {109630},
pmid = {40901687},
issn = {2219-2840},
mesh = {Humans ; *Carcinoma, Hepatocellular/therapy/pathology ; *Liver Neoplasms/therapy/pathology ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; Middle Aged ; Male ; *Chemoembolization, Therapeutic/adverse effects/methods ; Female ; Adult ; Double-Blind Method ; *Dexamethasone/therapeutic use/administration &amp; dosage ; Aged ; Treatment Outcome ; Incidence ; Thailand/epidemiology ; Syndrome ; Young Adult ; Adolescent ; },
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is a major health concern in Thailand, with most patients diagnosed at the intermediate stage. Transarterial chemoembolization (TACE) is the standard treatment; however, postembolization syndrome (PES) remains a common complication. Although both dexamethasone (DEXA) and N-acetylcysteine (NAC) have shown efficacy in reducing PES, no study has directly compared their effects.<br><br>AIM: To compare the incidence of PES between DEXA and NAC in intermediate-stage HCC patients undergoing conventional TACE (cTACE).<br><br>METHODS: A randomized, double-blind, controlled trial was conducted at two tertiary hospitals in Thailand from November 2024 to April 2025. Eligible HCC patients (aged 18-70 years) were randomized (1:1) to receive either NAC (150 mg/kg/hour loading dose, followed by 50 mg/kg over 4 hours, then 6.25 mg/kg/ hour for 48 hours post-cTACE) or DEXA (8 mg IV 1 hour before cTACE). cTACE was performed by blinded interventional radiologists. The primary outcome was PES occurrence within 48 hours, assessed using South West Oncology Group toxicity coding and the Common Terminology Criteria for Adverse Events. The secondary outcomes were post-cTACE liver decompensation and the dynamic changes in the albumin-bilirubin (ALBI) score.<br><br>RESULTS: A total of 56 intermediate-stage HCC patients were included (DEXA, n = 28; NAC, n = 28). Most had preserved liver function, with 92.9% classified as Child-Pugh A. The maximum tumor size was 6.2 cm, and 85.7% had multiple lesions. Additionally, 39 patients (69.6%) met the beyond up-to-7 criteria. Overall, 27 patients (48.2%) developed PES. After adjusting for confounding factors, the NAC group had a significantly lower incidence of PES than the DEXA group (32.1% vs 64.3%; adjusted odds ratio = 0.17, 95% confidence interval: 0.03-0.87, P = 0.033). Only two patients (3.6%) developed post-cTACE liver decompensation. Furthermore, 51.8% patients experienced worsening ALBI scores within 48 hours post-procedure; however, the rate of ALBI score worsening did not significantly differ between the groups.<br><br>CONCLUSION: Compared with DEXA, NAC significantly reduces the incidence of PES, regardless of its impact on liver function recovery. Therefore, NAC is a preferable option for reducing PES in Barcelona Clinic Liver Cancer-B stage HCC patients with preserved liver function.},
}
@article {pmid40900813,
year = {2025},
author = {Kumar, S and Agrawal, P and Mendhey, P and Dhatwalia, SK and Sitasawad, SL},
title = {Antioxidants ameliorates glucose/glucose oxidase-induced myocardial damage through mitochondrial and MAPK pathway.},
journal = {3 Biotech},
volume = {15},
number = {9},
pages = {323},
pmid = {40900813},
issn = {2190-572X},
abstract = {Diabetes is characterized by high blood glucose concentration that leads to the generation of elevated levels of free radicals (oxidative stress) via auto-oxidation. Oxidative stress plays a key role in diabetes-associated progressive pathologies including myocardial complications. The aim of the present study is to investigate the protective effects of antioxidants in glucose/glucose oxidase (G/GO)-dependent oxidative stress-induced cardiac cell damage. We found that exposure of G (33mM)/GO (1.6 milliunits) to cardiac muscle H9c2 cells resulted in a significant increase in apoptosis as indicated by accumulation of membrane phospholipid phosphatidylserine, DNA damage, and intracellular esterase activity. Confocal microscopy and FACS analysis further showed that G/GO induced the production of reactive oxygen and reactive nitrogen species which led to the loss of mitochondrial membrane potential and release of cytochrome c in H9c2 cells. Treatment of H9c2 cells with antioxidants like N-Acetyl Cysteine, catalase or glutathione abolished the G/GO-induced free radicals, perturbed the mitochondrial membrane potential, and induced cytochrome c release. These antioxidants also inhibited G/GO-induced cell death, caspases, and cleavage of PARP. In addition, antioxidants restored G/GO-induced suppression of antiapoptotic proteins, Bcl-2, Bcl-xL, cFLIP, XIAP, and survivin. Furthermore, G/GO impacted the MAPK pathway via activation of Raf1, MEK1 and ERK1/2 in oxidative stress-dependent manner. Pharmacologic inhibition of Raf1 also abolished G/GO-induced apoptosis. Thus, our data suggest that antioxidants have a strong protective efficacy against G/GO-induced oxidative stress through inhibition of mitochondrial and MAPK-mediated pathways in cardiac cells.},
}
@article {pmid40891511,
year = {2025},
author = {Narayanasamy, B and Helmueller, S and Zhang, Y and Lee, YJ},
title = {Current Advances in Anticancer Properties of Heptamethine Carbocyanine DZ-1 Conjugated to Artesunate: Generation of Reactive Oxygen Species.},
journal = {Journal of cellular biochemistry},
volume = {126},
number = {9},
pages = {e70062},
pmid = {40891511},
issn = {1097-4644},
support = {R01 CA265827/CA/NCI NIH HHS/United States ; R21 CA256419/CA/NCI NIH HHS/United States ; R21 CA259243/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Artesunate ; *Reactive Oxygen Species/metabolism ; *Antineoplastic Agents/pharmacology/chemistry ; Apoptosis/drug effects ; *Artemisinins/pharmacology/chemistry ; Cell Line, Tumor ; *Carbocyanines/pharmacology/chemistry ; Membrane Potential, Mitochondrial/drug effects ; HCT116 Cells ; Cell Survival/drug effects ; Mitochondria/metabolism/drug effects ; },
abstract = {Heptamethine cyanine dyes and anticancer agents based conjugates are being developed for enhanced targeting and killing of cancer cells. DZ-1 dye conjugated agents induced cytotoxicity and mechanism of action have been shown in previous studies. In this study, a conjugated form of DZ-1 and artesunate (DZ-1-ART) was used to evaluate its cytotoxicity and elucidate the mechanism of actions in various cancer cell lines. Cells survival assays indicated dose-dependent cytotoxic activities of DZ-1-ART in HCT116, BxPC-3, and OVCAR-3 cell lines. Immunoblotting and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay confirmed involvement of apoptosis in DZ-1-ART-induced cytotoxicity. To elucidate the anticancer mechanism of the action of DZ-1-ART, MitoTracker and JC-1 assay were used. The results showed that translocation of DZ-1-ART in the mitochondria was followed by disruption of mitochondrial outer membrane potential. Dichlorofluorescin diacetate assay confirmed the generation of reactive oxygen species (ROS) in DZ-1-ART treated cancer cells. An antioxidant, N-acetyl cysteine treatment with DZ-1-ART showed reduction in cell death as well as suppression of ROS generation. When compared to HCT116 wild-type cells, Bak and Bax-deficient HCT116 cells also showed similar levels of cytotoxicity of DZ-1-ART. Taken together, this study's results reported that DZ-1-ART could induce mitochondria-mediated, ROS-generated, and Bak and Bax-independent apoptosis in cancer cells.},
}
@article {pmid40881937,
year = {2025},
author = {Moody, TW and Ramos-Alvarez, I and Mantey, SA and Jensen, RT},
title = {Bombesin Receptor Subtype-3 Regulates Tumor Growth by HER2 Tyrosine Phosphorylation in a Reactive Oxygen Species-Dependent Manner in Lung Cancer Cells.},
journal = {Targets (Basel)},
volume = {3},
number = {1},
pages = {},
pmid = {40881937},
issn = {2813-3137},
support = {Z01 DK053101/ImNIH/Intramural NIH HHS/United States ; ZIA DK053101/ImNIH/Intramural NIH HHS/United States ; },
abstract = {Bombesin receptor subtype-3 (BRS-3) is a type 1 G-protein-coupled receptor. BRS-3 is an orphan GPCR which is structurally related to the neuromedin B and gastrin-releasing peptide receptors. When activated, BRS-3 causes phosphatidylinositol turnover in lung cancer cells. BRS-3 stimulates tyrosine phosphorylation of the epidermal growth-factor receptor (ErbB1), however it is unknown if it transactivates ErbB2/HER2. Adding the nonpeptide BRS-3 allosteric-agonist, MK-5046 or the peptide agonist, BA1 to the lung cancer cell line, NCI-H727 or BRS-3-transfected NCI-H1299 lung cancer cells, increased tyrosine phosphorylation of HER2/ERK2. This increase was antagonized by the BRS-3 peptide antagonist, Bantag-1 and the small molecule BRS-3 antagonist, ML-18. The increase in HER2/ERK phosphorylation caused by MK-5046 was inhibited by ROS inhibitors, N-acetylcysteine and Tiron (superoxide-scavenger). Adding MK-5046 to lung cancer cells increased reactive-oxygen species which was inhibited by NAC or Tiron. MK-5024 and BA1 increased NSCLC colony formation whereas, Bantag-1/ML-18 inhibited proliferation. These results indicate that in lung cancer cells activation of BRS-3 regulates HER2-transactivation in ROS-dependent manner which can mediate tumor growth. These results raise the possibility that the use of HER2-inhibiting compounds alone or in combination with other agents, could be a novel approach in the treatment of these tumors.},
}
@article {pmid40884714,
year = {2026},
author = {Sun, Y and Liu, C and Liang, Y and Lv, A and Nie, W and Bao, S and Li, X and Zhou, J and Tong, W and Tao, Y and Wang, X and Dong, T},
title = {Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.},
journal = {Neuroscience bulletin},
volume = {42},
number = {3},
pages = {630-648},
pmid = {40884714},
issn = {1995-8218},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Hearing Loss, Central/metabolism/genetics/pathology/prevention &amp; control ; *Mitophagy/drug effects/physiology ; Mitochondria/drug effects/metabolism/pathology ; Mice ; Evoked Potentials, Auditory, Brain Stem/drug effects/physiology ; Spiral Ganglion/drug effects/pathology/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; },
abstract = {Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60[+/-] mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60[+/-] mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.},
}
@article {pmid40871026,
year = {2025},
author = {Altowijri, MA and Abdelmageed, ME and El-Gamal, R and Saeedi, T and El-Agamy, DS},
title = {Pristimerin Dampens Acetaminophen-Induced Hepatotoxicity; The Role of NF-κB/iNOS/COX-II/Cytokines, PI3K/AKT, and BAX/BCL-2/Caspase-3 Signaling Pathways.},
journal = {Pharmaceutics},
volume = {17},
number = {8},
pages = {},
pmid = {40871026},
issn = {1999-4923},
abstract = {Background: Acetaminophen (APAP) is a popular and safe pain reliever. Due to its widespread availability, it is commonly implicated in intentional or unintentional overdoses, which result in severe liver impairment. Pristimerin (Prist) is a natural triterpenoid that has potent antioxidant and anti-inflammatory properties. Our goal was to explore the protective effects of Prist against APAP-induced acute liver damage. Method: Mice were divided into six groups: control, Prist control, N-acetylcysteine (NAC) + APAP, APAP, and two Prist + APAP groups. Prist (0.4 and 0.8 mg/kg) was given for five days and APAP on day 5. Liver and blood samples were taken 24 h after APAP administration and submitted for different biochemical and molecular assessments. Results: Prist counteracted APAP-induced acute liver damage, as it decreased general liver dysfunction biomarkers, and attenuated APAP-induced histopathological lesions. Prist decreased oxidative stress and enforced hepatic antioxidants. Notably, Prist significantly reduced the genetic and protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-II), p-phosphatidylinositol-3-kinase (p-PI3K), p-protein kinase B (p-AKT), and the inflammatory cytokines: nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins-(IL-6 and IL-1β) in hepatic tissues. Additionally, the m-RNA and protein levels of the apoptotic Bcl2-associated X protein (BAX) and caspase-3 were lowered and the anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) was increased upon Prist administration. Conclusion: Prist ameliorated APAP-induced liver injury in mice via its potent anti-inflammatory/antioxidative and anti-apoptotic activities. These effects were mediated through modulation of NF-κB/iNOS/COX-II/cytokines, PI3K/AKT, and BAX/BCL-2/caspase-3 signaling pathways.},
}
@article {pmid40868982,
year = {2025},
author = {Jung, EJ and Kim, HJ and Shin, SC and Kim, GS and Jung, JM and Hong, SC and Kim, CW and Lee, WS},
title = {Tetraarsenic Hexoxide Enhanced the Anticancer Effects of Artemisia annua L. Polyphenols by Inducing Autophagic Cell Death and Apoptosis in Oxalplatin-Resistant HCT116 Colorectal Cancer Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {16},
pages = {},
pmid = {40868982},
issn = {1422-0067},
support = {(2017R1D1A3B05030971)//Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; },
mesh = {Humans ; HCT116 Cells ; *Artemisia annua/chemistry ; *Apoptosis/drug effects ; *Polyphenols/pharmacology ; *Colorectal Neoplasms/metabolism/drug therapy/pathology ; *Drug Resistance, Neoplasm/drug effects ; *Autophagic Cell Death/drug effects ; Oxaliplatin/pharmacology ; *Antineoplastic Agents/pharmacology ; *Plant Extracts/pharmacology ; Cyclin D1/metabolism ; beta Catenin/metabolism ; Drug Synergism ; },
abstract = {It was reported that polyphenols extracted from Korean Artemisia annua L. (pKAL) have higher anticancer effects in oxaliplatin-resistant (OxPt-R) HCT116 cells than in HCT116 cells. In this study, it was tested whether and how As4O6 enhances anticancer effects of pKAL in HCT116 and HCT116-OxPt-R colorectal cancer cells. The CCK-8 assay, phase-contrast microscopy, and colony formation assay revealed that As4O6 enhanced anticancer effects of pKAL, with induction of nuclear deformity and intracytoplasmic vesicle formation in both cells. Western blot analysis revealed that co-treatment with As4O6 and pKAL significantly decreased the expression of NF-kB, EGFR, cyclin D1, CD44, and β-catenin, and upregulated the expression of p62 and LC3B in both cells. It also induced the activation of caspase-8 and γ-H2AX and the cleavage of β-catenin, PARP1, lamin A/C, and p62. These phenomena were inhibited by wortmannin, and further suppressed by co-treatment of wortmannin with an ROS inhibitor, N-acetyl cysteine. This study suggests that As4O6 enhanced the anticancer effects of pKAL by inducing autophagic cell death accompanied by apoptosis in both parental HCT116 and HCT116-OxPt-R cells. It also suggests that ROS generation and the downregulation of AKT, NF-κB p65, cyclin D1, EGFR, and β-catenin may play an important role in the As4O6-enhanced anticancer effect of pKAL.},
}
@article {pmid40867878,
year = {2025},
author = {Kontoghiorghes, GJ},
title = {New Approaches and Strategies for the Repurposing of Iron Chelating/Antioxidant Drugs for Diseases of Free Radical Pathology in Medicine.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {8},
pages = {},
pmid = {40867878},
issn = {2076-3921},
abstract = {There is an urgent need for new approaches and strategies for the introduction of antioxidant drugs in medicine. Despite hundreds of clinical trials with potential antioxidants, no antioxidant drugs have so far been developed for clinical use; this is mainly as a result of commercial reasons, but also due to insufficient data for regulatory authority approval. Antioxidant activity is a physiological process essential for healthy living. However, increased production of toxic free radicals and reactive oxygen species is observed in many clinical conditions, which are associated with serious and sometimes irreversible damage. Antioxidant drug strategies may involve short- to long-term therapeutic applications for the purpose of prevention, treatment, or post-treatment effects of a disease. These strategies are different for each disease and may include the design of protocols for the inhibition of oxidative damage through iron chelation, enhancing antioxidant defences by increasing the production of endogenous antioxidants, and activating antioxidant mechanisms, as well as the administration of synthetic and natural antioxidants. Both the improvement of antioxidant biomarkers and clinical improvement or disease remission are required to suggest effective therapeutic intervention. More concerted efforts, including new academic strategies, are required for the development of antioxidant drugs in clinical practice. Such efforts should be similar to the fulfilment of orphan or emergency drug regulatory requirements, which, in most cases, involve the treatment or clinical improvement of rare or severe diseases such as neurodegenerative diseases and cancer. Promising results of antioxidant therapeutic interventions include mainly the repurposing of the iron chelating/antioxidants drugs deferiprone (L1) and deferoxamine, and also the iron-binding drug N-acetylcysteine (NAC). In some clinical trials, the lack of pharmacodynamic and ferrikinetic data, wrong posology, and insufficient monitoring have resulted in inconclusive findings. Future strategies involving appropriate protocols and drug combinations, such as L1 and NAC, appear to improve the prospect of developing antioxidant drug therapies in different diseases, including those associated with ferroptosis. New strategies may also involve the use of pro-drugs such as aspirin, which is partly biotransformed into iron chelating/antioxidant metabolites with chemopreventive properties in cancer, and also in other therapeutic interventions. A consortium of expert academics on regulatory drug affairs and clinical trials could increase the prospects for antioxidant drug development in medicine.},
}
@article {pmid40879897,
year = {2025},
author = {Stoddart, K and Davies, M and Oughton, J and Malcolm, E and AlSharari, SD and Shoaib, M},
title = {Selective Effects of Acutely Administered N-Acetyl-Cysteine in Rodent Models of Nicotine-Conditioned Behaviours.},
journal = {Addiction biology},
volume = {30},
number = {9},
pages = {e70051},
pmid = {40879897},
issn = {1369-1600},
support = {ORF-2025-829//King Saud University, Riyadh, Saudi Arabia: Ongoing Research Funding program/ ; //Faculty of Medical Sciences, Newcastle University/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Nicotine/pharmacology/administration &amp; dosage ; Rats ; Male ; Motor Activity/drug effects ; Dose-Response Relationship, Drug ; Disease Models, Animal ; *Tobacco Use Disorder/drug therapy ; *Nicotinic Agonists/pharmacology/administration &amp; dosage ; Discrimination Learning/drug effects ; Conditioning, Operant/drug effects ; Rats, Sprague-Dawley ; Behavior, Animal/drug effects ; },
abstract = {Chronic nicotine administration leads to neuroadaptations, an important process in nicotine and tobacco dependence for which treatments are limited. The cysteine pro-drug, N-acetyl-cysteine (NAC), is a promising glutamatergic agent that has shown some clinical efficacy in reducing nicotine use in humans. The purpose of this study was to examine NAC in two rodent models of nicotine dependence. NAC (0, 5, 20, 50 and 100 mg/kg) was examined on locomotor activity in groups of rats previously exposed to nicotine or saline. In the second experiment, NAC (0, 50 and 100 mg/kg i.p.) was evaluated against the discriminative stimulus effects of nicotine (0.2 mg/kg) using a two-lever procedure under a tandem schedule (VI10"-FR10) of food reinforcement. Pre-treatment with NAC in doses greater than 20 mg/kg attenuated the expression of conditioned hyperactivity when rats were placed in locomotor boxes previously paired with chronic nicotine administration. The same doses of NAC had modest effects in attenuating nicotine-stimulated hyperactivity in nicotine-treated or saline-treated rats tested in the same locomotor boxes. In the discrimination task, NAC did not generalise to the nicotine stimulus and nor did it modify the dose-response curve to nicotine, suggesting that NAC may not modify the subjective effects of nicotine. These results suggest NAC selectively attenuates conditioned responses to nicotine-paired stimuli without modifying nicotine-induced hyperactivity or the discriminative stimulus effects of nicotine. Thus, the study proposes that if NAC was to act in a similar selective manner in humans, the specific action of NAC to attenuate conditioned responses may limit its potential as a treatment to manage nicotine dependence.},
}
@article {pmid40875537,
year = {2025},
author = {Back, SE and Gray, K and Jarnecke, AM and Saraiya, TC and Santa Ana, EJ and Killeen, T and Joseph, JE and Prisciandaro, JJ and Brown, DG and Nietert, PJ and Stecker, T and Rothbaum, A and Jones, JL and Flanagan, JC and Brady, KT},
title = {N-Acetylcysteine for the Treatment of Co-Occurring Posttraumatic Stress Disorder and Alcohol Use Disorder: A Double-Blind, Randomized Controlled Trial.},
journal = {The Journal of clinical psychiatry},
volume = {86},
number = {4},
pages = {},
doi = {10.4088/JCP.25m15803},
pmid = {40875537},
issn = {1555-2101},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage/adverse effects/pharmacology ; *Stress Disorders, Post-Traumatic/drug therapy/complications/therapy ; Adult ; Male ; Female ; Double-Blind Method ; Middle Aged ; *Alcoholism/drug therapy/complications/therapy ; Cognitive Behavioral Therapy/methods ; Aged ; Treatment Outcome ; Young Adult ; },
abstract = {Objective: Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are common co-occurring conditions associated with a more severe clinical profile and poorer treatment outcomes than either disorder alone. To date, no medications have proven efficacious in the treatment of co-occurring PTSD/AUD. Methods: This randomized, double-blind, placebo-controlled trial examined the efficacy of N-acetylcysteine (NAC; 2,400 mg/day) among individuals (N=182, aged 21-65 years) who met DSM-5 criteria for current PTSD/AUD. Participants were randomized 1:1 to receive 12 weeks of NAC (n=93) or placebo (n=89). All participants received weekly, individual, cognitive behavioral therapy (CBT) for AUD. Follow-up visits occurred at 3-, 6-, and 12-months posttreatment. Primary outcomes included the Clinician Administered PTSD Scale for DSM-5 (CAPS-5), PTSD Checklist for DSM-5 (PCL-5), Timeline Follow-Back (TLFB), and the Obsessive Compulsive Drinking Scale at 12 weeks. The TLFB evaluated the frequency and amount of alcohol consumption. A secondary measure evaluated depression symptoms. Results: Intent-to-treat analyses showed that participants in both the NAC and placebo groups evidenced significant reductions in the CAPS-5 (B=-0.19, P<.001) and PCL-5 (B=-0.20, P<.001) during treatment, with no significant group differences. Both groups also showed significant reductions in alcohol use (drinks per drinking day [B=-0.02, P<.001], percent heavy drinking days [B=-0.14, P<.001], percent days abstinent [B=0.29, P=.022]) and craving (B=-0.12, P<.001) during treatment, but with no significant group differences. There were no group differences in retention or adverse events. Conclusions: Although NAC was well tolerated, it was not more effective than placebo in improving symptoms of PTSD or AUD when added to individual CBT for AUD. Trial Registration: ClinicalTrials.gov identifier: NCT02966873.},
}
@article {pmid40873781,
year = {2025},
author = {Guan, H and Huang, L and Liu, Y and Zhu, E and Chen, L and Li, W and Wu, H and Zhang, X and Qin, R and Zheng, J and Mo, Y and Zhong, M and Xu, B and Dai, X and Wei, Q and Chen, Y and Wang, Q and Zheng, Z and Ma, K and Tang, C},
title = {Anti-PS IgG Immune Complexes Impair Macrophage Phagocytosis in SLE via LOX-Dependent Oxidative Stress.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {11521-11538},
pmid = {40873781},
issn = {1178-7031},
abstract = {PURPOSE: Systemic lupus erythematosus (SLE) is a severe autoimmune disease with systemic complications mediated by immune-complex formation. The elevated level of anti-phosphatidylserine (PS) IgG has been implicated in SLE pathogenesis. In this study, we aimed to explore the effector mechanisms of PS immune-complex during lupus development.<br><br>PATIENTS AND METHODS: Serological profiles of immune-complexes in SLE patients were analyzed. Immunofluorescence staining showed PS-IgG immune-complex deposition in kidney biopsies of lupus nephritis patients. C57BL/6J mice were immunized with PS for immune-complex and renal function assessment. The roles of PS-IgG immune-complex and lysyl oxidase (LOX) were validated from SLE PBMCs, THP-1 cell line and PS-immunized lupus mice. The intracellular reactive oxygen species (ROS) levels, and phagocytosis function were examined by flow cytometry in SLE PBMCs, THP-1 cell line and PS-immunized lupus mice. For in vitro treatment, the effects of antioxidant N-acetylcysteine (NAC) and LOX inhibitor &#x3b2;-Aminopropionitrile (BAPN) were verified in THP-1 cell line and cells from PS-immunized lupus mice.<br><br>RESULTS: SLE and lupus nephritis (LN) patients showed significant elevated circulating and glomerular PS-IgG immune-complex levels. ROC analysis indicated PS-IgG immune-complex as a strong biomarker in SLE and LN. Mechanistically, induced macrophages from SLE patients treated with PS-IgG immune-complex significantly increased cytoplasmic ROS levels, elevated LOX expression and exhibited dampened phagocytotic function. In mice, PS immunization triggered PS-IgG immune complex formation, increased LOX expression, immune-complex deposited glomerular nephritis, and impaired phagocytotic function of macrophages. NAC and BAPN treatment restored the phagocytotic function of human and murine macrophages.<br><br>CONCLUSION: Our results indicate that PS-IgG immune-complex can directly impair macrophage phagocytotic functions via LOX mediated-oxidative stress and may serve as a novel biomarker for SLE.},
}
@article {pmid40865250,
year = {2025},
author = {Li, L and Tan, J and Chen, D and Luo, J and Li, P},
title = {Ethacrynic acid regulates gentamicin ototoxicity via the blood-labyrinth barrier.},
journal = {Hearing research},
volume = {466},
number = {},
pages = {109405},
doi = {10.1016/j.heares.2025.109405},
pmid = {40865250},
issn = {1878-5891},
mesh = {Animals ; *Gentamicins/toxicity ; *Ethacrynic Acid/pharmacology ; Mice, Inbred C57BL ; *Ototoxicity/prevention &amp; control ; Hair Cells, Auditory/drug effects/pathology/metabolism ; Acetylcysteine/pharmacology ; *Anti-Bacterial Agents/toxicity ; Male ; Spiral Ganglion/drug effects/pathology ; Disease Models, Animal ; Mice ; *Ear, Inner/drug effects/blood supply/pathology ; *Hearing Loss/chemically induced/prevention &amp; control/physiopathology/pathology ; Dose-Response Relationship, Drug ; *Hearing/drug effects ; Cochlea/drug effects/pathology ; Cell Proliferation/drug effects ; },
abstract = {Gentamicin (GM), a widely used aminoglycoside antibiotic, has its clinical utility significantly limited by ototoxicity, which may be further exacerbated by co-administered drugs. This study systematically investigated the ototoxic mechanisms of GM combined with ethacrynic acid (EA) and the protective effects of N-acetylcysteine (NAC) using C57BL/6 J mice. Results revealed dose-dependent GM-induced ototoxicity. Intravenous administration caused more severe damage than intraperitoneal injection. Co-administration of EA synergistically potentiated GM toxicity. This exacerbated cochlear hair cell loss, auditory nerve fiber degeneration, and spiral ganglion neuron damage. Additionally, it induced systemic hepatorenal toxicity, manifested by increased macrophage activation and suppressed cell proliferation. EA disrupted inner ear homeostasis via a dual mechanism: impairing blood-labyrinth barrier integrity and triggering compensatory pericyte-mediated repair. NAC intervention significantly attenuated the combined toxicity. The pretreatment group showed the highest hair cell survival rate. Notably, EA facilitated NAC entry into the cochlea, enhancing its protective efficacy. Delayed EA administration (6 h post-GM) reduced hair cell damage by 50%. Furthermore, NAC ameliorated damage to neural fibers and synapses. This study shows that EA modulates GM ototoxicity by disrupting BLB equilibrium. The time-dependent nature of NAC intervention offers a strategy to prevent drug-induced hearing loss. These findings provide critical insights for optimizing clinical regimens involving aminoglycosides and loop diuretics.},
}
@article {pmid40863039,
year = {2025},
author = {Horvat Aleksijević, L and Lončar Brzak, B and Sikora, M and Škrinjar, I and Brailo, V and Andabak Rogulj, A and Aleksijević, M and Vidović Juras, D},
title = {Efficacy of N-Acetyl Cysteine in the Treatment of Burning Mouth Syndrome-A Randomized Controlled Trial.},
journal = {Dentistry journal},
volume = {13},
number = {8},
pages = {},
pmid = {40863039},
issn = {2304-6767},
support = {not applicable//University of Zagreb/ ; },
abstract = {Objectives: Burning mouth syndrome (BMS) is a chronic, painful, idiopathic condition of the oral cavity, characterized by the absence of visible pathological changes on the oral mucosa and normal laboratory findings. Recent evidence from the literature supports the classification of BMS as a neuropathic condition. It has been proposed that oxidative stress may contribute to neuropathic pain. N-acetylcysteine (NAC) is an antioxidant that exhibits neuroprotective properties. The aim of the study was to evaluate the efficacy of N-acetyl cysteine in the treatment of burning mouth syndrome (BMS). Methods: Eighty female patients with previously diagnosed BMS were randomly assigned to one out of two groups. One group received N-acetyl cysteine (600 mg/twice a day) and the other received placebo, for an eight-week period. The outcome was measured by the Oral Health Impact Profile-14 (OHIP-14) quality of life questionnaire and Numeric Pain Rating Scale, for burning and discomfort, both before and after completing the therapy. Results: Both groups experienced a significant reduction in burning and discomfort sensations, along with a significant improvement in oral health-related quality of life. However, the difference between the treatment and control group was not statistically significant. Conclusions: NAC does not significantly improve the oral health-related quality of life, burning sensations, and discomfort in BMS subjects compared to placebo.},
}
@article {pmid40859915,
year = {2026},
author = {Ma, C and Han, L and Yao, H and Zhao, W and Chen, F and Wu, X and Li, G and Huang, R and Pang, CH and Zhu, Z and Xu, J and Pan, G},
title = {Modulating G6PD/PGD to overcome FSP1/DHODH-mediated ferroptosis defence: A novel oridonin derivative suppresses liver cancer.},
journal = {British journal of pharmacology},
volume = {183},
number = {2},
pages = {249-267},
doi = {10.1111/bph.70160},
pmid = {40859915},
issn = {1476-5381},
support = {81872927//National Natural Science Foundation of China/ ; 82173679//National Natural Science Foundation of China/ ; XDA16020205//Chinese Academy of Sciences/ ; XDB1150102//Chinese Academy of Sciences/ ; CPU2018GY04//China Pharmaceutical University/ ; 2105DTPSIMM//University of Nottingham Ningbo China/ ; },
mesh = {*Ferroptosis/drug effects ; Humans ; *Liver Neoplasms/drug therapy/pathology/metabolism ; Animals ; *Diterpenes, Kaurane/pharmacology/chemistry ; *Carcinoma, Hepatocellular/drug therapy/pathology/metabolism ; Mice ; *Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Male ; Mice, Nude ; Mice, Inbred BALB C ; },
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC), a globally prevalent malignancy with high mortality rates, presents an unmet need for innovative effective therapies.<br><br>PURPOSE: This study aimed to explore the antitumour potential of compound XD, a novel oridonin derivative, on HCC and its underlying mechanism.<br><br>EXPERIMENTAL APPROACH: The antitumour effects of compound XD were investigated in several HCC cells lines and mice models. The mechanism of XD was investigated using FACS, qPCR, WB, ELISA, IHC, siRNA and plasmid transfection.<br><br>KEY RESULTS: Compound XD demonstrated potent inhibitory effects, surpassing sorafenib with a maximum of 10-fold lower IC50 values against HCC cell lines. Its anticancer activities were ferroptosis dependent, which could be attenuated by ferroptosis inhibitors including deferoxamine, ferrostatin-1 and N-acetyl-cysteine. Unlike sorafenib, XD decreased two pivotal regulator FSP1 and DHODH to induce ferroptosis, while their overexpression partially mitigated XD-induced cytotoxicity and lipid peroxidation. In addition, XD treatment decreased cellular NADPH levels and inhibited the expression of G6PD and PGD in NADPH generation. Overexpression of G6PD or PGD reversed FSP1 and DHODH down-regulation, rescuing the ferroptosis induced by XD. Bioinformation analysis indicated the significant up-regulation of G6PD and PGD in clinical HCC patients and was positively correlated with cancer stages. Molecular docking and CETSA assay confirmed the binding capacity of XD with G6PD and PGD protein. Finally, XD dose-dependently inhibited liver tumour growth and induced ferroptosis-related markers in mice.<br><br>CONCLUSION AND IMPLICATIONS: This study suggests XD as a potential ferroptosis inducer and the potential role of G6PD/PGD/FSP1/DHODH axis in governing ferroptosis sensitivity in HCC.},
}
@article {pmid40858780,
year = {2026},
author = {Chetcuti, L and Hardan, AY and Frazier, TW and Loth, E and McPartland, JC and Youngstrom, EA and Uljarevic, M},
title = {Advancing scientific understanding of the drive to socially engage: from broad constructs to transdiagnostic 'building blocks'.},
journal = {Molecular psychiatry},
volume = {31},
number = {1},
pages = {599-609},
pmid = {40858780},
issn = {1476-5578},
support = {1R01MH129833//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
mesh = {Humans ; *Social Behavior ; Reward ; Mental Disorders/physiopathology ; Learning/physiology ; },
abstract = {Reduced drive to socially engage is observed across neurodevelopmental and neuropsychiatric conditions. However, previous research has relied on disorder-specific conceptualizations and measurement approaches that might obscure important differences in how social drive manifests and its underlying neurobiological mechanisms, both within and across different diagnostic categories. In this commentary, we argue that a model of reward processing that deconstructs social drive into 'orienting', 'wanting', 'pursuing', 'liking' and 'learning' processes can advance mechanistic and phenomenological understanding. Implementing this framework necessitates a multimethod measurement approach, combining rigorously validated behavioral measures and neurobiological sampling while leveraging specific developmental principles within a longitudinal research framework. Through these concerted efforts, the field will make significant strides towards developing a biologically grounded account of clinical phenomena characterized by different profiles of atypical drive to engage with others, which is a first and critical step toward the development of accurate prediction models and specific treatments.},
}
@article {pmid40847608,
year = {2025},
author = {Varela, ELP and Gomes, ARQ and da Silva Barbosa Dos Santos, A and Dos Santos Guimarães, M and de Carvalho, EP and Ferreira, OO and de Oliveira, MS and Iriti, M and de Aguiar Andrade, EH and Percário, S},
title = {Lycopene Mitigates Malaria-Induced Reactive Oxygen and Nitrogen Species and Oxidative Damage in Mice Brain and Lungs.},
journal = {Parasite immunology},
volume = {47},
number = {8},
pages = {e70019},
pmid = {40847608},
issn = {1365-3024},
support = {//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior (CAPES; Brazil)/ ; //Funda&#xe7;&#xe3;o Amaz&#xf4;nia Paraense de Amparo &#xe0; Pesquisa (FAPESPA; Brazil)/ ; },
mesh = {Animals ; *Lung/pathology/drug effects ; Mice ; Lycopene ; *Brain/pathology/drug effects/metabolism ; Plasmodium berghei ; *Malaria/drug therapy/pathology ; *Antioxidants/administration &amp; dosage ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Carotenoids/administration &amp; dosage ; *Reactive Nitrogen Species/metabolism ; Thiobarbituric Acid Reactive Substances/analysis ; Male ; Nitric Oxide/analysis ; Female ; Disease Models, Animal ; },
abstract = {The severity of malaria is associated with low antioxidant availability and elevated free radical production, which induces oxidative damage in cerebral and pulmonary microcirculation. This can be mitigated by dietary antioxidants. We investigated the protective effects of lycopene (LYC) against oxidative changes induced by Plasmodium berghei (Pb). Mice were infected by intraperitoneal injection of 10[6] parasitized red blood cells and treated orally with LYC (3.11 mg/kg bw/day) or N-acetylcysteine (NAC, 62 mg/kg bw/day). Evaluations were conducted at 1-, 4-, 8- and 12-days post-infection. We measured thiobarbituric acid reactive substances (TBARS), antioxidant capacity by ABTS (AC-ABTS) and DPPH (AC-DPPH) inhibition, uric acid (UA) and nitric oxide (NO) in brain and lung tissues. Infection led to elevated TBARS, AC-ABTS, AC-DPPH, UA and NO, resulting in animal mortality. LYC significantly attenuated the infection-induced increases in TBARS, UA and NO levels compared to Pb (p < 0.0001) and NAC + Pb groups (p < 0.0001) normalising them to Sham levels. These findings highlight LYC's therapeutic potential against malaria-related oxidative stress.},
}
@article {pmid40846701,
year = {2025},
author = {Musillo, C and Samà, M and Creutzberg, KC and Begni, V and Collacchi, B and Bitraj, J and Collo, G and Riva, MA and Berry, A and Cirulli, F},
title = {Sex-dependent preventive effects of prenatal N-acetyl-cysteine on neuronal, emotional and metabolic dysfunctions following exposure to maternal high-fat diet in mice.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {306},
pmid = {40846701},
issn = {2158-3188},
mesh = {Animals ; Female ; *Diet, High-Fat/adverse effects ; Mice ; Pregnancy ; *Prenatal Exposure Delayed Effects/prevention &amp; control/metabolism ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Male ; Humans ; Neurons/drug effects/metabolism ; Neuronal Plasticity/drug effects ; Hippocampus/metabolism/drug effects ; Anxiety/prevention &amp; control ; Disease Models, Animal ; Behavior, Animal/drug effects ; *Cognitive Dysfunction/prevention &amp; control ; Sex Factors ; Mice, Inbred C57BL ; },
abstract = {While a clear association between maternal obesity and an increased risk for neuropsychiatric disorders in the offspring has been described, the underlying mechanisms remain poorly understood. We hypothesised that a maternal high-fat diet (mHFD) would act as a stressor, increasing glucocorticoids, resulting in an altered redox balance and disrupted neuronal plasticity of the limbic system. Such enduring effects would impair the emotional and cognitive profile, neuroendocrine responses, and metabolic and redox homeostasis in the adult offspring. We utilised a mouse model and a translational cellular model employing human neurons derived from inducible Pluripotent Stem Cells (iPSCs) to evaluate the impact of mHFD on neurodevelopment and to test the protection afforded by the antioxidant N-acetyl-cysteine (NAC). Our approach combined behavioural and metabolic phenotyping, biochemical assays, morphological assessment, and targeted gene expression analysis. Results indicate that prenatal administration of NAC prevented anxiety-like and risk-taking behaviours, cognitive impairments and metabolic alterations in mHFD adult mouse offspring, particularly in females. These changes were accompanied by hippocampal downregulation of genes involved in neuronal plasticity, such as BDNF. Using human neurons in vitro, pre-treatment with NAC rescued the negative effects of glucocorticoids on neuronal plasticity via a BDNF-mediated mechanism. The protective effects of NAC over mHFD in females suggest that rebalancing the redox status could be exploited as an overall strategy to buffer the negative effects of early adversities on neurodevelopment.},
}
@article {pmid40853509,
year = {2025},
author = {Malik, V and Kar, A and Venkatachalam, AM and Mandal, K},
title = {An Elegant Method of One-Pot Ligation-Desulfurization for High-Yielding Chemical Protein Synthesis.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {12},
number = {38},
pages = {e10194},
pmid = {40853509},
issn = {2198-3844},
support = {RTI-4007//Department of Atomic Energy, Government of India/ ; },
mesh = {*Proteins/chemical synthesis ; *Chemistry Techniques, Synthetic/methods ; Ligation ; Acetylcysteine/chemistry ; Acetamides ; },
abstract = {While native chemical ligation (NCL), combined with radical-mediated desulfurization, has enabled chemical syntheses of a vast array of proteins, the presence of aryl thiols as catalysts in the ligation mixture prevents performing both ligation and desulfurization reactions in one-pot, as aryl thiols are effective radical scavengers. Existing one-pot ligation and desulfurization approaches are not ideal as they rely on the use of inefficient alkyl thiols as NCL catalysts. Here an extremely efficient and impressively straightforward method is presented that utilizes bromoacetamide, in conjunction with N-acetyl cysteine, for selective quenching of arylthiol following NCL, enabling ligation and desulfurization in one-pot without any intermediate purification step. The reagent combination facilitates one-pot reactions by selectively capping aryl thiols in the presence of peptidic cysteine residue, leveraging the increased nucleophilicity of aryl thiols over alkyl thiols. N-acetyl cysteine additionally functions as the alkyl thiol additive for the desulfurization reaction. It is demonstrated the utility of this methodology by synthesizing three different proteins: ubiquitin, collagen, and barstar A. The strategy substantially enhances the efficiency of chemical protein synthesis, especially for cysteine-free proteins. Its operational simplicity and broad applicability make this one-pot ligation-desulfurization protocol promising for widespread adoption in synthesizing therapeutic proteins and related biomolecules.},
}
@article {pmid40851422,
year = {2025},
author = {Özer Aslan, &#x130; and Öz, M and Erdal, H and Karaboğa, &#x130; and Doğan, M},
title = {Protective effect of N-acetylcysteine in doxorubicin-induced primary ovarian failure in female rats.},
journal = {Turkish journal of obstetrics and gynecology},
volume = {22},
number = {3},
pages = {266-274},
pmid = {40851422},
issn = {2149-9322},
abstract = {OBJECTIVE: N-acetylcysteine (NAC), an aminothiol compound, eliminates free radicals and enhances glutathione (GSH) synthesis, thereby strengthening intracellular antioxidant defenses. Although its protective effects against ovarian injury have been reported, its efficacy in doxorubicin (DOX)-induced ovarian failure has not been demonstrated. This study aimed to investigate whether NAC exerts a protective role against DOX-induced ovarian toxicity in female rats.<br><br>MATERIALS AND METHODS: Twenty-one adult female rats were randomly assigned to three groups: Control, DOX (10 mg/kg, i.p., single dose), and DOX+NAC (150 mg/kg, i.p., for 5 days; DOX administered on day 3, one hour after NAC). Serum and tissue oxidative stress parameters, histopathological changes, proliferating cell nuclear antigen (PCNA) immunoreactivity, and TUNEL assay were evaluated.<br><br>RESULTS: DOX significantly reduced serum anti-M&#xfc;llerian hormone (AMH) (6.75 &#x2192; 5.31 ng/mL; p<0.001) and GSH (422.64 &#x2192; 280.98 mg/L; p<0.001), while increasing tumor necrosis factor alpha (TNF-&#x3b1;) (175.87 &#x2192; 260.77 ng/L; p<0.001) and total oxidant status (TOS) (7.18 &#x2192; 11.84 U/mL; p=0.002). NAC treatment reversed these alterations, namely: AMH (6.51 ng/mL; p=0.004), GSH (363.86 mg/L; p=0.018), TNF-&#x3b1; (184.55 ng/L; p<0.001), TOS (7.88 U/mL; p=0.003). In ovarian tissue, DOX reduced GSH (123.63 &#x2192; 80.64 mg/L; p=0.001) and total antioxidant status (14.88 &#x2192; 10.57 U/mL; p<0.001), while elevating TOS (7.14 &#x2192; 12.64 U/mL; p<0.001) and caspase-3 (2.06 &#x2192; 3.14 ng/mL; p<0.001). NAC significantly improved all these parameters (p&#x2264;0.005). Histologically, DOX caused edema, hemorrhage, infiltration, and a reduction in the percentage of healthy follicles, whereas NAC markedly ameliorated these alterations. Furthermore, NAC enhanced PCNA expression and reduced TUNEL-positive granulosa cells, supporting its anti-apoptotic effect.<br><br>CONCLUSION: NAC preserved ovarian reserve and follicular integrity by suppressing oxidative stress, inflammation, and apoptosis induced by DOX. These findings highlight NAC as a promising protective agent against chemotherapy-induced ovarian toxicity.},
}
@article {pmid40842893,
year = {2025},
author = {Yelleti, G and Aroor, AR and Shenoy, RP and Karmakar, A and Rao, A and Lewis, CR and Asok, A and Maripini, N and Biswas, M and Varier, V and Roy, A and Suryakanth, VB},
title = {Potential Effects of Selenium and N-Acetylcysteine Supplementation in Ameliorating Cardinal Symptoms of Nω-Nitro-L-Arginine Methyl Ester Hydrochloride (L-NAME) Induced Preeclampsia in Wistar Rats.},
journal = {Reports of biochemistry &amp; molecular biology},
volume = {13},
number = {4},
pages = {495-506},
pmid = {40842893},
issn = {2322-3480},
abstract = {BACKGROUND: Preeclampsia (PE) is a hypertensive disorder in pregnancy affecting multiple organ systems. This study hypothesized that oxidative stress and inflammatory responses contribute to the pathogenesis of Preeclampsia, and that selenium and N-acetylcysteine (NAC) could mitigate these effects.<br><br>METHODS: The study was initiated after approval from the Institutional Animal Ethics Committee. Twenty-four female Wistar rats were divided equally into four groups. Group I served as controls, while Groups II, III, and IV received N&#x3c9;-Nitro-L-arginine methyl ester hydrochloride (L-NAME) to induce hypertension from day 10 to 20 of gestation. Additionally, Group III received selenium (240 &#x3bc;g/kg/day) and Group IV received NAC (160 mg/kg). On day 20, Blood Pressure (BP) monitoring and urine protein estimation were carried out to assess hypertension and proteinuria, while blood samples were collected to measure malondialdehyde (MDA) and interleukin-6 (IL-6) levels, as markers of oxidative stress and inflammation, respectively. Statistical analysis was performed using GraphPad Prism 10.2.<br><br>RESULTS: Selenium improved L-NAME-induced hypertension (Mean BP 107.63&#xb1;5.22 mmHg vs 140.9&#xb1;8.38 mmHg in disease control (DC) and proteinuria (65.5&#xb1;4.09 vs 140.2&#xb1;11.85 mg/day in DC) and significantly reduced the inflammatory response (IL-6 23.4&#xb1;1.06 vs 50.63&#xb1;3.35 pg/mL in DC) but had little effect on oxidative stress (MDA 0.21&#xb1;0.02 vs 0.24&#xb1;0.02 nmol/mL in DC). NAC did not lower BP (Mean BP 129.33&#xb1;7.96 mmHg) but significantly reduced proteinuria (92.7&#xb1;6.37mg/day), IL-6 levels (18.24&#xb1;0.42 pg/mL), and oxidative stress (MDA 0.16&#xb1;0.01 nmol/mL).<br><br>CONCLUSIONS: These findings suggest that selenium and NAC play distinct protective roles in the pathophysiology of preeclampsia, potentially offering synergistic effects for cardiovascular and kidney health in hypertensive pregnancies.},
}
@article {pmid40834985,
year = {2025},
author = {Ghosh, C and Khaket, TP and Gunda, V and Yang, Z and Hu, J and Alamaw, ED and Zhang, L and Zhang, YQ and Shen, M and Tabdili, Y and Boufraqech, M and Kassu, R and Kebebew, E},
title = {Combination nitazoxanide and auranofin treatment has synergistic anticancer activity in anaplastic thyroid cancer through enhanced activation of oxidative stress that leads to apoptosis.},
journal = {Cancer letters},
volume = {633},
number = {},
pages = {217990},
pmid = {40834985},
issn = {1872-7980},
support = {ZIA BC011286/ImNIH/Intramural NIH HHS/United States ; },
abstract = {Anaplastic thyroid cancer (ATC) has one of the highest mortality rates of all human malignancies and has no cure. We used combination drug matrix screening of highly active compounds and identified that combination of nitazoxanide and auranofin was one of those with the highest synergistic anticancer activity. We investigated its synergistic anticancer activity and mechanism of action in preclinical ATC models. We performed in vitro, ex vivo, and in vivo ATC models to evaluate the synergistic anticancer activity and the mechanism of action of this combination. Combination nitazoxanide and auranofin treatment synergistically inhibited cellular proliferation, colony formation, and cellular migration compared to control and single agents. Combination treatment also significantly reduced ATC cell line and patient-derived ATC spheroid size. Nitazoxanide alone and in combination with auranofin caused ER stress and apoptosis. Auranofin alone and in combination with nitazoxanide induced activation of the ROS generating pathway. This led to enhanced increase in ROS and MDA levels with combination treatment associated with upregulation of HMOX-1 and cell death that was reversed by N-acetyl cysteine (NAC). The combination significantly inhibited tumor growth in vivo in 8505C ATC cells, and C643 ATC cells, without significant treatment-related toxicity. Combination nitazoxanide and auranofin treatment has synergistic anticancer activity in vitro, ex vivo, and in vivo in ATC, which is due to enhanced oxidative stress and induction of apoptosis compared to single-drug treatment. Both drugs are FDA approved; their combination is a potential candidate for evaluation in a clinical trial for ATC therapy.},
}
@article {pmid40834757,
year = {2025},
author = {Li, C and Yang, J and Cao, L and Yan, A and Zhang, X and Duan, J and Yu, X and Wang, D and Wang, X and Li, C},
title = {Hexafluoropropylene oxide dimer acid (GenX) induces apoptosis in primary cortical neurons via stimulating ROS production and NF-κB activation.},
journal = {Ecotoxicology and environmental safety},
volume = {303},
number = {},
pages = {118873},
doi = {10.1016/j.ecoenv.2025.118873},
pmid = {40834757},
issn = {1090-2414},
mesh = {Animals ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; *Neurons/drug effects/metabolism ; *NF-kappa B/metabolism ; Mice ; Cerebral Cortex/cytology/drug effects ; *Fluorocarbons/toxicity ; Cells, Cultured ; Cell Survival/drug effects ; },
abstract = {Hexafluoropropylene oxide dimer acid (HFPO-DA), commonly known as GenX, is a replacement for perfluorooctanoic acid (PFOA) which readily accumulates in the brain and exhibits neurotoxic effects. However, the adverse impacts of GenX on neurons and its underlying mechanisms remain poorly understood. In this study, primary cortical neurons isolated from neonatal mice were exposed to varying concentrations of GenX to assess cell viability, intracellular reactive oxygen species (ROS) levels, and morphological alterations. Additionally, the expression of apoptosis-related proteins Bcl-2, Bax, Caspase-3, NF-κB, and Tomm20 was examined. The results showed that increasing concentrations of GenX significantly elevated intracellular ROS levels and markedly reduced cell viability and the number of cells. Neuronal morphology was severely disrupted, characterized by decreased neurite branching, shortened neurite length, and reduced soma size. At 200 μM and 400 μM GenX, apoptosis rates were dramatically increased (p < 0.0001), accompanied by a pronounced increase in NF-κB fluorescence intensity and nuclear translocation. Western blot analysis further revealed a progressive downregulation of Bcl-2 and Tomm20, while levels of Bax, Cleaved Caspase-3/Caspase-3 increased in a dose-dependent manner. Notably, pretreatment with N-Acetylcysteine (NAC) effectively reversed GenX-induced ROS accumulation (p = 0.0001), NF-κB activation, and neuronal apoptosis. Collectively, these findings demonstrate that GenX exposure induces ROS accumulation in primary cortical neurons, leading to apoptosis through mitochondrial dysfunction mediated by Tomm20 downregulation and the activation of Caspase-3 and NF-κB. This study provides novel mechanistic insights into the neurotoxicity of the emerging environmental contaminant GenX and offers a theoretical basis for developing neuroprotective targets against such exposures.},
}
@article {pmid40834221,
year = {2025},
author = {Zanesco, MC and Yoshitani, MM and Fagundes, FL and Campos, FG and Pereira, PP and Pereira, QC and Pereira, JA and Santos, RC and Martinez, CAR},
title = {Enemas with sucralfate and n-acetylcysteine can reduce inflammation and oxidative stress in colonic mucosa without fecal stream.},
journal = {Acta cirurgica brasileira},
volume = {40},
number = {},
pages = {e406325},
pmid = {40834221},
issn = {1678-2674},
mesh = {Animals ; *Acetylcysteine/administration &amp; dosage/pharmacology ; *Oxidative Stress/drug effects ; *Sucralfate/administration &amp; dosage/pharmacology ; *Intestinal Mucosa/drug effects/pathology ; Male ; *Enema/methods ; Colon/drug effects/pathology ; Rats, Wistar ; *Colitis/drug therapy/pathology ; Malondialdehyde/analysis ; Rats ; Inflammation/drug therapy ; Disease Models, Animal ; Peroxidase/analysis ; Reproducibility of Results ; *Anti-Ulcer Agents/administration &amp; dosage ; Antioxidants ; Superoxide Dismutase/analysis ; Glutathione/analysis ; Treatment Outcome ; },
abstract = {PURPOSE: To evaluate whether enemas containing sucralfate (SCF) alone or in combination with n-acetylcysteine (NAC) reduces inflammation and oxidative stress (OS) in the colonic mucosa without fecal stream.<br><br>METHODS: Forty-eight rats were subjected to left colostomy and distal rectal mucous fistula. During the procedure, 2 cm of the colon was collected to constitute the sham group. Twelve weeks after the surgical procedure, the animals were divided into two groups (n = 24) and received daily enemas containing saline, SCF (2 g/kg), NAC (100 mg/kg), or SCF + NAC (2 g/kg + 100 mg/kg, respectively) for two or four weeks. At the end of the intervention period, the animals were euthanized, and colonic segments without fecal stream were removed for histological and biochemical analyses. The diagnosis of colitis was made by histological analysis, and the inflammatory score was assessed using a validated scale. The neutrophilic infiltrate was evaluated by quantifying the content of myeloperoxidase (MPO) in the tissue. OS was determined by evaluating the activity of colonic antioxidant systems (superoxide dismutase, catalase, and reduced glutathione) and malondialdehyde (MDA) levels. The differences among subgroups were analyzed with the Mann-Whitney's test, whereas changes over time were analyzed via the Kruskal-Wallis' test, with the significance level of 5% (p < 0.05).<br><br>RESULTS: Enemas with SCF and NAC alone or in combination reduced colonic inflammation and the tissue levels of MPO and MDA and increased the levels of antioxidant enzymes.<br><br>CONCLUSION: SCF and NAC enemas alone or in combination reduced inflammation activity and OS in colon segments without fecal stream.},
}
@article {pmid40833873,
year = {2025},
author = {Sato, Y and Tanaka, M and Kitamura, N and Araki, N and Kurata, W and Sasaki, A and Seo, Y and Kuribayashi, K and Kobayashi, S and Niitsu, Y},
title = {ROS-Driven PKCζ Signaling as a Widely Involved Mechanism for Cancer Cell Motility and Metastasis.},
journal = {Cancer science},
volume = {116},
number = {11},
pages = {3027-3039},
pmid = {40833873},
issn = {1349-7006},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Protein Kinase C/metabolism/antagonists &amp; inhibitors ; Animals ; *Cell Movement/drug effects ; *Signal Transduction/drug effects ; Mice ; Hepatocyte Growth Factor/pharmacology ; Hep G2 Cells ; Cell Line, Tumor ; Neoplasm Metastasis ; Female ; HCT116 Cells ; Protein Kinase C zeta ; },
abstract = {The enhancement of cell motility by bioactive molecules such as growth factors, hormones, and tissue factors is pivotal in cancer invasion and metastasis. However, the molecular mechanisms underlying this enhancement remain incompletely understood. In this study, we demonstrate that hepatoblastoma HepG2 cell motility is significantly increased following hepatocyte growth factor (HGF) treatment, as assessed by phagokinetic track assays, Transwell assays, and scratch assays. This enhancement is mediated by reactive oxygen species (ROS), which activate the PKCζ/Rho GTPase signaling pathway. Notably, the motility increase is markedly suppressed by superoxide dismutase (SOD), N-acetylcysteine (NAC), diphenyleneiodonium (DPI), and the PKCζ inhibitory peptide MyrPKCζ. Similar patterns of motility enhancement and its inhibition by MyrPKCζ were observed in HGF-treated colon cancer HCT116 cells, epidermal growth factor (EGF)-treated HepG2 and HCT116 cells, and transforming growth factor-β (TGF-β)-treated HepG2 cells, as evaluated using Transwell assays. Additionally, estradiol enhances the motility of breast cancer MDA-MB-231-luc cells via ROS generation and activation of the PKCζ/Rho GTPase signaling pathway, with this effect significantly suppressed by MyrPKCζ in Transwell assays. The inhibitory effect of MyrPKCζ was further confirmed in vivo, where it suppressed peritoneal invasion of HCT116 cells in NOD-SCID mice. Furthermore, in NOD-SCID mice injected with MDA-MB-231-luc cells carrying shRNA targeting PKCζ into the tail vein, doxycycline-induced shRNA expression resulted in marked suppression of pulmonary metastasis. These findings indicate that the ROS/PKCζ/Rho GTPase signaling cascade is a pivotal regulator of cancer cell motility and suggest that PKCζ represents a promising therapeutic target for preventing cancer invasion and metastasis.},
}
@article {pmid40828450,
year = {2025},
author = {Mundassery, AI and Latha, RR and Kulangara, V and Mampilli, P and Chitharalil, BK and Abbdulkhaderkunju, J and Meleppat, DP},
title = {Effect of N-Acetylcysteine on Oxidative Stress and Hematological Recovery in Dogs with Babesia Gibsoni Infection.},
journal = {Acta parasitologica},
volume = {70},
number = {5},
pages = {186},
pmid = {40828450},
issn = {1896-1851},
mesh = {Animals ; Dogs ; *Babesiosis/drug therapy/parasitology/blood ; *Dog Diseases/drug therapy/parasitology ; *Oxidative Stress/drug effects ; *Babesia/drug effects ; *Acetylcysteine/administration &amp; dosage/therapeutic use ; Female ; Male ; Drug Therapy, Combination ; },
abstract = {Babesia gibsoni infection in dogs causes hemolytic anemia, thrombocytopenia, and systemic inflammation, with many cases progressing to chronic or relapsing forms due to persistent parasitemia and oxidative stress. This study evaluated the clinical, hematobiochemical, and oxidative changes associated with B. gibsoni infection and assessed the therapeutic benefit of N-acetylcysteine (NAC) as an adjunct to triple therapy. Nineteen dogs confirmed positive for B. gibsoni via blood smear and PCR were identified; however, only twelve Labrador Retrievers of similar age (2-3 years) were enrolled for treatment to minimize variability in breed and age. The remaining dogs were excluded due to different breeds or incomplete treatment. Six healthy controls were also included. Infected animals exhibited significant alterations in leukocyte count, erythrocyte indices, platelet count, and urinary protein-to-creatinine ratio (UPC) compared to healthy controls, indicating systemic inflammation and renal involvement. Twelve infected dogs were randomly assigned to two groups: Group I received the triple therapy (doxycycline, clindamycin, metronidazole), while Group II received the same treatment with oral NAC (70 mg/kg for 5 days). Clinical, hematological, biochemical, and oxidative stress parameters were reassessed on Day 21. Both groups showed improvement post-treatment; however, Group II demonstrated greater recovery, including higher RBC counts, hemoglobin levels, platelet counts, and serum antioxidant capacity, along with reduced bilirubin and UPC levels. Mann-Whitney U test on Day 21 revealed significant improvements in serum antioxidant activity and mean corpuscular hemoglobin concentration (MCHC) in Group II (p < 0.05). Although other parameters did not reach statistical significance, several showed favorable trends toward improvement in the NAC group. These findings suggest that NAC supplementation enhances hematological recovery, reduces oxidative stress, and supports renal function in dogs with babesiosis. Given its favorable impact, NAC may serve as a valuable adjunct in managing canine babesiosis, particularly in cases with suspected or confirmed oxidative injury. Further studies with larger sample sizes are recommended.},
}
@article {pmid40827188,
year = {2025},
author = {Agrawal, A and Chowdhury, M and Winkie, C and Vijay, C},
title = {A Case of Acetaminophen Toxicity in a Patient With an Unusual Alpha-1 Antitrypsin Phenotype.},
journal = {Cureus},
volume = {17},
number = {7},
pages = {e88224},
pmid = {40827188},
issn = {2168-8184},
abstract = {Acetaminophen is a commonly used over-the-counter analgesic and antipyretic that can be hepatotoxic if taken in excess. We present a case of acetaminophen-mediated hepatotoxicity following ingestion of a non-toxic dose of acetaminophen in a 16-year-old male with short bowel syndrome and a remote history of severe liver dysfunction with a rare alpha-1 antitrypsin phenotype Pi*EM. The patient initially presented with nonspecific symptoms of abdominal pain, nausea, vomiting, and diarrhea. N-acetylcysteine (NAC) therapy was initiated for acetaminophen toxicity. We suspect that the patient's susceptibility to acetaminophen-induced liver injury was likely due to underlying intestinal failure-associated liver disease that occurred as a child, as well as the Pi*EM, making the liver more prone to insults. This case highlights the importance of prompt recognition and management of acetaminophen toxicity in patients with prior liver disease, even if the amount ingested is thought to be non-toxic. In addition, the case highlights that rare alpha-1 antitrypsin phenotypes should be treated with heightened caution for liver dysfunction, as there is limited literature indicating if these phenotypes are pathogenic or non-pathogenic.},
}
@article {pmid40823012,
year = {2025},
author = {Bi, X and Huang, X and Zhang, C and Zhao, X and Ma, J and Li, M and Li, X and Zeng, B and Li, R and Zhang, X and Ya, F},
title = {Sulforaphane attenuates aldose reductase-mediated platelet dysfunction in high glucose-stimulated human platelets via downregulation of the Src/ROS/p53 signaling pathway.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1663245},
pmid = {40823012},
issn = {2296-861X},
abstract = {BACKGROUND: Platelet abnormalities are well-recognized complications of type 2 diabetes mellitus (T2DM). High glucose (HG) increases platelet mitochondrial dysfunction, apoptosis and hyperreactivity in T2DM, which underlie the occurrence of thrombotic events. Sulforaphane (SFN) is a dietary isothiocyanate enriched in cruciferous vegetables and possesses multiple biological activities. This study aimed to explore the efficacy of SFN on platelet dysfunction in HG-stimulated human platelets in vitro.<br><br>METHODS: Washed human platelets from healthy donors were pre-incubated with SFN (5, 10, or 20 &#x3bc;M) or vehicle control (0.05% DMSO) for 40 min at 37&#xb0;C, with or without pharmacologic inhibitors (apalrestat, PP2, N-acetyl-cysteine, pifithrin-&#x3bc;). Platelets were then stimulated with normal glucose (NG, 5 mM) or HG (25 mM) for an additional 90 min. Functional assays were performed to evaluate SFN efficacy and investigate its underlying mechanisms.<br><br>RESULTS: The results demonstrated that SFN attenuated HG-induced platelet dysfunction by alleviating mitochondrial dysfunction (manifested as loss of mitochondrial membrane potential; p <&#x202f;0.001), apoptosis (characterized by increased caspase-9/-3 activation and phosphatidylserine exposure; p <&#x202f;0.01), and hyperreactivity (evidenced by enhanced aggregation and activation; p <&#x202f;0.05). Mechanistically, SFN significantly suppressed HG-induced aldose reductase (AR) activity (p <&#x202f;0.001). Pharmacological inhibition revealed that the beneficial effects of SFN on platelet function were mediated mechanistically through AR downregulation, which attenuated p53 phosphorylation via Src-dependent ROS generation.<br><br>CONCLUSION: These findings suggest that by inhibiting the Src/ROS/p53 signaling pathway and mitigating AR-mediated platelet dysfunction, SFN may confer significant protection against atherothrombosis during hyperglycemia.},
}
@article {pmid40819642,
year = {2025},
author = {Wu, Y and Li, Y and Huang, Y and Li, Q and Li, Z and Lv, L and Yuan, Y and Zhang, K and Liu, Y and Zheng, L},
title = {Nobiletin promotes ferroptosis in breast cancer through targeting AKR1C1-mediated ubiquitination and degradation of GPX4.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {146},
number = {},
pages = {157074},
doi = {10.1016/j.phymed.2025.157074},
pmid = {40819642},
issn = {1618-095X},
mesh = {*Ferroptosis/drug effects ; *Flavones/pharmacology ; Humans ; Female ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Animals ; Cell Line, Tumor ; Ubiquitination/drug effects ; Mice ; *Triple Negative Breast Neoplasms/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Cell Proliferation/drug effects ; Mice, Nude ; Molecular Docking Simulation ; Xenograft Model Antitumor Assays ; Mice, Inbred BALB C ; *Antineoplastic Agents, Phytogenic/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {BACKGROUND: Nobiletin, a major component derived from the natural product Citrus reticulata Blanco, has been shown to exhibit potent anti-cancer activity across various cancer types. However, the mechanisms underlying its anti-breast cancer effects, particularly in triple-negative breast cancer (TNBC), remain poorly understood.<br><br>PURPOSE: The study aims to explore the role of nobiletin in promoting ferroptosis in TNBC by targeting aldo-keto reductase family 1 member C1 (AKR1C1) to facilitate ubiquitination and degradation of glutathione peroxidase 4 (GPX4).<br><br>METHODS: Cell Counting Kit-8 (CCK-8), colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assay were conducted to evaluate the effect of nobiletin on TNBC cell proliferation. Transmission electron microscopy and mitochondrial membrane potential assays were used to observe mitochondrial changes. A ferrous ion detection kit was used to assess intracellular ferrous ion levels. Malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and dihydroethidium (DHE) and BODIPY 581/591 C11 detection kits were used to measure changes in redox-related molecules. Western blot analysis was performed to detect alterations in ferroptosis-related proteins following nobiletin treatment. Further, RNA sequencing was conducted to identify target genes and pathways affected by nobiletin treatment. Molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to determine the interaction sites between nobiletin and AKR1C1. Plasmid construction, viral transfection, co-immunoprecipitation (co-IP), and in vitro ubiquitination assays were employed to investigate the effect of the nobiletin-AKR1C1 interaction on GPX4 ubiquitination. Immunohistochemistry of breast cancer patient tumour tissues was performed to analyse AKR1C1 expression in tumour and adjacent normal tissues. In addition, an orthotopic breast tumour mouse model was established to explore the in vivo effects of nobiletin on tumour growth and ferroptosis. Swiss ADME analysis was conducted to predict the pharmacokinetic properties of nobiletin.<br><br>RESULTS: In our research, we demonstrate that nobiletin effectively suppresses proliferation and induces ferroptosis in TNBC cell liness, accompanied by the release of ROS, iron accumulation, production of MDA, and depletion of GSH, changes that can be reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the ROS scavenger N-acetylcysteine (NAC). Furthermore, RNA sequencing analyses revealed that nobiletin significantly upregulates the expression of AKR1C1 which correlates with improved patient survival, suggesting its potential as a prognostic marker. Using SPR, molecular docking techniques, and CETSA, we identified AKR1C1 as a direct binding target of nobiletin, with the likely binding sites being HIS117A, LYS207A, and SER217A. Subsequently, through co-IP and in vitro ubiquitination experiments, we demonstrated that the nobiletin-AKR1C1 complex promotes the degradation of GPX4 by enhancing its ubiquitination.<br><br>CONCLUSION: Our study demonstrates that nobiletin induces ferroptosis through a direct and previously unrecognised molecular mechanism: targeting AKR1C1 to promote GPX4 ubiquitination and degradation. These results emphasise the promising role of nobiletin as an effective therapeutic approach for TNBC.},
}
@article {pmid40817924,
year = {2025},
author = {Huang, WY and Xiong, Q and Yi, Y and Wu, MY and Chen, KT and Wang, XR and Lei, WB and Xiong, GX and Fang, SB},
title = {Pathological noise exposure results in elevated levels of extracellular vesicles enriched with Hsp70 in the plasma.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {103},
number = {11-12},
pages = {1373-1386},
pmid = {40817924},
issn = {1432-1440},
support = {20YFC2005204//National Key Research and Development Program of China/ ; 82101185//National Natural Science Foundation of China/ ; 2024A1515010530//Natural Science Foundation of Guangdong Province/ ; 2025A1515011837//Natural Science Foundation of Guangdong Province/ ; 202103000079//Science Plan Fund of Guangzhou/ ; 2024A04J4695//Basic Research Program of Guangzhou Municipal Science and Technology Bureau/ ; },
mesh = {Animals ; *HSP70 Heat-Shock Proteins/blood/metabolism ; *Extracellular Vesicles/metabolism ; Mice ; *Hearing Loss, Noise-Induced/metabolism/blood/etiology/pathology ; Disease Models, Animal ; Male ; Oxidative Stress ; Ear, Inner/metabolism ; *Noise/adverse effects ; Evoked Potentials, Auditory, Brain Stem ; },
abstract = {Noise-induced hearing loss (NIHL) significantly impacts the quality of life for patients. Extracellular vesicles (EVs) play crucial roles in cellular communication, but it is unclear if the inner ear releases EVs into peripheral circulation under NIHL conditions as well as specific constituents. The NIHL mouse model was established by exposing mice to continuous 120 dB SPL white noise for 2 h, and hearing loss was assessed with auditory brainstem response (ABR). EVs were isolated by size exclusion chromatography (SEC) and characterized. Protein profiling in plasma EVs from NIHL mice was assessed via mass spectrometry and validated by ELISA and Western blot. Inner ear Hsp70 expression was interfered with intra-tympanic delivery of siRNA-Hsp70 into the middle ear. Hsp70 expression in plasma EVs was determined by ELISA. Intraperitoneal N-acetylcysteine (NAC) was performed to understand the relationship between Hsp70 expression in plasma EVs and inner ear oxidative stress. Single-cell analysis identified potential sources of EV-associated Hsp70 in the inner ear. Stria vascularis endothelial cells (SV-ECs) were stimulated with H2O2, and EV-associated Hsp70 in supernatants was determined by ELISA. The NIHL mouse model was successfully established. Plasma EVs, isolated via SEC, exhibited membrane-bound nanoparticles, with CD63, Alix, and TSG101 markers identified. Proteomic analysis revealed increased Hsp70 expression in EVs from NIHL mice, which were further confirmed with ELISA and Western blot. Intra-tympanic delivery of siRNA-Hsp70 decreased expression of Hsp70 in plasma EVs, indicating the inner ear as one of the potential sources of plasma EV-associated Hsp70. NAC therapy reduced inner ear Hsp70 expression, suggesting its association with noise-induced oxidative stress. SV-ECs were identified as one of the key cells for secretion of Hsp70-carrying EVs. Hsp70 expression was significantly increased in plasma EVs from NIHL mice upon noise-induced inner ear oxidative stress, with SV-ECs potentially being key release sites, suggesting diagnostic and therapeutic applications for plasma EV-associated Hsp70 in NIHL. KEY MESSAGES: Hsp70 was significantly increased in plasma EVs of NIHL, which was partially derived from SV-ECs upon noise-induced oxidative stress. Plasma EV-Hsp70 could be the potential target for diagnosis and therapy of NIHL.},
}
@article {pmid40817266,
year = {2025},
author = {Sainglers, W and Khamwong, M and Chareonsudjai, S},
title = {N-acetylcysteine inhibits NETs, exhibits antibacterial and antibiofilm properties and enhances neutrophil function against Burkholderia pseudomallei.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {29943},
pmid = {40817266},
issn = {2045-2322},
support = {Grant No. 200582//Fundamental Fund of Khon Kaen University/ ; },
mesh = {*Acetylcysteine/pharmacology ; *Burkholderia pseudomallei/drug effects/physiology ; *Biofilms/drug effects/growth &amp; development ; *Neutrophils/drug effects/immunology/microbiology ; Humans ; *Anti-Bacterial Agents/pharmacology ; *Extracellular Traps/drug effects/immunology ; Phagocytosis/drug effects ; Melioidosis/drug therapy/microbiology/immunology ; },
abstract = {Burkholderia pseudomallei, the cause of melioidosis, forms biofilms that facilitate survival, alter antimicrobial susceptibility and promote disease recurrence. Neutrophils contribute to bacterial eradication through phagocytosis, degranulation and neutrophil extracellular traps (NETs). However, NETs are demonstrably insufficient to eradicate B. pseudomallei. This study has revealed the ability of NET fragments containing DNA to elevate B. pseudomallei biofilm formation, as evidenced by crystal-violet staining and confocal microscopy. Further investigation demonstrated that 15 mM N-acetylcysteine (NAC), efficiently suppressed NETs stimulated by B. pseudomallei and effectively prevented B. pseudomallei from forming NET-associated biofilm in the presence of polymorphonuclear leukocytes. Remarkably, we demonstrated that NAC has antibacterial properties against five clinical B. pseudomallei isolates through kinetic growth monitoring for 24 h. Interestingly, 15 mM NAC inhibits NET production and improves neutrophil-mediated killing through phagocytosis and degranulation, considerably diminishing survival of B. pseudomallei. Our findings suggest that NAC, a multifaceted therapeutic agent, holds significant potential as an adjunctive treatment against B. pseudomallei infection. NAC not only inhibits NETs but also enhances neutrophil functionality and exhibits remarkable antibacterial activity against B. pseudomallei. These properties may contribute to more effective eradication of B. pseudomallei by reducing biofilm formation associated with NETs and improving overall neutrophil-mediated immune responses.},
}
@article {pmid40808679,
year = {2025},
author = {Alyahya, B and Alalshaikh, A and Almohawes, M and Alnowiser, M and Alsuliman, O and Alrefaei, R and Alaidarous, S and Alnahdi, M and Tamur, S and Alfaifi, M and Al Deeb, M and Al Aseri, ZA},
title = {The clinical value of screening for acetaminophen in all patients with intentional overdose or altered mental status suspected to be secondary to overdose.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1633548},
pmid = {40808679},
issn = {1663-9812},
abstract = {BACKGROUND: Acetaminophen (APAP) is commonly coingested in cases of suicide or intoxication because it is widely available, effectively analgesic and antipyretic, and it is often combined with other medications, such as opioids and antihistamines. APAP overdose often causes no symptoms or nonspecific symptoms in the first 12-24 h after ingestion. Delayed diagnosis is associated with a reduced response to antidote and sometimes liver failure and mortality. However, ordering unnecessary test is not cost-effective specially if it is mostly negative, and empirical therapy is associated with significant cost and possible adverse effects.<br><br>METHODS: This single-center retrospective study was conducted at King Saud University Medical City (KSUMC) in Riyadh, Saudi Arabia. Our population included all patients who presented to the emergency department with intentional drug overdose or altered mental status (AMS) suspected to be related to an overdose between June 2015 and January 2024 but with a history that was not suggestive of APAP overdose. Medical records were reviewed for patient information on demographic data, overdose details, and documentation of the clinical features of toxicity. All the subjects were kept anonymous; we used code numbers as identifiers. The data collected by the investigators were entered into an Excel worksheet in an encrypted format.<br><br>RESULTS: A total of 2914 patients were screened for acetaminophen (APAP) levels and 1517 met our inclusion criteria. Fourteen (0.9%) patients had detectable levels (>10&#xa0;&#x3bc;g/mL) despite a negative history. Three (0.2%) patients had levels above 100&#xa0;&#x3bc;g/mL and were treated with N-acetylcysteine (NAC).<br><br>CONCLUSION: Our study revealed that a small number of patients who presented with intentional overdose but denied APAP ingestion or AMS suspected to be due to overdose had a positive APAP level. But, Given the serious consequences of APAP toxicity we cannot recommend stopping the screening for APAP specially in high-risk suicidal patients. A larger multicenter study is recommended to identify those high-risk patients. We also found deviation from the current guidelines regarding NAC administration in patients with positive APAP level when the time of ingestion is unknown.},
}
@article {pmid40806713,
year = {2025},
author = {Gong, K and Liang, K and Li, H and Luo, H and Chen, Y and Yin, K and Liu, Z and Luo, W and Lin, Z},
title = {Oxidative Ferritin Destruction: A Key Mechanism of Iron Overload in Acetaminophen-Induced Hepatocyte Ferroptosis.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
pmid = {40806713},
issn = {1422-0067},
support = {Grant No. 2024A1515010890//Guangdong Basic and Applied Basic Research Foundation/ ; },
mesh = {Animals ; *Acetaminophen/adverse effects ; *Ferroptosis/drug effects ; *Hepatocytes/metabolism/drug effects/pathology ; Mice ; *Ferritins/metabolism ; *Iron Overload/metabolism/pathology ; Oxidative Stress/drug effects ; Lipid Peroxidation/drug effects ; Iron/metabolism ; Deferoxamine/pharmacology ; Male ; Glutathione/metabolism ; Chemical and Drug Induced Liver Injury/metabolism/pathology ; Acetylcysteine/pharmacology ; Mice, Inbred C57BL ; Cells, Cultured ; Iron Chelating Agents/pharmacology ; },
abstract = {Although acetaminophen (APAP) overdose represents the predominant cause of drug-induced acute liver failure (ALF) worldwide and has been extensively studied, the modes of cell death remain debatable and the treatment approach for APAP-induced acute liver failure is still limited. This study investigated the mechanisms of APAP hepatotoxicity in primary mouse hepatocytes (PMHs) by using integrated methods (MTT assay, HPLC analysis for glutathione (GSH), Calcein-AM for labile iron pool detection, confocal microscopy for lipid peroxidation and mitochondrial superoxide measurements, electron microscopy observation, and Western blot analysis for ferritin), focusing on the role of iron dysregulation under oxidative stress. Our results showed that 20 mM APAP treatment induced characteristic features of ferroptosis, including GSH depletion, mitochondrial dysfunction, and iron-dependent lipid peroxidation. Further results showed significant ferritin degradation and subsequent iron releasing. Iron chelator deferoxamine (DFO) and N-acetylcysteine (NAC) could alleviate APAP-induced hepatotoxicity, while autophagy inhibitors did not provide a protective effect. In vitro experiments confirmed that hydrogen peroxide directly damaged ferritin structure, leading to iron releasing, which may aggravate iron-dependent lipid peroxidation. These findings provide evidence that APAP hepatotoxicity involves a self-amplifying cycle of oxidative stress and iron-mediated oxidative damaging, with ferritin destruction playing a key role as a free iron source. This study offers new insights into APAP-induced liver injury beyond conventional cell death classifications, and highlights iron chelation as a potential therapeutic strategy alongside traditional antioxidative treatment with NAC.},
}
@article {pmid40803992,
year = {2025},
author = {Tanveer, M and Imran, M and Saleemi, MK and Shareef, M and Imran, M and Umar, S},
title = {N-acetylcysteine as a feed additive to counteract ochratoxin A toxicity in poultry.},
journal = {Food additives &amp; contaminants. Part A, Chemistry, analysis, control, exposure &amp; risk assessment},
volume = {42},
number = {9},
pages = {1269-1283},
doi = {10.1080/19440049.2025.2544327},
pmid = {40803992},
issn = {1944-0057},
mesh = {*Acetylcysteine/therapeutic use ; *Ochratoxins/toxicity ; *Animal Feed ; Poultry ; Animals ; *Food Additives/therapeutic use ; Animal Husbandry ; Diet/veterinary ; *Antioxidants/therapeutic use ; *Chickens/microbiology/physiology ; Body Weight ; Eating ; Aspergillus ; Penicillium ; Aspergillosis/veterinary ; },
abstract = {Ochratoxin A (OTA), a toxic metabolite produced by Aspergillus and Penicillium species, is a significant contaminant in poultry feed and poses serious health risks by impairing growth, immunity, and organ function in broilers. This study was designed to evaluate the protective efficacy of N-acetylcysteine (NAC), a known antioxidant and glutathione precursor, against OTA-induced clinicopathological and histopathological changes in broiler chickens. A total of 125 day-old broiler chicks were randomly divided into five equal groups: control, OTA (400 µg/kg), NAC (100 mg/kg), OTA plus NAC, and OTA plus a commercial toxin binder. Birds were monitored over a five-week period for clinical signs, feed intake, body weight, gross and microscopic lesions, and serum biochemical parameters. Results revealed that OTA exposure significantly (p ≤ 0.05) reduced feed intake, weight gain, and serum protein levels, while increasing liver and kidney enzyme markers (ALT, AST, urea, and creatinine), indicating hepatic and renal impairment. Gross (macroscopic) and histological examinations confirmed organ damage in the OTA-treated group, with enlarged, pale, and friable livers, swollen kidneys, hepatocyte necrosis, and renal tubular degeneration. Notably, NAC supplementation mitigated these adverse effects, restoring performance, serum biochemistry, and tissue architecture that were comparable to those observed in the control group. The efficacy of NAC was comparable to the commercial toxin binder. These findings suggest that NAC is a promising and cost-effective feed additive for protecting poultry against OTA-induced toxicity.},
}
@article {pmid40803576,
year = {2025},
author = {Aithal, GP},
title = {From long to snappy and short regimens for paracetamol overdose: Reinventing the N-acetyl cysteine wheel.},
journal = {Journal of hepatology},
volume = {83},
number = {4},
pages = {830-832},
doi = {10.1016/j.jhep.2025.07.032},
pmid = {40803576},
issn = {1600-0641},
}
@article {pmid40802001,
year = {2025},
author = {Ahmed, A and Wong, M and Santamaria, A and Rocha, JB and Bowman, AB and Aschner, M and Ferrer, B},
title = {JAK2/STAT3 Signaling Pathway Modulates Acute Methylmercury Toxicity in the Mouse Astrocyte C8-D1A Cell Line.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {265},
pmid = {40802001},
issn = {1573-6903},
support = {R01 ES007331/ES/NIEHS NIH HHS/United States ; R01ES007331/ES/NIEHS NIH HHS/United States ; },
mesh = {*Methylmercury Compounds/toxicity ; Animals ; *STAT3 Transcription Factor/metabolism/antagonists &amp; inhibitors ; *Astrocytes/drug effects/metabolism ; *Signal Transduction/drug effects/physiology ; Mice ; *Janus Kinase 2/metabolism ; Oxidative Stress/drug effects/physiology ; Cell Line ; Cell Survival/drug effects/physiology ; Reactive Oxygen Species/metabolism ; },
abstract = {Methylmercury (MeHg), an environmental pollutant, reaches the human body predominantly through contaminated fish consumption, potentially leading to severe neurological disorders. Upon ingestion MeHg reaches the brain and selectively accumulates in astrocytes. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key early response to MeHg-induced oxidative injury, positioning it as a potential therapeutic target. However, recent studies suggest that Nrf2 activation alone may not be sufficient to mitigate MeHg toxicity, indicating the existence of other protective mechanisms. The signal transducer and activator of transcription 3 (STAT3) signaling pathway, known for its role in cell growth and survival, has emerged as a potential player in redox homeostasis. In this study, we investigated the role of STAT3 in acute (≤ 24 h) MeHg-induced neurotoxicity. MeHg exposure induced STAT3 expression in C8-D1A astrocytic cells. Our data demonstrated that pharmacological inhibition of STAT3 using AG490 or C188-9 exacerbated MeHg-induced cell death and compromised antioxidant responses. Furthermore, to fully characterize the role of STAT3 in oxidative stress, we used two different antioxidants, N-acetylcysteine (NAC) and Trolox. Conversely, reactive oxygen species (ROS)-scavenging antioxidants partially ameliorated STAT3 activation, suggesting that MeHg-induced STAT3 activation is mediated, at least in part, by mechanisms independent of ROS. Our findings suggest that STAT3 contributes to neuroprotection against MeHg exposure in astrocytes and is, at least in part, regulated by the increase in ROS levels within these cells.},
}
@article {pmid40801394,
year = {2025},
author = {Betancur-Moreno, C and Moraga-Escobar, E and Gómez, C and Casanova, MP and Bustos, C and Vicente, B},
title = {N-acetylcysteine Efficacy on Cocaine Base Paste Use Disorder: A Randomized Double-blind Placebo-controlled Clinical Trial.},
journal = {Journal of addiction medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/ADM.0000000000001561},
pmid = {40801394},
issn = {1935-3227},
support = {FONIS SA16I0192//CONICYT grant/ ; },
abstract = {OBJECTIVES: To evaluate the clinical safety and efficacy of N-acetylcysteine (NAC) in prolonging abstinence time among adults with cocaine base paste (CBP) use disorder.<br><br>METHODS: A phase II, randomised, double-blind, placebo-controlled clinical trial, with a parallel group design, was conducted in CBP use disorder treatment-seeking adults in public outpatient mental health units in the province of Concepci&#xf3;n, Chile (n = 140). Participants were randomised to receive daily doses of 2400&#xa0;mg of NAC or placebo. They were followed for 4 weeks, attending twice-weekly to assess medication-related evaluate adverse effects and to measure abstinence in terms of the days until first new CBP use after study entry. Statistical analysis was performed using the R statistical program, and survival analysis was conducted using Kaplan-Meier.<br><br>RESULTS: NAC was a safe treatment without a severe adverse reaction, but it was not better than placebo to prolong the CBP abstinence time (P = 0.12). However, when considering a previous abstinence time of more than 7 days, differences were found in the NAC treatment arm, with better survival in the subgroup that had greater prior abstinence (P = 0.0052), which was not observed in the placebo treatment arm (P = 0.12).<br><br>CONCLUSIONS: Although NAC did not demonstrate superiority over placebo in prolonging CBP abstinence, evidence suggests that its efficacy may be influenced by prior abstinence. These findings underscore the need for further research into how prior abstinence affects NAC efficacy, while also supporting the notion that NAC may be more effective for relapse prevention than for initiating abstinence.},
}
@article {pmid40796083,
year = {2025},
author = {Vivien, D and Lebatard, S and Mazighi, M and Brikci-Nigass, N and Desilles, JP and Tomadesso, C and Vallée, E and Legros, H and Saint-Paul, LP and Touzé, E and Martinez De Lizarrondo, S and Repesse, Y and Parienti, JJ and Gauberti, M and Boulanger, M},
title = {N-acetylcysteine (NAC) as an adjunct to intravenous fibrinolysis in patients with acute ischemic stroke: a single group study (NAC-Safety).},
journal = {Neuroscience},
volume = {584},
number = {},
pages = {107-112},
doi = {10.1016/j.neuroscience.2025.08.006},
pmid = {40796083},
issn = {1873-7544},
mesh = {Humans ; Male ; Female ; *Ischemic Stroke/drug therapy ; *Acetylcysteine/administration &amp; dosage/therapeutic use/adverse effects ; Middle Aged ; Aged ; *Tissue Plasminogen Activator/administration &amp; dosage/therapeutic use/adverse effects ; *Fibrinolytic Agents/administration &amp; dosage/therapeutic use/adverse effects ; Pilot Projects ; Prospective Studies ; von Willebrand Factor/metabolism ; Aged, 80 and over ; Fibrinolysis/drug effects ; Administration, Intravenous ; Treatment Outcome ; *Brain Ischemia/drug therapy ; *Thrombolytic Therapy/methods ; },
abstract = {Recombinant tissue plasminogen activator (alteplase) and its derivative tenecteplase are approved for acute ischemic stroke (AIS), but their low recanalization rates remain a limitation. Resistance to intravenous (IV) fibrinolysis may arise from platelet cross-linking during arterial thrombosis, mediated by von Willebrand factor (VWF) multimers. N-Acetylcysteine (NAC) has demonstrated potential to cleave large VWF multimers in preclinical studies, suggesting its potential as an adjunct therapy. The primary safety endpoint was the rate of symptomatic intracranial hemorrhagic (ICHs) transformation. Secondary endpoints included changes in circulating VWF multimer concentrations. We conducted a prospective, pilot, monocentric, single-arm phase IIa trial to evaluate the safety and effects of IV NAC (HIDONAC, 150 mg/kg) administered in adjunct of alteplase in AIS patients. The study was terminated early after enrolling 12 of the planned 19 patients due to the occurrence of two fatal ICHs among patients on prior antiplatelet therapy (17 %, exact 95 % confidence interval [2 % to 48 %]). Among the enrolled patients, 83 % (10/12) tolerated the combined NAC and alteplase therapy without severe adverse events. NAC administration resulted in a significant reduction in circulating large VWF multimers within hours of administration (-82 % for ULMWM-VWF, p < 0.001), aligning with preclinical findings. While NAC effectively cleaved circulating large VWF multimers in AIS patients, its combination with alteplase raises safety concerns, particularly in patients with a history of antiplatelet therapy.},
}
@article {pmid40795666,
year = {2025},
author = {Zhang, B and Zhao, Z and Chen, X and Wang, F and Luo, Z and Gu, L and Tong, Q and Zhang, Y},
title = {Kinsenoside derivatives mitigate acute liver injury in mice via MAPK pathway-mediated oxidative stress suppression.},
journal = {Bioorganic chemistry},
volume = {164},
number = {},
pages = {108840},
doi = {10.1016/j.bioorg.2025.108840},
pmid = {40795666},
issn = {1090-2120},
mesh = {Animals ; *Oxidative Stress/drug effects ; Mice ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/pathology ; Male ; Acetaminophen ; *MAP Kinase Signaling System/drug effects ; Molecular Structure ; *4-Butyrolactone/pharmacology/analogs &amp; derivatives/chemistry/chemical synthesis ; Thioacetamide ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinases/metabolism ; Disease Models, Animal ; Monosaccharides ; },
abstract = {Acute liver injury (ALI), primarily induced by drugs and toxins, is characterized by rapid progression and high mortality. The lack of effective therapeutic agents presents a serious clinical challenge, underscoring the urgent need for novel drug development. Herein, we report two novel kinsenoside (KD) derivatives, KCM and KCF, synthesized via a two-step chemical strategy, which exhibit potent hepatoprotective effects in acetaminophen (APAP)- and thioacetamide (TAA)-induced ALI mouse models. Both compounds demonstrated superior hepatoprotection, normalizing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, attenuating the inflammatory cascade and histopathological damage to an extent comparable to the clinical antioxidant N-acetylcysteine (NAC). Time-resolved analysis reveals a sequential therapeutic mechanism, where early mitogen-activated protein kinases (MAPK) pathway inhibition (within 2 h) precedes downstream ferroptosis and inflammation blockade, demonstrating a temporally orchestrated protective cascade. Mechanistically, KCM and KCF mitigate APAP- and TAA-induced oxidative stress primarily by dampening MAPK signaling, thereby blocking lipid peroxidation, ferroptosis, and pro-inflammatory pathways. This multilayered intervention ultimately halts ALI progression, underscoring their hepatoprotective potential. Collectively, our findings indicate that KCM and KCF exert hepatoprotective effects primarily through inhibition of MAPK, highlighting their potential as therapeutic agents for ALI and warranting further investigation.},
}
@article {pmid40794548,
year = {2025},
author = {Cohen, PD and Schultz, BRE and Schuette, J and Kudchadkar, SR},
title = {N-Acetylcysteine and Hemodialysis in Severe Acetaminophen Toxicity in a 15-Year-Old Adolescent: A Case Report.},
journal = {The American journal of case reports},
volume = {26},
number = {},
pages = {e948715},
pmid = {40794548},
issn = {1941-5923},
mesh = {Humans ; Male ; *Acetaminophen/poisoning ; *Acetylcysteine/therapeutic use ; *Renal Dialysis ; Adolescent ; *Analgesics, Non-Narcotic/poisoning ; *Chemical and Drug Induced Liver Injury/therapy/etiology ; Suicide, Attempted ; *Antidotes/therapeutic use ; },
abstract = {BACKGROUND Acetaminophen toxicity is a leading cause of liver injury in adolescents and is usually treated with N-acetylcysteine (NAC). Rarely, adjunctive therapies, including hemodialysis (HD) and fomepizole, are required. This report describes the case of a 15-year-old male adolescent who required 2 hemodialysis sessions greater than 24 hours apart after a massive, intentional ingestion of acetaminophen. CASE REPORT A 15-year-old male patient presented to care after a single, intentional ingestion of approximately 195 g of extended-release acetaminophen. He was started on NAC therapy, and due to concern for early mitochondrial failure, he underwent intermittent HD, with reduction of his acetaminophen level. However, over 24 hours later, his transaminases increased and liver synthetic function declined, and he underwent HD a second time. There was no evidence of bezoar formation on computed tomography (CT) scan, suggesting that ongoing absorption was due to the extended-release formulation consumed. After his second HD session, his laboratory values normalized and he was medically cleared for transfer to psychiatry. CONCLUSIONS The need for a second HD session in acetaminophen toxicity >24 hours after an initial successful HD session is unprecedented. Given an increasing market of extended-release products and the potential for co-ingestions with medications that slow gastrointestinal motility, HD may be more frequently employed going forward, potentially multiple times. While central lines should be removed promptly when no longer needed, we advise caution in removing dialysis catheters within 24 hours of initial HD in these patients, given the need to repeat HD in this case.},
}
@article {pmid40794323,
year = {2025},
author = {Rahimmi, A and Khademerfan, M},
title = {Selenium and resveratrol attenuate rotenone-induced Parkinson's disease in zebrafish model.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {823},
pmid = {40794323},
issn = {1573-4978},
support = {IR.MUK.REC.1402/165//Kurdistan University Of Medical Sciences/ ; },
mesh = {Animals ; *Resveratrol/pharmacology ; Zebrafish ; Rotenone/toxicity ; Disease Models, Animal ; *Selenium/pharmacology ; Oxidative Stress/drug effects ; Male ; Neuroprotective Agents/pharmacology ; *Parkinson Disease/drug therapy/etiology/metabolism ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Ubiquinone/analogs &amp; derivatives/pharmacology ; Dopamine/metabolism ; Autophagy/drug effects ; *Parkinson Disease, Secondary/chemically induced/drug therapy ; },
abstract = {ABRACTST: BACKGROUND AND AIMS: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons, leading to motor and non-motor symptoms. Oxidative stress and inflammation are key contributors to PD pathogenesis, yet current treatments primarily focus on dopamine replacement and fail to address these underlying mechanisms. This study investigates the neuroprotective potential of a combination of five compounds-N-acetylcysteine (NAC), resveratrol, quercetin, selenium, and coenzyme Q10 (CoQ10)-in a zebrafish model of PD induced by rotenone.<br><br>METHODS: Eighty adult male zebrafishes were divided into eight groups, including control, rotenone-only, and groups treated with individual compounds or the combination (2QRNS). Motor activity, dopamine levels, and expression of genes related to oxidative stress, apoptosis, autophagy, and inflammation were assessed.<br><br>RESULTS: Results showed that rotenone significantly reduced motor activity and dopamine levels, while the 2QRNS cocktail, selenium, and resveratrol were most effective in mitigating these effects. Selenium notably enhanced the expression of antioxidant genes (superoxide dismutase and glutathione peroxidase) and inhibited apoptosis and autophagy pathways. Resveratrol demonstrated strong anti-inflammatory effects by reducing interleukin-6 (IL-6) expression.<br><br>CONCLUSION: These findings suggest that the 2QRNS combination, particularly selenium and resveratrol, offers significant neuroprotection in a PD model by targeting oxidative stress, inflammation, and cell death pathways. Further studies on other PD models and detailed molecular pathways are recommended to validate these results and explore their clinical potential.},
}
@article {pmid40794023,
year = {2025},
author = {Corradi, C and Moreno, NC and Quintero-Ruiz, N and Silva Leandro, GD and Teatin Latancia, M and de Souza, TA and Munford, V and Menck, CFM},
title = {Uncovering the Role of DNA Repair Impairment in UVA-Induced Mutagenesis in Human Xeroderma Pigmentosum Variant Cells.},
journal = {Molecular carcinogenesis},
volume = {64},
number = {11},
pages = {1823-1837},
pmid = {40794023},
issn = {1098-2744},
support = {//This study was supported by the Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior (CAPES), Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico (CNPq), and Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo (FAPESP)./ ; },
mesh = {Humans ; *Ultraviolet Rays/adverse effects ; *DNA Repair/radiation effects ; *Xeroderma Pigmentosum/genetics/pathology ; *Mutagenesis/radiation effects ; DNA Damage/radiation effects ; Pyrimidine Dimers/genetics ; Oxidative Stress/radiation effects ; Mutation ; DNA-Directed DNA Polymerase/genetics ; Exome Sequencing ; Acetylcysteine/pharmacology ; *Skin Neoplasms/genetics/pathology ; Y-Family DNA Polymerases ; },
abstract = {Ultraviolet A (UVA) radiation induces DNA damage both directly, by forming cyclobutane pyrimidine dimers (CPDs), and indirectly, by generating oxidative stress. Cells rely on nucleotide excision repair (NER) and translesion synthesis (TLS) to tolerate these lesions. Xeroderma pigmentosum variant (XP-V) cells, deficient in DNA polymerase eta (pol eta), exhibit a heightened risk of skin cancer due to impaired TLS. While XP-V patients are considered NER-proficient, our findings challenge this assumption by demonstrating that UVA-induced oxidative stress impaired NER activity, leading to increased C > T transitions at CPD sites. Whole-exome sequencing of UVA-irradiated XP-V cells revealed a substantial rise in mutations, with a distinct C > T signature characteristic of defective CPD repair. Notably, pretreatment with the antioxidant N-acetylcysteine (NAC) mitigated this effect, reducing C > T transitions through enhanced NER function and decreasing C > A transversions via its antioxidant properties. These results redefine the mutagenic landscape of XP-V cells, revealing that oxidatively generated damage to NER proteins-rather than TLS deficiency alone-contributes to their elevated mutation burden. Our findings suggest that antioxidant strategies may partially protect XP-V patients from UVA-driven mutagenesis enhancing the cells' DNA repair capacity, ultimately reducing skin cancer and contributing to better overall health outcomes.},
}
@article {pmid40788469,
year = {2026},
author = {Singh, I and Agrawal, H and Maurya, S and Tanwar, H and Gupta, S and Singh, NP},
title = {Efficacy and safety of N-acetylcysteine vs. probiotics in in-vivo biofilm prevention on ureteral stents: a prospective randomized controlled pilot in vivo study.},
journal = {International urology and nephrology},
volume = {58},
number = {3},
pages = {811-820},
pmid = {40788469},
issn = {1573-2584},
mesh = {Humans ; *Biofilms/drug effects ; *Acetylcysteine/therapeutic use/adverse effects ; Female ; *Probiotics/therapeutic use/adverse effects ; Male ; Prospective Studies ; Middle Aged ; Pilot Projects ; *Stents/microbiology/adverse effects ; *Ureter/surgery ; Adult ; Aged ; Treatment Outcome ; },
abstract = {OBJECTIVE: To evaluate the efficacy and safety of N-acetylcysteine (NAC) vs. probiotics in preventing biofilm formation on ureteral stents in selected patients. Ureteral stents are essential for managing urinary obstructions and renal stones and are prone to complications such as biofilm formation, which can lead to infections and stent malfunction. NAC is known for its mucolytic and antimicrobial properties, has shown potential in preventing biofilm formation on ureteral stents; however, clinical evidence is limited.<br><br>METHODS: This prospective, open-label, randomized controlled experimental study was conducted in a tertiary care teaching hospital between October 2022 and March 2024. Sixty patients undergoing ureteral stent placement were randomized to receive NAC (600&#xa0;mg twice daily) in Group I vs. probiotics (containing Streptococcus faecalis, Clostridium butyricum, Bacillus mesentericus, and Lactic Acid Bacillus) in Group II for 5&#xa0;weeks. Primary outcomes included routine urine microscopy, culture, stent culture, and biofilm detection on the stent surfaces.<br><br>RESULTS: Group I showed significantly reduced (pyuria, positive urine cultures, and biofilm formation on stents) to group II. Biofilm was absent in group I but was detected in 6.7% of group II. No significant treatment-emergent adverse effects (TEAEs) were observed in either group.<br><br>CONCLUSION: NAC demonstrated a strong potential in preventing biofilm formation on ureteral stents, which correlated with improved outcomes in terms of reduced stent-associated bacterial growth, bacteriuria, and pyuria. However, further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings and assess the precise utility and long-term safety of NAC in clinical settings for ureteral stenting and UTIs.<br><br>DRUG TRIAL REGISTRY: TCTR20250511001 dt 11th May '2025, https://www.thaiclinicaltrials.org/show/TCTR20250511001.},
}
@article {pmid40787518,
year = {2025},
author = {Adhikari, A and Shrestha, A and Shilpakar, O and Majhi, M and Baniya, A and Bastola, NR and Basnet, J},
title = {Wild mushroom poisoning: a case series from Nepal highlighting diverse clinical presentation, management challenges, and regional insights.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {8},
pages = {4926-4930},
pmid = {40787518},
issn = {2049-0801},
abstract = {INTRODUCTION: Yearly, hundreds of people are hospitalized due to mushroom poisoning, and the mortality rate is high due to a variety of reasons, such as delayed presentation, diverse and complex clinical symptoms, and a lack of well-defined clinical guidelines for management.<br><br>CASE DISCUSSION: In June 2023, husband and wife (Case 1 and Case 2) unknowingly consumed wild mushrooms and were admitted after 4 days with a diagnosis of Hyperacute liver failure. Both of them were treated with N-acetyl cysteine (NAC), silymarin, and other supportive measures, including intravenous hydration along with correction of electrolyte abnormalities. Case 1 was successfully managed and was discharged with normal lab values. Whereas, Case 2 deteriorated and underwent disseminated intravascular coagulation, causing mortality. Another case (Case 3) presented with minimal symptoms and was managed supportively for 1 day, and didn't have any adverse outcomes.<br><br>DISCUSSION: Clinical presentation of Amanita poisoning may vary from asymptomatic to life-threatening acute liver failure. NAC, Silymarin, along with other supportive measures, are being seen as promising treatment options in resource-limited settings where urgent liver transplantation facilities are limited. Even with appropriate treatment, the course and prognosis are generally unpredictable.<br><br>CONCLUSION: Amanita mushroom poisoning has a diverse and complex presentation. Despite a lack of concrete guidelines on management, measures like NAC, Silymarin, and other supportive management, like intravenous hydration and correction of electrolyte abnormalities, have shown promising results in cases of delayed presentation and limited liver transplantation facilities.},
}
@article {pmid40783482,
year = {2025},
author = {Xu, H and Yang, J and Ye, R and Cao, M and Li, S and Liu, C and Li, L},
title = {Inhibition of Nrf2 Activity in Mitigating Cadmium-Induced Mitochondrial Damage and Pyroptosis.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {40783482},
issn = {1559-0720},
support = {2023AH051885//Chang Liu/ ; 31802242//lei li/ ; },
abstract = {Acute cadmium (Cd) exposure induces hepatic toxicity in murine models, where oxidative stress and subsequent inflammatory responses are recognized as principal contributors to hepatocyte damage. The NLRP3 inflammasome, a pivotal member of the NOD-like receptor family, mediates pyroptotic cell death in diverse hepatic inflammatory pathologies. While murine liver exhibits heightened susceptibility to heavy metal toxicity, the mechanistic basis of Cd-induced hepatocyte injury remains incompletely characterized. This study aims to clarify the cytotoxic effects of Cd on murine hepatocyte line BNL CL.2 and systematically dissect the underlying molecular mechanisms. Via molecular and cellular assays, we evaluated mitochondrial function, reactive oxygen species (ROS) levels, NLRP3 inflammasome activation, and pyroptotic features in BNL CL.2 cells post Cd exposure; intervened with ROS scavengers N-acetylcysteine (NAC) and Mito-TEMPO, and detected transcriptional activity of the antioxidant regulator Nrf2. Experimental data demonstrate that Cd exposure triggers mitochondrial dysfunction coupled with excessive ROS production, concomitant NLRP3 inflammasome activation, and characteristic plasma membrane rupture confirming pyroptosis. Notably, NAC and Mito-TEMPO effectively attenuate these pathological responses, establishing ROS as critical regulators of Cd-induced NLRP3 inflammasome activation; mechanistically, Cd suppresses Nrf2 transcriptional activity and downstream antioxidant gene expression, thereby disrupting redox homeostasis. These findings collectively delineate a pathogenic cascade where Cd impairs mitochondrial integrity and disrupts Nrf2-dependent antioxidant defenses, synergistically driving ROS-mediated NLRP3 inflammasome activation and subsequent hepatocyte pyroptosis. This mechanism provides novel insights into heavy metal hepatotoxicity and identifies potential targets for treating Cd-induced liver injury.},
}
@article {pmid40782535,
year = {2025},
author = {Ma, T and Jiang, D and Liu, W and Li, Z and Gao, K and Zhang, Y},
title = {Mechanistic insights into fluoride-induced reproductive toxicity in female ovine animals: Mitochondrial dysfunction and ER stress-driven apoptosis in ovine granulosa cells.},
journal = {Ecotoxicology and environmental safety},
volume = {303},
number = {},
pages = {118830},
doi = {10.1016/j.ecoenv.2025.118830},
pmid = {40782535},
issn = {1090-2414},
mesh = {Animals ; Female ; *Granulosa Cells/drug effects ; *Endoplasmic Reticulum Stress/drug effects ; Sheep ; Apoptosis/drug effects ; *Fluorides/toxicity ; Oxidative Stress/drug effects ; *Mitochondria/drug effects ; Reactive Oxygen Species/metabolism ; *Sodium Fluoride/toxicity ; },
abstract = {The aim of this study was to investigate the effects of fluoride on ovine granulosa cells (GCs). GCs were treated with NaF to assess the effects of fluoride exposure on their morphology and function. Reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), and malondialdehyde (MDA) and glutathione (GSH) contents were determined. The expression of genes and proteins related to oxidative stress and endoplasmic reticulum stress (ERS) was examined. Additionally, RNA sequencing (RNA-Seq) and molecular biological techniques were used to elucidate the potential mechanisms underlying fluoride-induced damage to GCs. Fluoride treatment generated oxidative stress in cells, resulting in the overproduction of intracellular ROS, accumulation of lipid peroxidation products, decreased cellular antioxidant enzyme activities, and increased cellular damage. Treatment with N-acetylcysteine (NAC) effectively increased the fluoride-induced decrease in catalase (CAT), superoxide dismutase 1 (SOD1), and glutathione peroxidase 1 (GPX1) expression (P < 0.01, P < 0.05). Fluoride exposure induced ERS in GCs. The mRNA expression of BIP, PERK, ATF4, ATF6, CHOP, GADD34, ERN1, and XBP1 significantly increase under NaF treatment (P < 0.01). Binding immunoglobulin protein (BIP), protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) expression significantly increased (P < 0.01). The ERS inhibitor GSK2656157 reduced the expression of BIP, PERK, and ATF6 (P < 0.01, P < 0.05). RNA-Seq analysis showed that the expression of genes associated with ERS was activated; genes associated with oxidative stress were repressed; and Environmental Information Processing, Genetic Information Processing, Metabolism, Cellular Processes, and Human Disease pathways were activated. This study provides a deep understanding of fluoride-induced reproductive toxicity and offers potential strategies to mitigate its effects to protect animal and human reproductive health.},
}
@article {pmid40780632,
year = {2025},
author = {Ameyaa-Sakyi, A and Harris, TR and Clarke, CE and McMullin, DR and Gordon, KL and Sherwood, D and Hartman, JH and Rand, AA},
title = {Human mitochondrial CYP2E1-mediated styrene metabolism increases oxidative stress and impairs antioxidant rescue in Caenorhabditis elegans.},
journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP},
volume = {298},
number = {},
pages = {110319},
doi = {10.1016/j.cbpc.2025.110319},
pmid = {40780632},
issn = {1532-0456},
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism/genetics ; *Oxidative Stress/drug effects ; *Mitochondria/enzymology/metabolism/drug effects ; *Cytochrome P-450 CYP2E1/metabolism/genetics ; *Styrene/toxicity/metabolism ; *Antioxidants/metabolism/pharmacology ; Humans ; Animals, Genetically Modified ; Reactive Oxygen Species/metabolism ; Caenorhabditis elegans Proteins/metabolism/genetics ; },
abstract = {Styrene is an environmental toxicant metabolized by cytochrome P450 2E1 (CYP2E1) to styrene oxide, a reactive intermediate product linked to oxidative stress. While the role of CYP2E1 in xenobiotic metabolism is well established, the influence of subcellular enzyme localization on styrene-induced toxicity remains unclear. This study used transgenic Caenorhabditis elegans (C. elegans) strains expressing CYP2E1 in different compartments, mitochondrial-derived (mtCYP2E1) and endoplasmic reticulum-derived (erCYP2E1), to investigate the impact of CYP2E1-mediated styrene metabolism on survival and oxidative stress. CYP2E1 containing C. elegans strains were also compared to a wildtype strain (N2) lacking CYP2E1. Styrene exposure significantly decreased survival across all strains. Antioxidant rescue assays revealed that Trolox and N-acetyl cysteine (NAC) improved survival in the N2 and erCYP2E1 C. elegans strains but not in mtCYP2E1, indicating a distinct oxidative stress mechanism in mitochondrial CYP2E1 metabolism. Fluorescent microscopy confirmed that ROS levels increased with styrene exposure, particularly in mtCYP2E1 C. elegans, where ROS levels were up to two-fold higher than in other strains. GC-MS analysis detected elevated styrene glycol production in styrene-exposed mtCYP2E1 C. elegans relative to N2 and erCYP2E1 strains. Given styrene oxide is a known cytotoxic intermediate, its accumulation in the mtCYP2E1 strain likely contributes to the observed oxidative stress and decreased survival. These findings suggest that CYP2E1 subcellular localization influences styrene metabolism and toxicity, with mitochondrial CYP2E1 potentially promoting higher oxidative stress and reduced detoxification efficiency. A better understanding of these mechanisms could provide insight into xenobiotic metabolism, environmental toxicology, and disease pathogenesis associated with CYP2E1-mediated oxidative stress.},
}
@article {pmid40780323,
year = {2025},
author = {Wen, J and Liu, S and Yang, B and Tan, M and Shen, X and Du, Z},
title = {Peroxiredoxin 4 (Prx 4) plays important gene expression regulatory roles in antimicrobial innate immune by regulating hydrogen peroxide (H2O2) in the hepatopancreas of freshwater crayfish Procambarus clarkii.},
journal = {Developmental and comparative immunology},
volume = {170},
number = {},
pages = {105438},
doi = {10.1016/j.dci.2025.105438},
pmid = {40780323},
issn = {1879-0089},
mesh = {Animals ; *Astacoidea/immunology/microbiology ; Immunity, Innate/genetics ; *Hydrogen Peroxide/metabolism ; *Hepatopancreas/immunology/metabolism ; *Peroxiredoxins/genetics/metabolism ; *Arthropod Proteins/genetics/metabolism ; *Vibrio/immunology/physiology ; Gene Expression Regulation ; *Vibrio Infections/immunology ; Apoptosis/genetics ; RNA, Double-Stranded/genetics ; Signal Transduction ; Reactive Oxygen Species/metabolism ; },
abstract = {This study focused on peroxiredoxin (Prx) as a core target to investigate its regulatory mechanism in the innate immunity of Procambarus clarkii (crayfish). We observed that a reduction in the expression of prx 4 via injection of double-stranded RNA (dsRNA) induced early upregulation of H2O2 levels in the hepatopancreas of crayfish. When the crayfish were subsequently infected with Vibrio harveyi, the H2O2 levels further increased, and the antioxidant enzyme system was activated. After injecting dsPc-Prx 4 and subsequently stimulating the crayfish with V. harveyi, we observed upregulated expression of genes related to the melanization pathway, reactive oxygen species (ROS) pathway, apoptosis pathway, and Toll pathway. Furthermore, after the injection of dsPc-Prx 4 followed by V. harveyi and subsequent N-acetylcysteine (NAC) exposure, the expression of genes related to the melanization, apoptosis, and Toll pathways was downregulated; moreover, the melanization phenomenon was significantly weakened, and the survival rate of the crayfish decreased. The abovementioned experimental results demonstrate that Pc-Prx 4 is an important regulatory enzyme in the antioxidant system of crayfish. It can influence the antibacterial innate immune response of P. clarkii by modulating H2O2 levels. This study provides a significant addition to the fundamental theory of antibacterial innate immunity in invertebrates and offers a theoretical basis for the prevention and control of bacterial diseases in P. clarkii.},
}
@article {pmid40779705,
year = {2025},
author = {Tatani, I and Kalaitzopoulou, E and Skipitari, M and Ntoukas, A and Tsaliki, EA and Giakoumakis, S and Lakoumentas, J and Varemmenou, A and Michail, E and Papadea, P and Georgiou, CD and Panagiotopoulos, E},
title = {Reduction of oxidative stress in total knee arthroplasty using tourniquet with a novel pharmaceutical combination.},
journal = {SICOT-J},
volume = {11},
number = {},
pages = {47},
pmid = {40779705},
issn = {2426-8887},
support = {2022-050-0502-52518//State Scholarships Foundation/ ; 33720000//Andreas Mentzelopoulos Foundation/ ; 653//Hellenic Foundation for Research and Innovation/ ; 33720000//Andreas Mentzelopoulos Foundation/ ; 33720000//Andreas Mentzelopoulos Foundation/ ; },
abstract = {INTRODUCTION: Tourniquet use in total knee arthroplasty (TKA) can cause ischaemia-reperfusion (I-R) injury via oxidative stress. This study evaluated whether combined administration of the antioxidant N-acetylcysteine (NAC) and the iron-chelator Deferiprone can mitigate oxidative damage and improve clinical outcomes.<br><br>MATERIALS AND METHODS: Twenty TKA patients were randomized into two groups, one group receiving NAC (600&#xa0;mg, 6&#xa0;h pre-op) and Deferiprone (1000&#xa0;mg, 2&#xa0;h pre-op) (intervention group) and the other group serving as placebo (control). Lipid hydroperoxides (LOOH) and protein malondialdehyde (PrMDA) were measured from quadriceps muscle tissue samples at 5&#xa0;min (T1) and 40&#xa0;min (T2) after tourniquet inflation, and 5&#xa0;min after deflation (T3). Blood markers including serum ferritin, white blood cell (WBC) count, and polymorphonuclear neutrophils (PMNs) were assessed along with tissue PrMDA and LOOH as primary outcome measurements, while pain scores and knee flexion were recorded postoperatively as secondary outcome measurements.<br><br>RESULTS: LOOH levels were significantly lower in the intervention group at T2 and T3. PrMDA levels showed no significant differences. Ferritin levels rose by 69% in controls vs. 18% in the intervention group. WBC and PMNs normalized faster, with reduced pain and improved range of motion in the intervention group.<br><br>CONCLUSION: The attenuation of LOOH elevation, the faster PMN deactivation, the inhibition of ferritin release from the cells along with the improved clinical outcomes suggest that combined NAC and Deferiprone administration may reduce tourniquet-related oxidative stress and inflammation, enhancing early recovery in TKA patients.},
}
@article {pmid40774821,
year = {2025},
author = {Marasinghe, CK and Suryaningtyas, IT and Jung, WK and Je, JY},
title = {Protective Effect of N-Acetylcysteine (NAC) on oxLDL-Induced Endothelial Dysfunction.},
journal = {Journal of microbiology and biotechnology},
volume = {35},
number = {},
pages = {e2504039},
pmid = {40774821},
issn = {1738-8872},
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Lipoproteins, LDL/metabolism ; Human Umbilical Vein Endothelial Cells/drug effects ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Lipid Peroxidation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Antioxidants/pharmacology ; Nitric Oxide/metabolism ; Oxidative Stress/drug effects ; Nitric Oxide Synthase Type III/metabolism ; Scavenger Receptors, Class E/metabolism ; Vascular Cell Adhesion Molecule-1/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; Endothelial Cells/drug effects ; },
abstract = {N-acetylcysteine (NAC), a well-known antioxidant and glutathione precursor, has been extensively studied for its free radical-scavenging properties, anti-inflammatory effects, and ability to enhance cellular redox balance. NAC has also been shown to mitigate oxidative damage in various disease models, yet its role in endothelial dysfunction remains underexplored. In this study, we evaluated the ability of NAC to counteract oxLDL-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs). NAC treatment significantly reduced ROS levels, lipid peroxidation, and apoptotic markers while restoring mitochondrial membrane potential (MMP) and NO bioavailability. Additionally, NAC regulated the expression of eNOS, LOX-1, ICAM-1, and VCAM-1, demonstrating its role in reducing endothelial inflammation and improving vascular homeostasis. Furthermore, NAC prevented excessive cholesterol accumulation, suggesting its potential to regulate lipid metabolism in endothelial cells. These findings highlight the therapeutic potential of NAC in protecting against oxLDL-induced endothelial dysfunction and preventing vascular complications associated with cardiovascular diseases.},
}
@article {pmid40759602,
year = {2025},
author = {Lo, CY and Wang, CH and Lin, CY and Lin, TY and Chang, PJ and Lo, YL and Wang, TY and Huang, TT and He, JR and Heh, CC and Luo, HR and Chuang, LP and Lin, SW and Chen, NH and Lin, SM and Lin, HC and Chung, KF},
title = {Corticosteroid insensitivity in asthma associated with obstructive sleep apnoea: Role of oxidative stress and histone acetylation.},
journal = {British journal of pharmacology},
volume = {182},
number = {23},
pages = {5790-5802},
doi = {10.1111/bph.70157},
pmid = {40759602},
issn = {1476-5381},
support = {NMRPG3M6171//National Science Research Project/ ; CMRPG3N1271//Chang Gung Memorial Hospital Research Project/ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Sleep Apnea, Obstructive/complications/metabolism ; *Asthma/drug therapy/metabolism/complications ; Histone Deacetylase 2/metabolism ; Male ; Middle Aged ; Female ; Adult ; *Adrenal Cortex Hormones/pharmacology/therapeutic use/administration &amp; dosage ; Acetylation ; *Histones/metabolism ; Leukocytes, Mononuclear/metabolism/drug effects ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Drug Resistance ; Interleukin-8/blood ; Reactive Oxygen Species/metabolism ; },
abstract = {BACKGROUND AND PURPOSE: Obstructive sleep apnoea (OSA) worsens asthma control. Oxygen desaturation increases oxidative stress, contributing to corticosteroid insensitivity, a hallmark of severe asthma. This study investigated the impact of hypoxaemia and reactive oxygen species on corticosteroid responsiveness in asthma with OSA.<br><br>EXPERIMENTAL APPROACH: Asthmatic patients with apnoea-hypopnoea index (AHI)&#x2009;&#x2265;&#x2009;5&#x2009;h[-1] were classified as OSA. Interleukin (IL)-8 and IL-6 production by peripheral blood mononuclear cells (PBMCs), serum cytokines, oxidative stress markers and nuclear histone deacetylase 2 (HDAC2) were quantified by enzyme-linked immunosorbent assay. HDAC2 and hypoxia-inducible factor-1&#x3b1; (HIF-1&#x3b1;) expression were evaluated by Western blotting and flow cytometry.<br><br>KEY RESULTS: Compared with non-OSA asthmatics, OSA patients used higher inhaled corticosteroid doses and had increased serum thiobarbituric acid-reactive substances and 8-hydroxy-2-deoxyguanosine, but lower superoxide dismutase and total antioxidant capacity. HDAC2 was lower in OSA PBMCs and in non-OSA PBMCs exposed to 5% O&#x2082; than in normoxia. HDAC2 was correlated inversely with AHI, corticosteroid dose, serum IL-8, oxidative stress, baseline production of IL-8/IL-6 and dexamethasone-induced IL-8 suppression. Dexamethasone inhibited TNF-&#x3b1;-induced IL-8 and lipopolysaccharide (LPS)-induced IL-6 in non-OSA PBMCs, but not in OSA PBMCs. HDAC2 inhibitor CAY10683 impaired corticosteroid action, while N-acetylcysteine and inhibitors of HIF-1&#x3b1; (CAY10585) or phosphoinositide 3-kinase (LY294002) restored HDAC2 and corticosteroid sensitivity.<br><br>CONCLUSIONS AND IMPLICATIONS: OSA is associated with oxidative stress, reduced HDAC2, and corticosteroid insensitivity in asthma. Antioxidants may help restore corticosteroid efficacy.},
}
@article {pmid40755945,
year = {2025},
author = {Dosanjh, HS and Dosanjh, PK and Ipalawatte, H and Mehdi, Z},
title = {An Unusual Case of Acute Epstein-Barr Virus Hepatitis Presenting as Severe Cholestatic Liver Disease Inducing Hemophagocytic Lymphohistiocytosis in a Young Adult: A Case Report.},
journal = {Cureus},
volume = {17},
number = {6},
pages = {e87066},
pmid = {40755945},
issn = {2168-8184},
abstract = {Epstein-Barr virus (EBV) infection is a common viral illness typically presenting with symptoms such as fever, sore throat, and lymphadenopathy. Hepatic involvement in EBV infection is usually mild and transient. However, severe cholestatic liver disease due to acute EBV hepatitis is rare, especially in young adults. Secondly, hemophagocytic lymphohistiocytosis (HLH), the abnormal activity of lymphocyte function leading to hemophagocytosis and multi-organ failure, is a rare complication of EBV. In the context of Los Angeles County, the locale of this study, the incidence of secondary nonfamilial HLH among patients over the age of 15 is reported at 0.9 cases per million annually, with epidemiological data specific to EBV-associated HLH even more notably limited. We report a case of a 20-year-old female patient presenting with fever and chills, ultimately diagnosed with acute EBV hepatitis causing severe cholestatic liver injury, with concurrent positive antimitochondrial antibody and HLH, without multi-organ failure, who showed significant improvement with the administration of N-acetylcysteine (NAC), highlighting its potential therapeutic role in EBV-associated liver diseases.},
}
@article {pmid40752156,
year = {2025},
author = {Uddin, MH and Salvador, C and Ritu, JR and Putnala, SK and Chivers, DP and Niyogi, S},
title = {Selenomethionine-induced neurotoxicity and behavioural alterations in larval zebrafish (Danio rerio).},
journal = {Ecotoxicology and environmental safety},
volume = {303},
number = {},
pages = {118788},
doi = {10.1016/j.ecoenv.2025.118788},
pmid = {40752156},
issn = {1090-2414},
mesh = {Animals ; *Zebrafish/physiology/embryology ; *Selenomethionine/toxicity ; *Water Pollutants, Chemical/toxicity ; Larva/drug effects ; *Behavior, Animal/drug effects ; Embryo, Nonmammalian/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; *Neurotoxicity Syndromes ; },
abstract = {Selenium (Se) plays a crucial role in fishes, but even a slight increase beyond physiological levels can make it highly toxic. In contaminated environments, fishes primarily accumulate Se as selenomethionine (SeMet). While pernicious effects of SeMet in adult fishes are well-documented, its embryotoxicity, beyond teratogenic outcomes, are underexplored. In current study, 2 h post fertilized (hpf) zebrafish embryos were subjected to waterborne Se at sub-lethal concentrations (0 [control], 5, 10, and 25 µg/L; as SeMet) until 5 days post-fertilization (dpf). Results revealed that SeMet exposure at 10 and 25 µg/L significantly increased larval mortality and deformity rates compared to the control group. Moreover, SeMet exposure (5 and 10 µg/L Se) impaired thigmotactic and reflexive behaviours at 5 dpf. Embryonic SeMet exposure also resulted in an escalation in reactive oxygen species levels and apoptosis with elevating concentration, along with dysregulation of proteins and genes related to nervous system development including dopaminergic, serotonergic, and cholinergic signaling pathways at 5 dpf. Interestingly, pretreatment with N-acetylcysteine (NAC), a potent antioxidant, resulted in amelioration of SeMet-induced oxidative stress, apoptosis, molecular and behavioural deficits, suggesting that oxidative stress is an initiating mediator in triggering neurobehavioural impairments in larval zebrafish. Overall, this study highlights that neurobehavioural responses are more sensitive to SeMet than its teratogenic effects in larval zebrafish, thus providing novel perspectives on the developmental toxicity of Se in fish.},
}
@article {pmid40751519,
year = {2025},
author = {Hooshmand Gharabagh, L and Heydaroghli, M and Esmaeili, A},
title = {Efficacy Of N-Acetyl-Cysteine as Adjuvant Therapy for Diabetic Foot Osteomyelitis: An Open-Label Randomized Controlled Trial.},
journal = {Archives of Iranian medicine},
volume = {28},
number = {5},
pages = {257-263},
pmid = {40751519},
issn = {1735-3947},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Diabetic Foot/complications/drug therapy ; Male ; *Osteomyelitis/drug therapy/etiology ; Female ; Middle Aged ; Aged ; *Anti-Bacterial Agents/therapeutic use ; Treatment Outcome ; C-Reactive Protein ; Adult ; Blood Sedimentation ; Chemotherapy, Adjuvant ; },
abstract = {BACKGROUND: Biofilm formation by bacteria on the lower limb arises from reduced peripheral arterial blood flow, which can lead to the failure of antibiotic therapy or require longer duration of intravenous antibiotic therapy in diabetic foot infection-associated osteomyelitis. N-acetyl cysteine (NAC), an agent known to prevent and treat biofilm-related infections, was used as a novel strategies beside antibiotic therapy in osteomyelitis of diabetic foot with the aim of accelerating the response to antibiotic therapy regimen.<br><br>METHODS: To assess the synergistic effect of NAC with antibiotic therapy, patients with diabetic foot osteomyelitis (DFO) (grade III or IV Wagner) were randomly assigned to either NAC 600 mg effervescent tablet twice daily for 2 weeks or the control group. Clinical and laboratory data, including white blood cell with differentiation and inflammatory factors (ESR and CRP) were measured at baseline (time 0), after one week and after three weeks of initiating the intervention.<br><br>RESULTS: Fifty-three eligible patients completed the study. All evaluated infectious-related laboratory parameters showed significant reductions in the NAC group compared to control (P<0.05), except for lymphocyte proportion and NLR (P; 0.11 and 0.84, respectively). The drop rate of ESR and CRP were accelerated by NAC compared to the control group (-49.44&#xb1;6.04 vs -7.17&#xb1;3.99; -44.43&#xb1;4.21 vs -14.02&#xb1;4.05, respectively, P<0.05).<br><br>CONCLUSION: In order to accelerate antibiotic responses and the trend of reduction in infectious inflammatory markers during the therapy, oral NAC 600 mg twice daily may be considered in the treatment protocol of patients with DFO.},
}
@article {pmid40747818,
year = {2025},
author = {Ma, L and Gao, X and Zhang, Q and Ren, X and Sun, Y and Zou, G},
title = {Near-Infrared Electrochemiluminescence of Gold Nanoclusters and Their Gene Assay Application with Thiol as the Bioconjugate Anchor.},
journal = {Analytical chemistry},
volume = {97},
number = {31},
pages = {17050-17057},
doi = {10.1021/acs.analchem.5c02783},
pmid = {40747818},
issn = {1520-6882},
mesh = {*Gold/chemistry ; *Sulfhydryl Compounds/chemistry ; Hepatitis B virus/genetics ; *Luminescent Measurements/methods ; *Electrochemical Techniques/methods ; *Metal Nanoparticles/chemistry ; *DNA, Viral/genetics/analysis ; Humans ; Acetylcysteine/chemistry ; Infrared Rays ; },
abstract = {Amide bonds are most frequently utilized to form the bioconjugates of nanoclusters (NCs) and biomolecules; however, the amide bonds involved in the bioconjugation process tend to dramatically alter the functional group of NCs, decrease storage stability, and eventually block their practical bioapplication. With N-acetyl-l-cysteine (NAC)-capped AuNCs (NAC-AuNCs) as a model, we propose a biocompatible electrochemiluminescence (ECL) luminophore with thiol as a stabilizer and bioconjugate anchor. The NAC-AuNCs can exhibit a solely oxidative-reduction ECL process around +0.94 V with a maximum emission wavelength of around 824 nm. By immobilizing SH-modified probe hepatitis B virus (HBV) DNA (p-DNA) onto NAC-AuNCs via Au-S bonds, NAC-AuNCs can be used as ECL tags for gene assays with thiol as the anchor of bioconjugates, which provides an alternative to conventional bioconjugates and proves that ECL reagent kits can be developed in a 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC)-free way. The NIR ECL of NAC-AuNCs can be utilized to linearly determine HBV from 10 pM to 5 nM with a limit of detection (LOD) of 5 pM (S/N = 3). Notably, NAC-AuNCs can be safely stored for over four months without signal attenuation and can link the SH-modified gene without permanent precipitation.},
}
@article {pmid40745148,
year = {2025},
author = {D'Aloia, M and Smith, D and Boley, R and Schamber, E and Thorpe, D and Thompson, TM and Chhabra, N},
title = {Trends in Fomepizole Use for Acetaminophen Poisoning in the United States; 2013-2024.},
journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology},
volume = {21},
number = {4},
pages = {404-408},
pmid = {40745148},
issn = {1937-6995},
mesh = {Humans ; *Acetaminophen/poisoning ; Male ; Female ; United States/epidemiology ; *Fomepizole/therapeutic use ; Cross-Sectional Studies ; *Antidotes/therapeutic use ; Middle Aged ; Adult ; Acetylcysteine/therapeutic use ; *Analgesics, Non-Narcotic/poisoning ; Young Adult ; Aged ; Adolescent ; Databases, Factual ; *Practice Patterns, Physicians'/trends ; Chemical and Drug Induced Liver Injury/mortality ; Treatment Outcome ; },
abstract = {BACKGROUND: Fomepizole has been suggested as adjunctive therapy for severe acetaminophen poisoning though clinical efficacy is unknown. We sought to determine trends in the use of fomepizole for acetaminophen poisoning.<br><br>METHODS: This is a cross-sectional analysis of hospitalized patients with acetaminophen poisoning from January 2013 through December 2024, using Epic Cosmos, a research database of 298&#xa0;million patients nationally. We identified encounters involving acetaminophen poisoning by International Classification of Diseases, version 10 (ICD-10-CM) code. Data extracted included administration of N-acetylcysteine (NAC) and fomepizole, demographic data, and outcomes of death and liver transplantation. Data were analyzed using descriptive statistics to identify trends and multivariable logistic regression to determine associations with death.<br><br>RESULTS: There were 114,111 hospital encounters involving acetaminophen poisoning with 64,957 (56.92%) receiving NAC, and 1,552 (1.36%) receiving fomepizole. In 2013, 0.44% of NAC-treated acetaminophen poisoning cases also received fomepizole. This rose to 6.27% in 2024. From 2013 to 2019, the proportion of NAC-treated acetaminophen cases receiving fomepizole was stable, but from 2019 to 2024, there was a 1029.64% increase in fomepizole use. Regression modeling indicated increased odds for death (OR&#x2009;=&#x2009;5.88, aOR&#x2009;=&#x2009;5.32 [95% CI: 4.52, 6.27]) among those who received fomepizole in addition to NAC, indicating increased fomepizole use in patients with severe toxicity.<br><br>CONCLUSION: Fomepizole use in acetaminophen poisoning has risen dramatically since 2019, particularly among patients at highest risk for death and liver transplantation. It is of critical importance to determine the efficacy of fomepizole for acetaminophen poisoning.},
}
@article {pmid40744504,
year = {2025},
author = {Güvenç, G and Erdoğan-Öner, A and Kavak, G and Akyol Bahçeci, S and Kutlu, O},
title = {Effects of N-Acetylcysteine and l-Carnitine on Wound Healing of Palatal Mucosa in a Rat Model.},
journal = {Journal of oral pathology &amp; medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology},
volume = {54},
number = {8},
pages = {667-675},
doi = {10.1111/jop.70018},
pmid = {40744504},
issn = {1600-0714},
support = {2023-TDU-D&#x130;&#x15e;F-0006//&#x130;zmir Katip &#xc7;elebi University Scientific Research Projects Coordinatorship/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Wound Healing/drug effects ; Rats, Wistar ; *Carnitine/pharmacology ; Rats ; *Mouth Mucosa/drug effects/pathology/injuries ; Male ; *Antioxidants/pharmacology ; Fibroblast Growth Factor 2/metabolism ; Actins/metabolism ; Collagen ; *Palate, Hard/drug effects/pathology ; Disease Models, Animal ; Re-Epithelialization/drug effects ; },
abstract = {BACKGROUND: Surgical procedures in oral and maxillofacial surgery inevitably cause wound formation, making the patient vulnerable to infections as well as discomfort. As antioxidant agents exert great potential to accelerate wound healing, we investigated the effects of N-acetylcysteine (NAC) and l-carnitine (LC) on palatal wound healing.<br><br>METHODS: Sixty-four Wistar rats were randomly divided into four groups. 5&#x2009;mm diameter wounds were created in the hard palates of the rats. 150&#x2009;mg/kg/day NAC, 100&#x2009;mg/kg/day LC, or both were injected intraperitoneally to the treatment groups until sacrification on Day 5 or 10. Hematoxylin and eosin, Masson's Trichrome staining, and immunohistochemistry (&#x3b1;-SMA, FGF-2) were performed on wound tissues.<br><br>RESULTS: On Days 5 and 10, reepithelialization was incomplete and inflammation was observed in all groups. Collagen density tended to increase in the LC and NAC&#x2009;+&#x2009;LC groups on Day 5, and significantly differed between the LC and NAC groups on day 10. A slight elevation in &#x3b1;-SMA expression was observed in the NAC group on Day 5, while NAC&#x2009;+&#x2009;LC treatment significantly reduced &#x3b1;-SMA levels compared to NAC alone. FGF-2 expression showed an increasing trend in the NAC&#x2009;+&#x2009;LC group on Day 5 and in the NAC and LC groups on Day 10. A significant increase in FGF-2 was observed in the NAC&#x2009;+&#x2009;LC group versus the NAC group on Day 5, and within the NAC group between Days 5 and 10.<br><br>CONCLUSION: Our findings have shown that LC in the late stage and NAC&#x2009;+&#x2009;LC combination in the early stage may positively affect palatal wound healing.},
}
@article {pmid40744390,
year = {2025},
author = {Tang, D and Xu, C and Jiang, Z and Meng, Z and Zhang, M and Fan, F and Liu, H},
title = {OTSSP167 suppresses TNBC brain metastasis via ROS-driven P38/JNK and FAK/ERK pathways.},
journal = {European journal of pharmacology},
volume = {1004},
number = {},
pages = {178017},
doi = {10.1016/j.ejphar.2025.178017},
pmid = {40744390},
issn = {1879-0712},
mesh = {*Reactive Oxygen Species/metabolism ; Animals ; Humans ; *Brain Neoplasms/secondary/drug therapy/metabolism ; *Triple Negative Breast Neoplasms/pathology/drug therapy/metabolism ; Cell Line, Tumor ; Mice ; Cell Proliferation/drug effects ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *MAP Kinase Signaling System/drug effects ; Female ; *Focal Adhesion Kinase 1/metabolism ; Apoptosis/drug effects ; Cell Movement/drug effects ; Xenograft Model Antitumor Assays ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Antineoplastic Agents/pharmacology/therapeutic use ; },
abstract = {The treatment of brain metastasis (BM) in triple negative breast cancer (TNBC) has long been an unavoidable dilemma. Our research mainly explored the effect and mechanism of OTSSP167, a selective MELK inhibitor, against TNBC BM. Through experiments, we verified that OTSSP167 suppresses TNBC cell proliferation, migration, and invasion while inducing apoptosis and G1-phase cell cycle arrest. Mechanistically, OTSSP167 triggers mitochondrial reactive oxygen species (ROS) overproduction, which bifurcates into dual signaling modulation: activating the p38 mitogen-activated protein kinase (P38)/c-Jun N-terminal kinase (JNK) stress-response pathways and inhibiting the focal adhesion kinase (FAK)/extracellular regulated protein kinases (ERK) pro-metastatic axis. ROS scavenging via N-acetylcysteine (NAC) reverses these effects, confirming ROS as the central mediator of antitumor activity of OTSSP167. In murine xenograft models, OTSSP167 administration inhibits primary tumor growth and BM without inducing hepatorenal toxicity. Notably, its efficacy in a brain-tropic metastasis model highlights that it can easily cross the blood-brain barrier (BBB) and reach the tumor site to kill tumor cells. These findings unveil a redox-centric mechanism by which OTSSP167 disrupts TNBC progression, positioning it as a promising therapeutic candidate for combating TNBC BM. The study underscores the translational relevance of targeting MELK and ROS-dependent kinase networks to address unmet clinical needs in TNBC management.},
}
@article {pmid40736078,
year = {2025},
author = {Raji, P and Seyedalipour, B and Yaqubi, S and Hosseini, SM and Hajizadeh Moghaddam, A},
title = {Mitigation of fenvalerate-induced oxidative stress in the liver and brain by garlic extract and N-acetylcysteine in rats: a biochemical and histopathological study.},
journal = {International journal of environmental health research},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/09603123.2025.2540472},
pmid = {40736078},
issn = {1369-1619},
abstract = {Fenvalerate (Fen), a pyrethroid pesticide, is widely used to control various pests. This study aimed to investigate the effects of garlic extract (GE) and N-acetylcysteine (NAC) on antioxidant enzyme activities and histopathological changes in the liver and brain tissues of rats exposed to Fen. Forty-two Wistar rats were divided into seven groups: Control, Sham, Fen (10 mg/kg), NAC (80 mg/kg), Fen+GE, Fen+NAC, and Fen+GE+NAC. Treatments were administered intraperitoneally. Results showed significant biochemical differences among groups (P<0.01). Fen exposure caused hepatic damage, including inflammatory cell infiltration and congestion, as well as brain injuries such as hyperemia, necrosis, and gliosis. Co-administration of NAC and GE mitigated Fen-induced damage, aligning with biochemical findings. Malondialdehyde (MDA), total antioxidant capacity (TAC), and glutathione (GSH) levels, along with Glutathione-S-transferase (GST) and catalase (CAT) activities, significantly increased in the Fen group compared to controls (P<0.01). NAC and GE, alone or combined, significantly reduced Fen's toxic effects (P<0.05). The study highlights the hepatoprotective and antioxidant roles of NAC and GE against Fen toxicity, suggesting their potential as natural therapeutic agents to counteract pesticide-induced damage, thereby contributing to human and environmental health protection.},
}
@article {pmid40732359,
year = {2025},
author = {Fereig, SA and Youshia, J and El-Zaafarany, GM and Arafa, MG and Abdel-Mottaleb, MMA},
title = {Chitosan Nanoparticles for Topical Drug Delivery in Chemotherapy-Induced Alopecia: A Comparative Study of Five Repurposed Pharmacological Agents.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {7},
pages = {},
pmid = {40732359},
issn = {1424-8247},
abstract = {Background/Objectives: Chemotherapy-induced alopecia is a common and distressing side effect of cancer treatment, significantly impacting patients' psychological well-being. Nanocarriers offer a promising strategy for targeted drug delivery to hair follicles, while chitosan nanoparticles have demonstrated hair-growth-promoting properties. This study explores the potential of chitosan nanoparticles as a topical delivery system for five pharmacological agents-phenobarbital, pioglitazone, rifampicin, N-acetylcysteine, and tacrolimus-to prevent chemotherapy-induced alopecia. Methods: Drug-loaded chitosan nanoparticles were prepared using the ionic gelation technique and characterized by particle size, zeta potential, entrapment efficiency, FT-IR spectroscopy, and TEM imaging. Their efficacy was assessed in a cyclophosphamide-induced alopecia model in C57BL/6 mice through macroscopic observation, histopathological examination, and scanning electron microscopy of regrown hair. Results: The prepared particles were spherical, cationic, and between 205 and 536 nm in size. The entrapment efficiencies ranged from 8% to 63%. All five drugs mitigated follicular dystrophy, shifting the hair follicle response from dystrophic catagen to dystrophic anagen. Phenobarbital demonstrated the most significant hair regrowth and quality improvements, followed by N-acetyl cysteine and pioglitazone. Tacrolimus showed moderate efficacy, while rifampicin was the least effective. Conclusions: These findings suggest that phenobarbital-loaded chitosan nanoparticles represent a promising approach for the prevention and treatment of chemotherapy-induced alopecia, warranting further investigation for clinical applications.},
}
@article {pmid40732302,
year = {2025},
author = {Zaobornyj, T and Perez, V and Ossani, G and Mazo, T and Godoy, E and Godoy, J and Yanaje, Y and Musci-Ferrari, C and Contin, M and Tripodi, V and Barchuk, M and Berg, G and Gelpi, RJ and Donato, M and D'Annunzio, V},
title = {N-Acetylcysteine Treatment Restores the Protective Effect of Heart Ischemic Postconditioning in a Murine Model in the Early Stages of Atherosclerosis.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {7},
pages = {},
pmid = {40732302},
issn = {1424-8247},
abstract = {Background/Objectives: Ischemic postconditioning (IP) is a well-established intervention that mitigates this damage by activating endogenous cardioprotective pathways. However, the presence of comorbidities such as dyslipidemia can disrupt these protective mechanisms and abolish the infarct-sparing effect typically induced by IP. In this context, identifying pharmacological strategies to restore cardioprotection is of clinical relevance. This study aimed to evaluate whether N-acetylcysteine (NAC), a glutathione precursor with antioxidant properties, can restore the infarct-limiting effect of IP compromised by HFD-induced oxidative stress. Methods: Male mice were fed a control diet (CD) or HFD for 12 weeks. NAC (10 mM) was administered in drinking water for 3 weeks before ex vivo myocardial ischemia/reperfusion (I/R) injury (30 min ischemia/60 min reperfusion). In IP groups, six cycles of brief I/R were applied at the onset of reperfusion. Infarct size, ventricular function, redox status (GSH/GSSG), lipid profile, and histology were evaluated. Results: NAC improved the lipid profile (HDL/non-HDL ratio) and enhanced the infarct-sparing effect of IP in CD-fed mice. In HFD-fed mice, NAC restored the efficacy of IP, significantly reducing infarct size (HFD-I/R-NAC: 39.7 ± 4.5% vs. HFD-IP-NAC: 26.4 ± 2.0%, p < 0.05) without changes in ventricular function. The ratio of oxidized/reduced glutathione (GSSG/GSH) is depicted. Under basal conditions, the hearts of mice fed an HFD exhibited a shift towards a more oxidized state compared to the control diet CD group. In the I/R protocol, a significant shift towards a more oxidized state was observed in both CD and HFD-fed animals. In the IP protocol, the GSSG/GSH ratio revealed a tendency to basal values in comparison to the I/R protocol. The analysis indicates that animals subjected to I/R and IP protocols in conjunction with NAC show a tendency to reach basal values, thus suggesting a potential for the reduction in ROS. Conclusions: NAC treatment mitigates oxidative stress and restores the cardioprotective effect of ischemic postconditioning in a model of early-stage atherosclerosis. These findings support NAC as a potential adjunct therapy to improve myocardial resistance to reperfusion injury under dyslipidemic conditions.},
}
@article {pmid40729925,
year = {2026},
author = {Liu, L and Ren, S and Hao, Y and Yue, L and Yue, C and Li, L and Zhang, W and Gao, Z and Hai, X},
title = {Development and validation of a sensitive assay for analysis of D/L-serine in cells using ultra-high performance liquid chromatography-fluorescence detector.},
journal = {Talanta},
volume = {297},
number = {Pt A},
pages = {128634},
doi = {10.1016/j.talanta.2025.128634},
pmid = {40729925},
issn = {1873-3573},
mesh = {*Chromatography, High Pressure Liquid/methods ; o-Phthalaldehyde/chemistry ; Stereoisomerism ; Humans ; Animals ; Acetylcysteine/chemistry ; Spectrometry, Fluorescence/methods ; },
abstract = {The aim of this study was to establish a simple, sensitive, and robust ultra-high performance liquid chromatography coupled with fluorescence detection method (UPLC-FLD) for the determination of chiral D/L-serine in cells. D/L-serine in cells were derivatizated by o-phthalaldehyde (OPA) and N-acetyl-L-cysteine (NAC). Carbocisteine was selected as the internal standard. The derivatives were separated on a C18 column by gradient elution. The excitation and emission wavelengths for fluorescence determination are 340 nm and 450 nm, respectively. The retention time of D-serine and L-serine was 23.3 and 23.9 min respectively, which presented a perfect separation. The accuracy of D-serine and L-serine were ranged from 96.46 % to 109.63 % and 95.50 %-102.20 %, respectively. The precision of D-serine and L-serine were ranged from 4.34 % to 14.56 % and 3.56 %-13.73 %. The limit of quantitation of D-serine and L-serine were 0.1 nmol/mL. The concentration of D/L-serine varies in different cell lines. This method can satisfy the determination of D/L-serine in astrocytes and other cells, which can be used for the study of D/L-serine metabolism and related mechanisms. In short, we have established a simple, stable, reliable and robust method for the determination of D/L-serine in cells. In addition, the D/L-serine levels in different cells were quantified in this study, which can provide a reference for the study of D/L-serine metabolism in cells.},
}
@article {pmid40729908,
year = {2025},
author = {Zhao, Y and Niu, Y and Wang, X and Wan, P and Ma, Z and Sun, J and Jiang, S and Xue, L and Liu, N},
title = {N-Acetyl-L-Cysteine modulates indium-tin oxide nanoparticles-caused interstitial lung diseases in male rats through oxidative stress-activated apoptosis and autophagy.},
journal = {Ecotoxicology and environmental safety},
volume = {302},
number = {},
pages = {118716},
doi = {10.1016/j.ecoenv.2025.118716},
pmid = {40729908},
issn = {1090-2414},
mesh = {Animals ; Male ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Rats, Sprague-Dawley ; Autophagy/drug effects ; *Acetylcysteine/pharmacology ; *Tin Compounds/toxicity ; Rats ; *Lung Diseases, Interstitial/chemically induced/drug therapy ; *Metal Nanoparticles/toxicity ; Lung/drug effects ; },
abstract = {Indium-tin oxide nanoparticles (Nano-ITO) are widely used in various applications as infrared shielding materials, which increase the risk of occupational exposure. According to reports, Nano-ITO can cause indium lung disease in occupational exposed workers, but the specific mechanism of Nano-ITO-induced pulmonary toxicity remains unclear. In this study, 50 8-week-old male Sprague-Dawley rats were divided into five groups (10 rats in each group) as follows: control group (physiological saline), 1.2 mg/kg Nano-ITO group, 6 mg/kg Nano-ITO group, N-Acetyl-L-Cysteine (NAC) control group (200 mg/kg), and NAC + Nano-ITO group (200 mg/kg NAC intraperitoneal injection, after 1.5 h, 6 mg/kg Nano-ITO intratracheal instillation), twice a week for 12 weeks. Pathological and ultrastructural changes in the rat lung tissue, immunofluorescence assays, immunohistochemistry, protein and mRNA levels of apoptosis- and autophagy-related genes were measured. The levels of ROS, MDA, H2O2, and LDH, and the activities of T-AOC and SOD, were determined using oxidative stress assay kits. The results showed that Nano-ITO caused strong pulmonary inflammation, pulmonary alveolar proteinosis, and pulmonary interstitial fibrosis. In addition, Nano-ITO-induced oxidative stress in rat lungs presented as increased levels of ROS and H2O2 in the lungs, increased LDH and MDA levels, SOD and T-AOC activity in BALF, and activation of the Nrf2/NQO1/HO-1 signaling pathway. Intriguingly, Nano-ITO significantly increased the protein expression of microtubule-associated protein light chain 3 (LC3-II), the protein levels of autophagy-related genes 5 (ATG5), and Beclin-1 (BECN1), and reduced the protein levels of phosphatidylinositol 3-kinase (PI3K) in lung tissues. In addition, transmission electron microscopy (TEM) showed a significant increase in autophagic vesicles in the cytoplasm of lungs treated with Nano-ITO, indicating that Nano-ITO induces autophagy in rat lungs. Moreover, apoptosis also participates in Nano-ITO-induced pulmonary injury in a synchronous manner, as evidenced by the enhancement of TUNEL-positive signals and activation of the apoptosis pathway (Bax and Bcl-2 positive proportions). NAC supplementation restored most of the pathological structural features of rat lung tissue to their physiological range and effectively weakened apoptosis, as demonstrated by the notable reductions in TUNEL, Bax, and Bcl-2 protein expression levels in the lungs. Although autophagy was detected in the lungs of rats in the Nano-ITO and NAC + Nano-ITO groups, we discovered that NAC could rescue the expression of ATG5 and BECN1 induced by Nano-ITO, thus indicating that exposure to Nano-ITO promotes pulmonary apoptosis and autophagy by mediating oxidative stress. These results indicate that Nano-ITO can cause pulmonary injury by inducing oxidative stress, which activates apoptosis and autophagy, ultimately leading to alveolar proteinosis and interstitial fibrosis.},
}
@article {pmid40729015,
year = {2025},
author = {Yuan, F and Qiao, Y and Chen, Z and He, H and Wang, F and Chen, J},
title = {Molecular Mechanisms of Lobelia nummularia Extract in Breast Cancer: Targeting EGFR/TP53 and PI3K-AKT-mTOR Signaling via ROS-Mediated Apoptosis.},
journal = {Current issues in molecular biology},
volume = {47},
number = {7},
pages = {},
pmid = {40729015},
issn = {1467-3045},
support = {ZY2023F143//Chinese Medicine Research Project of the Hubei Provincial Administration of Chinese Medicine/ ; },
abstract = {Lobelia nummularia Lam. is a traditional medicinal herb of which the anticancer mechanisms remain largely unexplored. Here, we demonstrated that its ethanolic extract (LNE) exerts potent anti-breast cancer activity by inducing ROS-dependent mitochondrial apoptosis in MDA-MB-231 cells, a mechanism confirmed via rescue experiments with the antioxidant N-acetylcysteine (NAC). This pro-apoptotic program is driven by a dual mechanism: potent suppression of the pro-survival EGFR/PI3K/AKT signaling pathway and simultaneous activation of the TP53-mediated apoptotic cascade, culminating in the cleavage of executor caspase-3. Phytochemical analysis identified numerous flavonoids, and quantitative HPLC confirmed that key bioactive compounds, including luteolin and apigenin, are substantially present in the extract. These mechanisms translated to significant in vivo efficacy, where LNE administration suppressed primary tumor growth and lung metastasis in a 4T1 orthotopic model in BALB/c mice. Furthermore, a validated molecular docking protocol provided a plausible structural basis for these multi-target interactions. Collectively, this study provides a comprehensive, multi-layered validation of LNE's therapeutic potential, establishing it as a mechanistically well-defined candidate for natural product-based anticancer drug discovery.},
}
@article {pmid40728675,
year = {2025},
author = {Kow, CS and Ramachandram, DS and Hasan, SS and Thiruchelvam, K},
title = {Effect of N-Acetylcysteine on mortality in COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.},
journal = {Inflammopharmacology},
volume = {33},
number = {8},
pages = {4871-4877},
pmid = {40728675},
issn = {1568-5608},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; Randomized Controlled Trials as Topic/methods ; *COVID-19 Drug Treatment ; *COVID-19/mortality ; },
abstract = {INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has prompted global interest in potential adjunctive therapies. N-acetylcysteine (NAC), a mucolytic agent that enhances intracellular glutathione synthesis, has antioxidant properties and may indirectly modulate inflammation through redox regulation. While preclinical and observational data suggest potential mortality benefits, findings from randomized controlled trials (RCTs) have been inconsistent.<br><br>OBJECTIVE: To systematically review and synthesize the evidence from RCTs evaluating the effect of NAC on mortality in patients with COVID-19.<br><br>METHODS: This systematic review and meta-analysis was conducted according to PRISMA guidelines. Six databases were searched from inception to March 21, 2025. Eligible studies were RCTs comparing NAC to placebo or standard care in adult COVID-19 patients, with mortality as a reported outcome. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane RoB 2 tool. Statistical analyses were performed with a random-effects model to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs).<br><br>RESULTS: Ten RCTs comprising 1,424 patients were included. NAC regimens varied by dose and route. The pooled OR for mortality was 0.49 (95% CI: 0.25-0.94; I[2]&#x2009;=&#x2009;67%), indicating a 51% reduction in the odds of death among patients receiving NAC. Seven studies had low risk of bias; three had some concerns, primarily due to open-label designs.<br><br>CONCLUSION: NAC may reduce mortality in COVID-19 patients, particularly when administered at higher doses or via non-oral routes. Further large-scale RCTs are needed to confirm these findings and establish optimal dosing and administration strategies.},
}
@article {pmid40726828,
year = {2025},
author = {Manoharan, A and Whiteley, G and Kuppusamy, R and Jensen, S and Glasbey, T and Chen, Z and Moshkanbaryans, L and Moore, KH and Das, T and Manos, J},
title = {Combating biofilm formation and bacterial killing: N-acetylcysteine's efficacy against Pseudomonas aeruginosa in urinary catheters.},
journal = {Biofilm},
volume = {10},
number = {},
pages = {100296},
pmid = {40726828},
issn = {2590-2075},
abstract = {Uropathogenic Pseudomonas aeruginosa is a significant contributor to catheter-associated urinary tract infections (CA-UTIs), distinguished by its unique biofilm-forming properties compared to other strains. Despite its clinical significance, optimized strategies for biofilm eradication in the bladder and on catheters remain limited. Thus, the aim of this study was to highlight the potent antibacterial and biofilm-inhibitory effects of N-acetyl cysteine (NAC) against uropathogenic P. aeruginosa. Additionally, we sought to investigate its effect against catheter obstruction caused by P. aeruginosa in a patient, and whether this phenomenon can be replicated in vitro to underscore the urgency of addressing this critical challenge. We demonstrated that uropathogenic P. aeruginosa form thick, mucoid biofilms in vitro that can heavily occlude catheters, with bacterial titres of between 10[8] and 10[11] CFU/cm, thus impairing catheter functionality. Furthermore, treatment with NAC significantly reduced viable bacteria by > 4log10 (p < 0.01), and inhibited biofilm formation and associated obstruction till experiment endpoint (96h). NAC also displayed significant bactericidal activity (p < 0.001) against P. aeruginosa and significantly impeded bacterial attachment and aggregation through modulation of colloidal forces and change in the structure of the bacterial cell surface, thus impairing the bacterium's ability to initiate biofilm development. Mechanistically, NAC alters the bacterial surface structure, disrupting biofilm-associated virulence. Hence our study found that NAC treatment physically disrupts uropathogenic P. aeruginosa biofilms and significantly alters its virulence. Our novel findings highlight the dual bactericidal and anti-biofilm properties of NAC in vitro, offering valuable insights into its potential application for preventing P. aeruginosa biofilm formation and catheter blockage in CA-UTI management.},
}
@article {pmid40724969,
year = {2025},
author = {Hsieh, CY and Lin, JN and Chou, YF and Hsu, CJ and Chen, PR and Wen, YH and Wu, CC and Sun, CH},
title = {Molecular Mechanisms of Aminoglycoside-Induced Ototoxicity in Murine Auditory Cells: Implications for Otoprotective Drug Development.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
pmid = {40724969},
issn = {1422-0067},
support = {TTCRD 113-04//Buddhist Tzu Chi Medical Foundation/ ; NSTC-113-2314-B-303-005//Minister of Science and Technology in Taiwan/ ; },
mesh = {Animals ; Mice ; *Ototoxicity/metabolism/etiology/prevention &amp; control/pathology ; *Aminoglycosides/adverse effects/toxicity ; Proto-Oncogene Proteins c-akt/metabolism ; Endoplasmic Reticulum Chaperone BiP ; *Hair Cells, Auditory/drug effects/metabolism/pathology ; Gentamicins/toxicity ; Cell Line ; Signal Transduction/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Endoplasmic Reticulum Stress/drug effects ; *Anti-Bacterial Agents/adverse effects ; *Protective Agents/pharmacology ; },
abstract = {Aminoglycoside antibiotics are critical in clinical use for treating severe infections, but they can occasionally cause irreversible sensorineural hearing loss. To establish a rational pathway for otoprotectant discovery, we provide an integrated, three-tier methodology-comprising cell-model selection, transcriptomic analysis, and a gentamicin-Texas Red (GTTR) uptake assay-to guide the development of otoprotective strategies. We first utilized two murine auditory cell lines-UB/OC-2 and HEI-OC1. We focused on TMC1 and OCT2 and further explored the underlying mechanisms of ototoxicity. UB/OC-2 exhibited a higher sensitivity to gentamicin, which correlated with elevated OCT2 expression confirmed via RT-PCR and Western blot. Transcriptomic analysis revealed upregulation of PI3K-Akt, calcium, and GPCR-related stress pathways in gentamicin-treated HEI-OC1 cells. Protein-level analysis further confirmed that gentamicin suppressed phosphorylated Akt while upregulating ER stress markers (GRP78, CHOP) and apoptotic proteins (cleaved caspase 3, PARP). Co-treatment with PI3K inhibitors (LY294002, wortmannin) further suppressed Akt phosphorylation, supporting the role of PI3K-Akt signaling in auditory cells. To visualize drug entry, we used GTTR to evaluate its applicability as a fluorescence-based uptake assay in these cell lines, which were previously employed mainly in cochlear explants. Sodium thiosulfate (STS) and N-acetylcysteine (NAC) significantly decreased GTTR uptake, suggesting a protective effect against gentamicin-induced hair cell damage. In conclusion, our findings showed a complex ototoxic cascade involving OCT2- and TMC1-mediated drug uptake, calcium imbalance, ER stress, and disruption of PI3K-Akt survival signaling. We believe that UB/OC-2 cells serve as a practical in vitro model for mechanistic investigations and screening of otoprotective compounds. Additionally, GTTR may be a simple, effective method for evaluating protective interventions in auditory cell lines. Overall, this study provides molecular-level insights into aminoglycoside-induced ototoxicity and introduces a platform for protective strategies.},
}
@article {pmid40724874,
year = {2025},
author = {Duensing, HM and Dixon, JM and Hunter, OR and Graves, NC and Smith, NC and Tomes, AJ and Fahrenholtz, CD},
title = {Preclinical Evaluation of Repurposed Antimalarial Artemisinins for the Treatment of Malignant Peripheral Nerve Sheath Tumors.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
pmid = {40724874},
issn = {1422-0067},
support = {2024-FLG-0073//North Carolina Biotechnology Center/ ; n/a//High Point University Natural Science Fellows Supply Grant/ ; },
mesh = {*Artemisinins/pharmacology/therapeutic use ; *Antimalarials/pharmacology/therapeutic use ; Humans ; Oxidative Stress/drug effects ; Cell Line, Tumor ; *Drug Repositioning ; Artesunate/pharmacology ; Schwann Cells/drug effects/metabolism ; Animals ; *Nerve Sheath Neoplasms/drug therapy/metabolism/pathology ; Lipid Peroxidation/drug effects ; },
abstract = {Malignant peripheral nerve sheath tumors (MPNSTs) are a rare type of soft tissue sarcoma associated with poor prognoses. The standard of care for non-resectable tumors consists of surgical excision followed by radiation and chemotherapy. MPNSTs are most common in patients with neurofibromatosis type 1 but can also occur sporadically. Regardless of origin, MPNSTs most often rely on signaling pathways that increase basal oxidative stress. This provides the basis for developing therapeutics with mechanisms that can potentiate oxidative stress to selectively eradicate tumor cells at doses that are tolerable for normal cells. Artemisinin derivatives are a mainstay of malaria therapy worldwide, with a well-established safety profile. Artemisinin's antimalarial effects are due to an endoperoxide bridge in its chemical structure that induces oxidative stress. We found that artesunate (ARS) and metabolite dihydroartemisinin (DHA) are selectively cytotoxic to MPNST cells relative to normal Schwann cells with the endoperoxide bridge required for activity. Mechanistically, DHA induced oxidative stress, lipid peroxidation, and DHA-mediated cytotoxicity could be prevented with co-administration of the antioxidant N-acetyl-cysteine. Furthermore, we found that DHA was able to selectively remove MPNST from co-culture with normal Schwann cells. These data supports the further development of artemisinins for the clinical management of MPNST.},
}
@article {pmid40723450,
year = {2025},
author = {Deshetty, UM and Oladapo, A and Mohankumar, Y and Horanieh, E and Buch, S and Periyasamy, P},
title = {Protective Effects of N-Acetylcysteine in Alleviating Cocaine-Mediated Microglial Activation and Neuroinflammation.},
journal = {Biology},
volume = {14},
number = {7},
pages = {},
pmid = {40723450},
issn = {2079-7737},
support = {P20GM130461 (Pilot)/GM/NIGMS NIH HHS/United States ; },
abstract = {Cocaine misuse induces microglial activation and neuroinflammation, contributing to neurodegeneration and behavioral impairments. Prior studies have shown that cocaine induces mitochondrial dysfunction, dysregulated mitophagy, and lysosomal impairment in microglia. Here, we investigated the therapeutic potential of N-acetylcysteine (NAC) in mitigating cocaine-induced microglial activation and neuroinflammation. Mouse primary microglial cells (MPMs) were pretreated with NAC (5 mM) for 1 h prior to cocaine exposure (10 µM, 24 h) and analyzed for markers of microglial activation, mitophagy, and lysosomal integrity using Western blot, Seahorse assays, lysosomal pH, and membrane potential measurements. In vivo, C57BL/6N mice received NAC (200 mg/kg, i.p.) 1 h before daily cocaine injections (20 mg/kg, i.p.) for 7 days. Behavioral assays (open field, novel object recognition) and brain biomarker analyses (frontal cortex, hippocampus) were performed. Cocaine exposure elevated CD11b, mitophagy markers (PINK1, PARK, and DLP1), and autophagy proteins (Beclin1, and p62), while impairing mitochondrial and lysosomal functions. NAC pretreatment restored mitochondrial and lysosomal function, reduced reactive oxygen species, and normalized protein expression. In vivo, NAC also alleviated cocaine-induced microglial activation and behavioral deficits. These findings highlight NAC as a promising therapeutic agent to counteract cocaine-mediated neuroinflammation and neurotoxicity.},
}
@article {pmid40722964,
year = {2025},
author = {Zhao, J and Zhao, Y and Song, S and Zhang, S and Yang, G and Qiu, Y and Tian, W},
title = {Gallic Acid Alleviates Acetaminophen-Induced Acute Liver Injury by Regulating Inflammatory and Oxidative Stress Signaling Proteins.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {7},
pages = {},
pmid = {40722964},
issn = {2076-3921},
support = {24A230003//Key R&amp;D Projects of Henan Provincial Colleges and Universities/ ; 252300420175//Natural Science Foundation of Henan Province/ ; 252102111024//Henan Provincial Key R&amp;D and Promotion Program/ ; },
abstract = {Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury (DILI) globally, which necessitates effective therapies. Gallic acid (GA), a naturally abundant polyphenol, possesses potent antioxidant and anti-inflammatory properties that may overcome the limitations of N-acetylcysteine (NAC), such as its narrow therapeutic window. This study systematically investigated the hepatoprotective effects and underlying molecular mechanisms of GA against APAP-induced acute liver injury (ALI). Mice received an intraperitoneal injection of APAP (300 mg/kg), followed by an oral administration of GA (50 or 100 mg/kg) or NAC (150 mg/kg) 1 h post-intoxication. Both GA and NAC significantly ameliorated hypertrophy and histopathological damage, as evidenced by reduced serum ALT/AST levels and inflammatory cytokines. TUNEL staining revealed a marked suppression of apoptotic and necrotic cell death, further supported by the downregulation of pro-apoptotic Bax and the upregulation of anti-apoptotic Bcl-2 mRNA expression. GA and NAC treatment restored hepatic glutathione (GSH) content, enhanced antioxidant enzyme gene expression, and reduced malondialdehyde (MDA) accumulation. Mechanistically, GA and NAC inhibited MAPK phosphorylation while activating AMPK signaling. Taken together, these findings demonstrate that GA mitigates APAP-induced ALI by modulating oxidative stress and inflammation through the regulation of MAPK/AMPK signaling proteins.},
}
@article {pmid40722832,
year = {2025},
author = {Rarinca, V and Gurzu, IL and Nicoara, MN and Ciobica, A and Visternicu, M and Ionescu, C and Balmus, IM and Plavan, GI and Todirascu-Ciornea, E and Gurzu, B},
title = {Neurobehavioral and Oxidative Stress Effects of SiO2 Nanoparticles in Zebrafish and the Protective Role of N-Acetylcysteine.},
journal = {Biomedicines},
volume = {13},
number = {7},
pages = {},
pmid = {40722832},
issn = {2227-9059},
abstract = {Background/Objectives: Silicon dioxide nanoparticles (SiO2NPs) do not exist in isolation in the environment but can interact with other substances, thus influencing their toxic effects on aquatic organisms. We assessed the combined impact of SiO2NPs and N-acetylcysteine (NAC), an antioxidant with the potential to counteract nanoparticle-induced oxidative stress (OS). Methods: Behavioral assessments, including the social interaction test and color preference test, were performed to evaluate neurobehavioral changes. OS biomarkers, including malondialdehyde (MDA) levels for lipid peroxidation and the activity of key antioxidant enzymes such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), were assessed to evaluate the extent of cellular damage. Results: The results indicate that prolonged exposure to SiO2NPs induces significant behavioral disruptions, including reduced exploratory behavior and increased anxiety-like responses. Furthermore, biochemical analysis revealed increased OS, suggesting nanoparticle-induced cellular toxicity. NAC co-treatment partially reversed these effects, particularly improving locomotor outcomes and antioxidant response, but was less effective on social behavior. Conclusions: These findings highlight the ecological and health risks posed by SiO2NPs and point toward the need for further toxicological studies on their long-term biological effects.},
}
@article {pmid40716720,
year = {2025},
author = {Gao, J and Liu, X and Wang, B and Huang, Y and Chen, R and Yuan, W and Luo, Q and Lu, H and Tian, G},
title = {Acute toxicity effects of rice paddy bactericide bismerthiazol on zebrafish (Danio rerio) embryos.},
journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP},
volume = {297},
number = {},
pages = {110303},
doi = {10.1016/j.cbpc.2025.110303},
pmid = {40716720},
issn = {1532-0456},
mesh = {Animals ; *Zebrafish/embryology ; *Embryo, Nonmammalian/drug effects/metabolism ; *Water Pollutants, Chemical/toxicity ; Oxidative Stress/drug effects ; *Anti-Bacterial Agents/toxicity ; Reactive Oxygen Species/metabolism ; *Thiazoles/toxicity ; Oryza ; Toxicity Tests, Acute ; Notochord/drug effects ; },
abstract = {Bismerthiazol is an extensively utilized agricultural bactericide in paddy fields. However, its toxicity to aquatic animals remains poorly understood. Through acute exposure of zebrafish (Danio rerio) embryos, we determined that the 72 h half-lethal concentration (LC50) of bismerthiazol was 7.38 mg/L, and 3 mg/L bismerthiazol induced systemic developmental abnormalities. Further studies showed that low concentrations (25 ng/L, 50 ng/L) of bismerthiazol selectively impaired notochord and muscle development in embryos and reduced their motility. Additionally, bismerthiazol exposure upregulated the Sonic hedgehog (SHH) signaling pathway and myogenic gene expression. It also increased reactive oxygen species (ROS) levels while decreasing the enzymatic activity of catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD). Notably, the antioxidant N-acetylcysteine (NAC) rescued the bismerthiazol-induced notochord and muscle defects. In summary, our findings demonstrate that acute bismerthiazol exposure causes developmental toxicity in aquatic organisms by inducing oxidative stress, highlighting its potential ecological risk.},
}
@article {pmid40715197,
year = {2025},
author = {Ben Ali, C and Morel, A and Morvan, M and Moktefi, A and Nguyen-Peyre, KA and Van Wynsberghe, M and Sakhi, H and Bartolucci, P and Audard, V and Hénique, C},
title = {Podocyte dysfunction driven by heme in sickle-cell nephropathy.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {27136},
pmid = {40715197},
issn = {2045-2322},
mesh = {Humans ; *Podocytes/metabolism/pathology/drug effects ; *Anemia, Sickle Cell/complications/metabolism/pathology ; *Heme/metabolism ; Oxidative Stress/drug effects ; Heme Oxygenase-1/metabolism ; Apoptosis/drug effects ; Glomerulosclerosis, Focal Segmental/pathology/metabolism/etiology ; Male ; NF-kappa B/metabolism ; Female ; Cell Line ; Hemin/pharmacology ; DNA Damage ; Adult ; },
abstract = {Sickle-cell disease (SCD) is characterized by vaso-occlusive crises and chronic hemolytic anemia, leading to tissue damage affecting various organs, including the kidneys. Hemolysis contributes to sickle-cell nephropathy (SCN) but the molecular mechanisms underlying the intravascular hemolysis and heme release involved in podocyte damage leading to proteinuria and chronic kidney disease remain uncertain. This study explored the impact of heme on podocyte function by exposing human podocytes cell line to hemin (5 μM hemin for 4 and 24 h), with or without the antioxidant N-acetyl cysteine (NAC). We then assessed the relevance of in vitro studies on renal biopsy specimens from controls with primary and secondary forms of focal segmental glomerulosclerosis (FSGS) and patients with SCD-related FSGS. After 4 h of hemin exposure, podocyte cytoskeleton alterations and increased apoptosis were observed. At 24 h, heme oxygenase-1 (HO-1) expression increased, alongside oxidative stress, DNA damage, and mitochondrial and endoplasmic reticulum dysfunctions. NF-κB pathway activation suggested an adaptive response. NAC partially reduced these effects, indicating oxidative stress's central role while implicating additional mechanisms in apoptosis induction. Renal biopsies from patients with focal segmental glomerulosclerosis (FSGS), including SCD-related cases, showed elevated HO-1 and BiP in podocytes compared to normal glomeruli, along with reduced synaptopodin, indicating damage. In conclusion, this study highlights the molecular mechanisms underlying heme-induced podocyte damage in SCN. Oxidative stress appears to play a key role, but other pathological pathways are also involved. These results open up new perspectives for understanding and treating SCN.},
}
@article {pmid40712831,
year = {2025},
author = {Mavraganis, G and Sakelliou, A and Georgiopoulos, G and Delialis, D and Papaioannou, M and Maneta, E and Angelidakis, L and Zervas, G and Poulios, A and Papanikolaou, K and Draganidis, D and Chatzinikolaou, A and Jamurtas, AZ and Stamatelopoulos, K and Fatouros, IG and Mitrakou, A},
title = {Evidence of a redox-dependent control of vascular function after muscle-damaging exercise in young adults: a randomized placebo-controlled trial.},
journal = {Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.hjc.2025.07.007},
pmid = {40712831},
issn = {2241-5955},
abstract = {OBJECTIVE: High-intensity resistance exercise may temporarily induce vascular dysfunction mediated by pro-oxidant and pro-inflammatory pathways. In the present study, we aimed to evaluate the possible protective effect of the antioxidant N-acetyl cysteine (NAC) on vascular function after a bout of high-intensity resistance exercise.<br><br>METHODS: In this randomized, crossover, placebo-controlled study, ten healthy male volunteers (mean age 24.2 &#xb1; 2.1 years) who exercised regularly were randomly allocated to a daily oral administration of NAC or placebo during an 8-day recovery after an acute intense eccentric exercise protocol. Pulse wave velocity (PWV) and flow-mediated dilation (FMD) measurements were performed pre- and post-exercise in both study arms.<br><br>RESULTS: Muscle exercise induced a significant decrease in FMD in the placebo arm (p = 0.017) during the first 48 h after exercise, recovering thereafter. In contrast, in the NAC arm, FMD did not decrease significantly. By linear mixed-model analysis, a higher increase in CD4 cells levels correlated with preserved FMD (p = 0.046) only in the placebo arm (p = 0.811 in the NAC arm). PWV did not present significant fluctuations before and after exercise in either arm (p > 0.05).<br><br>CONCLUSION: A bout of eccentric exercise induced endothelial dysfunction, which was attenuated by NAC, indicating that oxidative stress may be implicated in vivo in this setting.},
}
@article {pmid40712548,
year = {2025},
author = {Liu, JR and Wu, FN and Lin, S and Chen, C and Liu, Y and Fan, JW and Hong, Q and Chen, YH},
title = {Gestational zearalenone causes fetal intrauterine growth restriction partially through deriving ROS-Drp1 mediated placental PANoptosis.},
journal = {Ecotoxicology and environmental safety},
volume = {302},
number = {},
pages = {118636},
doi = {10.1016/j.ecoenv.2025.118636},
pmid = {40712548},
issn = {1090-2414},
mesh = {Female ; *Zearalenone/toxicity ; Animals ; *Fetal Growth Retardation/chemically induced ; Pregnancy ; *Reactive Oxygen Species/metabolism ; *Placenta/drug effects/metabolism ; Mice ; *Dynamins/metabolism ; Humans ; Apoptosis/drug effects ; },
abstract = {The ubiquity of zearalenone (ZEA) in cereal-based products and the aquatic environment raises growing concerns about health problems to humans and animals. Here, we explored the mechanism by which ZEA exposure during pregnancy induced fetal growth restriction (FGR). Interestingly, both fetal weights and crown-rump length were significant decreases when dams were administrated with ZEA. Consistently, the incidence of FGR is significantly increased in ZEA group in a dose-dependent manner. Moreover, mean placental weight and diameter was significantly reduced in ZEA group, suggesting that poor placental development may be involved in ZEA-induced FGR. The genome-wide expression profiles of mouse placentas were significantly different between two groups by RNA-sequencing. GO and KEGG analysis indicated significant enrichment of these differentially expressed genes in mitochondrial apoptotic signaling pathway, inflammatory cell apoptotic process, necroptosis, and regulation of mitochondrial membrane potential. Further study showed that mitochondrial quality control disorder and PANoptosis plays an important role in ZEA-induced poor placental development. Mdivi-1, an inhibitor of Drp-1, attenuated ZEA-induced mitochondrial quality control disorder and PANoptosis in mouse placentas and human placental trophoblasts. N-acetylcysteine (NAC), an antioxidant, abolished ZEA-induced mitochondrial quality control disorder and PANoptosis in mouse placentas and human placental trophoblasts. Importantly, Mdivi-1 and NAC rescued gestational ZEA exposure-induced poor placental development and FGR in mice. Our results indicate that ZEA exposure during pregnancy caused poor placental development and subsequently FGR may be via deriving ROS-Drp1 mediated placental PANoptosis.},
}
@article {pmid40710512,
year = {2025},
author = {Wu, L and Lv, L and Xiang, Y and Yi, D and Liang, Q and Ji, M and Deng, Z and Qin, L and Ren, L and Liang, Z and He, J},
title = {Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in Mice.},
journal = {Marine drugs},
volume = {23},
number = {7},
pages = {},
pmid = {40710512},
issn = {1660-3397},
support = {No. YCBZ2021007//the Innovation Project of Guangxi Graduate Education/ ; No. 31960717//the National Natural Science Foundation of China/ ; No. ABDC-b202305//Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention/ ; },
mesh = {Animals ; Rosmarinic Acid ; *Acetaminophen/toxicity/adverse effects ; NF-E2-Related Factor 2/metabolism ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/drug therapy/metabolism/etiology ; *Depsides/pharmacology ; Mice ; *Oxidative Stress/drug effects ; *Cinnamates/pharmacology ; *Ferroptosis/drug effects ; Male ; Antioxidants/pharmacology ; Liver/drug effects/pathology ; Disease Models, Animal ; Heme Oxygenase-1/metabolism ; Signal Transduction/drug effects ; Protective Agents/pharmacology ; Membrane Proteins ; },
abstract = {Liver injury caused by the irrational use of acetaminophen (APAP) represents a significant challenge in the field of public health. In clinical treatment, apart from N-acetylcysteine (NAC), the only approved antidote, there are extremely limited effective intervention measures for APAP-induced hepatotoxicity. Therefore, exploring novel liver-protecting drugs and elucidating their mechanisms of action is of great scientific significance and clinical value. Rosmarinic acid (RA), as a natural polyphenolic compound, has been proven to have significant antioxidant activity. Previous studies have shown that it has a protective effect against drug-induced liver injury. Nevertheless, the precise protective mechanism of RA in APAP-induced acute liver injury (AILI) has not been fully defined. This study was based on an AILI mouse model to systematically explore the liver-protecting effect of RA and its underlying molecular mechanisms. The research results showed that pretreatment with RA could notably mitigate liver pathological injury. It could decrease the activities of ALT and AST in the serum, suppress the liver inflammatory reaction, and reverse the decline in the levels of CAT, T-AOC, SOD, and GSH caused by APAP. Meanwhile, RA could enhance antioxidant defense capabilities by activating the Keap1/Nrf2/HO-1 signaling pathway, regulate the xCT/GPX4 axis to inhibit lipid peroxidation, and thus block the process of ferroptosis. In conclusion, this study confirmed that RA exerts a protective effect against AILI by regulating the Keap1/Nrf2/HO-1 axis to enhance antioxidant capacity and inhibit ferroptosis through the xCT/GPX4 pathway. Our research provides a theoretical basis for RA as a potential therapeutic agent for APAP-induced liver injury.},
}
@article {pmid40706520,
year = {2025},
author = {Zhang, SF and Li, N and Liu, DL and Li, YH and Yang, Y and Ma, Y and Wang, YQ and Ma, Y and Luan, ZJ},
title = {Yttrium nitrate activates the oxidative stress-mediated NF-κB pathway to induce testicular inflammatory response and reduce sperm quality in mice.},
journal = {Ecotoxicology and environmental safety},
volume = {302},
number = {},
pages = {118720},
doi = {10.1016/j.ecoenv.2025.118720},
pmid = {40706520},
issn = {1090-2414},
mesh = {Animals ; Male ; *Oxidative Stress/drug effects ; NF-kappa B/metabolism ; Mice ; *Testis/drug effects ; *Spermatozoa/drug effects ; *Yttrium/toxicity ; Sperm Motility/drug effects ; *Nitrates/toxicity ; Apoptosis/drug effects ; Inflammation/chemically induced ; Signal Transduction/drug effects ; },
abstract = {The rising environmental levels of yttrium have sparked concerns regarding its possible health hazards. Nevertheless, limited toxicological data are available to determine yttrium's toxicity and potential mechanisms on sperm. In our research, the action of oxidative stress and the NF-κB pathway on decreased sperm quality and testicular inflammatory reaction induced by yttrium exposure was analyzed. Yttrium nitrate (YN), N-Acetyl Cysteine (NAC), and JSH-23 were used to intervene in mice and cells in vivo and in vitro experiments. Eosin-nigrosine staining, in vitro fertilization, Annexin V-FITC/PI staining, ICP-MS, Hematoxylin-eosin staining, RT-qPCR, DCFH-DA staining, biochemical methods, ELISA, and western blot were applied to detect sperm motility, fertilizing capacity, apoptosis, Y[3+] accumulation, testicular structure, testicular function, and NF-κB gene expression, ROS, MDA, GSH, pro-inflammatory cytokines, and NF-κB protein expression, respectively. The results revealed that YN exposure reduced sperm motility, increased sperm apoptosis, disrupted testicular tissue structure and function in mice. Exposure to YN increased ROS content and NF-κB pathway activation in testicular tissue and cells, resulting in upregulation of pro-inflammatory cytokines in the testis. When NAC scavenged ROS, the YN-induced sperm damage and inflammatory reaction, and NF-κB pathway abnormal activation in the testis of mice were alleviated. In addition, sperm damage and testicular inflammatory reaction caused by YN were alleviated after blocking the NF-κB pathway with JSH-23 treatment. Our present study elucidated that YN could damage sperm quality and induce testicular inflammatory reaction, establishing YN's toxicological impact on the male reproductive system.},
}
@article {pmid40703903,
year = {2025},
author = {Mehta, PP and Annam, RS and Hadiyel, IN},
title = {Catastrophic Outcomes: Rapid Multi-Organ Failure from Paraquat Poisoning- A Case Report.},
journal = {Nigerian medical journal : journal of the Nigeria Medical Association},
volume = {66},
number = {2},
pages = {811-817},
pmid = {40703903},
issn = {0300-1652},
abstract = {Paraquat dichloride, a potent herbicide widely used in agriculture, poses a severe health risk due to its high toxicity. Ingesting even small amounts can cause fatal multi-organ failure. We report a case of a 19-year-old male who ingested approximately 5 ml of 24% paraquat dichloride. He presented with stable vital signs, but initial laboratory results showed elevated urea (26mg/dL), creatinine (0.97 mg/dL), and hypokalemia (3.2 mEq/L). Despite interventions including gastric lavage, N-Acetyl cysteine, methylprednisolone, and supportive care, he developed severe metabolic acidosis (HCO[3]- 22.8 to 16.3 mEq/L), acute renal failure (creatinine 0.97 to 4.62 mg/dL, urea 26 to 99 mg/dL, serum potassium 3.2 to 2.62 mEq/L), and multi-organ dysfunction. The unavailability of hemoperfusion has impacted the outcome. The patient's rapid deterioration highlights paraquat's aggressive nature and underscores the necessity for better therapeutic strategies and regulatory measures to prevent such poisoning.},
}
@article {pmid40690881,
year = {2025},
author = {Philips, TJ and N'guessan, BB and Dotse, E and Abankwah, JK and Appiah-Opong, R},
title = {Riboceine and N-acetylcysteine protect normal prostate cells from chemotherapy-induced oxidative stress while selectively modulating the cytotoxicity of methotrexate and docetaxel in prostate (PC-3) and breast cancer (MCF-7) cells.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {190},
number = {},
pages = {118355},
doi = {10.1016/j.biopha.2025.118355},
pmid = {40690881},
issn = {1950-6007},
mesh = {Humans ; *Docetaxel/pharmacology/toxicity ; *Acetylcysteine/pharmacology ; *Oxidative Stress/drug effects ; *Methotrexate/toxicity/pharmacology ; Male ; MCF-7 Cells ; Reactive Oxygen Species/metabolism ; *Breast Neoplasms/drug therapy/pathology/metabolism ; Molecular Docking Simulation ; *Prostatic Neoplasms/drug therapy/pathology/metabolism ; *Antineoplastic Agents/pharmacology/toxicity ; PC-3 Cells ; *Prostate/drug effects/metabolism/pathology ; Antioxidants/pharmacology ; Female ; Glutathione/metabolism ; Cell Survival/drug effects ; Apoptosis/drug effects ; },
abstract = {BACKGROUND: Cancer chemotherapy often results in severe side effects due to its non-selective cytotoxicity toward rapidly dividing normal cells. These adverse effects are largely driven by oxidative stress resulting from elevated reactive oxygen species (ROS) production. Riboceine (RIB), a synthetic precursor of glutathione (GSH), and N-acetylcysteine (NAC), a clinically used antioxidant, hold promise in mitigating oxidative damage; however, their impact on chemotherapy efficacy and the molecular mechanisms involved remain incompletely understood.<br><br>AIM: This study aimed to evaluate the cytoprotective potential of RIB and NAC against methotrexate (MET)- and docetaxel (DOC)-induced toxicity in normal and cancer cells, and to explore mechanistic pathways using integrative network pharmacology and molecular docking approaches.<br><br>METHODOLOGY: Cytotoxic effects of MET and DOC, alone or in combination with RIB or NAC, were assessed in normal prostate epithelial (PNT-2), prostate cancer (PC3), and breast cancer (MCF-7) cell lines using the Resazurin assay. Intracellular ROS and GSH levels were quantified using DCF and OPA fluorescence assays, respectively. Network pharmacology, protein-protein interaction (PPI) analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and molecular docking were conducted using SwissTargetPrediction, STRING, ShinyGO, Cytoscape, and AutoDock Vina platforms.<br><br>RESULTS: MET and DOC showed dose-dependent cytotoxicity in PNT-2 and PC3 cells, but limited efficacy in chemoresistant MCF-7 cells. RIB and NAC significantly reduced ROS and restored GSH levels in PNT-2 cells, protecting them against oxidative injury. These antioxidants preserved anticancer effects in PC3 cells but reduced chemotherapy efficacy in MCF-7 cells, likely due to elevated redox buffering and transporter expression. Network analyses identified BCL-2, MAPK8, and SOD among key antioxidant and apoptotic targets. However, no direct experimental validation of these mechanisms was performed, and apoptotic markers such as Annexin V or caspase-3 were not assessed.<br><br>CONCLUSION: RIB and NAC provide selective cytoprotection to normal prostate cells during chemotherapy while maintaining anticancer effects in sensitive prostate cancer cells. However, their concurrent use in resistant cancers like MCF-7 may reduce drug efficacy, warranting cautious clinical application. Time-shifted antioxidant administration (e.g., post-chemotherapy) could be explored as a strategy to balance protection and efficacy. Future studies should include in vivo validation, apoptosis profiling, and protein-level mechanistic assays to confirm the predicted pathways.},
}
@article {pmid40689471,
year = {2025},
author = {Zhu, L and Li, X and Yu, S and Huang, L and Chen, S and Zheng, Z and Su, L},
title = {Dual role of reactive oxygen species in the effects of cadmium on microglial survival and phagocytosis.},
journal = {Environmental science. Processes &amp; impacts},
volume = {27},
number = {8},
pages = {2579-2587},
doi = {10.1039/d5em00299k},
pmid = {40689471},
issn = {2050-7895},
mesh = {*Microglia/drug effects/physiology ; *Reactive Oxygen Species/metabolism ; *Phagocytosis/drug effects ; *Cadmium/toxicity ; Animals ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; *Environmental Pollutants/toxicity ; Mice ; Cells, Cultured ; },
abstract = {Cadmium (Cd), a significant occupational and environmental pollutant, poses significant health risks due to its bioaccumulation and long biological half-life. Although Cd exposure has been identified as a risk factor for neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, its specific effects on microglia-the resident immune cells of the central nervous system (CNS)-remain poorly understood. Here, we demonstrate that Cd exerts dual, dose-dependent effects on primary microglia. High doses (1-2 μM) triggered oxidative stress, apoptosis, and viability loss, whereas subtoxic doses (0.125-0.5 μM) enhanced phagocytic activity and ATP production. Notably, low-dose Cd elevated glutathione (GSH) levels, suggesting adaptive redox activation. Pretreatment with N-acetylcysteine (NAC) prevented high-dose Cd-induced cytotoxicity but suppressed the stimulatory effects of low-dose Cd on phagocytic activity and ATP production. Interestingly, NAC pretreatment paradoxically amplified phagocytosis at 1 μM Cd, despite partial ROS reduction. Collectively, our findings reveal that mild oxidative stress from low-dose Cd exposure promotes microglial phagocytosis via antioxidant responses, offering new insights into Cd's neurotoxic mechanisms.},
}
@article {pmid40684828,
year = {2025},
author = {Yoon, B and Suresh, RN and Shivakumara, CS and Harsha, KB and Mohan, CD and Sethi, G and Rangappa, KS and Ahn, KS},
title = {Triazolyl-indolo-quinoxaline triggers differential cell death pathways in pancreatic cancer via ROS/p38 axis.},
journal = {Chemico-biological interactions},
volume = {420},
number = {},
pages = {111668},
doi = {10.1016/j.cbi.2025.111668},
pmid = {40684828},
issn = {1872-7786},
mesh = {Humans ; *Pancreatic Neoplasms/pathology/metabolism/drug therapy ; *Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Apoptosis/drug effects ; *Quinoxalines/pharmacology/chemistry ; Membrane Potential, Mitochondrial/drug effects ; *Indoles/pharmacology/chemistry ; Antineoplastic Agents/pharmacology/chemistry ; },
abstract = {Pancreatic cancer is characterized by aggressive progression, rapid metastasis, and resistance to conventional therapies, resulting in poor survival outcomes. Despite significant advances in research, effective treatment options for pancreatic cancer remain limited. In this study, we investigated the mechanisms of SRN-19-induced cell death in pancreatic cancer cells. Our findings demonstrated that SRN-19 promotes both apoptosis and paraptosis. Molecular analyses confirmed the upregulation of apoptotic markers, including cleaved PARP, Bax, and caspase-9/3, along with the downregulation of anti-apoptotic proteins Bcl-2 and Bcl-xL in both MIA PaCa-2 and AsPC-1 cells. Additionally, SRN-19 treatment led to reduced Alix expression and elevated levels of ATF4 and CHOP, markers associated with paraptosis, accompanied by alterations in mitochondrial membrane potential (MMP) in BxPC-3 cells. SRN-19 also induced a dose-dependent increase in reactive oxygen species (ROS) production and a corresponding decrease in the GSH/GSSG ratio. Pretreatment with N-acetylcysteine (NAC) attenuated ROS accumulation, restored Alix expression, and reduced cleaved PARP levels, confirming the involvement of ROS in apoptosis induction. Furthermore, SRN-19 activated the p38 MAPK pathway, and inhibition of p38 by SB203580 diminished ROS levels, reduced cleaved PARP expression, and restored MMP. Collectively, these results suggest that SRN-19 promotes ROS generation, activates the p38 MAPK pathway, and induces cell death in pancreatic cancer cells through both apoptotic and paraptotic mechanisms.},
}
@article {pmid40684388,
year = {2025},
author = {Zhu, Y and Wang, G and Feng, D and Li, S and Zhang, X and Yao, J and Deng, L and Lei, X},
title = {NEFA Induces Ferroptosis in Transition Dairy Cattle Liver by Increasing Lipid Reactive Oxygen Species and Downregulating SLC7A11.},
journal = {Journal of agricultural and food chemistry},
volume = {73},
number = {30},
pages = {18733-18745},
doi = {10.1021/acs.jafc.5c00935},
pmid = {40684388},
issn = {1520-5118},
mesh = {Animals ; *Ferroptosis/drug effects ; Cattle/metabolism ; *Reactive Oxygen Species/metabolism ; *Fatty Acids, Nonesterified/metabolism ; *Liver/metabolism/drug effects ; Down-Regulation ; *Amino Acid Transport System y+/genetics/metabolism ; Hepatocytes/metabolism/drug effects ; Female ; *Cattle Diseases/metabolism/genetics/physiopathology ; Lipid Peroxidation ; },
abstract = {Excessive lipid mobilization in transition dairy cattle leads to elevated levels of nonesterified fatty acids (NEFA), causing liver injury. Ferroptosis, a novel cell death mechanism, has significant roles in liver disease progression. However, its potential role in NEFA-induced liver injury remains unclear. In this study, we demonstrated ferroptosis occurrence in the transition cattle liver through histopathological damage, increased lipid peroxidation, and iron accumulation. In vitro, using ferroptosis inducer RAS-selective lethal 3 (RSL3), NEFA significantly enhanced ferroptosis in bovine hepatocytes. Subsequent experiments with ferroptosis inhibitor ferrostatin-1 (Fer-1) showed Fer-1 markedly reduced NEFA-enhanced ferroptosis, confirming ferroptosis' critical role. Mechanistic studies revealed that NEFA promoted ferroptosis by inducing lipid ROS production effectively inhibited by N-acetylcysteine (NAC) and by downregulating SLC7A11 expression. In conclusion, ferroptosis critically mediates NEFA-induced liver injury in transition dairy cattle, indicating that targeting this pathway may offer potential therapeutic strategies to mitigate liver damage associated with excessive lipid mobilization.},
}
@article {pmid40683237,
year = {2025},
author = {Sarangi, P and Pradhan, LK and Bhoi, S and Sahoo, BS and Chauhan, NR and Raut, S and Das, SK},
title = {N-acetyl cysteine mediated inhibition of glucose regulated protein-78 abrogates activating transcription factor-4 dependent endoplasmic reticulum stress and neurodegeneration following exposure to di-2-ethylhexyl phthalate in zebrafish brain.},
journal = {The Science of the total environment},
volume = {995},
number = {},
pages = {180068},
doi = {10.1016/j.scitotenv.2025.180068},
pmid = {40683237},
issn = {1879-1026},
mesh = {Animals ; *Zebrafish ; *Endoplasmic Reticulum Stress/drug effects ; *Diethylhexyl Phthalate/toxicity ; *Activating Transcription Factor 4/metabolism ; Brain/drug effects/metabolism ; *Water Pollutants, Chemical/toxicity ; Endoplasmic Reticulum Chaperone BiP ; *Acetylcysteine/pharmacology ; *Heat-Shock Proteins/metabolism ; *Plasticizers/toxicity ; *Zebrafish Proteins/metabolism ; },
abstract = {Recent findings have highlighted the neurological consequences of exposure to the plasticizer di-2-ethylhexyl phthalate (DEHP), including neurobehavioral transformation, cognitive dysfunction, and neurodegeneration. Endoplasmic reticulum (ER) stress plays a distinct role in altering cellular responses by inducing cell death. Based on existing literature, we were primarily interested in understanding whether the gross biochemical and neuromorphological outcomes of DEHP are associated with augmented ER stress in the neuronal microenvironment. Furthermore, we aimed to establish the neuroprotective efficacy of N-acetyl cysteine (NAC) against DEHP-induced ER stress in the zebrafish brain. Our core findings strongly support the argument that DEHP, being a global neurotoxicant, induces heightened oxidative stress and dysregulated calcium homeostasis, which contribute to ER stress mediated neurodegeneration via ATF4-dependent upregulation of GRP78 in the zebrafish brain. However, NAC reversed DEHP-induced calcium dysregulation (F4,20 = 11.97, p < 0.05; n = 6/group) and ATF4-mediated (F4,8 = 11.05; p < 0.05; n = 6/group) ER stress by inhibiting GRP78 (F4,8 = 31.83; p < 0.05; n = 6/group) in the zebrafish brain. NAC also promoted neuroprotection through upregulation of endogenous BDNF (F4,8 = 13.93, p < 0.05; n = 6/group) and NeuN (F4,8 = 56.95, p < 0.05; n = 6/group) expression and inhibition of CC3-mediated (F4,8 = 22.03, p < 0.05; n = 6/group) neurodegeneration in the periventricular grey zone (PGZ) of the zebrafish brain. To summarize these observations, our study establishes a strong correlation between NAC co-supplementation and restoration of DEHP-induced ER stress and neuropathology in zebrafish, but the study needs further validation to warrant the NAC-mediated potential therapeutic development against DEHP.},
}
@article {pmid40679610,
year = {2025},
author = {Özocak, AB and Şen, LS and Arıtürk, LA and Özkeçeci, N and Yüksel, M and Eyüboğlu, &#x130;P and Erzik, C and Yenal, N&#xd6; and Ercan, F and Atıcı, AE and Yeğen, B&#xc7;},
title = {Elabela alleviates ischemia/reperfusion-induced hepatic and remote organ injury by inhibiting oxidative stress in rats.},
journal = {Pflugers Archiv : European journal of physiology},
volume = {477},
number = {8},
pages = {1103-1118},
pmid = {40679610},
issn = {1432-2013},
support = {TTU-2022-10530//Marmara University Scientific Research Projects Unit/ ; },
mesh = {Animals ; *Reperfusion Injury/metabolism/drug therapy ; *Oxidative Stress/drug effects ; Male ; Rats, Sprague-Dawley ; Rats ; *Liver/drug effects/metabolism/pathology/blood supply ; Female ; Interleukin-6/metabolism/blood ; *Liver Diseases/drug therapy/metabolism ; Antioxidants/pharmacology ; },
abstract = {Hepatic injury is one of the most critical problems in major liver surgeries, trauma, sepsis or shock. The novel Elabela (ELA) peptide was shown to exert protective effects against cardiac and renal injury. We hypothesized that ELA could also have protective effects in hepatic ischemia-reperfusion (HI/R) injury and associated remote organ injury. Male (n = 37) and female (n = 37) Sprague-Dawley rats were used. Rats were divided into short-term and long-term HI/R injury groups. Each group was then divided into saline-treated, N-acetylcysteine-treated (NAC, 150 mg/kg) and ELA-treated (40 μg/kg) subgroups. Immediately before hepatic ischemia and during reperfusion, rats were subcutaneously injected with saline, NAC or ELA, while injections in long-term groups were continued twice a day for four days. Short-term and long-term sham-operation groups received saline injections. Hepatic blood flow was measured via laser Doppler flowmetry. Intracardiac blood was obtained for analyses of aminotransferase, alanine aminotransferase, bilirubin, urea, creatinine and interleukin (IL)-6. Caspase-3 and 8-hydroxy-2'-deoxyguanosine levels were determined and histopathological analyses (hematoxylin-eosin and alpha-smooth muscle actin (SMA) immunohistochemical staining) were performed in hepatic tissues. Levels of malondialdehyde, antioxidant glutathione, myeloperoxidase activity, luminol and lucigenin-enhanced chemiluminescence were measured in liver, lung, and kidney. Significant improvement in hepatic blood flow was observed in both short- and long-term ELA-treated groups. HI/R-induced elevations in reactive oxygen species in all the studied tissues were decreased by ELA, indicating its efficient radical scavenging function similar to NAC treatment. ELA treatment improved hepatic function tests and alleviated liver fibrosis, as detected by increased alpha-SMA-immunoreactivity. Serum IL-6 levels were increased by ELA treatment, suggesting its role in the activation of IL-6-dependent intracellular pathways which may contribute to hepatocyte proliferation and liver regeneration. Similar to the common use of NAC in hepatic surgery, Elabela appears to have a therapeutic potential in alleviating the consequences of hepatic postreperfusion injury.},
}
@article {pmid40679014,
year = {2025},
author = {Liu, D and Yang, Z and Lu, Y and Yang, W},
title = {Construction and characterization of thiolated chitosan coated TPGSylated nanodiamonds for oral delivery of curcumin.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {38},
number = {3},
pages = {1095-1105},
pmid = {40679014},
issn = {1011-601X},
mesh = {*Curcumin/administration &amp; dosage/chemistry ; *Chitosan/chemistry ; Administration, Oral ; *Nanodiamonds/chemistry ; *Vitamin E/chemistry/analogs &amp; derivatives ; Particle Size ; Drug Liberation ; *Drug Carriers/chemistry ; *Sulfhydryl Compounds/chemistry ; Solubility ; Drug Delivery Systems ; Humans ; },
abstract = {Low water solubility and poor intestinal permeability hinder the oral absorption of curcumin (CUR). To address this, we designed a core-shell structured nanoparticle based on nanodiamonds (NDs) and thiolated chitosan (TCS). First, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) covalently modified NDs were prepared and loaded with CUR (CUR@NDs-TPGS). N-acetylcysteine (NAC) was then coupled to chitosan (CS) to obtain positively charged CS-NAC, which electrostatically coated the negatively charged NDs-TPGS/CUR. Particle size (PS), zeta potential (ZP) and drug loading efficiency (DLE) were selected as screening indices to optimize the formulation and preparation process of CUR@NDs-TPGS/CS-NAC via single-factor experiments. The results showed that after coating with CS-NAC, the PS of optimized CUR@NDs-TPGS/CS-NAC increased from 183.63±5.24 nm to 245.24±3.95 nm, the ZP value flipped from -25.47±1.36 to +25.81±1.06 and the DLE value decreased slightly. Moreover, the nanoparticles adopted a spherical morphology and the cumulative release percentage of the nanocomplexes within 24 h decreased from 35.69% to 25.54% after coating. CUR@NDs-TPGS/CS-NAC remained stable within 48 h in simulated intestinal fluid. Mucin adsorption, GI retention and oral absorption of CUR@NDs-TPGS/CS-NAC were further enhanced compared to CUR@NDs-TPGS. These findings suggest that CUR@NDs-TPGS/CS-NAC is a promising carrier for oral delivery of CUR.},
}
@article {pmid40677760,
year = {2025},
author = {Kim, M and Lee, HK and Lee, H and Lee, HS},
title = {Prdx6 regulates in vivo myeloid cell development via redox control during Xenopus embryogenesis.},
journal = {Animal cells and systems},
volume = {29},
number = {1},
pages = {438-445},
pmid = {40677760},
issn = {1976-8354},
abstract = {Peroxiredoxin6 (Prdx6) is a bifunctional antioxidant enzyme with both peroxidase and phospholipase A2 activities. Although its molecular roles are well established, the developmental role of Prdx6 remains poorly understood. To address this gap in the literature, this study aimed to examine the in vivo function of Prdx6 in primitive myelopoiesis using Xenopus laevis embryos. We found that prdx6 is specifically expressed in myeloid progenitors originating from the anterior ventral blood island during early embryogenesis. Knockdown of prdx6 significantly reduced the number of myeloid cells, without affecting their migration ability. Embryos depleted of prdx6 exhibited elevated levels of reactive oxygen species (ROS) and decreased cellular proliferation. Co-injection of morpholino (MO)-resistant prdx6 mRNA or treatment with N-acetylcysteine (NAC) successfully restored both ROS levels and myeloid cell numbers, suggesting that Prdx6 supports primitive myeloid cell development by maintaining redox homeostasis. These findings reveal a novel role of Prdx6 in ROS-dependent proliferation of myeloid progenitors during early vertebrate development.},
}
@article {pmid40672024,
year = {2025},
author = {Mavridis, C and Zisis, IE and Docea, AO and Buga, AM and Tsatsakis, A and Mamoulakis, C},
title = {Reducing Contrast-Induced Nephropathy Risk in a Murine Model: Role of Avanafil and Vardenafil in Modulating Oxidant/Antioxidant Balance.},
journal = {Cureus},
volume = {17},
number = {6},
pages = {e86136},
pmid = {40672024},
issn = {2168-8184},
abstract = {INTRODUCTION: Contrast-induced nephropathy (CIN) is a major clinical problem, particularly under conditions of preexisting renal insufficiency and comorbidities. The present study evaluates the potential of phosphodiesterase type 5 inhibitors (PDE5is), avanafil (AVA), and vardenafil (VAR) to prevent CIN by modulating oxidative stress in a murine model.<br><br>METHODS: Two sets of 25 male Wistar rats were allocated into five groups: control, CIN, N-acetylcysteine (NAC), VAR, and AVA. Indomethacin, L-NG-Nitro arginine methyl ester (L-NAME), and iopromide were used to induce CIN. Oxidative stress markers were evaluated, i.e., total antioxidant capacity (TAC), protein carbonyl (PROTC), thiobarbituric acid reactive substances (TBARS), glutathione (GSH), and catalase (CAT) activity.<br><br>RESULTS: In comparison with the control group, TAC, GSH, and CAT activity were reduced, while TBARS and PROTC levels were elevated in the CIN group. Variations in treatment by VAR, AVA, and NAC induced a notable rise in TAC and blood levels of GSH while lowering TBARS in tissue.<br><br>CONCLUSION: The treatment groups with VAR, AVA, and NAC were noted with higher values of TAC, CAT, and GSH, while lower values of TBARS and PROTC indicated a protective effect against oxidative injury. The findings indicate that VAR and AVA effectively control the oxidant/antioxidant status, preventing oxidative stress and the incidence of CIN. Further research would be required to replicate these findings and identify the therapeutic potential of VAR and AVA in clinical conditions.},
}
@article {pmid40671632,
year = {2025},
author = {Hunt, RL and Oh, J and Jain, A and Kuo, TH and Berardi, D and Jian, W and Song, D and Wu, Q and Goodman, AL and Palm, NW and Zimmermann, M and Johnson, CH and Crawford, JM},
title = {Discovery of a Widespread Polyamine-Low-Molecular-Weight Thiol Hybrid Pathway in Clostridioides difficile.},
journal = {ACS infectious diseases},
volume = {11},
number = {8},
pages = {2246-2264},
pmid = {40671632},
issn = {2373-8227},
support = {R35 GM118159/GM/NIGMS NIH HHS/United States ; RM1 GM141649/GM/NIGMS NIH HHS/United States ; T32 GM149444/GM/NIGMS NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; },
mesh = {*Clostridioides difficile/genetics/metabolism ; *Sulfhydryl Compounds/metabolism ; *Biogenic Polyamines/metabolism ; Biosynthetic Pathways/genetics ; Humans ; Microbiota ; Colorectal Neoplasms/etiology ; Animals ; Mice ; Clostridium Infections/complications/microbiology ; },
abstract = {Clostridioides difficile infection can cause severe inflammation in the gastrointestinal (GI) tract, leading to diarrhea, colitis, and an increased risk of colorectal cancer. Colonization of C. difficile is associated with microbial community-level changes in the expression of polyamine and polyamine precursor biosynthesis genes. Polyamines are abundant cationic metabolites that serve indispensable functions for all kingdoms, particularly in gut homeostasis. Catabolism of the polyamine precursors arginine and ornithine offers C. difficile supplemental nutrition while subverting host immunity, yet existing models of C. difficile metabolism are incomplete regarding polyamines with comparable importance in the gut (e.g., spermidine). In this study, we conducted feeding studies with isotope-labeled polyamines and discovered a network of low-molecular-weight thiol (LMWT) molecules termed clostridithiols (CSHs) constructed from polyamines conjugated with N-acetylcysteine (NAC) moieties. NAC is clinically used as a mucolytic agent and is a well-established redox molecule. Through the analysis of a human microbiota diversity collection, we established that these previously uncharacterized hybrid metabolites are widely detected in Firmicutes and Bacteroidetes. A genetic screen using DNA from an alternative CSH producerBacteroides uniformis enabled the identification and validation of a two-gene operon, including a gene encoding a domain of unknown function, that was conserved in both producing organisms and other members of the microbiome. CSH abundance in GI mucosal biopsies positively correlated with colorectal cancer compared with matched healthy control samples. These studies indicate that human microbial metabolism broadly unites polyamine and LMWT functionalities to generate metabolites that may be associated with disease.},
}
@article {pmid40661819,
year = {2025},
author = {Ramezaninejad, S and Zaboli, E and Eslamijouybari, M and Mirzakhani, L and Shaki, F and Moosazadeh, M and Namvar, HR and Shabani, AM and Salehifar, E},
title = {Evaluation of the Safety and Efficacy of N-acetylcysteine in the Prevention of Paclitaxel-induced Peripheral Neuropathy: A Randomized, Double-blind, and Placebo-controlled Trial.},
journal = {Journal of research in pharmacy practice},
volume = {14},
number = {1},
pages = {18-26},
pmid = {40661819},
issn = {2319-9644},
abstract = {OBJECTIVE: Paclitaxel-induced peripheral neuropathy (PIPN) is a disabling condition that leads to discontinuation or dose reduction of chemotherapy and reduces the patient's quality of life (QOL). We investigated the effect of N-acetylcysteine (NAC) in preventing PIPN.<br><br>METHODS: This study was a randomized, double-blind, and placebo-controlled clinical trial conducted at a chemotherapy center of Mazandaran University of Medical Sciences. Breast cancer patients receiving the Adriamycin/Cyclophosphamide-Taxol regimen were enrolled. All patients received 1200 mg NAC or placebo in two doses before each cycle of paclitaxel. Response to treatment was assessed based on improvements in the Numeric Pain Rating Scale (NRS), NCI-CTCAE, NPS, FACT/GOG-Ntx, and EORTC-QLQ. Two blood samples were taken at baseline and last cycle to determine the oxidative factors.<br><br>FINDINGS: Sixty patients were enrolled. At the last cycle, changes in NRS were decreasing in the NAC group but increasing in the placebo group. Thirteen patients (44.8%) in the NAC group and only one patient (3.4%) in the placebo group still reported no neuropathy in the end. A significant difference was observed between the two groups in the Ntx subscale and the Fact-G total score at the last cycle (P < 0.001). The QOL increased in the NAC and decreased in the placebo group. Glutathione levels, MDA, and TAC differed significantly between the two groups (P < 0.001, <0.001, and 0.04, respectively), but no significant difference in NO levels (P = 0.5).<br><br>CONCLUSION: Oral NAC at a dose of 1200 mg daily for two doses can reduce the incidence and severity of PIPN and improve patients' QOL.},
}
@article {pmid40659140,
year = {2025},
author = {Yan, L and Zeng, Q and Wang, W and Liang, Y and Lang, R and Zhan, J and Yang, J and Yu, R and Wang, X},
title = {Jianpi Qushi Heluo formula ameliorates podocytes injury related with ROS-mediated NLRP3 inflammasome activation in membranous nephropathy by promoting PINK1-dependent mitophagy.},
journal = {Journal of ethnopharmacology},
volume = {353},
number = {Pt A},
pages = {120291},
doi = {10.1016/j.jep.2025.120291},
pmid = {40659140},
issn = {1872-7573},
mesh = {Animals ; *Podocytes/drug effects/metabolism/pathology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Reactive Oxygen Species/metabolism ; *Mitophagy/drug effects ; *Inflammasomes/metabolism ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Glomerulonephritis, Membranous/drug therapy/pathology/metabolism ; *Protein Kinases/metabolism/genetics ; Rats ; Male ; Rats, Sprague-Dawley ; Disease Models, Animal ; Humans ; PTEN-Induced Putative Kinase ; },
abstract = {Jianpi Qushi Heluo formula (JQHF) is an evidence-based herbal formula based on "Fangji Huangqi Decoction" in the classic of traditional Chinese medicine (TCM) synopsis of the Golden Chamber. Its effectiveness in reducing idiopathic membranous nephropathy (IMN) proteinuria, edema and other clinical symptoms and improving kidney injury has been confirmed by clinical trials and animal experiments. These results demonstrate the critical significance of reducing podocyte injury by regulating mitophagy through integrating ethnopharmacology.<br><br>AIM OF THE STUDY: This study aimed to explore the protective effects of JQHF on podocyte injury in IMN, focusing on its role in promoting PINK1-dependent mitophagy to inhibit reactive oxygen species (ROS) mediated activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome.<br><br>MATERIALS AND METHODS: The main components of JQHF were identified by ultra-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MSE). Passive Heymann nephritis (PHN) was induced in rats using anti-Fx1A antiserum, while podocyte injury in vitro was stimulated with sublytic complement C5b-9 (sC5b-9). The PHN rats were treated with JQHF, and autophagy inhibitor 3-methyladenine (3-MA) combined with JQHF was used for pathway verification, and Benazepril served as a positive control. In vitro, podocytes were exposed to palmitic acid (PA, a ROS inducer) and N-acetylcysteine (NAC, a ROS scavenger). Further, we silenced the expression of PINK1 in podocytes model and intervened with JQHF-containing serum. Renal function was assessed through biochemical analyses and histopathology. Mitochondrial function was measured by detecting mitochondrial membrane potential (MMP), ROS levels as well as mitochondrial ultrastructure. The expression of podocyte structural proteins (desmin, nephrin, podocin) and inflammasome-related markers (NLRP3, caspase-1, IL-1&#x3b2;, IL-6) was analyzed to assess podocyte injury and inflammasome activation.<br><br>RESULTS: (1) In vitro, in contrast to the control group, PA intervention caused increased ROS accumulation, reduced MMP, upregulated NLRP3 and caspase-1 expression, as well as elevated expression of inflammatory factors IL-1&#x3b2; and IL-6. The expression of nephrin and podocin was notably reduced. By contrast, NAC reversed these effects. (2) In vivo, JQHF effectively ameliorated mitochondrial damage, reduced NLRP3 expression and mitigated podocyte injury in PHN rats. The protective effects of JQHF were diminished by 3-MA, confirming the involvement of autophagy. (3) In vitro, JQHF-containing serum attenuated C5b-9-induced podocyte injury, improved mitochondrial dysfunction, and inhibited ROS-mediated activation of NLRP3 inflammasome. Silencing PINK1 significantly reversed these protective effects.<br><br>CONCLUSION: JQHF can alleviate podocyte damage, that through inhibiting ROS-mediated NLRP3 inflammasome activation by improving PINK1-mediated mitophagy.},
}
@article {pmid40656400,
year = {2025},
author = {Maalbi, O and Elachhab, N and Elkabbaj, A and Arfaoui, M and Hindi, S and Lahbabi, S and Oudghiri, N and Tachinante, R},
title = {Management of Acute Fatty Liver of Pregnancy: A Retrospective Study of 12 Cases Compared With Data in the Literature.},
journal = {Cureus},
volume = {17},
number = {6},
pages = {e85753},
pmid = {40656400},
issn = {2168-8184},
abstract = {Introduction Acute fatty liver of pregnancy (AFLP) is a rare and potentially life-threatening obstetric condition marked by hepatic dysfunction due to fat accumulation in liver cells. It generally arises in the later stages of pregnancy or shortly after delivery. Clinical presentation is often nonspecific, with symptoms such as gastrointestinal discomfort, nausea, and increased thirst or urination. In more severe cases, signs of liver failure may develop, including jaundice, altered mental status, and coagulation abnormalities. Laboratory tests typically reveal elevated liver enzymes, impaired coagulation, and abnormalities in blood counts. The condition poses significant risks for both mother and fetus, and timely diagnosis and appropriate multidisciplinary management are essential for favorable outcomes. Methods The objective of our study was to analyze the management of this pathology in our intensive care unit and compare it with the literature. This is a retrospective, descriptive, and analytical study conducted in the intensive care unit of Souissi Maternity Hospital, including 12 cases admitted from January 1, 2023, to December 31, 2024. We used a data extraction sheet covering demographic, diagnostic criteria, complications, and maternal and obstetric management, to analyze the data collected from medical records of pregnant women. Results Our retrospective study of 12 AFLP cases revealed a mean patient age of 29.8 ± 5.24 years and an average gestational age of 34.8 weeks. Gravidity and parity medians were 2 and 2.5, respectively. Gestational hypertension was present in five of the patients (41.7%), with some complicated by preeclampsia or eclampsia. All 12 patients met the Swansea diagnostic criteria (more than six criteria for each patient), with jaundice in 11 patients (91.7%), nausea/vomiting in nine of them (75%), and epigastric pain in seven parturients (58.3%) being the most common clinical presentations. Laboratory findings showed elevated transaminases in 10 patients (83% >3x normal, mean aspartate aminotransferase (AST) of 683.36 IU/L, mean alanine aminotransferase (ALT) of 428 IU/L), and total bilirubin was elevated >14 µmol/L in all patients, mean 169 µmol/L). Coagulopathy was common, with eight patients (66%) having a prothrombin time (PT) < 70%. Maternal complications were frequent in 11 patients (95%), including renal failure in eight of them (72%), hemorrhagic complications in five patients (45%), often necessitating blood transfusions, altered consciousness, and sepsis. Fetal complications included four intrauterine fetal death (33%) and three acute fetal distress (25%). Management was multidisciplinary, focusing on prompt uterine evacuation, hemostasis correction, and management of renal, infectious, neurological, and respiratory complications. No patients in our cohort received plasmapheresis due to equipment unavailability. Conclusion Both the existing literature and our service's protocol prioritize immediate fetal delivery as the definitive intervention to halt disease progression. While the literature explores adjunctive therapies such as N-acetylcysteine (NAC) and plasmapheresis, the core focus remains on meticulous supportive care to address the numerous complications arising from liver failure.},
}
@article {pmid40651645,
year = {2025},
author = {Yao, L and Xiang, F and Peng, S and Wang, L and Li, H and Chen, X and Hu, L and Mo, H},
title = {Ferrous gluconate-loaded sodium alginate hydrogel facilitates ferroptosis in Streptococcus hemolyticus and cures Streptococcal infections.},
journal = {International journal of biological macromolecules},
volume = {320},
number = {Pt 3},
pages = {145900},
doi = {10.1016/j.ijbiomac.2025.145900},
pmid = {40651645},
issn = {1879-0003},
mesh = {*Alginates/chemistry/pharmacology ; Humans ; *Hydrogels/chemistry/pharmacology ; *Ferroptosis/drug effects ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Streptococcal Infections/drug therapy/microbiology/metabolism ; *Ferrous Compounds/pharmacology/chemistry ; Reactive Oxygen Species/metabolism ; *Gluconates/pharmacology/chemistry ; },
abstract = {Streptococcus hemolyticus has recently regained public attention as "man-eating bacteria" and raised significant public health concerns due to the ever-increasing incidence of infections and severe toxic shock syndrome resulting from inadequate treatment. The growing challenge of antimicrobial resistance further emphasizes the urgent need for the development of novel wound dressings to prevent infections. This study demonstrated that ferrous gluconate (FeGlu) facilitated ferroptosis in S. hemolyticus accompanied with hallmarks of iron dependence, reactive oxygen species (ROS) burst, and lipid peroxidation. Moreover, the addition of inhibitors, including liproxstatin-1 (LIP-1), N-Acetylcysteine (NAC) and glutathione (GSH) hindered the happening of ferroptosis. In light of this, an antibacterial hydrogel was formulated by cross-linking FeGlu with sodium alginate (SA). This hydrogel exhibited excellent fluidity, self-healing properties, biocompatibility, and exceptional bactericidal efficacy. Furthermore, it displayed a superior therapeutic effect while posing no toxic risk in human skin fibroblast (HSF) cells. Proteomic analysis revealed that the FeGlu-hydrogel induced cell death by disrupting various pathways, including transmembrane transport, biomacromolecule synthesis, and cellular metabolism. Additionally, the FeGlu-hydrogel displayed a broad bactericidal spectrum against Streptococcus species, including Streptococcus pneumoniae and Streptococcus mutans. Collectively, these results proved that the FeGlu-hydrogel is a promising biomaterial for the treatment of Streptococcus-related infections.},
}
@article {pmid40649839,
year = {2025},
author = {Orea, W and Carrillo, ED and Hernández, A and Moreno, R and García, MC and Sánchez, JA},
title = {Pharmacological Preconditioning with Diazoxide Upregulates HCN4 Channels in the Sinoatrial Node of Adult Rat Cardiomyocytes.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
pmid = {40649839},
issn = {1422-0067},
mesh = {Animals ; *Diazoxide/pharmacology ; *Sinoatrial Node/metabolism/drug effects/cytology ; *Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism/genetics ; Rats ; *Myocytes, Cardiac/metabolism/drug effects ; Reactive Oxygen Species/metabolism ; Male ; *Up-Regulation/drug effects ; Rats, Sprague-Dawley ; Heart Rate/drug effects ; Decanoic Acids ; Hydroxy Acids ; Potassium Channels ; },
abstract = {Cardioprotection against ischemia is achieved using openers of mitochondrial ATP-sensitive K[+] (mitoKATP) channels such as diazoxide (DZX), leading to pharmacological preconditioning (PPC). We previously reported that PPC decreases the abundance of ventricular Cav1.2 channels, but PPC's effects on other channels remain largely unexplored. In this study, we hypothesized that DZX regulates the expression of hyperpolarization-activated cyclic nucleotide potassium channel 4 (HCN4) channels in sinoatrial node cells (SANCs), the specialized cardiomyocytes that generate the heartbeat. DZX increased the heart rate in intact adult rats. Patch-clamp experiments revealed an increase in the magnitude of ionic currents through HCN4 channels, which was abolished by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the selective mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot assays showed that DZX increased HCN4 channel expression at the mRNA and protein levels. Immunofluorescence analyses revealed that PPC increased HCN4 fluorescence, which was abolished by NAC. DZX increased nuclear translocation of c-Fos and decreased protein abundance of RE1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), suggesting the involvement of these factors. Our results suggest that PPC increases the heart rate by upregulating HCN4 channel expression through a mechanism involving c-Fos, REST, and ROS.},
}
@article {pmid40642398,
year = {2025},
author = {Kindlon, EA and Pidgeon, GP},
title = {N-Acetyl Cysteine as a promising therapeutic approach in ovarian cancer: potential and perspectives.},
journal = {Academia oncology},
volume = {2},
number = {2},
pages = {},
pmid = {40642398},
issn = {2998-7741},
support = {R01 CA114051/CA/NCI NIH HHS/United States ; },
abstract = {Ovarian cancer is the seventh most common cancer in women and the eighth most common cause of cancer death worldwide. It is an aggressive disease with five-year survival rates below 45% and many patients relapse within 2 years. Further treatments become more intense, resulting in chemotherapy drug resistance and increased toxicity. This has created the need to develop new therapeutic strategies to improve the quality of life and treatment options for ovarian cancer patients. Studies have reported the role of cysteine in ovarian cancer, primarily as a precursor of glutathione (GSH), contributing to the endogenous antioxidant mechanism. The membrane-permeable cysteine precursor N-acetylcysteine (NAC) can enhance the intracellular cysteine pool and thus results in decreased oxidative stress. This characteristic provides NAC with a rationale as a potentially effective chemo-protectant in ovarian cancer treatment. In this review, we summarize the effects of NAC supplementation in ovarian cancer from recent preclinical studies. The role of NAC in chemotherapy response, and mechanisms to overcome chemo resistance in ovarian cancer (including targeting the Mirk/dyrk1B kinase pathway) are also explored. While NAC holds therapeutic promise in alleviating treatment-associated toxicities, its application in ovarian cancer requires careful consideration based on tumour subtype, redox context, and treatment timing. Future research incorporating subtype-specific models and clinical trials will be essential to delineate the precise role of NAC and optimize its integration into ovarian cancer treatment regimens.},
}
@article {pmid40640645,
year = {2025},
author = {Chaudhary, KR and Viegas, C and Pirela, P and Atalaia, M and Ruivinho, B and Arora, S and Singh, A and Brandão, P and Singh, C and Fonte, P},
title = {Inhalable N-Acetylcysteine-loaded Lactose-coated PLGA Nanoparticles for Tuberculosis Treatment.},
journal = {Pharmaceutical research},
volume = {42},
number = {7},
pages = {1153-1165},
pmid = {40640645},
issn = {1573-904X},
support = {2020.08839. BD//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UIDB/04326/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UIDP/04326/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; LA/P/0101/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UIDB/04565/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UIDP/04565/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; LA/P/0140/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; UIDB/04585/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; },
mesh = {*Lactose/chemistry ; *Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; *Acetylcysteine/administration &amp; dosage/chemistry/pharmacokinetics ; Administration, Inhalation ; *Nanoparticles/chemistry ; Particle Size ; *Tuberculosis/drug therapy ; Animals ; Mycobacterium tuberculosis/drug effects ; *Antitubercular Agents/administration &amp; dosage/chemistry/pharmacokinetics ; Lung/metabolism ; Drug Liberation ; Drug Carriers/chemistry ; Humans ; Excipients/chemistry ; Drug Delivery Systems/methods ; },
abstract = {OBJECTIVE: Glutathione (GSH), known for having mucolytic, anti-inflammatory, and antioxidant activities, is used in clinical practice in several pathologies, including tuberculosis (TB). N-acetylcysteine (NAC) has been primarily used to treat lung conditions and paracetamol-induced liver toxicity. However, NAC exhibits potential antimycobacterial activity through several mechanisms including immunomodulation, enhancement of GSH levels, and direct antimycobacterial effect. In this work, we aim to develop an effective drug delivery system for NAC for inhalable formulations.<br><br>METHODS: Herein, we report the development of lactose-coated NAC-loaded Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NAC-PLGA NPs) obtained by double emulsion methodology. Lactose has a double role, as a cryoprotectant agent and dispersant for inhalable formulations. The physicochemical properties of lactose-coated NAC-PLGA NPs were examined in terms of particle size, polydispersity index (PdI), zeta potential (ZP), encapsulation efficiency, and morphology. The in vitro release and lung deposition studies were assessed.<br><br>RESULTS: The physicochemical characterization studies revealed the compatibility of the drug with the selected excipients. Moreover, lactose-coated NAC-PLGA NPs showed particle size of 310&#x2009;&#xb1;&#x2009;3 nm, PdI of 0.15&#x2009;&#xb1;&#x2009;0.01, and of -11.5&#x2009;&#xb1;&#x2009;0.4 mV. The in vitro release study suggested a biphasic release profile. Likewise, in vitro lung deposition studies revealed desirable lung deposition parameters, indicating effective particle size for efficient pulmonary delivery. Additionally, in vitro studies for antimycobacterial activity exhibited superior antibacterial activity against Mycobacterium Tuberculosis (MTB) H37Rv.<br><br>CONCLUSIONS: These preliminary findings suggest that lactose-coated NAC-PLGA NPs can open the door to new therapeutic options against one of the most drug-refractory and drug-resistant infectious diseases, TB.},
}
@article {pmid40640553,
year = {2025},
author = {Musillo, C and Ajmone-Cat, MA and De Simone, R and Tassinari, R and Maranghi, F and Tait, S and Samà, M and Giona, L and Pieroni, EM and Alessi, R and Henning, T and Weber, D and Lippert, RN and Pisanu, ME and Chirico, M and Iorio, E and Fratini, F and Berry, A and Cirulli, F},
title = {Maternal stressors disrupt mouse placental proteome and fetal brain development in a sex-specific fashion through inflammation and oxidative stress.},
journal = {Molecular psychiatry},
volume = {30},
number = {11},
pages = {5072-5083},
pmid = {40640553},
issn = {1476-5578},
mesh = {Female ; Animals ; Pregnancy ; Oxidative Stress/physiology/drug effects ; *Placenta/metabolism ; Male ; *Brain/metabolism/embryology ; Mice ; Proteome/metabolism ; Inflammation/metabolism ; Mice, Inbred C57BL ; Fetal Development/physiology ; Prenatal Exposure Delayed Effects/metabolism ; Diet, High-Fat/adverse effects ; Proteomics/methods ; Sex Characteristics ; Acetylcysteine/pharmacology ; Sex Factors ; Stress, Psychological/metabolism ; Fetus/metabolism ; },
abstract = {Adverse maternal conditions during pregnancy result in an increased risk for neuropsychiatric disorders in the offspring, although the underlying mechanisms are poorly understood. We have recently shown that two distinct insults, prenatal stress (PNS) or maternal high-fat diet (mHFD), increase inflammation and oxidative stress in the brain of adolescent female mice. Here, we sought to investigate the early mechanisms underlying such effects, focusing on the placenta and fetal brain, as well as the protective effects of the antioxidant N-acetyl-cysteine (NAC), in C57Bl6/N mice. We used a multi-disciplinary approach combining proteomic, metabolomic, lipidomic and histological analysis to characterize the structural and functional changes of the placenta; moreover, a targeted gene expression analysis was carried out in the brains of male and female fetuses to evaluate oxidative stress and inflammatory-related changes. Our data highlight comparable, but sex-specific, responses to the two maternal stressors, which target placenta and fetal brain, and are buffered by NAC administration. Placental function was specifically disrupted in males, with signaling pathways of cardio-metabolic risk emerging in this sex. By contrast, fetal brain was affected in females, with an increased expression of genes related to inflammation and oxidative stress. In conclusion, we provide evidence for an early origin of sex-dependent embedding of prenatal adverse experiences in different organs which might explain differential susceptibility to later disease trajectories.},
}
@article {pmid40637414,
year = {2025},
author = {Han, GZ and Li, S and Cui, YY and Shao, B and Song, Y and Jiang, SL and Zhang, ZQ},
title = {ROS-Dependent Endoplasmic Reticulum Stress Is Involved in Silica-Induced Pulmonary Fibrosis through the GRP78/CHOP/TXNIP/NLRP3 Signaling Pathway in Rats.},
journal = {Chemical research in toxicology},
volume = {38},
number = {7},
pages = {1257-1265},
doi = {10.1021/acs.chemrestox.5c00135},
pmid = {40637414},
issn = {1520-5010},
mesh = {Animals ; *Silicon Dioxide/toxicity/administration &amp; dosage ; *Endoplasmic Reticulum Stress/drug effects ; Male ; *Pulmonary Fibrosis/chemically induced/metabolism/pathology ; *Reactive Oxygen Species/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; Signal Transduction/drug effects ; Heat-Shock Proteins/metabolism ; Transcription Factor CHOP/metabolism ; Endoplasmic Reticulum Chaperone BiP ; Carrier Proteins/metabolism ; Rats, Sprague-Dawley ; Thioredoxins/metabolism ; Cell Cycle Proteins ; },
abstract = {Several studies have suggested that silica-induced reactive oxygen species (ROS) stimulate the endoplasmic reticulum to undergo endoplasmic reticulum stress (ERS), which eventually leads to pulmonary fibrosis. However, the mechanisms by which ROS-dependent ERS leads to silicosis and fibrosis remain unclear. In this study, male rats were intratracheally instilled with a single dose of crystalline silica (SiO2) suspension (100 mg/mL, 1 mL) to establish silicosis and then were injected intravenously with 1 mL of N-Acetylcysteine (NAC) (at the dose of 20, 40, or 80 mg/kg, respectively) daily to inhibit ROS-dependent ERS. Rats given a single intratracheal dose of SiO2 suspension and subsequently receiving daily intravenous injections of phosphate buffer solution (PBS) served as models, while those given a single intratracheal dose of PBS and subsequently receiving daily intravenous injections of PBS served as controls. After 40 days, lung samples were taken for pathological observation, and the levels of glucose-regulated protein 78(GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), thioredoxin-interacting protein (TXNIP), and nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 inflammasome (NLRP3 inflammasome) were assessed. The results showed that compared with the control group, the lung tissues of the model rats exhibited obvious fibrosis and ERS, accompanied by the elevated levels of GRP78, CHOP, TXNIP, and NLRP3 inflammasome. After ROS were inhibited with NAC, the degree of lung fibrosis and ERS was significantly alleviated, and the levels of the aforementioned cytokines were also reduced. Moreover, the higher the dose of NAC intervention, the more pronounced the effects. The results demonstrated that ROS-dependent ERS is deeply involved in silica-induced pulmonary fibrosis through the GRP78/CHOP/TXNIP/NLRP3 signaling pathway in rats.},
}
@article {pmid40636588,
year = {2025},
author = {Roy, D and Sarkar, S and Biswas, SC},
title = {N-acetyl L-cysteine and Growth Factors Impede Endoplasmic Reticulum Stress and Inflammatory Responses in Astrocytes to Amyloid-β in Serum-free Culture.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531251340150},
pmid = {40636588},
issn = {0972-7531},
abstract = {BACKGROUND: Astrocytes play an integral role in Alzheimer's disease (AD) pathology, where they may act as a double-edged sword. The existing serum-supplemented in vitro astrocyte culture models are not suitable to study certain stress response mechanisms that occur in AD.<br><br>PURPOSE: Here, we tried to develop a serum-free murine primary cortical astrocyte culture model to study endoplasmic reticulum (ER) stress and inflammation to investigate the effect of amyloid-beta (A&#x3b2;1-42).<br><br>METHODS: Astrocytes were cultured in a controlled serum-free environment to minimise interference from serum components. Serum-free astrocytes were exposed to oligomeric A&#x3b2; and subjected to imaging, immunocytochemistry, real-time PCR and western blot analysis.<br><br>RESULTS: Using an established protocol, no significant activation of eIF2&#x3b1;, a key marker of ER stress, was observed under serum-free conditions, but with the removal of N-acetyl cysteine (NAC), ER stress response was enhanced after 24 hours of A&#x3b2; exposure. Subsequently, the A&#x3b2;-induced inflammatory response, assessed through TNF-&#x3b1; expression, which was minimal in the presence of growth factors, became pronounced when these factors were withdrawn. Concomitantly, a significant increase in astrocytes reactivity, assessed by GFAP expression upon 24 hours of A&#x3b2; exposure, was observed. Transcript analysis revealed a time-dependent shift in the expression of inflammatory molecules, with early time points showing an increase in anti-inflammatory markers, while late exposure promoting pro-inflammatory responses.<br><br>CONCLUSION: This study identifies that NAC and growth factors impede ER stress and inflammatory responses in astrocytes upon A&#x3b2; exposure in serum-free culture. These findings also highlight the potential of a serum-free culture system for studying ER stress and inflammation in astrocytes to understand the complex role of these cells in AD pathophysiology.},
}
@article {pmid40633428,
year = {2025},
author = {Zhang, M and Lin, X and He, J and Zuo, Y and Fan, Q and Agida, I and Tan, H and Zhu, C and Cheng, J and Wang, T},
title = {SENP1-Sirt3 axis regulates type II alveolar epithelial cell activity to confer resistance against oxidative damage in lung tissue.},
journal = {Redox biology},
volume = {85},
number = {},
pages = {103752},
pmid = {40633428},
issn = {2213-2317},
mesh = {*Sirtuin 3/metabolism/genetics ; *Oxidative Stress ; Animals ; *Alveolar Epithelial Cells/metabolism ; Mice ; *Cysteine Endopeptidases/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Mitochondria/metabolism ; *Pulmonary Fibrosis/metabolism/pathology/chemically induced ; Disease Models, Animal ; Bleomycin/adverse effects ; Humans ; Lung/metabolism/pathology ; Signal Transduction ; Male ; Superoxide Dismutase/metabolism ; },
abstract = {Oxidative damage exacerbates pulmonary fibrosis by impairing alveolar type II epithelial (AT2) cell function. This study demonstrates that the SUMO-specific protease 1 (SENP1)-Sirtuin 3 (Sirt3) axis, critical for mitochondrial redox regulation, is suppressed in AT2 cells during lung injury. In bleomycin-induced pulmonary fibrosis models, activating the SENP1-Sirt3 axis via Sirt3 SUMOylation site mutation (Sirt3 K223R) reduced Superoxide Dismutase 2 (SOD2) acetylation, thereby lowering mitochondrial reactive oxygen species (mtROS) accumulation and apoptosis. This intervention increased AT2 cell proliferation and differentiation into alveolar type I cells while reducing Keratin 8 (KRT8)[+] transitional cell number, a profibrotic population. Additionally, SENP1-Sirt3 activation attenuated inflammation and fibrosis in lung tissue. Transcriptomic analysis linked the axis to enhanced Wnt signaling and lipid metabolism pathways, promoting AT2 stemness. Antioxidant N-acetylcysteine (NAC) supplementation mirrored these benefits, reinforcing ROS clearance as a therapeutic mechanism. These findings highlight SENP1-Sirt3 as a pivotal regulator of AT2 resilience, offering a potential strategy to mitigate fibrosis by targeting mitochondrial oxidative stress and cellular plasticity.},
}
@article {pmid40631939,
year = {2025},
author = {Masini, S and Bruschi, M and Menotta, M and Canonico, B and Montanari, M and Ligi, D and Monittola, F and Mannello, F and Piersanti, G and Crinelli, R and Magnani, M and Fraternale, A},
title = {Redox modulation by a synthetic thiol compound reduces LPS-induced pro-inflammatory cytokine expression in macrophages via AP-1/NLRP3 axis and influences the crosstalk with endothelial cells.},
journal = {Free radical research},
volume = {59},
number = {6-7},
pages = {487-505},
doi = {10.1080/10715762.2025.2529914},
pmid = {40631939},
issn = {1029-2470},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Humans ; *Lipopolysaccharides/pharmacology ; *Macrophages/metabolism/drug effects ; Oxidation-Reduction/drug effects ; *Transcription Factor AP-1/metabolism ; *Cytokines/metabolism ; *Sulfhydryl Compounds/pharmacology ; Human Umbilical Vein Endothelial Cells/metabolism ; Inflammation/metabolism ; *Endothelial Cells/metabolism/drug effects ; Signal Transduction/drug effects ; },
abstract = {Perturbation in redox status elicits multiple cellular pathways, including those involved in the inflammatory response. A thiol-based molecule (I-152), releasing N-acetyl-cysteine (NAC) and β-mercaptoethylamine (MEA), was exploited as a redox-modulating agent, and its effects on pro-inflammatory cytokine expression and secretion in lipopolysaccharide (LPS)-stimulated macrophages (MΦ) were investigated. I-152 inhibited cytokine gene expression as well as protein secretion of the most important inflammatory cytokines in three different MΦ models in vitro and ex vivo. It alleviated inflammation via the c-Jun/AP-1 and NF-κB signaling pathways, depending on the dose, and regulated NLRP3 inflammasome expression, leading to decreased IL-1β and IL-18 release and reduced pyroptotic cell death. Consequently, the influence of redox-modulated MΦ secretome on the crosstalk with endothelial cells was evaluated. Co-culture experiments between THP-1 MΦ, that had been pretreated with I-152 before LPS stimulation, and Human Vascular Endothelial Cells (HUVECs) showed reduced VCAM/ICAM expression in these cells in concomitance with a less oxidized and inflamed MΦ proteomic portrait. Overall, our findings suggest that I-152 redox modulation could target the AP-1/NLRP3 axis, affecting LPS-induced inflammation in MΦ and influencing HUVEC responses, revealing a complex and bidirectional interchange.},
}
@article {pmid40626337,
year = {2025},
author = {Roque-Torres, JL and Woolcock, AD and Santos, A and Serpa, PBDS and Mukhopadhyay, A and Moore, GE},
title = {Effect of N-Acetylcysteine, Ascorbic Acid, and a Vitamin E Analog on Oxidative and Storage Lesions in Canine Packed Red Blood Cells.},
journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)},
volume = {35},
number = {3},
pages = {207-213},
pmid = {40626337},
issn = {1476-4431},
mesh = {Animals ; Dogs/blood ; *Acetylcysteine/pharmacology ; *Ascorbic Acid/pharmacology ; *Antioxidants/pharmacology ; *Vitamin E/pharmacology/analogs &amp; derivatives ; *Erythrocytes/drug effects ; Prospective Studies ; *Blood Preservation/veterinary ; Oxidative Stress/drug effects ; },
abstract = {OBJECTIVE: To describe storage and oxidative lesions in canine packed red blood cells (pRBCs) during routine storage with additives, including saline, N-acetylcysteine (NAC), ascorbic acid (AA), and vitamin E analog (VE).<br><br>DESIGN: Prospective, comparative study of canine pRBCs with or without antioxidant additives during routine 42-day storage.<br><br>SETTING: University teaching hospital.<br><br>ANIMALS: Nine leukoreduced units of canine pRBCs were aseptically separated into three aliquots (Groups 1, 2, and 3) on the same day as collection (day 0). All aliquots were shipped overnight and received by the investigators on day 1.<br><br>INTERVENTIONS: Antioxidants (or control solution) were added on day 1, with three treatment groups that included saline (control, Group 1), NAC and AA (Group 2), and AA and&#xa0;a VE (Group 3).<br><br>MEASUREMENTS AND MAIN RESULTS: Blood was collected from each aliquot on day 1, before the addition of antioxidants for baseline measurement of glutathione and intraerythrocytic reactive oxygen species (ROS). Additional samples were collected from each aliquot on days 7, 28, and 42. Type 3 fixed-effects tests were used to compare the impact of group and time on each measurement. All groups showed storage lesions and glutathione depletion by day 42 compared with baseline, regardless of the antioxidant additive. Intraerythrocytic ROS accumulation was lower in Group 3 (AA and a VE) compared with other groups at all time points after baseline (p&#xa0;<&#xa0;0.0001).<br><br>CONCLUSIONS: The addition of AA and a VE to canine pRBCs reduced ROS accumulation but did not prevent glutathione depletion during routine storage. Further studies using antioxidants as additives in canine pRBCs are warranted.},
}
@article {pmid40623627,
year = {2025},
author = {Kim, JE and Wang, SH and Kang, TC},
title = {Reciprocal c-Abl-GPx1 regulation controls CA1 neuronal viability to oxidative stress via ERK1/2-DRP1-mediated mitochondrial dynamics.},
journal = {Neuropharmacology},
volume = {278},
number = {},
pages = {110586},
doi = {10.1016/j.neuropharm.2025.110586},
pmid = {40623627},
issn = {1873-7064},
mesh = {Animals ; *Oxidative Stress/physiology/drug effects ; *Mitochondrial Dynamics/physiology/drug effects ; *Dynamins/metabolism ; Glutathione Peroxidase GPX1 ; *Proto-Oncogene Proteins c-abl/metabolism/antagonists &amp; inhibitors ; *Neurons/drug effects/metabolism ; *Glutathione Peroxidase/metabolism/genetics ; *CA1 Region, Hippocampal/metabolism/drug effects ; Phosphorylation/drug effects ; Male ; Cell Survival/drug effects/physiology ; Buthionine Sulfoximine/pharmacology ; *MAP Kinase Signaling System/drug effects/physiology ; Rats ; Imatinib Mesylate/pharmacology ; Status Epilepticus/metabolism ; Mitochondria/metabolism/drug effects ; },
abstract = {Abelson murine leukemia viral oncogene homolog 1 (c-Abl, also known as ABL1) is a potent selenium-independent regulator of expression and activity of glutathione peroxidase-1 (GPx1) and extracellular signal-regulated kinase 1/2 (ERK1/2). Since GPx1-ERK1/2 pathway modulates dynamin-related protein 1 (DRP1) serine (S) 616 phosphorylation, we investigated whether c-Abl participates in GPx1-ERK1/2 interaction and DRP1-mediated mitochondrial dynamics in CA1 neurons in response to oxidative stress induced by L-buthionine sulfoximine (BSO, an oxidative stress inducer) and status epilepticus (SE). In the present study, BSO enhanced c-Abl tyrosine (Y) 245 phosphorylation, ERK1/2 activity and GPx1 upregulation in the CA1 region under physiological condition. Imatinib (a c-Abl inhibitor) ameliorated BSO-induced c-Abl Y245, but elicited further ERK1/2 phosphorylation without affecting GPx1 expression. GPx1 knockdown enhanced BSO-induced c-Abl Y245 phosphorylation, but decreased ERK1/2 activity. BSO also facilitated mitochondrial fission in CA1 neurons by augmenting DRP1 expression and its S616 phosphorylation in the CA1 region, which were diminished by GPx1 knockdown and U0126 (an ERK1/2 inhibitor), but reinforced by imatinib. SE increased c-Abl Y245 phosphorylation and mitochondrial length in CA1 neurons, accompanied by reduced GPx1 expression and ERK1/2 phosphorylation. Imatinib and N-acetylcysteine (NAC, an antioxidant) attenuated these post-SE events and CA1 neuronal death. However, GPx1 knockdown deteriorated SE-induced CA1 neuronal degeneration accompanied by augmenting c-Abl Y245 phosphorylation and mitochondrial elongation in CA1 neurons. These findings indicate that the impaired reciprocal regulation between c-Abl and GPx1 may cause CA1 neuronal degeneration in response to oxidative stress by abrogating ERK1/2-DRP1-mediated mitochondrial fission.},
}
@article {pmid40619022,
year = {2025},
author = {Fang, L and Zuo, L and Xing, F and Wang, Y and Chen, R and Zhang, F and Zuo, D},
title = {Repositioning miconazole: a novel drug for inducing cell death and differentiation in myeloid leukemia.},
journal = {Biochemical pharmacology},
volume = {241},
number = {},
pages = {117126},
doi = {10.1016/j.bcp.2025.117126},
pmid = {40619022},
issn = {1873-2968},
mesh = {Humans ; Acetylcysteine/pharmacology ; Adenine/pharmacology/analogs &amp; derivatives ; Amino Acid Chloromethyl Ketones/pharmacology ; *Antifungal Agents/pharmacology/therapeutic use ; *Apoptosis/drug effects ; Caspase Inhibitors/pharmacology ; Cell Differentiation/drug effects ; *Drug Repositioning ; HL-60 Cells ; K562 Cells ; *Leukemia, Myeloid, Acute/drug therapy ; *Miconazole/pharmacology/therapeutic use ; *Myeloid Cell Leukemia Sequence 1 Protein/antagonists &amp; inhibitors ; Male ; Animals ; Mice ; Mice, Nude ; Xenograft Model Antitumor Assays ; },
abstract = {Myeloid leukemia is a common form of blood cancer worldwide. Myeloid cell leukemia-1 (MCL-1), an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family, is frequently overexpressed in various solid tumors and hematological cancers. Miconazole, a broad-spectrum anti-fungal agent, has exhibited anti-tumor properties against multiple cancer types, but its specific effects on leukemia remain unknown. The purpose of our research is to investigate whether miconazole targets MCL-1 to exert an anti-leukemic effect. Our research has demonstrated that miconazole directly binds to MCL-1 in HL60 and K562 cells, significantly inhibiting cell growth and decreasing MCL-1 protein levels, presumably by promoting MCL-1 degradation. Miconazole induces apoptosis, autophagy, and the production of reactive oxygen species (ROS). However, these effects can be attenuated by Z-VAD-FMK, 3-methyladenine (3-MA), and N-acetyl-L-cysteine (NAC). Meanwhile, miconazole-induced reduction of MCL-1 protein is reversed. Animal studies confirm the anti-myelocytic leukemia efficacy of miconazole in vivo. Unexpectedly, at low concentrations and with prolonged exposure, miconazole also promotes cell differentiation. This differentiation effect is positively associated with autophagy and ROS accumulation induced by miconazole, without altering MCL-1 expression. In conclusion, miconazole, identified through a drug repositioning (DR) approach, might be a potential therapeutic candidate for myeloid leukemia by either facilitating cell death or promoting cell differentiation.},
}
@article {pmid40618512,
year = {2025},
author = {Renaldi, R and Persico, AM and Wiguna, T and Tanra, AJ},
title = {Breaking the cycle of oxidative stress for better behavioral health in autism spectrum disorder: A scoping review.},
journal = {Asian journal of psychiatry},
volume = {110},
number = {},
pages = {104575},
doi = {10.1016/j.ajp.2025.104575},
pmid = {40618512},
issn = {1876-2026},
mesh = {Humans ; *Autism Spectrum Disorder/metabolism/therapy/physiopathology ; *Oxidative Stress/physiology/drug effects ; *Antioxidants/pharmacology/therapeutic use ; },
abstract = {Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by socio-communicative and behavioral challenges. ASD is increasingly linked to oxidative stress, which stems from a destructive imbalance state whereby excessive reactive oxygen species (ROS) overwhelm antioxidant defenses. This redox imbalance triggers a cascade of cellular dysfunctions, which in neurons include synaptic inefficiency, altered receptor function, excitotoxicity, and chronic neuroinflammation. All these dysfunctions add an additional burden to the genetic and epigenetic contributions underlying autism pathophysiology in each single individual, ultimately exacerbating ASD core symptoms. Strikingly, children with ASD exhibit diminished antioxidant capacity, correlated with heightened behavioral severity and impaired quality of life. This scoping review explores the intricate relationship between oxidative stress and ASD, evaluating current therapeutic strategies aimed at restoring redox balance while identifying critical research gaps. Interventions such as N-acetylcysteine (NAC), vitamin and mineral supplementation, and dietary antioxidants have shown promise in mitigating oxidative damage and improving social responsiveness. Other strategies, in particular hyperbaric oxygen therapy (HBOT) and cleanroom environments, are highly controversial. Well-designed randomized placebo-controlled trials (RCTs) integrating clinical and psychodiagnostic measures with precision medicine frameworks, are crucial for developing targeted therapies that, restoring redox homeostasis, may optimize neurodevelopmental outcomes. By summarizing current evidence and addressing these gaps, this review underscores the therapeutic potential of oxidative stress correction in improving the quality of life of individuals with ASD.},
}
@article {pmid40617496,
year = {2025},
author = {Hu, H and Liu, Y and Xu, C and Chen, J and Xu, S and Tang, Y and Ren, Y and Lian, Z and Wang, R and Chen, S and Sun, Y and Wei, Q and Shen, Y and Qiu, N and Xu, X},
title = {Mitochondria-targeted ROS-scavenging polymer protects the hepatocytes and macrophages against hepatic ischemia-reperfusion injury.},
journal = {Acta biomaterialia},
volume = {202},
number = {},
pages = {489-502},
doi = {10.1016/j.actbio.2025.07.004},
pmid = {40617496},
issn = {1878-7568},
mesh = {*Reperfusion Injury/pathology/metabolism/prevention &amp; control/drug therapy ; Animals ; *Reactive Oxygen Species/metabolism ; *Hepatocytes/metabolism/pathology/drug effects ; *Macrophages/metabolism/pathology/drug effects ; Mice ; *Mitochondria/metabolism/drug effects ; *Liver/pathology/metabolism ; Male ; Mice, Inbred C57BL ; *Polymers/pharmacology/chemistry ; Humans ; Cyclic N-Oxides/chemistry/pharmacology ; Antioxidants/pharmacology/chemistry ; },
abstract = {While liver transplantation (LT) is the most effective therapeutic intervention for end-stage liver diseases, hepatic ischemia-reperfusion injury (HIRI) remains a major determinant of adverse clinical outcomes. Mitochondrial reactive oxygen species (ROS) have been implicated in HIRI pathogenesis. In this study, we conjugated the small molecule, antioxidant 4‑hydroxy‑2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) with a neutral, long-circulating, and mitochondria-targeted polymer, poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), to obtain a conjugate containing 10 % TEMPO (OPT10). OPT10 exhibited reliable biocompatibility and efficiently mitigated mitochondrial ROS in hepatocytes; it was also readily internalized into hepatic macrophages, promoting polarization to the anti-inflammatory M2 phenotype for over 24 h. Through these effects, together with reducing oxidative stress and decreasing activation of the MAPK pathway, OPT10 could attenuate innate immune-driven inflammation and alleviate HIRI. Compared with clinically used antioxidants such as N-acetylcysteine (NAC) and glutathione (GSH), OPT10 exhibited superior efficacy in ameliorating HIRI in a mouse model and can be considered a promising candidate for clinical translation. STATEMENT OF SIGNIFICANCE: Liver transplantation remains an effective therapeutic intervention for end-stage liver diseases. Alleviating hepatic ischemia-reperfusion injury (HIRI) is crucial for enhancing graft viability and improving long-term patient outcomes. Excessive production of mitochondrial reactive oxygen species (mtROS) during HIRI not only exacerbates hepatocellular damage but also promotes macrophage M1 polarization, thereby driving hepatic inflammation and injury. In this study, we synthesized a mitochondria-targeted ROS-scavenging polymer that enabled precise delivery to both hepatocytes and macrophages, effectively alleviating liver injury and offering novel insights into therapeutic strategies for HIRI.},
}
@article {pmid40614987,
year = {2025},
author = {Ghosh, M and Viswaroopan, N and Kshirsagar, SM and Khan, J and Mohiuddin, S and Srivastava, RK and Athar, M and Banga, AK},
title = {Sustained delivery of 4-phenylbutyric acid via chitosan nanoparticles in foam for decontamination and treatment of lewisite-mediated skin injury.},
journal = {International journal of pharmaceutics},
volume = {682},
number = {},
pages = {125928},
doi = {10.1016/j.ijpharm.2025.125928},
pmid = {40614987},
issn = {1873-3476},
mesh = {*Chitosan/chemistry/administration &amp; dosage ; Animals ; *Phenylbutyrates/administration &amp; dosage/chemistry/pharmacokinetics ; *Nanoparticles/chemistry/administration &amp; dosage ; Skin/drug effects/metabolism ; Mice ; Delayed-Action Preparations/administration &amp; dosage ; Skin Absorption/drug effects ; Humans ; Drug Liberation ; Decontamination/methods ; Administration, Cutaneous ; Particle Size ; Chemical Warfare Agents/toxicity ; Mice, Hairless ; Drug Carriers/chemistry ; },
abstract = {Lewisite, a chemical warfare agent, induces severe skin injury by oxidative stress and endoplasmic reticulum (ER) dysfunction, necessitating innovative antidote strategies. This study developed chitosan nanoparticle-loaded foam formulations for rapid skin decontamination and sustained topical delivery of 4-phenylbutyric acid (4-PBA), an ER stress-reducing chaperone. Nanoparticles were synthesized via ionic gelation using low (LMW) and medium molecular weight (MMW) chitosan. The optimized formulations, N31 (LMW) and N35 (MMW), achieved drug loadings of 5.04 % and 10.09 % w/w, particle sizes of 141.88 ± 26.31 nm and 176.10 ± 36.97 nm, monodisperse distributions (PDI < 0.3), high entrapment efficiency (>93 %) and good stability with zeta potential of -16.67 mV and -19.37 mV, respectively. Incorporation into foam enabled both effective decontamination (>70 % efficiency) and sustained 4-PBA delivery. In vitro release studies demonstrated sustained drug release over 24 h. Permeation studies using dermatomed human skin revealed that nanoparticle formulations significantly reduced 4-PBA delivery: N35 decreased permeation by 38.4 % (214.35 ± 16.6 µg/cm[2] vs. 348.10 ± 5.37 µg/cm[2] for free 4-PBA), while N31 reduced it by 81.35 % (64.90 ± 6.89 µg/cm[2]). Both formulations retained efficacy in PAO challenged skin, with N35 delivering 158.54 ± 53.93 µg/cm[2] and N31 138.25 ± 14.72 µg/cm[2] over 24 h. Furthermore, in vivo studies showed that the optimized formulation with N35 chitosan (4-PBA N35 + N-acetyl cysteine (NAC)) significantly protects against PAO-induced skin injury and inflammatory cytokine production in Ptch1+/-/SKH-1 hairless mice. Thus, the translational feasibility and effective treatment by the foam formulated 4-PBA N35 + NAC against arsenical-induced skin injury is demonstrated.},
}
@article {pmid40610674,
year = {2025},
author = {Chen, X and Zhang, F and Zhou, Z and Jiang, D and Wen, L},
title = {Xuebijing inhibits alveolar macrophage M1 polarization by regulating ROS-mediated NLRP3 inflammasome signaling.},
journal = {In vitro cellular &amp; developmental biology. Animal},
volume = {61},
number = {7},
pages = {789-800},
pmid = {40610674},
issn = {1543-706X},
support = {2023JJ60067//Natural Science Foundation of Hunan Province/ ; kq2208449//Natural Science Foundation of Changsha/ ; 202103020580//Hunan Provincial Health and Family Planning Commission/ ; },
mesh = {*Macrophages, Alveolar/drug effects/metabolism ; *Reactive Oxygen Species/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Inflammasomes/metabolism/drug effects ; Animals ; *Signal Transduction/drug effects ; Lipopolysaccharides ; Acute Lung Injury/drug therapy/pathology/chemically induced ; *Drugs, Chinese Herbal/pharmacology ; *Cell Polarity/drug effects ; Oxidative Stress/drug effects ; Mice ; Cytokines/metabolism ; },
abstract = {BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are devastating acute pulmonary conditions with high mortality rates and limited effective treatment options. This study aimed to investigate the therapeutic potential of XBJ on ALI and its potential mechanism.<br><br>METHODS: We developed an in vitro model of lipopolysaccharide (LPS)-induced ALI and evaluated the effects of XBJ pre-treatment on oxidative stress, inflammatory responses, and the polarization state of alveolar macrophages.<br><br>RESULTS: LPS exposure significantly elevated the levels of reactive oxygen species (ROS) and oxidants 8-hydroxy-2'-deoxyguanosine (8-OHDG) and malondialdehyde (MDA) in alveolar macrophages. It also elevated the concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-&#x3b1;, interleukin (IL)-1&#x3b2;, IL-6, and IL-23. XBJ and quercetin significantly mitigated the increase in these indicators. Moreover, XBJ and quercetin both downregulated the expression of key proteins in the NLRP3 inflammasome pathway in the ALI model. Similar to the ROS inhibitor N-acetylcysteine (NAC), XBJ and quercetin significantly decreased M1 polarization markers like CD86 and inducible nitric oxide synthase (iNOS), while increasing M2 polarization markers such as CD206 and arginase-1 (Arg-1). Notably, the overexpression of NLRP3 was able to reverse the inhibitory effect of XBJ on macrophage M1 polarization.<br><br>CONCLUSION: XBJ inhibits the M1 polarization of alveolar macrophages by targeting ROS-mediated NLRP3 inflammasome signaling, thereby reducing the inflammatory response. These results indicate that XBJ may offer a novel therapeutic strategy for ALI/ARDS by modulating macrophage polarization and inflammation.},
}
@article {pmid40609922,
year = {2025},
author = {Ye, T and Tang, C and Yang, D and Zhang, Q and Liao, Y and Dai, J and Tang, H and Ke, C and Peng, Y and Ye, Y and Li, W and Zheng, J},
title = {Metabolic activation and cytotoxicity of bavachin mediated by CYP3A in mice.},
journal = {Chemico-biological interactions},
volume = {419},
number = {},
pages = {111630},
doi = {10.1016/j.cbi.2025.111630},
pmid = {40609922},
issn = {1872-7786},
mesh = {Animals ; *Cytochrome P-450 CYP3A/metabolism ; Mice ; Hepatocytes/drug effects/metabolism/cytology ; Microsomes, Liver/metabolism/drug effects ; Male ; *Flavonoids/metabolism/toxicity/pharmacokinetics ; Glutathione/metabolism ; Activation, Metabolic ; Ketoconazole/pharmacology ; Cells, Cultured ; Acetylcysteine/metabolism ; Triazoles/pharmacology ; Oxidation-Reduction ; },
abstract = {Bavachin (BVC), a flavonoid, is found in Psoraleae fructus (PF) which has been reported to induce various adverse effects, particularly hepatotoxicity, such as increases of serum alanine transaminase (ALT) and aspartate transaminase (AST) in mice given BVC. However, the mechanisms underlying its hepatotoxicity remain unclear. During the incubation of mouse microsomes with BVC in the presence of glutathione (GSH) or N-acetylcysteine (NAC), one oxidative metabolite (M1), one GSH conjugate (M2), and one NAC conjugate (M3) were observed. M1 was successfully synthesized by selective oxidation of BVC. Similar microsomal incubations of synthetic M1 offered M2 and M3. Following oral administration of BVC, the presence of biliary M2 and urinary M3 was observed in mice given BVC. CYP3A identified as the major enzyme was involved in the metabolic activation of BVC. The metabolic activation of BVC involved hydroxylation of BVC and sequential oxidation of the hydroxylation product to the corresponding o-quinone derivative. BVC treatment resulted in significant cytotoxicity in cultured mouse primary hepatocytes, and pretreatment with 1-aminobenzotriazole and ketoconazole decreased the susceptibility of hepatocytes to the cytotoxicity of BVC. Oral administration of PF extract resulted in a quick decline in hepatic GSH, along with the detection of GSH conjugate M2, in mice. BVC, a principal component of PF, was also found to deplete hepatic GSH in mice over a brief period. This evidence suggests that metabolic activation of BVC leads to depletion of GSH in vivo and that BVC contributes to the depletion of hepatic GSH caused by PF extract.},
}
@article {pmid40605647,
year = {2025},
author = {Gok, O and Sharma, A and Kambhampati, SP and Smith Khoury, E and Kannan, S and Kannan, RM},
title = {Sustained and Step-Wise Drug Release by a Novel Double Responsive Dendrimer-N-Acetylcysteine Conjugate.},
journal = {Biomacromolecules},
volume = {26},
number = {7},
pages = {4274-4285},
doi = {10.1021/acs.biomac.5c00283},
pmid = {40605647},
issn = {1526-4602},
mesh = {*Dendrimers/chemistry ; *Acetylcysteine/chemistry/pharmacology ; Drug Liberation ; Animals ; Microglia/drug effects/metabolism ; Delayed-Action Preparations/chemistry ; Mice ; Blood-Brain Barrier ; Drug Delivery Systems ; *Anti-Inflammatory Agents/pharmacology/chemistry ; Humans ; Antioxidants/chemistry/pharmacology ; },
abstract = {Polyamidoamine (PAMAM) dendrimers have emerged as promising vehicles for targeting the brain due to their intrinsic ability to penetrate through the injured blood-brain barrier. Herein, we present a novel drug delivery system based on a fourth generation PAMAM dendrimer as a brain targeting nanomedicine for the delivery of an anti-inflammatory drug N-acetyl cysteine with a sustained drug release profile. This D"ester"(NAC"ss"NAC) design enables NACs conjugated to the periphery of PAMAM dendrimers in the dimer form with ester and disulfide bonds to be sequentially released in a stepwise manner, responding to environmental pH and redox potential. Moreover, in vitro studies were conducted with a fluorescently labeled conjugate to confirm its nontoxic behavior and time-dependent cellular uptake, together with improved anti-inflammatory and antioxidative effects over endotoxin-activated microglia. These findings demonstrate that the DNACNAC conjugate has a high potential to be utilized as a promising dendrimer-based nanomedicine platform for prolonged treatment of neuroinflammation-related CNS disorders.},
}
@article {pmid40603753,
year = {2025},
author = {Tang, Y and Luo, J and Jiang, B and Deng, J and Li, J and Qin, L},
title = {Overexpression of MEOX2 inhibits breast cancer cell metastasis by targeting oxidative stress-induced RGS5.},
journal = {In vitro cellular &amp; developmental biology. Animal},
volume = {61},
number = {7},
pages = {871-885},
pmid = {40603753},
issn = {1543-706X},
mesh = {Humans ; *Breast Neoplasms/pathology/genetics/metabolism ; *Oxidative Stress/genetics/drug effects ; Female ; *RGS Proteins/metabolism/genetics ; Animals ; Neoplasm Metastasis ; Cell Adhesion/drug effects/genetics ; Reactive Oxygen Species/metabolism ; *Homeodomain Proteins/genetics/metabolism ; Mice ; MCF-7 Cells ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; Cell Proliferation/genetics/drug effects ; Hydrogen Peroxide/pharmacology ; Mice, Nude ; Cell Movement/genetics ; Cell Survival/drug effects/genetics ; Endothelial Cells/metabolism/pathology ; Mice, Inbred BALB C ; },
abstract = {This study aimed to investigate the role of mesenchymal homeobox 2 (MEOX2) on breast cancer cell metastasis and its underlying mechanism. Overexpression of MEOX2 in human lymphatic endothelial cell (HLEC) lines was established to assess the adhesion and transendothelial migration of MCF7 and MDA-MB-231 cells to the HLEC cells. After being treated with the oxidative stress inducer H2O2 and the antioxidant N-acetylcysteine (NAC), cell viability, reactive oxygen species (ROS) levels, adhesion, and transendothelial migration of MCF7 and MDA-MB-231 cells to HLEC cells were detected. Tumor volume changes were observed in the xenograft model. The expression of C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 7 (CCR7), MEOX2, and G protein signal transduction regulator 5 (RGS5) in tumor tissues and ROS levels were detected. MEOX2 was lowly expressed in breast cancer tissues. Upregulated MEOX2 inhibited the proliferation of lymphatic endothelial cells and the adhesion and transendothelial migration of MCF7 and MDA-MB-231 cells to HLEC cells. After MCF7 and MDA-MB-231 cells were treated with oxidative stress inducer H2O2, ROS levels increased, and cell viability and MEOX2 expression decreased. After NAC or overexpressed MEOX2 treatment, MEOX2 expression increased, ROS and RGS5 levels, adhesion, and transendothelial migration ability decreased in HLEC cells. Overexpression of MEOX2 resulted in smaller tumor volume, lower ROS levels, and lower CXCR4 and CCR7 expression levels. MEOX2 and RGS5 are pivotal in regulating breast cancer metastasis, offering valuable insights into potential therapeutic strategies for breast cancer metastasis.},
}
@article {pmid40603325,
year = {2025},
author = {Asgharzadeh, J and Derakhshan, L and Asgharzadeh, N and Mardani, M and Shahrani, D and Shahrani, M and Shahrani Korrani, M},
title = {N-acetylcysteine reduces the hepatic complications of social isolation stress through modulation of interleukin 1 and 6 gene expression and liver enzymes in mice.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23166},
pmid = {40603325},
issn = {2045-2322},
support = {IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Social Isolation/psychology ; Mice ; Male ; *Liver/drug effects/enzymology/metabolism ; Female ; *Interleukin-6/genetics/metabolism ; *Stress, Psychological/complications/drug therapy ; *Interleukin-1beta/genetics/metabolism ; Oxidative Stress/drug effects ; Catalase/metabolism ; Antioxidants/pharmacology/metabolism ; Malondialdehyde/metabolism/blood ; *Liver Diseases/etiology/drug therapy ; },
abstract = {Social isolation stress can alter liver function. This study examined the effects of N-acetylcysteine (NAC) on biochemical and genetic liver changes in mice under social isolation stress. Ten male and ten female mice were individually placed in Plexiglas cages for mating. Their pups were divided into six groups of eight (three male and three female): a control group receiving normal saline, a social isolation stress group (SIS + NS) also receiving saline, and a social isolation stress group treated with intraperitoneal NAC (SIS + NAC). Behavioral tests, including Resident Intruder, Sociability Index, and Social Novelty Preference Index, were conducted. Liver catalase, serum antioxidant capacity, malondialdehyde, and gene expression of interleukin 1 beta and interleukin 6 in the liver were assessed. NAC reduced violent behaviors while increasing interaction duration and frequency in the Sociability test. It enhanced liver catalase and serum antioxidant capacity while reducing serum malondialdehyde and liver interleukin 1 beta and interleukin 6 expression. The results of this study showed that N-acetylcysteine exerts its effects by reducing oxidative stress and reducing genes involved in inflammation. These findings suggest that NAC, with its antioxidant and anti-inflammatory properties, mitigates liver damage caused by social isolation stress.},
}
@article {pmid40601178,
year = {2025},
author = {Azarmehr, Z and Poshtareh, F and Shafiei, N and Shirinsokhan, A and Rahmati, F},
title = {The neuroprotective effect of N-acetylcysteine by regulating inflammation and expression ‎of TNF-α and ERK gene expression in the rats exposed to different doses of cadmium.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {666},
pmid = {40601178},
issn = {1573-4978},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Rats ; *Cadmium/toxicity ; *Tumor Necrosis Factor-alpha/genetics/metabolism ; Rats, Wistar ; *Inflammation/metabolism/drug therapy/genetics ; Male ; *Neuroprotective Agents/pharmacology ; Gene Expression Regulation/drug effects ; MAP Kinase Signaling System/drug effects ; Brain/drug effects/metabolism/pathology ; Gene Expression/drug effects ; Interleukin-1beta/metabolism ; },
abstract = {BACKGROUND: Cadmium is known to disrupt cellular proliferation through unregulated cell division. This process leads to activation of TNF-α cytokines, resulting in cellular damage and increased inflammation in cells, including brain cells. This study investigates the regulation of TNF-α and ERK gene expression patterns mediated by N-acetylcysteine in response to cadmium exposure in Wistar rats.‎.<br><br>METHODS AND RESULTS: Wistar rats (n&#x2009;=&#x2009;37) were divided into five groups: control (G1), acute cadmium exposure (G2), chronic cadmium exposure (G3), acute cadmium with N-acetylcysteine (G4), and chronic cadmium with N-acetylcysteine (G5). Brain tissue sections were prepared and stained with H&amp;E. Then, the G-FAP was measured &#x200e;using immunohistochemistry. ELISA was employed to detect IL-1&#x3b2; and IL-10 levels. TNF and ERK gene expression &#x200e;was assessed using RT-PCR. Histopathological examination revealed increased glial inflammatory cells in groups G2 and G3. N-acetylcysteine reduced inflammatory cell infiltration, and G-FAP staining confirmed decreased astrocytic accumulation in G5. IL-1&#x3b2; levels significantly decreased in G5 after N-acetylcysteine therapy, while IL-10 levels increased after treatment but subsequently declined due to chronic cadmium exposure. TNF gene expression increased in G2 and G3 but decreased significantly in G5, demonstrating N-acetylcysteine's suppressive effect. Furthermore, ERK gene expression significantly increased in G2 and &#x200e;G3. However, there were notable decreases in both G4 and G5 compared to cadmium-exposed controls.<br><br>CONCLUSION: This study demonstrated that N-acetylcysteine mitigates oxidative stress-induced tissue damage, prevents apoptosis, and exhibits anti-inflammatory properties by downregulating TNF-&#x3b1; and upregulating ERK gene expression.},
}
@article {pmid40600170,
year = {2025},
author = {Soleimani, P and Nekoonam, S and Zafari, F and Sabbaghziarani, F},
title = {Effects of the combination of melatonin and N-acetylcysteine on the inflammatory response in a rat model of cerebral ischemia.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {83-90},
pmid = {40600170},
issn = {2667-2421},
abstract = {Stroke is the second leading cause of death and long-term damage globally. Inflammation is a significant factor in the onset of ischemic stroke. This study investigated the simultaneous administration of melatonin and N-acetylcysteine (NAC) on inflammation in rat cerebral ischemia. First, 30 male Wistar rats were randomly divided into five groups (n = 6), including the sham group without ischemia, the ischemic group, and the ischemic groups treated with NAC, melatonin, and NAC + melatonin, respectively. To induce ischemia, a silicone-coated monofilament was placed from the common carotid artery towards the middle cerebral artery and stained for 60 min. The rats were treated by administering NAC (50 mg/kg), melatonin (5 mg/kg) and the combination of NAC + melatonin by intraperitoneal injection after ischemia induction. The animals were assessed for sensory-motor activity at 24 and 72 h. Following sacrifice, the rats' brain was dissected to estimate infarct volume after triphenyltetrazolium chloride (TTC) staining. Inflammatory parameters were then analyzed through gene expression analysis using reverse transcription quantitative polymerase chain reaction (RT-qPCR) for nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and nucleotide oligomerization domain (NOD)-like receptor family with pyrin domain 1 and 3 (NLRP1 and NLRP3). The results showed a significant decrease in mRNA expression of the target genes in the rats treated with NAC + melatonin compared to the ischemic group (p < 0.05). The group that received the combined treatment exhibited enhanced sensory-motor function and a reduced brain infarct volume compared to the other groups (p < 0.05). In summary, the combined use of NAC and melatonin has shown promise in enhancing neurobehavioral function and decreasing the volume of cerebral infarction by regulating the inflammatory signaling pathway.},
}
@article {pmid40599576,
year = {2025},
author = {Zertuche-Arias, T and Alatorre-Meda, M and Rivero, IA and Juárez, P and Castro-Ceseña, AB},
title = {N-Acetylcysteine and pro-adrenomedullin dual-crosslinked gelatin-chitosan hydrogels with enhanced mechanical and mineralization performance.},
journal = {RSC advances},
volume = {15},
number = {28},
pages = {22524-22533},
pmid = {40599576},
issn = {2046-2069},
abstract = {Bone regeneration requires coordination between bone formation, vascularization, and inflammatory regulation. However, current biomaterials often fail to provide mechanical stability and sustained bioactivity while supporting cell viability. This study presents the development and characterization of hydrogels composed of methacrylated gelatin (GelMA) and chitosan methacrylate (ChMA), crosslinked by photopolymerization (GC hydrogels). These were evaluated for their mineralization potential in vitro and ex vivo when loaded with N-acetylcysteine (NAC), a bioactive antioxidant (GCN); a pro-angiogenic peptide derived from adrenomedullin (PAMP, GCP); or both compounds (GCNP). FT-IR spectroscopy confirmed successful polymer methacrylation and the interaction of NAC with the polymer network. Scanning electron microscopy revealed that NAC increased the pore size from 24.49 ± 14.19 μm (GC) to 200.49 ± 80.42 μm (GCN). NAC also enhanced mechanical performance, with GCN exhibiting the highest compressive strength (151.79 ± 44.81 kPa) and GCNP the highest stiffness (Young's modulus: 55.26 ± 5.79 kPa). NAC-containing hydrogels degraded faster than GC, enabling biphasic release over 14 days. In vitro and ex vivo assays using pre-osteoblastic cells and a calvarial defect model demonstrated that GCNP hydrogels significantly enhanced cell viability and mineralization, increasing calcium deposition by 2.5-fold compared to GC (p < 0.01). These findings suggest that NAC not only reinforces the mechanical strength of hydrogel scaffolds designed for temporary support in non-load-bearing bone defects, but also acts as a bioactive agent upon release. Its combination with the pro-adrenomedullin peptide (PAMP) results in synergistic effects on mineralization. GCNP hydrogels are therefore promising candidates for drug delivery and bone tissue regeneration.},
}
@article {pmid40599236,
year = {2025},
author = {Tan, J and Bao, Z and Qin, K and Zhu, L and Zheng, C and Jin, J and Zhang, L and Xu, H},
title = {Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E-Dependent Pyroptosis in Pancreatic Cancer Cells.},
journal = {MedComm},
volume = {6},
number = {7},
pages = {e70250},
pmid = {40599236},
issn = {2688-2663},
abstract = {Mutations in mitogen-activated protein kinase kinase (MEK) are prevalent in pancreatic ductal adenocarcinoma (PDAC), but many MEK inhibitors inadvertently activate protein kinase B (AKT). We propose a promising PDAC treatment strategy by combining the MEK inhibitor trametinib with neobractatin (NBT), a natural compound from Garcinia bracteata. Our results demonstrated that this combination significantly impeded cell growth by inducing gasdermin E (GSDME)-mediated pyroptosis and apoptosis. GSDME, overexpressed in PDAC tissues and correlated with histological differentiation, underscores the role of pyroptosis in PDAC. RNA-seq results indicated that the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was the primary target of the combination treatment. Mechanistic studies revealed the combination effectively reduced both total and phosphorylated AKT levels, thereby inhibiting protein kinase B/IκB kinase (AKT/IKK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathways. Additionally, the combination disrupted mTOR complex 2 (mTORC2), preventing the trametinib-induced AKT activation. MicroRNA sequencing analysis indicated that the combination reduced AKT levels by upregulated miR-149-5p. Further research demonstrated that the combination increased intracellular reactive oxygen species (ROS), while N-acetylcysteine (NAC, a ROS scavenger) reversed the cell growth inhibition and AKT suppression. In vivo, the combination significantly inhibited tumor growth by inducing pyroptosis and apoptosis, outperforming gemcitabine. Our findings provide novel insights into the potential of combining NBT and trametinib to induce pyroptosis and apoptosis through the ROS/AKT/GSDME axis, offering a theoretical basis for future PDAC treatment.},
}
@article {pmid40598772,
year = {2025},
author = {Wang, Y and Liu, J and Zhu, S and Hu, S and Chen, X and Mandon, E and Tran, NT and Zhang, S and Qi, Y and Ma, H and He, R and Cao, Y and Su, Q and Gallagher, TL and Li, Z and Zhou, C and Tai, PWL and Gao, G and Xie, J},
title = {miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {33},
number = {10},
pages = {4874-4888},
pmid = {40598772},
issn = {1525-0024},
mesh = {*MicroRNAs/genetics ; *Acetaminophen/adverse effects ; Animals ; *Liver Failure, Acute/chemically induced/genetics/metabolism/etiology/prevention &amp; control/pathology ; Mice ; Disease Models, Animal ; Humans ; *Chemical and Drug Induced Liver Injury/genetics/metabolism/etiology ; *Gene Expression Regulation ; Dependovirus/genetics ; Cytochrome P-450 CYP2E1/genetics/metabolism ; Male ; Glutathione Transferase/genetics/metabolism ; Liver/metabolism/pathology ; Genetic Vectors/genetics ; },
abstract = {Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), primarily through the excessive production of N-acetyl-p-benzoquinone imine (NAPQI). N-acetylcysteine (NAC) is the Food and Drug Administration-approved treatment for APAP overdose, but there is a growing interest in microRNAs as potential therapeutic agents. We delivered miR-375 ectopically via a liver-tropic adeno-associated virus serotype 8 (AAV8) and demonstrated its potent protection in a murine model of APAP overdose-induced ALF. Slc16a2, Cyb5b, and Acsl5 were identified as critical targets acting synergistically to mitigate toxicity. Liver transcriptome revealed that miR-375 overexpression or silencing of the targets of miR-375 increased Gstm3 expression in mice. AAV8-mediated Gstm3 expression protects against APAP-ALF, and the protection was further enhanced by disrupting the expression of Cyp2e1. Additionally, CYP2E1 and GSS, which contribute to APAP detoxification, were down- and upregulated by miR-375, respectively. These findings suggest that miR-375 prevents APAP-ALF by orchestrating the expression of pharmacogenes and enhancing glutathione synthesis. We conclude that miR-375 and its targets are promising therapeutic targets for APAP-ALF.},
}
@article {pmid40596939,
year = {2025},
author = {Shiau, JP and Yang, CW and Liu, W and Yu, SY and Yen, CH and Chang, FR and Sheu, JH and Chang, HW},
title = {Excavatolide C has oxidative-stress-dependent antiproliferative and apoptotic effects against breast cancer cells.},
journal = {BMC cancer},
volume = {25},
number = {1},
pages = {1023},
pmid = {40596939},
issn = {1471-2407},
support = {KMUH108-8M37, KMUH109-9M35, and KMUH111-1M32//Kaohsiung Medical University Hospital/ ; MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology, Taiwan/ ; #NSYSUKMU 112-P06//National Sun Yat-sen University-KMU Joint Research Project/ ; KMU-TC113A04//Kaohsiung Medical University Research Center/ ; KMU-DK(A)113003 and KMU-TB114009//Kaohsiung Medical University/ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Cell Proliferation/drug effects ; Female ; Cell Line, Tumor ; *Triple Negative Breast Neoplasms/drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; DNA Damage/drug effects ; Membrane Potential, Mitochondrial/drug effects ; *Antineoplastic Agents/pharmacology ; Anthozoa/chemistry ; *Macrolides/pharmacology ; Animals ; MCF-7 Cells ; *Breast Neoplasms/drug therapy ; },
abstract = {BACKGROUND: Triple negative breast cancer (TNBC) shows a poor response to targeted therapy drugs for non-triple-negative breast cancer (non-TNBC). Developing anticancer drugs that are effective for both TNBC and non-TNBC cells is necessary. The marine coral Briareum excavatum-derived excavatolide C (EXCC) exhibits anti-bladder cancer cell proliferation. However, the anti-breast cancer properties and drug safety of are unclear.<br><br>METHODS: This study aimed to evaluate the antiproliferative effect and mechanisms (oxidative stress, DNA damage, and apoptosis) caused by EXCC on TNBC and non-TNBC cells in parallel with normal cells.<br><br>RESULTS: EXCC demonstrated higher antiproliferative effects in various breast cancer cell lines (MDA-MB-231, Hs578t, MDA-MB-468, and MCF7) than in normal breast cell lines (H184B5F5/M10; M10) as detected in a 48&#xa0;h ATP assay. MDA-MB-231 and MCF7 were chosen as representative TNBC and non-TNBC cells, respectively, to clarify the underlying molecular mechanisms. EXCC highly upregulated reactive oxygen species and mitochondrial superoxide, reduced the mitochondrial membrane potential, and downregulated glutathione in breast cancer compared with normal cells. These EXCC-triggered antiproliferative and oxidative stress changes were attenuated by the ROS inhibitor N-acetylcysteine (NAC). Consistently, in breast cancer cells, EXCC triggered subG1 accumulation, apoptosis, caspase activation, and DNA damage (&#x3b3;H2AX and 8-hydroxy-2'-deoxyguanosine), all of which were alleviated by NAC.<br><br>CONCLUSION: Overall, the antiproliferative effects and molecular mechanisms caused by EXCC in breast cancer treatment depend on oxidative stress. Without cytotoxicity to normal cells, EXCC is a potential antiproliferative marine natural product for TNBC and non-TNBC cells.},
}
@article {pmid40596396,
year = {2025},
author = {Bozdemir, N and Cakir, C and Cinar, O and Cinar, FU},
title = {Antioxidant-supplemented media modulates ROS by regulating complex I during mouse oocyte maturation.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23029},
pmid = {40596396},
issn = {2045-2322},
support = {1919B012303439//The Scientific and Technological Research Council of Turkey/ ; 1919B012303439//The Scientific and Technological Research Council of Turkey/ ; },
mesh = {Animals ; *Reactive Oxygen Species/metabolism ; Mice ; *Oocytes/metabolism/drug effects/cytology ; *Antioxidants/pharmacology ; Female ; Oogenesis/drug effects ; *In Vitro Oocyte Maturation Techniques/methods ; *Electron Transport Complex I/metabolism ; *Culture Media/pharmacology/chemistry ; Ubiquinone/analogs &amp; derivatives/pharmacology ; Acetylcysteine/pharmacology ; },
abstract = {In Vitro Oocyte Maturation (IVM) is a technique used to mature oocytes in laboratory setting. However, IVM can lead to an imbalance of reactive oxygen species (ROS), which can damage the oocytes. To prevent this, antioxidants are added to the culture medium. How these antioxidants affect Complex I, a crucial ROS-producing protein within the mitochondrial membrane, remains uncertain. To address this gap, our study aimed to achieve two key objectives. First, we investigated, for the first time, the Complex I expression during mouse oogenesis. Second, we examined the influence of an antioxidant-containing medium on Complex I and ROS levels. Germinal vesicle (GV)-stage oocytes were incubated in culture media containing acetyl-l-carnitine (ALC), α-lipoic acid (ALA), MitoQ, N-acetyl-l-cysteine (NAC) until the metaphase I (MI) and metaphase II (MII) stages. Complex I and ROS levels increased in MI and MII oocytes. Additionally, ALA and NAC increased Complex I and ROS levels, while MitoQ decreased these levels in MI and MII oocytes. Interestingly, ALC did not affect MI oocytes, but decreased the Complex I and ROS levels in MII oocytes. By elucidating the interplay between antioxidants, Complex I, and ROS during oogenesis, we pave the way for future research to improve female fertility.},
}
@article {pmid40590290,
year = {2025},
author = {Nikoosokhan, P and Ghezelayagh, Z and Hajiaghalou, S and Alizadeh Moghadam Masouleh, A and Ebrahimi, B},
title = {In Vitro Culture of Vitrified Immature Mouse Testicular Tissue in The Presence of N-acetylcysteine Antioxidant.},
journal = {International journal of fertility &amp; sterility},
volume = {19},
number = {3},
pages = {296-304},
pmid = {40590290},
issn = {2008-076X},
abstract = {BACKGROUND: Cryopreservation of immature testicular tissue is a suitable method for spermatogonial stem cell (SSC) preservation in prepubertal boys, who are at risk of infertility due to cancer treatments. Viable spermatozoa can be obtained by transplantation or in vitro culture of cryopreserved testicular tissue. Optimizing the culture conditions is essential for reducing tissue damage caused by oxidative stress produced during cryopreservation and culture. Our objective was to improve the culture conditions of vitrified immature mouse testicular tissue by using N-acetylcysteine (NAC) antioxidant.<br><br>MATERIALS AND METHODS: In this experimental study, testicular tissues of 6-day-old immature NMRI mice were isolated, vitrified, and distributed into three groups: control, culture I (cultured without NAC), and culture II (cultured in the presence of 125 mM NAC). After seven days of culture, histological analysis, cell viability, apoptotic-related gene expression, promyelocytic leukaemia zinc finger (Plzf) gene expression, and Caspase-3 protein expression were assessed. Moreover, the malondialdehyde (MDA) level was measured in the culture media.<br><br>RESULTS: Tissue integrity and higher viability level were observed in the culture II group compared to the other two groups. Furthermore, the Bax/Bcl-2 ratio and MDA level were decreased significantly in the culture &#x4c0;&#x4c0; group, whereas Caspase-3 and Plzf gene expression were significantly increased.<br><br>CONCLUSION: Our data revealed that the presence of 125 mM NAC improves the developmental process of vitrifiedwarmed immature mouse testicular fragments during in vitro culture, thus it may have potential implications for in vitro culturing of human prepubertal testicular tissues.},
}
@article {pmid40584623,
year = {2025},
author = {Lounici, A},
title = {Guarding minds: a narrative review on how n-acetylcyteine and ketones could shield sensitive patients from antibiotic neurotoxicity.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1613152},
pmid = {40584623},
issn = {1663-9812},
abstract = {BACKGROUND: Antibiotics, indispensable in combating infectious diseases and extending life expectancy, are among the most commonly prescribed medications globally. However, neurotoxicity, encompassing neurological and psychiatric adverse effects, is an underrecognized phenomenon associated with all major classes of antibiotics. Certain antibiotics, such as fluoroquinolones, carry risks of permanent damage, including central and peripheral nervous system injury and mitochondrial dysfunction. Sensitive populations, such as the elderly and individuals with compromised organ function or genetic predispositions, are particularly vulnerable.<br><br>AIMS: To review evidence on the neurological and psychiatric side effects of antibiotics and evaluate potential neuroprotective strategies like N-acetylcysteine (NAC) and ketone bodies.<br><br>METHOD: Narrative review of preclinical and clinical studies, clnical case reports and epidemiological data.<br><br>RESULTS: Neurological and psychiatric side effects are rare, but they can be devastating. NAC shows promise in preclinical studies for mitigating oxidative stress and cellular damage. Ketones, through ketogenic diets or exogenous supplementation, may provide neuroprotection via enhanced mitochondrial function and anti-oxidative and anti-inflammatory effects.<br><br>CONCLUSION: While initial findings are promising, further research is required to validate the clinical efficacy of these protective agents. Improved understanding of antibiotic neurotoxicity and potential mitigation strategies could lead to safer prescribing practices, particularly for vulnerable populations, balancing risk mitigation with the essential benefits of antibiotics.},
}
@article {pmid40583489,
year = {2025},
author = {Niu, C and Li, RT and Hao, XS and Qi, X and Wang, FZ and Fei, HR},
title = {Scutebarbatine B Exerts Anti-Breast Cancer Activity by Inducing Cell Cycle Arrest and Apoptosis Through Multiple Pathways.},
journal = {Phytotherapy research : PTR},
volume = {39},
number = {8},
pages = {3432-3449},
doi = {10.1002/ptr.70007},
pmid = {40583489},
issn = {1099-1573},
support = {ZR2022MH178//Shandong Provincial Natural Science Foundation, China/ ; ZR2022MH178//Shandong ProvincialNatural Science Foundation, China/ ; },
mesh = {*Apoptosis/drug effects ; Humans ; Female ; Animals ; *Breast Neoplasms/drug therapy/pathology ; *Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Mice ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays ; *Scutellaria/chemistry ; Signal Transduction/drug effects ; Cell Proliferation/drug effects ; Mice, Inbred BALB C ; *Diterpenes/pharmacology ; *Antineoplastic Agents, Phytogenic/pharmacology ; DNA Damage/drug effects ; Mice, Nude ; Cyclin B1/metabolism ; Cell Survival/drug effects ; MCF-7 Cells ; },
abstract = {Breast cancer is the most commonly occurring cancer among women with high mortality. Identifying effective anticancer compounds to improve the overall survival is imperative. The present study was designed to evaluate the effects and underlying mechanisms of Scutebarbatine B (SBT-B), a diterpenoid alkaloid extracted from Scutellaria barbata D. Don (S. barbata), on breast cancer. Cell viability assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, immunofluorescence, flow cytometry analysis, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining, Western blot analysis, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), and dihydroethidium (DHE) staining were performed to elucidate the anticancer mechanisms of SBT-B in vitro. Mice xenograft models were used to assess the anticancer properties in vivo. We demonstrated that SBT-B suppressed the proliferation of breast cancer cells in a dose-dependent manner. SBT-B treatment induced DNA damage response, G2/M phase arrest and downregulated the expression of cyclinB1, cyclinD1, Cdc2, and p-Cdc2. SBT-B could trigger apoptosis through increasing the cleavage of caspase-8, caspase-9 and PARP in breast cancer cells. Additionally, SBT-B elevated the generation of intracellular reactive oxygen species (ROS). Treatment with a ROS scavenger N-acetyl cysteine (NAC) partially blocked viability reduction and cleavage of caspase-8 and PARP induced by SBT-B. Moreover, SBT-B blocked pRB/E2F1 and Akt/mTOR pathways. Incubation with SBT-B increased the expression of IRE1 and phospho-JNK. In vivo, SBT-B exhibited significant suppression of tumor growth in xenograft models. We demonstrate firstly that SBT-B induces DNA damage, cell cycle arrest and apoptosis in breast cancer cells. ROS generation, suppression of oncogenic signaling and activation of IRE1/JNK pathway play an essential role in the anticancer activity of SBT-B. Our study highlights the potential of SBT-B as an alternative candidate to treat human breast cancer.},
}
@article {pmid40582321,
year = {2025},
author = {Ziari, HA and Shaki, F and Seyedabadi, M and Safarzade, A and Amiri, FT and Talebi-Garakani, E and Sayyad, MS},
title = {Protective effects of benfotiamine supplementation and aerobic training against noise-induced cardiovascular damage: A focus on oxidative stress and inflammatory pathways.},
journal = {Biochemical and biophysical research communications},
volume = {777},
number = {},
pages = {152235},
doi = {10.1016/j.bbrc.2025.152235},
pmid = {40582321},
issn = {1090-2104},
mesh = {Animals ; *Oxidative Stress/drug effects ; Male ; Mice ; *Physical Conditioning, Animal ; *Noise/adverse effects ; Inflammation ; *Cardiovascular Diseases/prevention &amp; control/etiology ; Antioxidants ; Dietary Supplements ; Thiamine/analogs &amp; derivatives ; },
abstract = {BACKGROUND: Environmental pollution, particularly noise exposure, may contribute to the development and progression of cardiovascular disorders by triggering oxidative stress and inflammatory pathways. This study evaluated the protective effects of benfotiamine (BFT) supplementation and moderate-intensity continuous training (MICT), alone or in combination, against noise-induced cardiac damage in male mice.<br><br>METHODS AND RESULTS: Eight-week-old mice (n&#xa0;=&#xa0;8/group) were divided into six groups: control, noise-exposed (Noise) subjected to 100&#xa0;dB (dB), noise&#xa0;+&#xa0;moderate-intensity continuous exercise training (MICT), noise&#xa0;+&#xa0;BFT group (200&#xa0;mg/kg/day), noise&#xa0;+&#xa0;MICT&#xa0;+&#xa0;BFT, and noise&#xa0;+&#xa0;N-acetylcysteine (NAC) groups. Noise exposure and other treatments were administered over four weeks. Histopathological changes, oxidative stress parameters, and the gene expression of inflammatory markers were evaluated. Noise exposure markedly increased cardiac ROS, NO, MDA, and protein carbonyl content, while significantly decreasing GSH and FRAP levels (all p&#xa0;<&#xa0;0.001 vs. control). Treatment with BFT or MICT partially restored redox balance, whereas combined BFT&#xa0;+&#xa0;MICT treatment produced more pronounced improvements (e.g.<br><br>, MDA: 9.91&#xa0;&#xb1;&#xa0;4.45; GSH: 101.2&#xa0;&#xb1;&#xa0;20.1&#xa0;&#x3bc;M). Inflammatory markers IL-6, TNF-&#x3b1;, IL-1&#x3b2;, and NF-&#x3ba;B were upregulated by noise and significantly attenuated by all interventions, with the greatest reduction observed in the combined group. Histological analysis confirmed that the combined therapy more effectively preserved myocardial architecture compared to monotherapies.<br><br>CONCLUSION: Our findings suggest that BFT's antioxidant and anti-inflammatory properties, in combination with MICT as a non-pharmacological approach, may protect against noise-induced cardiovascular problems. BFT and MICT mitigate noise-induced cardiac injury via antioxidant and anti-inflammatory mechanisms, with additive benefits evident in the combined treatment group.},
}
@article {pmid40579121,
year = {2025},
author = {Ma, H and Cao, T and Zhang, F and Sun, D and Chen, L and Lin, Y and Lai, S and Jiang, B and Zhou, Y and You, J and Liu, X and Wang, Y and Lin, F and Liu, Y and Wang, J and He, W and Li, Q},
title = {Nuclear Pirin promotes HCC by acting as a key inflammation-facilitating factor.},
journal = {Gut},
volume = {},
number = {},
pages = {},
doi = {10.1136/gutjnl-2024-334087},
pmid = {40579121},
issn = {1468-3288},
abstract = {BACKGROUND: Chronic inflammation and elevated reactive oxygen species are key contributors to hepatocellular carcinoma (HCC) progression.<br><br>OBJECTIVE: This study aims to investigate the role of the oxidative stress sensor protein Pirin (PIR) as a critical mediator of inflammation in HCC progression.<br><br>DESIGN: We investigated PIR's role in HCC tumourigenesis through RNA interference, genetic knockout and pharmaceutical inhibition in HCC cell lines and various mouse models. Furthermore, we used transcriptomics, quantitative reverse transcription PCR, western blot, immunofluorescence staining and immunohistochemistry analysis to elucidate the molecular details.<br><br>RESULTS: This study reveals a novel redox-dependent mechanism governing PIR's nuclear shuttling, contributing to liver inflammation and HCC progression. We identified a positive feedback axis where nuclear PIR amplifies inflammatory responses, leading to hepatitis and HCC advancement. Cytokines in this loop are regulated by PIR-enhanced v-rel reticuloendotheliosis viral oncogene homolog A (RELA) transcription, promoting PIR's nuclear translocation, increasing proinflammatory cytokine levels, and disrupting redox balance. We confirmed that liver parenchymal cells produce autocrine cytokines supporting their growth and malignancy. Notably, PIR's redox-mediated nuclear shift can be inhibited by N-acetyl cysteine or PIR inhibitors, reducing HCC promotion in mice.<br><br>CONCLUSION: We elucidate a novel redox-dependent regulatory mechanism governing the nuclear localisation of PIR and its role in promoting liver inflammation and HCC progression. Our findings underscore the significance of cellular redox status in regulating PIR's activity and highlight the potential of targeting this pathway with antioxidants to mitigate HCC progression.},
}
@article {pmid40566670,
year = {2026},
author = {Dorodian, P and Shahverdi, A and Alizadeh, A and Rashki Ghaleno, L and Abbasihormozi, S and Esmaeili, V and Akbarinejad, V and Sharafi, M},
title = {Effects of N-Acetyl Cysteine on Human Post-Thaw Sperm Quality and Mitochondrial Uncoupling Protein 2 Relative Quantity.},
journal = {Biopreservation and biobanking},
volume = {24},
number = {1},
pages = {63-69},
doi = {10.1089/bio.2024.0007},
pmid = {40566670},
issn = {1947-5543},
mesh = {Humans ; Male ; *Uncoupling Protein 2/metabolism ; *Acetylcysteine/pharmacology ; *Spermatozoa/drug effects/metabolism ; Cryopreservation/methods ; Sperm Motility/drug effects ; *Semen Preservation/methods ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Adult ; Semen Analysis ; },
abstract = {Reactive oxygen species (ROS) during cryopreservation causes mechanical, biochemical, and structural damage to the sperm, which leads to reduced sperm motility and fertility. N-acetyl cysteine is a cysteine-derived amino acid antioxidant that functions as a scavenger of ROS and regulates mitochondrial activity. Mitochondrial uncoupling protein 2 (UCP2) plays a leading role in this process and is one of the major regulators of human spermatozoa motility and metabolism. The purpose of the study was to examine the changes in UCP2 in frozen-thawed human sperm when exposed to N-acetyl cysteine, an effective antioxidant commonly used in human semen freezing. Semen samples were collected from 20 normozoospermia men and were divided into four experimental groups: fresh, frozen control, frozen N-Acetylcysteine (NAC, 100 μM), and frozen negative control with Genipin (25 μM). Subsequently, post-thaw sperm quality parameters, as well as UCP2 relative quantity, ROS, mitochondrial membrane potential (MMP), and malondialdehyde, were assessed. Semen treated with NAC exhibited significantly higher total and progressive motility, as well as viability, when compared to the control and genipin groups (p < 0.05). Moreover, UCP2 relative quantity was significantly lower in all frozen groups compared to the fresh group (p < 0.0001). The UCP2 relative quantity was not significantly different between NAC and control groups (p ≥ 0.05). Also, there were no significant differences in MMP, ROS, and malondialdehyde levels among the frozen groups (p ≥ 0.05). It can be concluded that UCP2 undergoes a modification during cryopreservation, and it could be an explanation of the reduction in post-thaw motility of sperm. Additionally, NAC supplementation in freezing media enhances post-thaw sperm motility and viability.},
}
@article {pmid40566456,
year = {2025},
author = {Moldovan, M and Muntean, M and Schauer, SA and Moldovan, R and Mitrea, DR},
title = {Oxidative Stress and Ultrastructural Analysis in Heart, Aorta, Skeletal Muscle and Lung of Rats Treated with N-Acetylcysteine or Rutin After Sprint Running.},
journal = {Journal of functional morphology and kinesiology},
volume = {10},
number = {2},
pages = {},
pmid = {40566456},
issn = {2411-5142},
abstract = {Background: Sprinting, a high-intensity, short-duration exercise, induces oxidative stress. This causes molecular and ultrastructural alterations. Antioxidant supplementation may mitigate side effects of near or complete exhaustion. Methods: Twenty-eight healthy male adult rats received orally normal saline, carboxymethylcellulose (vehicle), artificial, N-acetylcysteine or a natural antioxidant, Rutin. Rats were subjected to treadmill sprinting at increasing speeds for 5 days/week. After 26 days, samples were collected to measure oxidative stress (malondialdehyde, MDA; the ratio of reduced-to-oxidized glutathione, GSH/GSSG), inflammation markers (enzymatic level of inducible nitric oxide synthase, iNOS; cytokine level of tumor necrosis factor alpha, TNFα) and for transmission electron microscopy (TEM) analysis. Results: Rutin attenuated MDA levels and increased antioxidant protection in all tissues, while NAC decreased the lipid peroxidation in all tissues except the lungs. NAC increased aortic inflammation, with higher TNF-α and iNOS. Sprinting caused intimal detachment in the heart and aorta. Rutin and NAC minimized endocardium alterations. Additionally, Rutin prevented myocardial disorganization. Conclusions: Rutin mitigated the oxidative stress damage of sprinting in the heart, aorta, skeletal muscle and lung. NAC protected against oxidative injury caused by sprinting in the heart, aorta and muscle but not the lung, and it induced aortic inflammation.},
}
@article {pmid40564126,
year = {2025},
author = {Armeli Grigio, L and Boci, D and Di Vieste, G and Cassanelli, G and Epis, OM and Viadana, A and Bertuzzi, F and Pintaudi, B},
title = {Real-World Effectiveness of Different Nutraceutical Formulations on Pain Intensity of Subjects with Diabetic Peripheral Neuropathy: An Observational, Retrospective, Case-Control Study.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
pmid = {40564126},
issn = {2227-9059},
abstract = {Background/Objectives. Diabetic peripheral neuropathy is a debilitating disease-related complication with a significant impact on quality of life. Its management represents a therapeutic challenge. Antioxidant agents such as α-lipoic acid, N-acetyl cysteine, and glutatione may be useful treatment strategies. Methods. A real-world, observational, retrospective, case-control study involving consecutive subjects with type 2 diabetes with diabetic peripheral neuropathy was performed. Participants who were supplemented with three different formulations for 12 weeks (high-dose α-lipoic acid (800 mg); low-dose α-lipoic acid (100 mg) plus glutathione (200 mg) plus Vitamin D (800 IU); N-acetyl cysteine (600 mg) plus glutathione (200 mg) plus Vitamin D (800 IU)) were compared with a non-treated control group. Questionnaires aimed at investigating the degree of disability and quality of life were administered. The primary endpoint was the change in neuropathic pain intensity measured by the Numerical Rating Scale (NRS). Results. Among 750 consecutive screened subjects with type 2 diabetes, 98 (13%) had diabetic neuropathy (mean age 66.7 ± 7.6 years, diabetes duration 11.3 ± 6.7 years, HbA1c 8.1 ± 1.5%, 43.8% insulin-treated). When comparing the differences between treatment groups in the changes in individual questionnaire scores between baseline and follow-up, all three supplements showed significant reductions compared to the control group in the NRS scale scores. No side effects have been reported during the study. Conclusions. As well as lipoic acid, other substances with specific activity on the genesis of neuropathic pain, such as N-acetyl cysteine and glutathione, have proved effective in reducing the intensity of pain.},
}
@article {pmid40563994,
year = {2025},
author = {Elkalla, N and Elhamammsy, MH and Bedair, NI and Elazazy, O and El Kholy, AA},
title = {A Promising Approach to Psoriasis Vulgaris Management with N-Acetylcysteine and Vitamin E: Targeting the Interplay of Inflammatory and Oxidative Stress.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
pmid = {40563994},
issn = {2227-9059},
abstract = {Background: Psoriasis is a persistent, inflammatory skin disease with autoimmune characteristics. Beyond the obvious signs of skin lesions, it has negative systemic repercussions that impair the patient's quality of life. This study aimed to determine the effectiveness of N-acetylcysteine (NAC) alone or in combination with Vitamin E in the treatment of mild to moderate active psoriasis vulgaris. Methods: This study was an open-label, prospective, randomized, controlled interventional clinical trial conducted at Cairo Hospital for Dermatology and Venereology (Al-Haud Al-Marsoud). In total, 45 patients with mild to moderate symptoms were randomly assigned to three groups, with fifteen patients each, as follows: the control group received the standard psoriatic treatment of topical steroids and salicylic acid; the acetylcysteine group received standard psoriatic treatment in addition to NAC 600 mg per day 30 min prior to breakfast for 8 weeks; and the acetylcysteine and Vitamin E group received standard psoriatic treatment in addition to NAC 600 mg per day, in a similar way of dosing like the previous group, and Vitamin E 1000 mg per day. All participants performed a comprehensive assessment including hematological parameters, the Psoriasis Area and Severity Index (PASI), the Dermatology Life Quality Index (DLQI), malondialdehyde (MDA), and interleukin-36 gamma (IL-36γ). Results: The treatment strategy involving the use of NAC alone and in combination with Vitamin E showed significant improvement in the assessed parameters compared to the control group receiving conventional therapy. The acetylcysteine group showed improvements of 41% in PASI and 49.4% in DLQI, a decrease of 34.3% in MDA, and a decrease of 31% in IL-36γ. Similarly, the acetylcysteine and Vitamin E group showed improvements of 52% in PASI and 42% in DLQI, a decrease of 37% in MDA, and a decrease of 35% in IL-36γ. There were no significant differences found between the N-acetylcysteine and N-acetylcysteine and Vitamin E groups. Moreover, significant positive correlations were found between MDA, IL-36γ, and PASI at baseline and after the third follow-up. Conclusions: This study found promising therapeutic benefits in the addition of NAC to the conventional therapy in psoriatic patients with mild to moderate symptoms, as it significantly improved psoriasis disease outcomes and improved the patient's quality of life. However, the addition of Vitamin E to the NAC regimen did not show additional benefits.},
}
@article {pmid40559816,
year = {2025},
author = {Cui, L and Duan, J and Mao, P and Zhong, J and He, S and Dong, J and Liu, K and Guo, L and Li, J and Wang, H},
title = {Meloxicam Alleviates Oxidative Stress Through Nrf2/HO-1 Activation in Bovine Endometrial Epithelial Cells.},
journal = {Veterinary sciences},
volume = {12},
number = {6},
pages = {},
pmid = {40559816},
issn = {2306-7381},
support = {32072937//National Natural Science Foundation of China/ ; 32102735//National Natural Science Foundation of China/ ; 8//International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions/ ; JATS[2023]456//the earmarked fund for Jiangsu Agricultural Industry Technology System/ ; 2023YFD1801100//the National Key R&amp;D Program of China/ ; BK20210808//Natural Science Foundation of Jiangsu Province/ ; D18007//the 111 Project/ ; N/A//the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; },
abstract = {Meloxicam has been identified as an adjuvant therapeutic component in the management of bovine uterine diseases, exhibiting anti-inflammatory and antioxidant effects. However, the mechanisms underlying its antioxidant actions in the context of bovine uterine diseases remain incompletely understood. The objective of this research was to determine whether meloxicam exerts its antioxidant effects through the Nrf2/HO-1 signaling pathway. By employing N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), along with inhibitors directed against heme oxygenase-1 (HO-1) or nuclear factor erythroid 2-related factor 2 (Nrf2), we investigated the dynamic changes in oxidative stress markers (ROS and malondialdehyde) and antioxidant indices (comprising catalase, superoxide dismutase, and glutathione), as well as the expression profiles of Nrf2 and inflammation-associated genes and proteins in bovine endometrial epithelial cells (BEECs) subjected to lipopolysaccharide (LPS) stimulation. As a result, meloxicam alleviated the LPS-induced elevation of oxidative stress marker levels and the reduction in antioxidant enzyme activities and antioxidant substance contents in BEECs. Compared to NAC, meloxicam demonstrated superior efficacy in activating the Nrf2 pathway, with the promotion of NRF2 expression (~1.6-fold) and nuclear translocation. The pretreatment of cells with HO-1 or Nrf2 inhibitors markedly attenuated the antioxidant activity of meloxicam. In summary, meloxicam primarily alleviates LPS-induced oxidative stress through the activation of the Nrf2/HO-1 pathway in BEECs.},
}
@article {pmid40557447,
year = {2026},
author = {Heun, F and Meißner, J and Schieder, AK and Ohnesorge, B and Busse, C},
title = {Pantoea agglomerans in Equine Ulcerative Keratitis: Prevalence and Comparative Efficacy of Four Topical Antiseptics.},
journal = {Veterinary ophthalmology},
volume = {29},
number = {1},
pages = {e70044},
pmid = {40557447},
issn = {1463-5224},
mesh = {Animals ; Horses ; *Horse Diseases/microbiology/drug therapy/epidemiology ; *Corneal Ulcer/veterinary/microbiology/drug therapy/epidemiology ; *Pantoea/drug effects/isolation &amp; purification ; *Anti-Infective Agents, Local/pharmacology/therapeutic use/administration &amp; dosage ; Prevalence ; *Enterobacteriaceae Infections/veterinary/microbiology/epidemiology/drug therapy ; Microbial Sensitivity Tests/veterinary ; },
abstract = {OBJECTIVE: To determine the minimal bactericidal concentration (MBC) and effective contact time of four topical antiseptics-polyhexanide, povidone-iodine (PVP-I), hypochlorous acid (HOCl), and N-acetylcysteine (NAC)-against Pantoea agglomerans, a pathogen frequently isolated in equine ulcerative keratitis.<br><br>ANIMALS STUDIED: Over a 17-month sampling period, clinical isolates were collected from horses with ulcerative keratitis. The most frequently isolated strain (Pantoea agglomerans, n&#x2009;=&#x2009;14) was selected for in&#xa0;vitro analysis.<br><br>PROCEDURE(S): All isolates were used to determine the MBCs of the four antiseptics. Each was tested in triplicate at serial dilutions per isolate. Additionally, the requisite contact time for a bactericidal effect was evaluated at a supratherapeutic dilution for each substance with each isolate at defined time points ranging from 15&#x2009;s to 5&#x2009;min.<br><br>RESULTS: The MBCs of polyhexanide, PVP-I, HOCL, and NAC were 3.2&#x2009;ppm (0.00032%), 16&#x2009;ppm (0.0016%), 0.8&#x2009;ppm (0.00008%), and 3200&#x2009;ppm (0.32%), respectively. Polyhexanide (6.4&#x2009;ppm), PVP-I (64&#x2009;ppm), and HOCL (6.4&#x2009;ppm) were effective within 15&#x2009;s. NAC (6400&#x2009;ppm) required 1-2&#x2009;min to achieve bactericidal effects.<br><br>CONCLUSIONS: All antiseptics tested demonstrated efficacy against P. agglomerans. Polyhexanide, PVP-I, and HOCl achieved rapid bactericidal activity, while NAC required higher concentrations and longer exposure. These results support the use of these agents-particularly the faster-acting three-as potential alternatives to antibiotics in treating equine ulcerative keratitis. They may aid the reduction of antibiotic use in line with the One Health approach.},
}
@article {pmid40553255,
year = {2025},
author = {Chen, ZW and Li, YF and Qiu, HL and Xie, W and Chen, TY and Zhang, Y and Chen, JM and Zhuang, J and Wen, SS},
title = {Maternal Electronic Cigarette Exposure Induces Dysregulation of Autophagy via Oxidative Stress/DNA Methylation in Pulmonary Hypertension Offspring.},
journal = {Current medical science},
volume = {45},
number = {4},
pages = {854-866},
pmid = {40553255},
issn = {2523-899X},
support = {82300268//National Natural Science Foundation of China/ ; 2023B03J1255//Guangzhou Municipal Science and Technology Project/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *DNA Methylation/drug effects ; *Autophagy/drug effects/genetics ; Female ; Pregnancy ; Rats ; *Hypertension, Pulmonary/chemically induced/pathology/genetics/metabolism/etiology ; Male ; *Prenatal Exposure Delayed Effects/genetics/pathology/metabolism ; *Maternal Exposure/adverse effects ; Electronic Nicotine Delivery Systems ; Rats, Sprague-Dawley ; Autophagy-Related Protein 5/genetics/metabolism ; Monocrotaline/toxicity ; Disease Models, Animal ; },
abstract = {OBJECTIVE: Electronic cigarettes (ECs) differ from traditional tobacco smoke but may contribute to cardiopulmonary remodeling. Pulmonary hypertension (PH), characterized by pulmonary artery and right ventricle remodeling, poses a significant risk of mortality in infants, children, and adolescents. However, the impact of maternal EC exposure on PH development in offspring remains unclear. To address this, we established a PH rat model with maternal EC exposure.<br><br>METHODS: Maternal EC exposure was initiated on gestation day&#xa0;12 via electronic nicotine delivery systems. Offspring were administered monocrotaline (MCT)&#xa0;at 6&#xa0;weeks of age (6-wo)&#xa0;to induce PH. Mechanistic experiments were conducted at 10-week-old (10-wo).&#xa0;Protein expression of NADPH oxidases, DNA methyltransferases, and autophagy-related markers was analyzed by Western blot. Morphological changes and the severity of PH were evaluated via hematoxylin and eosin (HE) staining and echocardiography, respectively. Furthermore, the involvement of the oxidative stress/DNA methylation/autophagy axis in response to maternal EC exposure was confirmed through a combination of ELISA, Western blot, HE staining, and echocardiography. Additionally, ATG5 mRNA expression was measured by qRT-PCR.<br><br>RESULTS: Compared with control conditions, maternal EC exposure significantly worsened MCT-induced PH in male offspring. This was associated with increased oxidative stress, DNA hypomethylation, and anomalous autophagy in the offspring. In vivo treatment with chloroquine inhibited autophagy and ameliorated PH development in offspring exposed to maternal EC. Furthermore, N-acetylcysteine (NAC), an antioxidant, attenuated maternal EC exposure-induced oxidative stress, DNA hypomethylation, and excessive autophagy, thereby improving PH. DNA hypermethylation also reversed PH development, accompanied by reduced oxidative stress and suppressed autophagy. ATG5, a key regulator of autophagy, was identified as a potential therapeutic target, as its repression mitigated PH in maternal EC-exposed offspring.<br><br>CONCLUSION: Maternal EC exposure induces oxidative stress and DNA hypomethylation in offspring, leading to anomalous autophagy and exacerbation of PH development. Targeting ATG5-mediated autophagy may represent a novel therapeutic approach for improving PH outcomes in offspring exposed to maternal EC.},
}
@article {pmid40553253,
year = {2025},
author = {Ding, WC and Chen, J and Li, Q and Ren, Y and Wang, MM and Zhang, W and Ji, XH and Wu, XY and Nie, SN and Huang, CB and Sun, ZR},
title = {Quercetin Confers Protection against Sepsis-Related Acute Respiratory Distress Syndrome by Suppressing ROS/p38 MAPK Pathway.},
journal = {Chinese journal of integrative medicine},
volume = {31},
number = {11},
pages = {1011-1020},
pmid = {40553253},
issn = {1993-0402},
mesh = {Animals ; *Sepsis/complications/drug therapy ; *Quercetin/pharmacology/therapeutic use ; *Respiratory Distress Syndrome/drug therapy/etiology/prevention &amp; control/complications/pathology/enzymology ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Mice, Inbred C57BL ; *Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Male ; Oxidative Stress/drug effects ; *MAP Kinase Signaling System/drug effects ; Lung/pathology/drug effects ; Mice ; Lipopolysaccharides ; Macrophages, Alveolar/drug effects/pathology ; Inflammation/pathology ; *Protective Agents/pharmacology/therapeutic use ; },
abstract = {OBJECTIVE: To identify the underlying mechanism by which quercetin (Que) alleviates sepsis-related acute respiratory distress syndrome (ARDS).<br><br>METHODS: In vivo, C57BL/6 mice were assigned to sham, cecal ligation and puncture (CLP), and CLP+Que (50 mg/kg) groups (n=15 per group) by using a random number table. The sepsisrelated ARDS mouse model was established using the CLP method. In vitro, the murine alveolar macrophages (MH-S) cells were classified into control, lipopolysaccharide (LPS), LPS+Que (10 &#x3bc;mol/L), and LPS+Que+acetylcysteine (NAC, 5 mmol/L) groups. The effect of Que on oxidative stress, inflammation, and apoptosis in mice lungs and MH-S cells was determined, and the mechanism with reactive oxygen species (ROS)/p38 mitogen-activated protein kinase (MAPK) pathway was also explored both in vivo and in vitro.<br><br>RESULTS: Que alleviated lung injury in mice, as reflected by a reversal of pulmonary histopathologic changes as well as a reduction in lung wet/dry weight ratio and neutrophil infiltration (P<0.05 or P<0.01). Additionally, Que improved the survival rate and relieved gas exchange impairment in mice (P<0.01). Que treatment also remarkedly reduced malondialdehyde formation, superoxide dismutase and catalase depletion, and cell apoptosis both in vivo and in vitro (P<0.05 or P<0.01). Moreover, Que treatment diminished the release of inflammatory factors interleukin (IL)-1&#x3b2;, tumor necrosis factor-&#x3b1;, and IL-6 both in vivo and in vitro (P<0.05 or P<0.01). Mechanistic investigation clarifified that Que administration led to a decline in the phosphorylation of p38 MAPK in addition to the suppression of ROS expression (P<0.01). Furthermore, in LPS-induced MH-S cells, ROS inhibitor NAC further inhibited ROS/p38 MAPK pathway, as well as oxidative stress, inflammation, and cell apoptosis on the basis of Que treatment (P<0.05 or P<0.01).<br><br>CONCLUSION: Que was found to exert anti-oxidative, anti-inflammatory, and anti-apoptotic effects by suppressing the ROS/p38 MAPK pathway, thereby conferring protection for mice against sepsis-related ARDS.},
}
@article {pmid40541897,
year = {2025},
author = {Karmakar, C and Sarkar, D and Ghosh, A and Haldar, D and Chatterjee, M},
title = {Evaluating the leishmanicidal activity of m-Nitrocinnamic acid containing lipophilic peptide against leishmania donovani.},
journal = {Acta tropica},
volume = {268},
number = {},
pages = {107703},
doi = {10.1016/j.actatropica.2025.107703},
pmid = {40541897},
issn = {1873-6254},
mesh = {*Leishmania donovani/drug effects ; *Antiprotozoal Agents/pharmacology/chemistry ; Reactive Oxygen Species/metabolism ; *Peptides/pharmacology/chemistry ; Animals ; Cell Survival/drug effects ; *Cinnamates/pharmacology/chemistry ; Lipid Peroxidation/drug effects ; Inhibitory Concentration 50 ; Membrane Potential, Mitochondrial/drug effects ; Apoptosis/drug effects ; Oxidation-Reduction/drug effects ; Mice ; Leishmaniasis, Visceral/drug therapy/parasitology ; },
abstract = {Studies have demonstrated that m-Nitrocinnamic acid containing Lipophilic Peptide (LP) exhibits leishmanicidal activity against Leishmania major promastigotes; however, its efficacy against the amastigote form remains unclear. In this study, we evaluated the activity of LP against Leishmania donovani, the causative agent of Visceral Leishmaniasis (VL), wherein LP demonstrated both anti-promastigote and anti-amastigote activity, as measured by MTS cell viability assay and droplet digital PCR (ddPCR) respectively, the IC50 derived being 22.0 and 6.0 µM respectively, while the CC50 was >500 µM, which translated into a safety index >83. LP induced leishmanicidal activity by triggering a redox imbalance in promastigotes, by enhancing the generation of reactive oxygen species (ROS) and caused lipid peroxidation, but failed to impact on generation of mitochondrial superoxide. Furthermore, as N-acetyl cysteine (NAC) attenuated the parasiticidal properties of LP via scavenging the free radicals, it substantiated that the cytotoxicity of LP was mediated by inducing a redox imbalance. An apoptotic-like cell death was demonstrated in promastigotes, features being an enhanced annexin V positivity, altered mitochondrial membrane potential, and cell cycle arrest at sub G0/G1. Collectively, this study confirmed that LP exhibited leishmanicidal activity against L. donovani that was mediated by an apoptotic-like cell death via disruption of redox homeostasis, and could be considered as a compound worthy of further pharmacological consideration.},
}
@article {pmid40541750,
year = {2025},
author = {Lin, D and Li, G and Deng, H and Wang, S},
title = {The protective effect of Schisandra lignans on the hepatotoxicity induced by the metabolic activation of dictamnine.},
journal = {Journal of ethnopharmacology},
volume = {352},
number = {},
pages = {120170},
doi = {10.1016/j.jep.2025.120170},
pmid = {40541750},
issn = {1872-7573},
mesh = {Animals ; *Lignans/pharmacology/isolation &amp; purification/therapeutic use ; *Schisandra/chemistry ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/pathology/metabolism/etiology ; Male ; Mice ; Liver/drug effects/pathology/metabolism ; *Dioxoles/toxicity ; Activation, Metabolic ; *Protective Agents/pharmacology ; Glutathione/metabolism ; Microsomes, Liver/drug effects/metabolism ; Cytochrome P-450 CYP3A/metabolism ; },
abstract = {Dictamnine (DIC) is the predominant pharmacological and hepatotoxic component of Cortex Dictamni (CD). CYP3A-mediated metabolic activation plays an important role in DIC-induced hepatotoxicity. Schisandra lignans (SCLs) are the major hepatoprotective ingredients of Schisandra chinensis (SC). CD and SC are frequently used as herb pairs in traditional Chinese medical formulas particularly for the treatment of eczema and urticarial. Our preliminary studies have shown that SC can protect against CD-induced liver injury. However, the underlying protective mechanism of SC against CD-induced liver injury has remained unknown.<br><br>AIM OF THE STUDY: This study aims to investigate the effects of SCLs on the hepatotoxicity and metabolic activation of DIC and elucidate the underlying hepatoprotective mechanism from the perspective of the inhibition of CYP3A-mediated metabolic activation.<br><br>MATERIAL AND METHODS: The protective effect of SCLs against DIC-induced hepatotoxicity was evaluated by biochemical analysis and liver histological observation. The effect of SCLs on the in vitro metabolic activation of DIC was assessed by detecting the level of DIC-N-acetylcysteine (NAC) conjugates in mouse liver microsomal incubations. The effect of SCLs on the metabolic activation in vivo of DIC was examined by monitoring the toxicokinetic behaviors of DIC, DIC-induced hepatic GSH depletion, the cumulative urine excretion of DIC, the levels of DIC-NAC conjugates in urine and liver of mice, and the formation of DIC-derived cysteine-protein adducts.<br><br>RESULTS: Our findings indicated that SCLs protected against DIC-induced hepatotoxicity in a dose-dependent manner. SCLs exhibited dose-dependent inhibitory effect on the formation of DIC-NAC conjugates in liver microsomal incubations, indicating SCLs inhibited the metabolic activation of DIC in vitro. SCLs increased Cmax and AUCs of DIC in the blood and liver of mice, leading to the enhancive accumulation of DIC in the circulation. Pretreatment with SCLs relieved hepatic GSH depletion induced by DIC, promoted the urinary excretion of DIC, inhibited the formation of reactive metabolite of DIC in urine and liver of mice, and reduced the production of DIC-derived cysteine-protein adducts, suggesting that SCLs influenced absorption, distribution, metabolism, and excretion (ADME) of DIC by suppressing the metabolic activation of DIC in vivo.<br><br>CONCLUSIONS: The study demonstrated the protective effect of SCLs against hepatotoxicity induced by DIC was related to the inhibition of CYP3A-mediated metabolic activation of DIC. Therefore, the study demonstrated that SCLs may serve as the candidate drugs for the intoxication of DIC. Moreover, our findings may interpret the protective mechanism of SC against CD-induced liver injury.},
}
@article {pmid40539306,
year = {2025},
author = {Zahaki Nosrat, F and Yari, S and Mahmoodi, B and Hasanein, P},
title = {Effects of N-acetylcysteine on rat sperm treated with hydrogen peroxide in in vitro conditions.},
journal = {Biotechnic &amp; histochemistry : official publication of the Biological Stain Commission},
volume = {100},
number = {5},
pages = {303-311},
doi = {10.1080/10520295.2025.2516582},
pmid = {40539306},
issn = {1473-7760},
mesh = {Male ; Animals ; *Acetylcysteine/pharmacology ; *Spermatozoa/drug effects ; *Hydrogen Peroxide/pharmacology ; Rats, Wistar ; Rats ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; },
abstract = {Infertility affects around 15% of couples worldwide, with male factors being responsible for nearly half of these cases. Oxidative stress is a significant contributor to male infertility, leading to damaged sperm. This research examines the protective effects of Nacetylcysteine (NAC) on sperm exposed to hydrogen peroxide (H2O2) induced oxidative stress in rats. Sperm samples from adult male Wistar rats were divided into four groups: control, H2O2, NAC, and H2O2+NAC. Various parameters, including sperm viability, abnormal morphology, chromatin condensation, and plasma membrane integrity were evaluated after incubation using established assays. Exposure to H2O2 significantly decreased sperm viability, increased the rate of abnormal morphology, heightened chromatin condensation abnormalities, and compromised plasma membrane integrity. Treatment with NAC significantly ameliorated these effects, demonstrating its protective role against oxidative damage. NAC effectively counteracts oxidative damage in sperm, improving viability, morphology, chromatin integrity, and membrane integrity. These findings demonstrate the protective effects of NAC against oxidative stress-induced sperm damage under in vitro conditions, underscoring its potential as a subject for further investigation in the context of oxidative stress-related male infertility.},
}
@article {pmid40538547,
year = {2025},
author = {Shen, YC and Wang, YH and Liou, KT and Wei, WC and Cheng, JJ and Liu, HK and Huang, NK and Lo, IW and Chang, CC and Chiou, WF and Tsai, KC and Chiou, CT and Liaw, CC and Su, YC},
title = {Synergistic protective effects of TCM formula NRICM102 and N-acetylcysteine against hepatorenal injury in a mouse model of bongkrekic acid poisoning.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1596785},
pmid = {40538547},
issn = {1663-9812},
abstract = {Bongkrekic acid (BKA), a mitochondrial toxin produced by Burkholderia cocovenenans subsp. farinofermentans, is typically found in contaminated fermented rice products such as tempeh bongkrek, causing severe foodborne illnesses marked by systemic inflammation, multi-organ failure (MOF), and high mortality rates (40%-100%). A recent outbreak in Taiwan (2024) resulted in six fatalities among 33 affected individuals, underscoring the urgent clinical need for effective treatments. This study evaluated the therapeutic potential of NRICM102, a novel traditional Chinese medicine (TCM) formulation, combined with the antioxidant N-acetylcysteine (NAC), against BKA-induced hepatorenal toxicity in a mouse model. NRICM102 (1.5-3.0 g/kg), NAC (0.5 g/kg), and their combination significantly improved survival, reduced serum biomarkers (GOT, GPT, BUN), and alleviated liver and kidney histopathological damage following acute (5.0 mg/kg) and subacute (2.0 mg/kg) BKA exposure. RNA-seq analyses suggested that the NRICM102-NAC combination synergistically modulated critical pathways, including mitochondrial function, cytochrome P450 enzyme activity, oxidative stress, immune responses, and cell death regulation. Despite these promising findings, mechanistic conclusions remain associative and require further validation using targeted mitochondrial studies. Collectively, NRICM102 combined with NAC offers a promising, translationally relevant therapeutic strategy warranting additional preclinical safety and pharmacokinetic assessments to advance toward clinical application.},
}
@article {pmid40534932,
year = {2025},
author = {Brown, S and Kennard, B and Thigpen, J},
title = {Chemical Compatibility of N-Acetylcysteine After the Simultaneous Intravenous Administration of Ondansetron.},
journal = {The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG},
volume = {30},
number = {3},
pages = {362-366},
pmid = {40534932},
issn = {1551-6776},
abstract = {OBJECTIVE: This study evaluated the chemical compatibility of N-acetylcysteine (NAC) and ondansetron to simplify the treatment of acute nausea and vomiting during intravenous (IV) NAC administration. NAC is commonly used to treat acetaminophen overdose, but its 21-hour IV infusion is often interrupted for ondansetron administration, which can pose risks.<br><br>METHODS: High-performance liquid chromatography with ultraviolet detection was used to quantify NAC. To simulate IV administration, a closed-circuit pump with multiple independent lines, was plumbed with Y-sites to circulate NAC at concentrations matching 30- and 100-kg loading doses and 4-mg ondansetron was pushed into the flow paths. Control lines without ondansetron were also maintained. Samples were collected at 10, 20, and 30 minutes postondansetron introduction. NAC concentrations in single-drug and combination lines were compared using an unpaired t-test with Welch's correction (p = 0.05).<br><br>RESULTS: The mean concentrations for the 100-kg dose were 55.23 and 55.28 mg/mL for control and with ondansetron, respectively. The 30-kg cohort included 36.38 mg/mL for control and 36.49 mg/mL with ondansetron. The results of the unpaired t-test for either weight illustrated that no statistical significance was achieved. Furthermore, the t-values of 0.2013 for 100 kg and 0.8556 for 30 kg support a less likely chance of significant difference.<br><br>CONCLUSION: Based on this experiment, ondansetron can be introduced into an NAC infusion via IV push in vitro without affecting the NAC concentration in the solution. The likelihood of IV compatibility for NAC and ondansetron could permit no infusion interruptions, reducing unnecessary risk of acetaminophen toxicity.},
}
@article {pmid40533050,
year = {2025},
author = {Nakhaee, S and Kooshki, A and Mehrpour, O and Hosseini, M and Farrokhfall, K},
title = {Effects of anti-oxidants, NOX inhibitor (DPI), and anti-apoptotic pathways on carbohydrate metabolism and liver function in acute aluminum phosphide toxicity exposed rats.},
journal = {Regulatory toxicology and pharmacology : RTP},
volume = {162},
number = {},
pages = {105890},
doi = {10.1016/j.yrtph.2025.105890},
pmid = {40533050},
issn = {1096-0295},
mesh = {Animals ; *Phosphines/toxicity ; Male ; *Antioxidants/pharmacology/therapeutic use ; *Liver/drug effects/metabolism/pathology ; *Aluminum Compounds/toxicity ; *Onium Compounds/pharmacology/therapeutic use ; Rats ; *Apoptosis/drug effects ; Acetylcysteine/pharmacology ; Rats, Wistar ; Insulin/metabolism/blood ; Oxidative Stress/drug effects ; Blood Glucose/drug effects/metabolism ; Tumor Necrosis Factor-alpha/blood ; Interleukin-1beta/metabolism ; Liver Function Tests ; },
abstract = {Aluminum phosphide (AlP) is widely used in suicide attempts. We evaluated the effects of Diphenylene iodonium (DPI), N- N-acetyl cysteine (NAC), and Nivocasan therapeutics on AlP toxicity. Thirty rats were kept in five groups: control (receiving normal saline); the remaining groups were exposed to oral AlP, and treatments (NAC, DPI, and Nivocasan). Liver function tests (LFTs), serum and liver oxidative markers, insulin, glucose, tumor necrosis factor-α (TNF-α), serum and islets interleukin 1β (IL-1β), and glucose-stimulated insulin secretion through islet isolation were assessed. LFTs significantly increased in AlP poisoned animals, and NAC, DPI, and Nivocasan decreased their levels to near control (P < 0.05). DPI and Nivocasan recovered AlP-induced hypoglycemia. Plasma catalase, GPx, and MDA increased in the AlP group, and NAC, DPI, and Nivocasan had protective effects (P < 0.05). DPI significantly decreased serum TNF-α, and NAC decreased IL-1β levels. NAC reversed AlP-induced lower insulin secretion (P < 0.05). Aluminum phosphide (AlP) induces hypoglycemia and liver damage. AlP-related hypoglycemia is associated with elevated inflammatory and oxidative stress markers and impaired insulin secretion from pancreatic islets which improved by NAC. DPI and Nivocasan treat hypoglycemia. DPI and NAC were effective in reducing inflammatory markers.},
}
@article {pmid40532836,
year = {2025},
author = {Zhou, X and Yan, H and Hong, Y and Ding, Y and Chen, J and Tang, H and Wei, Y and Long, C and Shen, L and Wei, G and Wu, S},
title = {PPARγ mediated lysosomal membrane permeabilization and lipophagy blockage were involved in microplastics and di (2-ethylhexyl) phthalate co-exposure induced immature testis injury.},
journal = {Free radical biology &amp; medicine},
volume = {237},
number = {},
pages = {615-630},
doi = {10.1016/j.freeradbiomed.2025.06.023},
pmid = {40532836},
issn = {1873-4596},
mesh = {Male ; Animals ; *Diethylhexyl Phthalate/toxicity ; *PPAR gamma/metabolism/genetics ; Mice ; *Testis/drug effects/pathology/metabolism ; *Microplastics/toxicity ; *Lysosomes/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; Autophagy/drug effects ; Polystyrenes/toxicity ; Leydig Cells/drug effects/metabolism/pathology ; Humans ; Lipid Metabolism/drug effects ; },
abstract = {Polystyrene microplastics (PS-MPs) and di (2-ethylhexyl) phthalate (DEHP), two main composites of plastic products, are always exposed to human at the same time. However, most existing research has focused on single exposure, which is not consistent with the actual exposure circumstance. In this study, single and co-exposure animal model were established. C57/BL6J mice were exposed to corn oil, 20 mg/kg PS-MPs, 200 mg/kg DEHP and PS-MPs + DEHP for 28 days. The HE staining showed more serious seminiferous epithelium disorganization in co-exposed mice, indicating that PS-MPs and DEHP co-exposure could aggravate testicular injury. Compared with control group, integrative analysis of transcriptomics and proteomics revealed that PPARγ pathway played a crucial role in PS-MPs and DEHP co-exposure induced testis injury. In vitro, spermatocytes (GC-2) and leydig cells (TM3) were exposed to 50 μM MEHP, 10 mg/L PS-MPs and PS-MPs + MEHP for 48 h. Though PS-MPs and MEHP single exposure also triggered oxidative stress and PPAR pathway, the protein levels showed more remarkable difference in co-exposure group. Furthermore, co-exposure to PS-MPs and MEHP induced lysosomal membrane permeabilization (LMP), which significantly impaired lysosomal-mediated lipid degradation, thereby exacerbating lipid metabolism dysfunction in testicular cells. Treatment with N-Acetylcysteine (NAC) and knockdown of fatty acid-binding protein (FABP4) restored lipophagy flux and reduced lipid droplets deposition. Overall, co-exposure of PS-MPs and DEHP has synergistic toxic effect, inducing oxidative stress, PPARγ activation and lipophagy blockage, finally resulting in unbalanced lipid metabolism and testicular damage.},
}
@article {pmid40531753,
year = {2025},
author = {Assis, EIT and Godinho, AN and Freire, JMO and Lima Neto, MF and Costa, JJN and Souza, ALP and Monte, APOD and Matos, MHT and Sousa, ALM and Silva, JRV and Silva, AWB},
title = {Protective effects of Aloe vera extract against doxorubicin-induced degeneration in ovarian follicles and stromal cells in mice.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {58},
number = {},
pages = {e14402},
pmid = {40531753},
issn = {1414-431X},
mesh = {Animals ; Female ; *Doxorubicin/toxicity ; *Aloe/chemistry ; *Plant Extracts/pharmacology ; *Ovarian Follicle/drug effects/pathology ; Mice ; *Stromal Cells/drug effects/pathology ; Random Allocation ; Antibiotics, Antineoplastic/toxicity ; Superoxide Dismutase/analysis ; },
abstract = {The present study aimed to evaluate the protective effects of Aloe vera on doxorubicin (DOX)-induced degeneration in ovarian follicles and stromal cells in mice. Mice (n=48) were randomly divided into six groups. The positive control group mice received pretreatment of N-acetylcysteine orally (po), followed by a single intraperitoneal (ip) dose of DOX after 1 h (NAC+DOX). The negative control group mice were pre-treated with saline (po) and administered a single DOX dose (ip) after 1 h (SAL+DOX). The other groups of mice were pre-treated with different concentrations (0.1, 1.0, or 10.0 mg/kg; po) of Aloe vera and then received a single dose of DOX (ip) after 1 h (AV0.1+DOX, AV1.0+DOX, and AV10.0+DOX). The control group received saline po and ip (SAL+SAL). Aloe vera was administered once daily for 3 consecutive days. On the fourth day, the ovaries were processed for histological analysis, immunohistochemistry, and real-time PCR (mRNA for superoxide dismutase (SOD), catalase (CAT), nuclear factor erythroid 2-related factor 2 (NRF2), and tumor necrosis factor-α (TNF-α). Results showed that 0.1 and 1.0 mg/kg Aloe vera protected ovarian follicles and stromal density against DOX-induced degeneration. Furthermore, 0.1 and 1.0 mg/kg Aloe vera reduced TNF-α protein expression and increased NRF2, SOD, and CAT mRNA levels. In conclusion, 0.1 and 1.0 mg/kg Aloe vera had protective effects against DOX-induced degeneration in ovarian follicles and stromal cells in mice.},
}
@article {pmid40524738,
year = {2025},
author = {Duttenhefner, JN and Reindl, KM},
title = {GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.},
journal = {Molecular &amp; cellular oncology},
volume = {12},
number = {1},
pages = {2518773},
pmid = {40524738},
issn = {2372-3556},
abstract = {Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options, underscoring the need for novel therapeutic targets. Metabolic reprogramming is a hallmark of PDAC, enabling tumor cells to sustain rapid proliferation and survive under nutrient-deprived conditions. While glutathione S-transferase pi 1 (GSTP1) is a known regulator of redox homeostasis in PDAC, its role in metabolic adaptation remains unclear. Here, we show that GSTP1 knockdown disrupts PDAC metabolism, leading to downregulation of key metabolic enzymes (ALDH7A1, CPT1A, SLC2A3, PGM1), ATP depletion, mitochondrial dysfunction, and phospholipid remodeling. Phospholipid remodeling, including an increase in phosphatidylcholine (PC) levels, further suggests a compensatory response to metabolic stress. Importantly, GSTP1 knockdown led to elevated lipid peroxidation, increasing 4-hydroxynonenal (4-HNE) accumulation. Treatment with the antioxidant N-acetyl cysteine (NAC) partially restored metabolic gene expression, reinforcing GSTP1's role in the interplay between redox regulation and metabolism in PDAC. By disrupting multiple metabolic pathways, GSTP1 depletion creates potential therapeutic vulnerabilities that could be targeted through metabolic and oxidative stress-inducing therapies to enhance treatment efficacy.},
}
@article {pmid40523886,
year = {2025},
author = {Tang, G and Cao, X and Chen, J and Hui, F and Xu, N and Jiang, Y and Lu, H and Xiao, H and Liang, X and Ma, M and Qian, Y and Liu, D and Wang, Z and Liu, S and Yu, G and Sun, L},
title = {Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis.},
journal = {Cell death &amp; disease},
volume = {16},
number = {1},
pages = {452},
pmid = {40523886},
issn = {2041-4889},
mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology/metabolism ; *Lung Neoplasms/drug therapy/genetics/pathology/metabolism ; *Tumor Suppressor Protein p53/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Pyroptosis/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; *Proto-Oncogene Proteins c-mdm2/antagonists &amp; inhibitors/metabolism ; Caspase 3/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Drug Repositioning ; Cell Line, Tumor ; Mutation/genetics ; Apoptosis/drug effects ; para-Aminobenzoates/pharmacology ; Phosphate-Binding Proteins/metabolism ; Gasdermins ; },
abstract = {Non-small cell lung cancer (NSCLC) is highly malignant with limited treatment options, largely due to the inherent tumoral heterogeneity and acquired resistance towards chemotherapy and immunotherapy. RG7388, a known MDM2 inhibitor, exhibited anticancer activity in TP53-wild-type (TP53[WT]) NSCLC by triggering the p53/PUMA axis-dependent apoptosis. However, our study uncovered previously unrecognized p53-independent anticancer effects of RG7388 in TP53-mutant (TP53[mutant]) NSCLC, although the underlying mechanisms remained elusive. Here, we demonstrated that RG7388 specifically induced the NOXA/caspase-3 axis-dependent apoptosis and gasdermin E (GSDME)-mediated secondary pyroptosis in TP53[mutant] NSCLC, as validated through in silico analyses and multiple biological assays. Mechanically, we identified reactive oxygen species (ROS) as the critical mediator in NOXA upregulation and p38 MAPK pathway activation in RG7388 treated TP53[mutant] NSCLC. This was further supported by the use of ROS scavengers, N-acetylcysteine (NAC), and Ferrostatin-1 (Fer-1), which attenuated these effects. Pharmacologic inhibition of p38 MAPK signaling by SB203580 rescued RG7388-induced ROS-dependent NOXA accumulation and subsequent apoptosis and pyroptosis, highlighting the central role of the ROS/phosphorylated p38 MAPK (p-p38)/NOXA/caspase-3 axis in RG7388-induced TP53[mutant] NSCLC cell death. Our findings revealed a novel mechanism for selectively targeting mutant p53-derived cancer through ROS/p-p38-mediated NOXA accumulation, offering potential therapeutic implications given the current lack of direct mutant p53 targeting strategies in cancer. Furthermore, immunohistochemical (IHC) analysis of an NSCLC tissue microarray confirmed a strong positive correlation between p-p38 and NOXA expression. Clinical data analysis further suggested that the p-p38/NOXA axis might be a potential prognostic biomarker for overall survival (OS) in NSCLC patients.},
}
@article {pmid40522608,
year = {2025},
author = {Zhou, K and Wu, G and Dong, R and Kan, C and Xie, L and Gao, L and Li, H and Sun, J and Ning, W},
title = {Mitochondrial deoxyguanosine kinase depletion induced ROS causes melanocyte stem cell exhaustion and hair greying.},
journal = {Cell regeneration (London, England)},
volume = {14},
number = {1},
pages = {25},
pmid = {40522608},
issn = {2045-9769},
support = {32270846//National Natural Science Foundation of China/ ; 202401AT070443//Applied Basic Research Foundation of Yunnan Province/ ; 202501AT070205//Applied Basic Research Foundation of Yunnan Province/ ; },
abstract = {Hair pigmentation is regulated by melanocyte stem cells (MeSCs) within the hair follicle. Mitochondrial dysfunction is associated with hair depigmentation, primarily due to defects in melanogenesis. However, the mechanisms by which mitochondria support MeSCs during hair pigmentation remain obscure. In this study, we investigated the role of mitochondrial deoxyguanosine kinase (DGUOK), which provides guanosine and adenosine nucleotides for mitochondrial DNA (mtDNA) replication, in hair pigmentation and MeSCs maintenance. Dguok depleted and conditional knockout mice exhibit premature hair greying. This phenotype was not due to impaired melanin production by melanocytes but was associated with a significant loss of MeSCs and mature melanocytes. Notably, Dguok deficiency decreased the expression of 13 mtDNA-encoded genes, increased the levels of reactive oxygen species (ROS) and apoptosis in MeSCs. Treatment with N-acetylcysteine (NAC), an ROS inhibitor, effectively mitigated the depigmentation and rejuvenated the MeSCs population. These findings underscore the critical role of DGUOK in regulating mtDNA integrity, which is vital for sustaining MeSCs and ensuring hair pigmentation, providing valuable insights that may inform therapeutic strategies for combating hair greying.},
}
@article {pmid40516766,
year = {2025},
author = {Spilere, DA and Lodetti, G and de Farias, ACS and Teixeira, AG and Dondossola, ER and Rico, EP},
title = {Effects of N-acetylcysteine after repeated exposure to ethanol in memory and neurotransmission in zebrafish.},
journal = {Neurotoxicology and teratology},
volume = {110},
number = {},
pages = {107508},
doi = {10.1016/j.ntt.2025.107508},
pmid = {40516766},
issn = {1872-9738},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Ethanol/toxicity/administration &amp; dosage ; Zebrafish ; *Synaptic Transmission/drug effects ; *Memory/drug effects ; Acetylcholinesterase/metabolism ; Choline O-Acetyltransferase/metabolism ; Glutamic Acid/metabolism ; *Neuroprotective Agents/pharmacology ; Avoidance Learning/drug effects ; Male ; },
abstract = {INTRODUCTION: In the brain, alcohol metabolites alter the functioning of several neurotransmission systems, such as glutamatergic and cholinergic, in addition to impairing memory and learning. Medications for Alcohol Use Disorders (AUD) cause adverse effects and contraindications. N-acetylcysteine (NAC) has been shown to protect memory and restore acetylcholinesterase (AChE) levels. Additionally, it functions as an antioxidant that works alongside glutathione, which is associated with the glutamatergic synapse. In this context, the current research aimed to examine the neuroprotective effects of NAC in animals that underwent repeated ethanol exposure (REE), along with the impacts on memory and the cholinergic and glutamatergic signaling pathways in zebrafish.<br><br>METHODS: The animals were exposed to 1&#xa0;% ethanol for 8&#xa0;days for 20&#xa0;min daily. They received treatment with NAC after the eighth exposure to ethanol for 10 or 60&#xa0;min. Euthanasia occurred 24&#xa0;h after the last exposure. Inhibitory avoidance and object recognition tests were performed. Also, the choline acetyltransferase (ChAT) enzyme activities, AChE activity, and glutamate uptake were evaluated.<br><br>RESULTS: The results show a significant AChE activity increase in the REE group and a decrease in those exposed to alcohol and treated with NAC for 10&#xa0;min. No significant differences were found regarding ChAT activity. REE significantly reduced glutamate uptake. All groups except the ethanol group acquired aversive memory in inhibitory avoidance tests. Only the NAC-treated group demonstrated longer new object exploration in the recognition test. The study indicates that REE affects AChE, glutamate uptake, and aversive memory and that a single NAC treatment can mitigate these effects. These findings enhance the understanding of REE mechanisms and NAC's protective properties against ethanol-induced damage in zebrafish.},
}
@article {pmid40511989,
year = {2025},
author = {Rosenhall, U and Muhr, P and Duan, M},
title = {Is pharmaceutical treatment of noise-induced hearing loss a realistic option? Debate article.},
journal = {Acta oto-laryngologica},
volume = {145},
number = {8},
pages = {695-698},
doi = {10.1080/00016489.2025.2509662},
pmid = {40511989},
issn = {1651-2251},
mesh = {*Hearing Loss, Noise-Induced/drug therapy ; Humans ; Animals ; },
abstract = {Essential conclusions The need for pharmaceutical treatment of noise-induced hearing loss (NIHL) is pronounced.Animal studies indicate that such treatment is possible.Clinical trials must be designed so that the participants are not exposed to harmful noise.This implicates that prospective, randomised studies of possible drug effects on permanent NIHL are difficult to perform of ethical reasons.Indirect outcome measures of noise effects on hearing are considered less reliable and informative than permanent NIHL for the evaluation of the efficacy of a drug therapy.If drug therapies aiming to reduce NIHL are looked for, issues related to the design of clinical trials must be discussed and possibly revised.},
}
@article {pmid40510771,
year = {2025},
author = {Muthmainah, M and Wiyono, N and Syah, FK and Purnianto, A and Yudhani, RD and Wasita, B},
title = {Current trends and future prospects of N-acetylcysteine utilizations in Parkinson's disease: A literature network analysis.},
journal = {Journal of Taibah University Medical Sciences},
volume = {20},
number = {3},
pages = {298-306},
pmid = {40510771},
issn = {1658-3612},
abstract = {Parkinson's disease (PD) is a prevalent neurodegenerative disorder without a definitive cure. Oxidative stress is significantly implicated in its pathogenesis, prompting interest in N-acetylcysteine (NAC), a strong antioxidant and cysteine precursor, as a potential therapeutic agent. We conducted a bibliometric analysis of 421 Scopus articles to assess current trend and future potential of research on the use of NAC in Parkinson's disease. The number of publications related to this topic reached the peaked in 2010 and gradually decreased afterward. We identified 4 main clusters of research theme related to the potential mechanism of NAC effects on Parkinson's disease progression. These include research focusing on NAC effects on oxidative stress, dysfunction of the mitochondria, aberrant protein accumulation and clearance and inflammation. Investigating NAC effect for Parkinson's disease in human is a potential research area.},
}
@article {pmid40509229,
year = {2025},
author = {Barbosa-Azevedo, M and Igreja-Cardoso, MB and Carvalho, F and Costa, VM},
title = {Comparative Neurotoxic Effects of Doxorubicin and Sunitinib: An In Vitro Study on Human Dopaminergic Neuronal Cells.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {11},
pages = {},
pmid = {40509229},
issn = {1420-3049},
support = {UIDB/04046/2020 and UIDP/04046/2020//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e tecnologia/ ; },
mesh = {Humans ; *Doxorubicin/pharmacology/adverse effects/toxicity ; *Sunitinib/pharmacology/toxicity/adverse effects ; Autophagy/drug effects ; *Dopaminergic Neurons/drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Sulfoxides ; Isothiocyanates ; },
abstract = {Chemotherapy-induced cognitive impairment, commonly referred to as chemobrain, is a well-documented adverse outcome of anticancer treatments. While the neurotoxicity of doxorubicin (DOX) has been extensively studied, targeted therapies such as sunitinib (SUN) remain largely unexplored concerning this outcome. This study aimed to compare the neurotoxic effects of DOX and SUN in dopaminergic neuronal cells and to explore the involvement of oxidative stress and autophagy as potential mechanisms underlying their cytotoxicity. Human neuronal SH-SY5Y cells were differentiated into a dopaminergic phenotype and exposed to clinically relevant concentrations of DOX (0.1-10 µM) and SUN (1-10 µM) for 24 or 48 h. To investigate the involvement of oxidative stress in their cytotoxicity, redox modulators [N-acetylcysteine (NAC); dimethyl fumarate (DMF); sulforaphane (SFN); and cheirolin (CH)] were tested alongside DOX and SUN for their potential protective effects. The role of autophagy in SUN-induced toxicity was assessed using 3-methyladenine (3-MA; an early-stage inhibitor); chloroquine (CH; a late-stage inhibitor); and rapamycin (RAP; an autophagy inducer). Additionally, LC3-I and LC3-II expression levels were determined. Both DOX and SUN exhibited time- and concentration-dependent cytotoxicity and induced mitochondrial membrane depolarization. NAC conferred partial protection against SUN toxicity but enhanced DOX's cytotoxicity at the lowest concentration tested. DMF and SFN had dual effects, depending on the drug's concentration, while CH exhibited a consistent protective effect towards the cytotoxicity induced by both drugs. Regarding autophagy, 3-MA partially protected against SUN-induced toxicity, whereas CLQ and RAP exacerbated it. LC3-II levels were increased in some conditions, suggesting that SUN-induced toxicity involves autophagy. This study shows that SUN, though less studied in chemobrain, has a cytotoxic profile similar to DOX, which is a known contributor to chemobrain, in SH-SY5Y cells. These findings highlight the need for further research on neuroprotective strategies targeting oxidative stress and autophagy to reduce chemobrain in cancer patients and survivors.},
}
@article {pmid40505349,
year = {2025},
author = {Asghar, MA and Wan, B and Li, L and Zhang, J and Tang, S and Han, H and Yang, Y and Chu, L and Zhang, Q and Zhang, X and Zhao, Q},
title = {Micronutrient antioxidant supplementation alleviates valproic acid-induced oxidative stress and male infertility via the NRF2/HO-1 pathway.},
journal = {Redox biology},
volume = {85},
number = {},
pages = {103685},
pmid = {40505349},
issn = {2213-2317},
mesh = {Male ; *Oxidative Stress/drug effects ; Animals ; *NF-E2-Related Factor 2/metabolism/genetics ; *Valproic Acid/adverse effects ; *Infertility, Male/metabolism/drug therapy/chemically induced/etiology/pathology ; Mice ; *Antioxidants/pharmacology/administration &amp; dosage ; Humans ; *Heme Oxygenase-1/metabolism/genetics ; Signal Transduction/drug effects ; Dietary Supplements ; Hep G2 Cells ; Apoptosis/drug effects ; Membrane Proteins ; },
abstract = {BACKGROUND: Valproic Acid (VPA), a widely used anticonvulsant, is known to induce oxidative stress, contributing to male infertility. This study explores the potential of micronutrient antioxidants to improve fertility in VPA-treated individuals.<br><br>METHODS: Six-week-old male mice were treated with VPA and supplemented with antioxidants, including l-Arginine (120&#xa0;mg/kg), N-Acetylcysteine (NAC) (2&#xa0;mg/kg), Taurine (200&#xa0;mg/kg), L-Tryptophan (0.5&#xa0;mg/kg), Zinc chloride (ZnCl2) (1.5&#xa0;mg/kg), and Selenium (0.5&#xa0;mg/kg). The dosing regimen lasted for 34 days. Sperm quality, oxidative stress, and inflammatory biomarkers were assessed through gene expression analysis, western blotting, histological assessments, TUNEL assays, and immunohistochemistry. Additionally, GC-2spd(ts) and HepG2 cell lines were used to examine the testicular and systemic effects of VPA and antioxidants. Network pharmacology was applied to identify key molecular targets and pathways.<br><br>RESULTS: Antioxidant supplementation significantly improved sperm count, with l-Arginine showing an approximately 296.1&#xa0;% increase, NAC a 270.7&#xa0;% increase, and Taurine a 255.9&#xa0;% increase compared to the VPA-only group. Furthermore, antioxidants enhanced semen volume, testosterone levels, sperm motility, morphology, and viability. Gene expression analysis revealed significant upregulation of key oxidative stress-related proteins such as SOD1, HO-1, NRF2, and NQO1. Western blot and histological analyses showed a reversal of oxidative stress and preservation of seminiferous tubule integrity. TUNEL assays demonstrated a reduction in apoptotic damage, and IHC confirmed an increase in HO-1 and SOD1. In vitro studies with GC-2spd(ts) and HepG2 cells confirmed that antioxidants alleviated VPA-induced oxidative stress. Network pharmacology identified key molecular targets, such as GPX4, SOD1, HO-1, and NRF2, which are involved in oxidative stress, apoptosis, and inflammation pathways, that were modulated by antioxidants.<br><br>CONCLUSION: Micronutrient antioxidants effectively reduce VPA-induced oxidative stress and improve male fertility. These results suggest that antioxidant supplementation could be a promising strategy to mitigate oxidative damage and enhance fertility in individuals undergoing VPA therapy.},
}
@article {pmid40501637,
year = {2025},
author = {Zhang, H and Valestil, K and Pierce, EA},
title = {Oxidative DNA Damage Drives Apoptotic Photoreceptor Loss in NMNAT1 -Associated Inherited Retinal Degeneration: A Therapeutic Opportunity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.05.658162},
pmid = {40501637},
issn = {2692-8205},
abstract = {Early-onset inherited retinal degenerations (IRDs), such as Leber congenital amaurosis (LCA) caused by pathogenic variants in the NMNAT1 gene, lead to severe vision loss in children. Despite its ubiquitous expression, reduced NMNAT1 function primarily affects photoreceptor cells (PRs) of the retina, yet the mechanisms underlying their heightened vulnerability remain incompletely understood. Here, we demonstrate that reduced NMNAT1 enzyme function due to the p.V9M mutation leads to DNA damage in PRs, characterized by the progressive accumulation of the oxidative DNA adduct 8-oxo-dG in Nmnat1 [V9M/V9M] mutant mice. Cells with oxidative DNA damage also demonstrate DNA double-strand breaks, as evidenced by co-staining with antibodies to phosphorylated H2AX (γH2A.X). This DNA damage correlates with apoptosis-driven PR degeneration, as evidenced by caspase-9 activation and TUNEL staining in the PRs of the Nmnat1 [V9M/V9M] mutant mice, while alternative cell death pathways such as necroptosis and parthanatos were not significantly activated. Treatment with the antioxidant N-acetylcysteine (NAC) effectively reduced oxidative DNA damage and retinal immune responses, mitigated apoptosis, and preserved cone PRs. Longitudinal assessment via optical coherence tomography (OCT) and electroretinography (ERG) revealed sustained structural and functional protection in NAC-treated mice. These findings establish oxidative DNA damage as a key driver of PR degeneration in the Nmnat1 [V9M/V9M] model and highlight NAC's potential as a causal gene variant-independent therapeutic strategy for NMNAT1 -associated IRD and potentially other IRDs in which oxidative DNA damage contributes to disease pathogenesis.},
}
@article {pmid40497192,
year = {2025},
author = {Abutineh, MA and Lodha, C and Mitchell, G},
title = {Multiorgan Failure Secondary to Intentional Acetaminophen Overdose-Induced Methemoglobinemia.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e83833},
pmid = {40497192},
issn = {2168-8184},
abstract = {Although acetaminophen toxicity has been reported to cause methemoglobinemia, its recognition remains limited in the clinical literature. Methemoglobinemia often necessitates a high index of clinical suspicion, as it may contribute to lactic acidosis and multiorgan dysfunction due to impaired tissue oxygenation. A 21-year-old man presented to the emergency department (ED) via emergency medical services (EMS) with reports of an intentional overdose of an unknown amount of bupropion, two pill bottles of acetaminophen, and an unknown amount of bleach. The patient was emergently intubated. Despite reported bleach ingestion, esophagogastroduodenoscopy (EGD) revealed no evidence of caustic injury or esophagitis. The poison center was contacted, and the patient was started on N-acetylcysteine (NAC). The exact time of acetaminophen ingestion was unknown; however, liver function tests were normal at presentation. Transaminases became abnormal 48 hours later (well after NAC administration had begun). Persistent lactic acidosis in the context of normal initial transaminase levels raised clinical suspicion for methemoglobinemia, given the potential for tissue hypoxia. Methemoglobin levels were confirmed to be elevated, potentially explaining tissue ischemia. The patient received methylene blue as the antidote. The liver transplant team was consulted and agreed with the poison center's recommendation of excluding acetaminophen-induced liver injury. Due to unexplained elevated lactic acid and multisystem organ failure, the family elected for a Do Not Resuscitate (DNR) status. The patient expired four days later with multisystem organ failure.},
}
@article {pmid40490445,
year = {2025},
author = {Kundukad, B and Rice, SA and Doyle, PS and Kjelleberg, S},
title = {Alginate exopolymer significantly modulates the viscoelastic properties and resilience of bacterial biofilms.},
journal = {NPJ biofilms and microbiomes},
volume = {11},
number = {1},
pages = {98},
pmid = {40490445},
issn = {2055-5008},
mesh = {*Biofilms/growth &amp; development/drug effects ; *Alginates/metabolism/chemistry ; *Pseudomonas aeruginosa/physiology/drug effects/genetics ; Elasticity ; Viscosity ; *Polysaccharides, Bacterial/metabolism ; Extracellular Matrix/chemistry ; },
abstract = {Biofilms are viscoelastic gels with a cross-linked network of biopolymers forming an extracellular matrix that protects bacteria from most antimicrobial treatments. This study examines the physical role of the matrix in preventing recolonisation using a mucoid Pseudomonas aeruginosa (P. aeruginosa ΔmucA) and isogenic wild-type Pseudomonas aeruginosa PAO1. We investigated the recolonisation of pre-formed live biofilms and the residual matrix left behind after bacterial eradication with N-acetyl cysteine (NAC). P. aeruginosa ΔmucA, which overproduces alginate, prevented recolonisation through swelling and increased elastic modulus. In contrast, the wild-type P. aeruginosa biofilm matrix exhibited minimal swelling and decreased elasticity, suggesting crosslink breakage. These observations align with polymer physics theories where alginate's polyelectrolyte nature drives swelling through the Donnan effect, enhancing matrix stability. Meanwhile, the Psl-rich wild-type matrix limited swelling but showed reduced mechanical stability. This study underscores the critical role of matrix composition in biofilm mechanics, influencing bacterial protection regardless of viability.},
}
@article {pmid40489761,
year = {2025},
author = {Harpavat, S and Borovsky, KA and Scheurer, ME and Cavallo, L and Erhiawarie, FE and Vasudevan, S and Vogel, AM and Cerminara, D and Tessier, EM and Patel, KR and Devaraj, S and Shneider, BL},
title = {A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy.},
journal = {Hepatology communications},
volume = {9},
number = {7},
pages = {},
pmid = {40489761},
issn = {2471-254X},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/adverse effects ; *Biliary Atresia/surgery/drug therapy/blood ; Male ; Female ; *Portoenterostomy, Hepatic ; Infant ; Treatment Outcome ; Administration, Intravenous ; },
abstract = {BACKGROUND: For infants with biliary atresia, the only treatment that can establish bile flow and delay need for liver transplant is the Kasai portoenterostomy (KP). Unfortunately, the KP has variable success. In this study, we hypothesized that intravenous N-acetylcysteine (IV NAC) treatment following KP would improve bile flow.<br><br>METHODS: This was a phase 2 study following the two-stage "minimax" trial design. Participants received IV NAC (150&#xa0;mg/kg/day) for 7 days after KP, and the primary endpoint was achieving total serum bile acids (TSBA) &#x2264;10&#xa0;&#x3bc;mol/L within 24 weeks of KP. Secondary endpoints were clinical markers and the occurrence of sentinel events.<br><br>RESULTS: There were 12 participants in stage 1 who received treatment, with none achieving TSBAs &#x2264;10&#xa0;&#x3bc;mol/L within 24 weeks of KP. As a result, no participants were enrolled in stage 2. There were 32 adverse events in 11 participants, including 5 serious adverse events which were considered part of the participants' natural clinical course and not directly attributable to NAC treatment. Analyses of secondary outcomes demonstrated no difference in clinical markers or occurrence of sentinel events between study participants and matched historical controls.<br><br>CONCLUSIONS: This study demonstrates how the two-stage "minimax" trial design can be used to efficiently evaluate potential therapies for BA. Although the primary endpoint was not met, NAC therapy was generally well-tolerated. NAC therapy may prove efficacious in future trials with (i) a less stringent primary endpoint and/or (ii) a longer course of treatment (NCT03499249).},
}
@article {pmid40488120,
year = {2025},
author = {Al-Younis, I and Martín-Jiménez, R and Khan, M and Baussan, Y and Jose, C and Thibeault, Y and Hebert-Chatelain, E},
title = {N-acetyl-L-cysteine improves mitochondrial and oxidative defects in the acadian variant of fanconi syndrome.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {250},
number = {},
pages = {10448},
pmid = {40488120},
issn = {1535-3699},
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Oxidative Stress/drug effects ; Fibroblasts/drug effects/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; *Fanconi Syndrome/drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; *Antioxidants/pharmacology ; Cells, Cultured ; Electron Transport Complex I/metabolism ; Cell Respiration/drug effects ; Malondialdehyde/metabolism ; },
abstract = {The Acadian variant of Fanconi Syndrome (AVFS) is a rare genetic disorder characterized by renal deficiencies. AVFS is caused by a mutation to NDUFAF6 encoding a complex I assembly factor, and leading to metabolic alterations. We confirmed that fibroblasts derived from AVFS patients have lower complex I activity, mitochondrial membrane potential and cellular respiration. These mitochondrial defects were accompanied by higher levels of 8-hydroxy-2'deoxyguanosine, malondialdehyde and carbonyl, which are markers of oxidative damage to DNA, lipids and proteins, respectively. Thus, we hypothesized that the antioxidant N-Acetyl-L-cysteine (NAC) would reduce oxidative stress and mitochondrial defects in AVFS fibroblasts. Treatment with NAC during 5 days partially restored complex I activity, mitochondrial membrane potential and cellular respiration in AVFS fibroblasts. NAC also prevented oxidative damage in AVFS fibroblasts. This work shows for the first time that the physiopathology of AVFS includes high oxidative stress. It also reveals that NAC and other antioxidant-based strategies might represent an effective pharmacological treatment for AVFS.},
}
@article {pmid40485434,
year = {2025},
author = {Pandey, S and Arachchige, DL and Schwandt, RJ and Dwivedi, SK and Kathuria, I and Liu, H and Luck, RL},
title = {Rhodamine-derived ratiometric fluorescent probes for high-sensitivity detection and real-time imaging of mitochondrial pH and viscosity in HeLa cells and Drosophila melanogaster.},
journal = {Journal of materials chemistry. B},
volume = {13},
number = {26},
pages = {7865-7881},
pmid = {40485434},
issn = {2050-7518},
support = {R15 GM146206/GM/NIGMS NIH HHS/United States ; R15 GM152969/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; HeLa Cells ; Animals ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Rhodamines/chemistry/chemical synthesis ; Hydrogen-Ion Concentration ; *Mitochondria/chemistry/metabolism ; Drosophila melanogaster/chemistry ; Viscosity ; Fluorescence Resonance Energy Transfer ; Optical Imaging ; Molecular Structure ; },
abstract = {The spirolactam on/off switch attached to rhodamine dye is known to be a highly selective and sensitive fluorescent probe, yet few studies have explored extending the π-conjugation system within its skeleton for pH detection in live cells. An extended π-conjugated rhodamine section should enable ratiometric pH detection in the near-infrared region. In this study, we synthesized probes A and B by coupling a rhodamine derivative with 7-nitrobenzofurazan and 7-(diethylamino)-2-oxo-3,8a-dihydro-2H-chromene-3-carbaldehyde sections, respectively. Probe A exhibits emission via a Förster resonance energy transfer (FRET) mechanism. Under excitation at 370 nm, the conjugated 7-nitrobenzofurazan in probe A exhibits fluorescence at 465 nm in the ring-closed state, while fluorescence at 660 nm appears in the ring-open state due to increased conjugation in the rhodamine moiety. Excitation of probe B at 325 nm resulted in reduced emission around 350 nm and a significantly enhanced response at 525 nm. Probe A was evaluated for mitochondrial pH detection through ratiometric fluorescence emission measurements. Additional tests in living HeLa cells, including responses to stimuli such as carbonyl cyanide-4(trifluoromethoxy)phenylhydrazone (FCCP), hydrogen peroxide (H2O2), N-acetyl cysteine (NAC), mitophagy induced by nutrient deprivation, and hypoxia triggered by cobalt chloride (CoCl2) treatment, as well as pH changes in fruit fly larvae, further validated its applicability for ratiometric measurement of mitochondrial pH variations. Probe A's emission was dependent on the pH level under basic conditions, but under acidic conditions, the change in conformation upon ring opening resulted in the emission also being affected by viscosity.},
}
@article {pmid40482471,
year = {2025},
author = {Miller, A and Lombardo, GP and Spiccia, L and Natale, V and Migliorato, A and Bednarski, M and Iciek, M and Bilska-Wilkosz, A and Sablik, M and Lauriano, ER and Kotańska, M and Pergolizzi, S},
title = {Characterization of immune cells in the rat intestinal mucosa and liver involved in inflammation caused by LPS and evaluation of the effects of N-acetylcysteine and disulfiram (well-known sulfur drugs) for this inflammation.},
journal = {Acta histochemica},
volume = {127},
number = {3},
pages = {152272},
doi = {10.1016/j.acthis.2025.152272},
pmid = {40482471},
issn = {1618-0372},
mesh = {Animals ; *Disulfiram/pharmacology ; *Lipopolysaccharides/toxicity ; Rats ; *Intestinal Mucosa/immunology/drug effects/pathology ; *Acetylcysteine/pharmacology ; *Inflammation/drug therapy/chemically induced/immunology/pathology ; *Liver/immunology/drug effects/pathology ; Male ; Rats, Wistar ; },
abstract = {Lipopolysaccharide (LPS)-induced inflammation is an experimental rat model often used as a tool for testing new drugs as candidates for treating various diseases associated with inflammation. New methods now allow for precise imaging of tissues and changes induced by various factors. To increase knowledge about LPS-induced inflammation and promote strategies for investigating new therapies, this study aims to characterize immune cells involved in inflammation in the rat intestinal mucosa and liver and to evaluate the therapeutic effect of two well-known sulfur drugs N-acetylcysteine (NAC) and disulfiram (DSF) on this model LPS was administered intraperitoneally to rats once a day, for 10 days. NAC and DSF were administered 5 h after LPS. At the end of experiment, animals were euthanized, and the intestine and liver were collected. The immune cells of the intestinal mucosa and liver were characterized with the following antibodies: Toll-like receptors (TLR2 and TLR4), smooth muscle alpha-actin (α-SMA), major histocompatibility complex II (MHC-II), and serotonin (5-HT). In samples obtained from inflamed rat intestinal mucosa, it was possible to detect TLR2-positive and TLR4-positive cells, and numerous α-SMA-positive cells, indicating an inflammatory state. Furthermore, an increase in serotonin positive neuroendocrine cells compared to normal was demonstrated, which could be associated with intestinal inflammation. The number of these positive cells was much smaller in the samples derived from animals treated with NAC or DSF, suggesting anti-inflammatory action of these drugs. In the inflamed rat liver, several immune cells positive for these antibodies were observed and NAC or DSF decreased the amount of these positive cells. In conclusion, this study shows that bacterial LPS can activate various innate immune system cell populations, such as dendritic cells, neutrophils, Kupffer cells, myofibroblasts and enterocytes. Moreover, this study demonstrates the beneficial effects on NAC and DSF in alleviating inflammation and relieving tissue fibrosis in the LPS-induced inflammation in the rat intestinal mucosa and liver.},
}
@article {pmid40481912,
year = {2025},
author = {Bakirhan, EG and Yanilmaz, EMB and Tüfekci, KK and Bakirhan, F and Susam, S},
title = {Maternal high-fat diet impairs cognitive performance by altering hippocampal GRP78/PERK axis and BDNF expression in adult female rat offspring: the potential protective role of N acetylcysteine.},
journal = {Journal of molecular histology},
volume = {56},
number = {3},
pages = {189},
pmid = {40481912},
issn = {1567-2387},
mesh = {Animals ; Female ; *Brain-Derived Neurotrophic Factor/metabolism ; *Hippocampus/metabolism/drug effects ; *Diet, High-Fat/adverse effects ; Rats ; Pregnancy ; *Acetylcysteine/pharmacology ; *Heat-Shock Proteins/metabolism ; *eIF-2 Kinase/metabolism ; *Prenatal Exposure Delayed Effects ; Endoplasmic Reticulum Stress/drug effects ; *Cognition/drug effects ; Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects ; Endoplasmic Reticulum Chaperone BiP ; Maze Learning/drug effects ; Rats, Sprague-Dawley ; },
abstract = {Maternal high fat diet (HFD) affects the neurodevelopment of offspring and has long-term consequences on cognitive behavior. This study investigated changes occurring in GRP78 and PERK, important markers of endoplasmic reticulum stress (ERS) signaling, in the hippocampus of female adult rats exposed to maternal HFD, and in brain-derived neurotrophic factor (BDNF) signaling, with its important role in the regulation of cognitive behavior, and the potential neuroprotective effects of N-acetylcysteine (NAC) against these changes. A maternal obesity model was created with HFD (60% kcal). NAC (150 mg/kg) was administered intragastrically to both the NAC and HFD + NAC groups. The animals were mated at 12 weeks of age. The same diet was maintained throughout pregnancy and lactation. All female rat pups were subjected to the water maze test at eight weeks of age. Hippocampal GRP78 and PERK expressions increased in the HFD rats. However, maternal HFD suppressed hippocampal BDNF levels and reduced hippocampal neuronal volume. NAC supplementation reduced GRP78 and PERK expressions and increased BDNF and hippocampal volume values in the HFD + NAC group. At behavioral assessments, rats in the HFD group exhibited decreased memory and learning ability, but the HFD + NAC group exhibited stronger responses than the HFD group. Our findings suggest that the decrease in BDNF expression, which plays a role in memory and learning, after maternal HFD exposure may be due to ERS associated with increased GRP78 and PERK expressions. Furthermore, NAC supplementation may ameliorate the impairment in memory and spatial learning ability by attenuating hippocampal ERS in HFD rats.},
}
@article {pmid40480879,
year = {2025},
author = {Zakaria, AY and Badawi, R and Osama, H and Abdelrahman, MA and El-Kalaawy, AM},
title = {New Approach Combination-Dosed Therapy for Nonalcoholic Steatohepatitis Versus Vitamin E: A Randomized Controlled Trial.},
journal = {Clinical therapeutics},
volume = {47},
number = {8},
pages = {e19-e30},
doi = {10.1016/j.clinthera.2025.05.006},
pmid = {40480879},
issn = {1879-114X},
mesh = {Humans ; *Vitamin E/administration &amp; dosage/therapeutic use/adverse effects ; Non-alcoholic Fatty Liver Disease/drug therapy ; Male ; Middle Aged ; Female ; Double-Blind Method ; *Acetylcysteine/administration &amp; dosage/therapeutic use ; Drug Therapy, Combination ; Rosuvastatin Calcium ; Adult ; Quality of Life ; Treatment Outcome ; *Fatty Liver/drug therapy/pathology ; *Sulfonamides/administration &amp; dosage/therapeutic use ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration &amp; dosage/therapeutic use ; *Antioxidants/administration &amp; dosage/therapeutic use ; },
abstract = {PURPOSE: There is currently no US Food and Drug Administration-approved remedy for nonalcoholic steatohepatitis (NASH). The present study evaluated the efficacy of N-acetyl cysteine (NAC) and rosuvastatin (RSV) compared with conventional vitamin E in patients with NASH.<br><br>METHODS: This study was designed as a parallel, double-blinded, randomized controlled trial. Ninety patients who met the eligibility criteria were enrolled in this study. Subsequently, 45 patients were allocated to each group as follows: group 1 reported consistent administration of vitamin E 400 IU[&#x24c7;] (PHARCO-Pharmaceuticals) twice daily over a duration of 6 months. Group 2 included patients with NASH who received NAC, Gemacysteine 300 mg[&#x24c7;] (GEMA-Pharma) at 1200 mg twice daily, along with RSV, Crestor 20 mg[&#x24c7;] (AstraZeneca). To achieve the study's objective, FibroScan[&#x24c7;] examination of liver tissue and fibrosis scores, as well as tests for liver aminotransferases, lipid profile, glycemic parameters, and hepatic and renal functions, besides health-related quality of life using the Short-Form 36 were evaluated before and after 6 months of treatment.<br><br>FINDINGS: In group 1, a statistically significant decrease in the mean value of steatosis was observed after 6 months by 6.05% (P = 0.017), whereas treated group 2 exhibited a reduction of 16.49% (P = 0.001). Group 2 reported a statistically significant decrease in the mean fibrosis value of approximately 19.5% (P = 0.001). Fibrosis-4 Index score's significance stated a reduction in the mean values within treatment group 2, with decreases of 51.70%. MACK-3 score which is a combination of homeostatic model assessment, aspartate aminotransferase, and cytokeratin-18, exhibited a notable reduction in mean values within treatment group 2 by 25.06% (P = 0.001). Concerning biological markers, malondialdehyde, both groups reported significant reductions in mean values of 11.90% (P = 0.006) and 27.43% (P = 0.001), respectively. Group 2 exhibited substantial reductions in mean levels of all biological markers: NOD-like receptor-associated protein 3 inflammasome decreased by 24.40%, tumor necrosis factor-&#x3b1; by 9.64%, tissue inhibitor of metalloproteinases 1 by 10.28%, N-terminal propeptide of procollagen type III by 14.58%, cytokeratin-18 by 23.44%, and fibroblast growth factor-21 by 15.08% (P < 0.05), whereas group 1 did not demonstrate significant differences. Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters.<br><br>IMPLICATIONS: Patients in group 2 treated with the combination of NAC/RSV exhibited tolerability and efficacy in improving liver steatosis and fibrosis, besides metabolic parameters, indicating a new combination approach to the management of NASH.<br><br>CLINICALTRIALS: gov identifier: NCT06105060.},
}
@article {pmid40478359,
year = {2025},
author = {Saniei, H and Naderi, R},
title = {The effect of N-acetylcysteine on apoptosis and NGF-Akt/Bad pathway in the hippocampus tissue of cerebral ischemia-reperfusion in male rats.},
journal = {Metabolic brain disease},
volume = {40},
number = {5},
pages = {217},
pmid = {40478359},
issn = {1573-7365},
mesh = {Animals ; Male ; *Apoptosis/drug effects/physiology ; *Hippocampus/drug effects/metabolism/pathology ; *Reperfusion Injury/metabolism/drug therapy/pathology ; *Nerve Growth Factor/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Acetylcysteine/pharmacology/therapeutic use ; Rats ; *bcl-Associated Death Protein/metabolism ; *Brain Ischemia/metabolism/drug therapy/pathology ; Signal Transduction/drug effects ; Rats, Sprague-Dawley ; },
abstract = {Apoptosis is the primary pathological feature of neuronal injury caused by cerebral ischemia-reperfusion (I/R). The detailed molecular mediators are still being debated. This study aims to examine the effects of cerebral ischemia-reperfusion on apoptosis and NGF-Akt/Bad axis in rat hippocampus alone and in combination with NAC (N-Acetylcysteine). Rats were subjected to common carotid artery occlusion (CCAO) for 20 min followed by 24 h reperfusion. NAC (150 mg/kg) was given intraperitoneally (ip) one hour before ischemia and five minutes before reperfusion. TUNEL staining of hippocampus neurons revealed that the number of apoptotic neurons was elevated 24 h after reperfusion. At the molecular levels, I/R injury resulted in an increased protein expression of cleaved caspase3/procaspase3 ratio and cytochrome c level with a concomitant down-regulation of NGF, p-AKT/AKT, p-Bad/Bad and p-Trk/Trk ratio. NAC treatment significantly reduced the apoptotic damage and also reversed NGF, p-AKT/AKT, p-Bad/Bad, and p-Trk/Trk ratio in hippocampus neurons in I/R rats. In conclusion, our data showed that NGF-Akt/Bad axis may play a regulatory role in hippocampus cell death, providing a new target for a novel therapeutic strategy during transit ischemic stroke. NAC has been shown to reverse molecular alterations, suggesting its potential as an effective agent against hippocampal apoptosis following acute I/R injury.},
}
@article {pmid40470288,
year = {2025},
author = {Wolff, HT and Piroth, AC and Oltmanns, H and Meißner, J and Verspohl, J and Volk, HA and Busse, C},
title = {Commercially available antiseptics show high in vitro efficacy against pathogens most commonly associated with canine and feline infectious keratitis.},
journal = {Frontiers in veterinary science},
volume = {12},
number = {},
pages = {1552230},
pmid = {40470288},
issn = {2297-1769},
abstract = {PURPOSE: To determine the minimal bactericidal concentration (MBC) of polyhexanide (PHMB), povidone-iodine (PVP-I), N-acetylcysteine (NAC), and hypochlorous acid (HOCl) for bacterial species commonly found in canine and feline infectious keratitis.<br><br>METHODS: MBCs for clinical isolates of Staphylococcus (S.) pseudintermedius (n = 11), including 3 methicillin-resistant strains, Pseudomonas (P.) aeruginosa (n = 8), and Streptococcus (Str.) canis (n = 11), including the corresponding control strains, were examined. All testing substances were serially diluted in phosphate-buffered saline (PBS) and cation-adjusted Mueller-Hinton Broth (CAMHB) and inoculated with the bacterial suspension for 10 min. Afterwards, a neutralisation with Dey-Engley neutralising broth was performed, followed by plating onto Columbia sheep-blood agar. After incubation, plates were visually examined for bacterial growth. Tests were carried out in triplicate.<br><br>RESULTS: MBCs in PBS for polyhexanide ranged 0.8-1.6 mg/L for S. pseudintermedius and 1.6-3.2 mg/L for P. aeruginosa and Str. canis. For povidone-iodine, MBCs in PBS were observed at concentrations ranging 8-32 mg/L for S. pseudintermedius and P. aeruginosa and 8-16 mg/L for Str. canis. MBCs in PBS for NAC were recorded at a range of 6,400-12,800 mg/L for S. pseudintermedius, whereas those for P. aeruginosa and Str. canis ranged 3,200-6,400 mg/L. Results for HOCl in PBS ranged 0.4-1.6 mg/L for S. pseudintermedius and 0.4-0.8 mg/L for P. aeruginosa and Str. canis. MBCs in CAMHB for polyhexanide were found in the range between 3.2 and >12.8 mg/L, those for povidone-iodine between 6,400 and >12,800 mg/L, and for NAC between 6,400 and >12,800 mg/L, across the tested species. When dissolved in CAMHB, no antimicrobial effect could be observed for HOCl in concentrations up to 137.5 mg/L.<br><br>CONCLUSION: All tested substances had an in vitro bactericidal effect against all three bacterial species with MBCs below known tolerated ocular concentrations when dissolved in PBS. Povidone-iodine and hypochlorous acid showed a marked reduction in their in vitro efficacy in the presence of protein. Nevertheless, our results provide a promising outlook on alternatives or adjuvants to antibiotics in ophthalmology that align with the One Health approach.},
}
@article {pmid40464516,
year = {2025},
author = {Ma, HY and Wu, HY and Xiang, YT and Liu, YY and Xie, J and Cai, PY and Zhang, B and Zhang, YH and Wu, MX},
title = {Mechanism of SLC1A5 Regulation of Glutamine Metabolism to Promote Ferroptosis Sensitivity in Endometriosis.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {5},
pages = {36781},
doi = {10.31083/FBL36781},
pmid = {40464516},
issn = {2768-6698},
mesh = {*Ferroptosis/drug effects ; Female ; *Glutamine/metabolism ; Humans ; Animals ; *Amino Acid Transport System ASC/metabolism/genetics ; Rats ; Reactive Oxygen Species/metabolism ; *Endometriosis/metabolism/pathology/drug therapy/genetics ; *Minor Histocompatibility Antigens/metabolism/genetics ; Piperazines/pharmacology ; Proto-Oncogene Proteins c-myc/metabolism ; Cell Line ; Rats, Sprague-Dawley ; Disease Models, Animal ; Stromal Cells/metabolism ; Endometrium/metabolism ; },
abstract = {BACKGROUND: Endometriosis (EMs) is a chronic gynecological disorder associated with ectopic endometrial tissue, inflammation, oxidative stress, and mitochondrial dysfunction. A promising strategy for treating EMs is to target ferroptosis, a programmed cell death mechanism regulated by reactive oxygen species (ROS) and glutamine metabolism. Solute carrier family 1 member 5 (SLC1A5), a glutamine transporter, and c-Myc play key roles in ferroptosis, forming a "ROS/c-Myc/SLC1A5" feedback loop. The aim of this study was to investigate the regulatory role of SLC1A5 in ferroptosis. In addition, we evaluated the ferroptosis inducer Erastin as a potential therapeutic agent for EMs.<br><br>METHODS: The human endometrial stromal cells (ESCs) line hEM15A was used in this study, together with a rat model of EMs. hEM15A cells and rats were treated with Erastin, with or without SLC1A5 modulation or ROS scavenging with N-acetylcysteine (NAC). Cell viability, ROS levels, glutamine metabolism, mitochondrial function, and ferroptosis markers (glutathione peroxidase 4 (GPX4)) were subsequently analyzed by Cell Counting Kit-8 (CCK-8) assay, reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot, and fluorescent probes. Pathological changes, lesion volumes, and pelvic adhesions in the rat EM model were assessed using hematoxylin and eosin (HE) staining, ultrasound imaging, and Haber scoring.<br><br>RESULTS: Erastin treatment of ESCs induced ferroptosis by upregulating SLC1A5 and c-Myc expression, increasing ROS levels, and altering glutamine metabolism. Overexpression of SLC1A5 enhanced sensitivity to ferroptosis, whereas SLC1A5 knockdown and NAC treatment reversed these effects. Mechanistically, c-Myc bound to the SLC1A5 promoter, forming positive feedback with ROS. In the rat model of EMs, Erastin treatment reduced ectopic lesion volume, pelvic adhesions, and inflammatory markers (TNF-&#x3b1;, IL-6, IL-1&#x3b2;). These therapeutic effects were mitigated by NAC, highlighting the importance of the ROS/c-Myc/SLC1A5 pathway.<br><br>CONCLUSIONS: This study confirmed the involvement of the ROS/c-Myc/SLC1A5 pathway in regulating EMs sensitivity to ferroptosis and demonstrated the potential of Erastin as a therapeutic agent. Targeting this pathway offers a promising approach for the treatment of EMs.},
}
@article {pmid40459775,
year = {2025},
author = {Singh, J and Phogat, A and Malik, V},
title = {N-acetylcysteine: a potential therapeutic agent against toxicity of pesticides.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {539},
pmid = {40459775},
issn = {1573-4978},
mesh = {*Acetylcysteine/pharmacology/therapeutic use/metabolism ; *Pesticides/toxicity ; Humans ; Oxidative Stress/drug effects ; Animals ; Antioxidants/pharmacology/metabolism ; Signal Transduction/drug effects ; },
abstract = {N-acetylcysteine (NAC) is a well-known health supplement that acts as a precursor to glutathione and exhibits antioxidative, anti-inflammatory, and modulatory activities. Several studies have extensively investigated the biological efficacy of NAC, including its effects on oxidative stress, cellular antioxidants, signal transduction, and structural anomalies caused by xenobiotics, including pesticides. This review summarizes the evidence of the ameliorative potential of NAC against oxidative stress and details its therapeutic potential in alleviating the toxicity of pesticides. Both in vivo and in vitro experiments have shown that NAC exerts its biological efficacy via regulation of TGF-β1/Smad3, MAPK, NF-κB, and PGC-1α/Tfam signaling pathways and rejuvenation of endogenous antioxidants.The present review provides insights into the recent findings and the mechanistic basis of the therapeutic potential of NAC for implementing it as an ameliorative agent against pesticide toxicity.},
}
@article {pmid40456742,
year = {2025},
author = {Romero, JC and Tonapi, SS and Parihar, M and Loranc, E and Miller, HE and Lawrence, LA and Bassani, N and Robledo, DG and Cao, L and Nie, J and Kanda, K and Stoja, A and Garcia, N and Gorthi, A and Stoveken, BJ and Fan, TW and Cassel, TA and Zha, S and Lechleiter, JD and Musi, N and Dong, LQ and Lane, AN and Bishop, AJR},
title = {Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5109},
pmid = {40456742},
issn = {2041-1723},
support = {T32 AG021890/AG/NIA NIH HHS/United States ; R01 CA241554/CA/NCI NIH HHS/United States ; F31 AG072902/AG/NIA NIH HHS/United States ; TL1 TR002647/TR/NCATS NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; K22 ES012264/ES/NIEHS NIH HHS/United States ; P30 CA177558/CA/NCI NIH HHS/United States ; T32 CA148724/CA/NCI NIH HHS/United States ; },
mesh = {*Ataxia Telangiectasia Mutated Proteins/metabolism/genetics ; Animals ; Phosphorylation ; *Glutamic Acid/metabolism/toxicity ; *Ataxia Telangiectasia/metabolism/genetics/pathology ; Humans ; Mice ; *Fusion Regulatory Protein 1, Heavy Chain/metabolism/genetics ; *Antiporters/metabolism ; Endothelial Cells/metabolism ; Mice, Knockout ; Oxidative Stress ; Protein Transport ; },
abstract = {Ataxia-telangiectasia is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in Ataxia-telangiectasia, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of this disorder is not understood. CD98HC chaperones cystine/glutamate and cationic/neutral amino acid antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on heterodimeric amino acid transporters relevant to Ataxia-telangiectasia phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes), with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance in ATM-deficient cells and mouse models. These findings provide insight into the long-known benefits of N-acetyl cysteine in Ataxia-telangiectasia cells beyond oxidative stress through removing glutamate excess by producing glutathione.},
}
@article {pmid40452041,
year = {2025},
author = {Pan, Y and Shih, HJ and Chuang, SH and Chang, CP and Hsiao, CH and Chiu, YH and Wang, PF and Lin, CC and Shih, PH},
title = {Effects of functional antioxidants on the expansion of gamma delta T-cells and their cellular cytotoxicity against bladder cancer cells.},
journal = {BMC cancer},
volume = {25},
number = {1},
pages = {980},
pmid = {40452041},
issn = {1471-2407},
support = {112-CCH-IRP-087//Changhua Christian Hospital, Taiwan/ ; 112-CCH-IRP-087//Changhua Christian Hospital, Taiwan/ ; 112-CCH-IRP-087//Changhua Christian Hospital, Taiwan/ ; },
mesh = {Humans ; *Urinary Bladder Neoplasms/immunology/pathology/drug therapy/metabolism ; *Antioxidants/pharmacology ; *Receptors, Antigen, T-Cell, gamma-delta/metabolism/immunology ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; *Intraepithelial Lymphocytes/immunology/drug effects ; Cell Survival/drug effects ; *Cytotoxicity, Immunologic/drug effects ; Acetylcysteine/pharmacology ; Lymphocyte Activation/drug effects ; Ascorbic Acid/pharmacology ; Vitamin E/pharmacology ; *T-Lymphocytes/drug effects/immunology ; Oxidative Stress/drug effects ; },
abstract = {PURPOSE: Results of previous studies have demonstrated that T-cell receptor cross-linking rapidly generates reactive oxygen species, which play essential signaling roles within mitochondria for the antigen-specific expansion of T-cells. However, oxidative stress also causes damage to cellular organelles. Thus, modulating ROS metabolism using antioxidants during naïve T-cell activation may promote the expansion and generation of functional T-cells. Notably, urothelial cancer is a sex-specific malignancy with high mortality rates worldwide. The present study aimed to evaluate the effects of various antioxidants on γδ T-cell proliferation, and the associated cytotoxicity against urothelial carcinoma cells (UCs).<br><br>METHODS: Over a period of cell induction and expansion, peripheral blood mononuclear cells were cultured with or without different antioxidants, including N-acetyl cysteine (NAC), vitamin C and vitamin E. Subsequently, phenotypic characterization of &#x3b3;&#x3b4; T-cells and their cytolytic effects against UCs were analyzed by flow cytometry and cell viability assays, respectively.<br><br>RESULTS AND CONCLUSIONS: The results revealed that NAC partially inhibited T-cell expansion in a dose-dependent manner. In addition, CD3[+]/V&#x3b3;9[+] levels and natural killer group 2D receptor expression were mildly reduced following treatment with a high dose of NAC, whereas CD3[+]/CD56[+] levels and CD314 expression in natural killer-like cells were moderately decreased following treatment with vitamin E. Particularly, the direct co-incubation of bladder cancer cells with &#x3b3;&#x3b4; T-cells supplemented with antioxidants significantly enhanced bladder cancer cytolysis. Collectively, results of the present study revealed that co-administration of functional antioxidants during &#x3b3;&#x3b4; T-cell expansion may enhance the quality and efficacy of adoptive T-cell therapies for cancer treatment.},
}
@article {pmid40449641,
year = {2025},
author = {Ruangjaroon, T and Paricharttanakul, NM and Chokchaichamnankit, D and Srisomsap, C and Lirdprapamongkol, K and Svasti, J},
title = {Toxicoproteomic study of fipronil in SH-SY5Y cells reveals induction of endoplasmic reticulum stress and necrotic cell death as neurodegenerative mechanisms.},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {108},
number = {},
pages = {106098},
doi = {10.1016/j.tiv.2025.106098},
pmid = {40449641},
issn = {1879-3177},
mesh = {Humans ; *Pyrazoles/toxicity ; Endoplasmic Reticulum Chaperone BiP ; *Insecticides/toxicity ; *Endoplasmic Reticulum Stress/drug effects ; Proteomics ; Cell Line, Tumor ; Necrosis/chemically induced ; Glutathione/metabolism ; Cell Survival/drug effects ; Cell Death/drug effects ; Heat-Shock Proteins/metabolism ; },
abstract = {Exposure to pesticides has been considered as a risk factor for developing neurodegenerative diseases. The increasing use of fipronil, a phenylpyrazole insecticide, poses a risk to human health. This study aims to use toxicoproteomics for exploring neurodegenerative mechanism of fipronil in SH-SY5Y human neuroblastoma cells. In this study, fipronil at sub-cytotoxic and cytotoxic concentrations (43 and 78 μM) caused increases in superoxide level from 3 to 48 h after treatment, while intracellular glutathione level was decreased at 48 h. Neurite outgrowth of the cells was impaired by fipronil at both concentrations, while significant increase of cell death via apoptosis and necrosis modes were observed with fipronil at cytotoxic concentration. Pretreatment with antioxidant N-acetylcysteine (NAC) effectively relieved impairment of neurite outgrowth and induction of cell death by fipronil. Proteomic analysis showed that expression of proteins involving endoplasmic reticulum (ER) stress and unfolded protein responses were predominantly affected by fipronil. Immunoblotting confirmed the increased expression of ER stress markers, GRP78/BiP (78 kDa glucose-regulated protein/Binding immunoglobulin protein) and PDI (protein disulfide isomerase), in fipronil-treated cells. Improved understanding of the neurotoxic mechanism of fipronil may help in developing a strategy for reducing risk of neurodegenerative development from intense and prolonged use of fipronil.},
}
@article {pmid40446373,
year = {2025},
author = {Fang, X and Pan, B and Xie, Y and Shao, W and Li, J and Han, D and Hong, X and Tu, W and Zhao, Y and Wu, J and Zhu, Y and Zhang, Y and Li, W and Xu, Y and Kan, H and Chen, R},
title = {Mechanistic insights into ozone-induced asthma exacerbation: role of oxidative stress and IL-33.},
journal = {Journal of hazardous materials},
volume = {494},
number = {},
pages = {138760},
doi = {10.1016/j.jhazmat.2025.138760},
pmid = {40446373},
issn = {1873-3336},
mesh = {*Ozone/toxicity ; *Oxidative Stress/drug effects ; *Asthma/chemically induced/physiopathology/immunology ; Animals ; *Interleukin-33/metabolism/immunology ; Male ; Mice ; Humans ; Female ; *Air Pollutants/toxicity ; Lung/drug effects/pathology/physiopathology/immunology ; Mice, Inbred BALB C ; },
abstract = {Short-term exposure to ozone is linked to the onset and exacerbation of asthma, yet the underlying mechanisms remain unclear. This study aims to elucidate the molecular pathways and key mediators involved in ozone-induced asthma exacerbation. In a longitudinal epidemiological study, each 10 µg/m[3] increase in ozone is associated with decreases in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF) of 26.24 ml (95 % confidence interval [CI]: 11.16 ml, 41.33 ml), 19.10 ml (95 % CI: 6.96 ml, 31.24 ml), and 41.65 ml/s (95 % CI: 3.87 ml/s, 79.43 ml/s), respectively. In asthmatic mice, ozone exposure induces oxidative stress and worsens pulmonary dysfunction, lung tissue damage, and inflammation, disrupting the balance of type 2 innate lymphoid cells (ILC2s), T helper type 2 (Th2), and T helper type 17 (Th17) cells. These effects are partially mitigated by N-acetylcysteine (NAC). Furthermore, ozone exposure significantly increases the interleukin (IL)-33 level, while treatment with an IL-33 neutralizing antibody markedly improves lung dysfunction, inflammatory cell infiltration, and immune response dysregulation. In conclusion, this study highlights that short-term exposure to ozone has deleterious effects on asthmatic patients and animals by inducing oxidative stress in lungs and disrupting immune function via IL-33.},
}
@article {pmid40443238,
year = {2025},
author = {Elangovan, A and Singh, A and Iyer, M and Kumar, SM and Kinoshita, M and Krishnan, J and Parkash, J and Verma, N and Yadav, MK and Wander, A and Reddy, DH and Vellingiri, B},
title = {Unravelling the Mechanistic Approach of Aflatoxin Contaminated Food on Neurodegenerative Diseases-A Novel Approach.},
journal = {Journal of applied toxicology : JAT},
volume = {45},
number = {10},
pages = {1947-1967},
doi = {10.1002/jat.4817},
pmid = {40443238},
issn = {1099-1263},
mesh = {Humans ; Animals ; *Food Contamination ; *Neurodegenerative Diseases/etiology/prevention &amp; control ; *Aflatoxins/toxicity ; Aspergillus/metabolism ; *Neuroprotective Agents/therapeutic use ; Blood-Brain Barrier/metabolism ; Mitochondrial Diseases/etiology ; },
abstract = {Aflatoxins (AFs) are a group of toxic secondary metabolites and a dietary toxin produced predominantly by Aspergillus species such as Aspergillus flavus and Aspergillus parasiticus. The four most common and harmful forms of AFs include Aflatoxin B1 (AFB1), Aflatoxin B2 (AFB2), Aflatoxin G1 (AFG1), and Aflatoxin G2 (AFG2), which pose a significant health threat due to their widespread contamination of food and feed products. Particularly, AFB1 has raised a major global health concern. Noxious neurological outcomes have been associated with chronic exposure to AF-contaminated food, contributing to development of neuropathies, demyelinating diseases, and cognitive decline. Disrupted tight junctions of blood-brain barrier (BBB) said to have implicated by AFs toxicity by directly damaging brain endothelial cells. Compromised BBB leads to the formation of DNA adducts, mitochondrial dysfunction, and impaired oxidative phosphorylation, contributing to oxidative stress in neuronal cells. AFs disrupt neuronal signaling pathways by generating reactive oxygen species (ROS) and initiating chronic inflammation, impairing cognitive function and motor control. Mounting evidences suggests that these factors trigger neurological disorders especially neurodegenerative disorders. Neuroprotective compounds, such as hesperetin, N-acetylcysteine (NAC), curcumin, and artichoke extract, have shown promise in counteracting AF-induced neurotoxicity. These compounds could reduce oxidative stress, attenuate inflammation, and support mitochondrial function, offering potential therapeutic strategies to mitigate AF-induced neurodegeneration. This review focuses on the molecular pathways through which AFs exert neurotoxic effects, highlighting their role in the onset of neurodegenerative diseases and potential neuroprotective compounds for therapies have been highlighted.},
}
@article {pmid40438181,
year = {2025},
author = {Liu, Y and Zhao, W and Huang, Q and Wan, L and Ren, Z and Zhang, B and Han, C and Yang, J and Zhang, H and Zhang, J},
title = {Advances in Research on the Release of von Willebrand Factor from Endothelial Cells through the Membrane Attack Complex C5b-9 in Sepsis.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {6719-6733},
pmid = {40438181},
issn = {1178-7031},
abstract = {Sepsis, a lethal organ dysfunction syndrome driven by aberrant host responses to infection, intertwines excessive inflammatory responses and dysregulated coagulation processes in its pathophysiology. Emerging research reveals the complement terminal membrane attack complex C5b-9 orchestrates ultralarge von Willebrand factor (ULVWF) release from vascular endothelial cells (ECs) through multifaceted mechanisms: C5b-9 compromises EC membrane integrity, activates calcium influx cascades, and provokes NLRP3 inflammasome signaling, triggering massive exocytosis of ULVWF stored within Weibel-Palade bodies (WPBs). When ADAMTS13 activity falters, undegraded ULVWF complexes with platelets to spawn microthrombi, precipitating microvascular occlusion and multiorgan collapse. Strikingly, elevated plasma von Willebrand factor (vWF) antigen levels in sepsis patients correlate robustly with endothelial injury, thrombocytopenia, and mortality-underscoring C5b-9-driven vWF release as a linchpin of septic coagulopathy. Current therapeutic strategies targeting these pathways, including recombinant ADAMTS13 (rhADAMTS13), N-acetylcysteine (NAC), and complement inhibitors like eculizumab, face limitations in clinical translation, necessitating further validation of their efficacy. Additionally, investigating complement regulatory molecules such as CD59 may unlock novel therapeutic avenues. Deciphering the intricate interplay within the C5b-9-vWF axis and advancing precision therapies hold transformative potential for ameliorating sepsis outcomes.},
}
@article {pmid40432447,
year = {2025},
author = {Máchalová, A and Landa, L and Máchal, J and Demlová, R and Slíva, J},
title = {The Effect of N-Acetylcysteine on Behavioral Sensitization to Methamphetamine in Mice.},
journal = {Physiological research},
volume = {74},
number = {2},
pages = {337-346},
pmid = {40432447},
issn = {1802-9973},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Methamphetamine/pharmacology/administration &amp; dosage ; Mice ; Male ; *Central Nervous System Stimulants/pharmacology ; *Behavior, Animal/drug effects ; },
abstract = {Behavioral sensitization is a phenomenon occurring after repeated administration of various psychotropic substances and it is characterized by gradually increasing response to the particular drug. It has been described for majority of addictive substances including amphetamines. It is considered to reinstate drug-seeking behaviour and plays important role in the processes associated with drug abuse and addiction. There are published reports, particularly on preclinical level, that N-acetylcysteine (NAC) may affect addictive properties of different classes of drugs (e.g., cocaine, heroin, alcohol, cannabinoids, nicotine). Since the lack of information on possible effects of NAC on amphetamine derivatives we decided to test possible influence of this substance on behavioral sensitization to methamphetamine (MET) in the mouse open field test. Our results have shown a decreased acute stimulatory effect of MET caused by NAC and moreover, there was a non-significant trend of attenuated development of behavioral sensitization to MET after simultaneous long-term administration of MET and NAC. This suppression of MET stimulatory effects therefore suggested on the preclinical level possible promising efficacy of NAC on addictive properties associated with MET similarly as it was demonstrated by other authors in association with cocaine or heroin. Key words: N-acetylcysteine, Methamphetamine, Behavioral sensitization.},
}
@article {pmid40430469,
year = {2025},
author = {Zakaria, AY and Badawi, R and Osama, H and Abdelrahman, MA and El-Kalaawy, AM},
title = {A Comparative Study of N-Acetyl Cysteine, Rosuvastatin, and Vitamin E in the Management of Patients with Non-Alcoholic Steatohepatitis: A Randomized Controlled Trial.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {5},
pages = {},
pmid = {40430469},
issn = {1424-8247},
abstract = {Background: Non-alcoholic steatohepatitis (NASH) is characterized by increased production of proinflammatory cytokines, fibrosis, and hepatocyte apoptosis. This study aimed to assess the efficacy of N-acetyl cysteine (NAC), rosuvastatin (RSV), and vitamin E (VE) in patients with NASH. Methods: A double-blinded, parallel, randomized, controlled study was conducted and registered on clinicaltrials.gov (Identifier: NCT06105060), involving 135 NASH participants, who were divided into three groups: the control group (group 1), consisting of patients receiving standard therapy VE at a dosage of 400 IU twice daily. In the treated group (group 2), patients were administered NAC at a dosage of 1200 mg twice daily, while treatment (group 3) received RSV at a dosage of 20 mg once daily. FibroScan[®] examination of liver tissue and fibrosis scores, along with tests for liver aminotransferases, lipid profile, glycemic parameters, and renal and hepatic functions, were assessed before and after six months of treatment. Results: The analyzed groups demonstrated a significant reduction in steatosis and lipid peroxidation (p < 0.05). The NAC group demonstrated greater anti-inflammatory and anti-apoptotic effects compared to the RSV group, although this difference was not significant in the control group. NAC is conceded as the only significant antifibrotic agent in liver stiffness measurement (LSM), biological marker findings, and non-invasive liver fibrosis scores (p < 0.05), in addition to its improvement of several metabolic parameters and health-related quality of life. Conclusions: Patients receiving NAC demonstrated safety and efficacy in enhancing steatosis, fibrosis, and metabolic parameters, representing a novel strategy in the management of NASH.},
}
@article {pmid40429784,
year = {2025},
author = {Recinella, L and Pinti, M and Di Lodovico, S and Brenciani, A and Giovanetti, E and Diban, F and Di Giulio, M and Brunetti, L and Leone, S},
title = {A New Bromelain-Based Polyenzymatic Complex Plus N-Acetylcysteine: A Promising Approach for the Treatment of Urinary Tract Infections.},
journal = {International journal of molecular sciences},
volume = {26},
number = {10},
pages = {},
pmid = {40429784},
issn = {1422-0067},
support = {Difass International Spa 2024//Difass International Spa/ ; },
mesh = {Biofilms/drug effects ; *Urinary Tract Infections/drug therapy/microbiology ; Ciprofloxacin/pharmacology ; Animals ; Microbial Sensitivity Tests ; Escherichia coli/drug effects ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Acetylcysteine/pharmacology/chemistry ; *Bromelains/chemistry/pharmacology ; Moths/microbiology ; Humans ; },
abstract = {Biofilm plays a crucial role in the pathogenesis and chronicity of urinary tract infections (UTIs). The present work aimed to evaluate the anti-biofilm effects of Formulation (DIF17BRO[®] plus NAC) in combination with ciprofloxacin (CPX) on Escherichia coli strains. The antimicrobial activity of ciprofloxacin was evaluated by minimum inhibitory concentration (MIC) determination, and the antibiofilm effects of ciprofloxacin alone and combined with Formulation were evaluated on E. coli ATCC700926, E. coli ATCC10536, E. coli PNT, and E. coli PCA mature biofilms in terms of CFU/mL and biomass quantifications. Moreover, the potential protective effects of Formulation plus ciprofloxacin was tested in a Galleria mellonella in vivo infection assay. Our results underlined the increased microbial reduction in the mature biofilm in the presence of the combination Formulation and CPX, even at a lower concentration of CPX. Formulation increased the percentage of biofilm biomass reduction, inducing a disruption of the biofilm structure itself. Our present findings confirm that MIC CPX combined with Formulation also induced an antimicrobial effect in the G. mellonella assay. Formulation facilitated the perturbation of the biofilm polymeric matrix, enhancing the antibiotic penetration and its antimicrobial action on bacteria, underlining Formulation's role as an enhancer of ciprofloxacin antibacterial action.},
}
@article {pmid40427046,
year = {2025},
author = {Hwang, I and Kang, CG and Lim, SJ and Kim, HJ and Kang, R and Jeon, SH and Lee, SH and Kim, JW and Kang, JS},
title = {Human Placenta Hydrolysate Protects Against Acetaminophen-Induced Liver Injury in Mice.},
journal = {Biomedicines},
volume = {13},
number = {5},
pages = {},
pmid = {40427046},
issn = {2227-9059},
support = {N/A//Green Cross Wellbeing/ ; },
abstract = {Background/Objectives: Acetaminophen (APAP) is a widely used analgesic and antipyretic, but overdose can lead to APAP-induced liver injury (AILI), a major cause of acute liver failure. While N-acetylcysteine (NAC) is the current standard of care, its efficacy is significantly reduced when administered after the peak time of liver injury, highlighting the need for alternative therapeutic strategies. Human placenta hydrolysate (HPH) has shown potential as a therapeutic agent for various liver diseases due to its rich content of bioactive compounds. This study aimed to investigate the hepatoprotective effects of HPH in a mouse model of AILI. Methods: HPH was administered to mice for three days prior to APAP treatment. The effects of HPH on liver morphology, necrosis, liver enzymes, phase I/II detoxification enzymes, oxidative stress markers, and inflammatory cytokines were evaluated. Results: HPH pretreatment attenuated APAP-induced liver necrosis and congestion, reduced serum levels of liver enzymes. In addition, HPH showed a concentration-dependent attenuation of APAP-induced decrease in human hepatocyte viability. HPH modulated phase I/II enzyme expression by downregulating CYP2E1 and upregulating SULT1A1, UGT1A6, GSTP1, and TPMT. HPH also exhibited antioxidant effects by increasing SOD and GPx activities, reducing MDA levels, and restoring the GSH/GSSG ratio. Furthermore, HPH attenuated the APAP-induced increase in the inflammatory cytokines TNF-α and IL-6. These findings suggest that HPH protects against AILI through multiple mechanisms, including the modulation of phase I/II detoxification, activation of antioxidants, and inhibition of inflammation. Conclusions: HPH could be a potential therapeutic option for APAP overdose and related liver injuries.},
}
@article {pmid40425069,
year = {2025},
author = {Morales, EN and Malecki, CC and Maruri, A and Sánchez, VR and Portu, A and Goldman, A and Chiaramoni, NS and Fenoy, IM},
title = {Preclinical evaluation of N-acetyl-cysteine in association with liposomes of lung surfactant's lipids for the treatment of pulmonary fibrosis and asthma.},
journal = {Toxicology and applied pharmacology},
volume = {502},
number = {},
pages = {117412},
doi = {10.1016/j.taap.2025.117412},
pmid = {40425069},
issn = {1096-0333},
mesh = {Animals ; *Acetylcysteine/administration &amp; dosage/pharmacology/chemistry ; *Asthma/drug therapy/pathology/chemically induced ; *Pulmonary Fibrosis/drug therapy/chemically induced/pathology ; Liposomes ; *Pulmonary Surfactants/administration &amp; dosage/chemistry ; Mice ; Lung/drug effects/pathology/metabolism ; Mice, Inbred BALB C ; Bleomycin ; Disease Models, Animal ; Male ; Female ; Drug Evaluation, Preclinical/methods ; Lipids/chemistry ; Ovalbumin ; },
abstract = {PURPOSE: There is a need to generate new treatments against pulmonary diseases such as idiopathic fibrosis and asthma. N-acetylcysteine (NAC) has multiple clinical applications, but its unstable nature and route of administration limits its effectiveness. New pulmonary delivery strategies, such as liposomes made of lung surfactant lipids, could overcome NAC's limitations. This work aims to evaluate the efficacy of NAC combined with liposomes as a treatment for asthma and in preventing fibrotic development.<br><br>METHODS: Unilamellar vesicles were obtained through the dehydration-rehydration method followed by multiple membrane extrusion and characterized by Dynamic Light Scattering and Transmission electron microscopy. Lung fibrosis was induced by bleomycin administration, and liposomal formulation of NAC (LipoNAC) was evaluated as a preventive treatment. LipoNAC formulation was also evaluated in a therapeutic regimen for asthma using the classic ovalbumin model. For both models, the administration of the treatment was via the intranasal route.<br><br>RESULTS: NAC treatments (free NAC and LipoNAC) improved lung histopathology and decreased collagen deposition when tested in the lung fibrosis model. Only LipoNAC decreased serum levels of lactate dehydrogenase, myeloperoxidase activity in lung fluid and lung TGF-&#x3b2;. Although both treatments decreased Th2 cytokine and histopathological inflammation in the asthma model, only LipoNAC treatment significantly decreased mucus in asthmatic mice.<br><br>CONCLUSIONS: These results indicate that surfactant liposomal delivery of NAC potentiates its anti-inflammatory, mucolytic, and antioxidant activity, rendering it a promising therapy for respiratory diseases.},
}
@article {pmid40421021,
year = {2025},
author = {Rastgoo, S and Pourvali, K and Raeissadat, SA and Eslamian, G and Zand, H},
title = {Co-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1570441},
pmid = {40421021},
issn = {1664-3224},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage ; Aged ; Male ; Female ; *Vitamin D/administration &amp; dosage ; *Immunosenescence/drug effects ; *Vitamin D Deficiency/drug therapy/immunology/blood ; Leukocytes, Mononuclear/immunology/drug effects/metabolism ; Middle Aged ; Cellular Senescence/drug effects ; Dietary Supplements ; Aged, 80 and over ; },
abstract = {BACKGROUND: Immunosenescence is an important factor in the impaired immune response in older adults and plays a significant role in the development of biological aging. Targeting immunosenescence could present a novel pharmacological approach to mitigating aging and age-related diseases. We aimed to investigate the effect of N-acetylcysteine (NAC) and vitamin D (Vit-D) on the senescence of peripheral blood mononuclear cells (PBMCs).<br><br>METHOD: This randomized clinical trial was conducted on older adults with Vit-D deficiency. Eligible participants were randomly assigned to one of four groups to receive either (A) 1000 IU of Vit-D daily (D1) (B), 1000 IU of Vit-D plus 600 mg of NAC daily (D1N) (C), 5000 IU of Vit-D daily (D5), or (D) 5000 IU of Vit-D plus 600 mg of NAC daily (D5N) for 8 weeks. Senescence-associated beta-galactosidase (SA-&#x3b2;-gal) staining, expression of senescence-related genes, and serum inflammatory factors were measured at baseline and after 8 weeks.<br><br>RESULTS: After the intervention, supplementation with D5N and D5 significantly downregulated p16, interleukin-6 (IL-6), and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) expression and decreased SA-&#x3b2;-gal activity compared to the D1 group. Additionally, co-administration of NAC with 1000 IU of Vit-D significantly downregulated p16 transcripts in PBMCs compared to Vit-D 1000 IU alone. No significant differences were observed between the groups in serum IL-6, C-reactive protein (CRP), or the neutrophil-to-lymphocyte ratio (NLR) after the intervention.<br><br>CONCLUSIONS: The loading dose of Vit-D significantly attenuates senescence in PBMCs of older adults. However, co-administration of NAC with both the standard and loading doses of Vit-D further enhances these beneficial effects.<br><br>CLINICAL TRIAL REGISTRATION: https://irct.behdasht.gov.ir, identifier IRCT20230508058120N1.},
}
@article {pmid40420092,
year = {2025},
author = {Li, L and Lu, J and Fu, S and Li, W and Wang, Y and Wang, K and Tao, Y and Liu, S},
title = {Evodiamine induces ferroptosis in prostate cancer cells by inhibiting TRIM26-mediated stabilization of GPX4.},
journal = {Chinese medicine},
volume = {20},
number = {1},
pages = {71},
pmid = {40420092},
issn = {1749-8546},
support = {82203167//National Natural Science Foundation of China/ ; 82460722//National Natural Science Foundation of China/ ; GSWSQNPY2024-12//gansu provincial health industry science and technology innovation project/ ; CY2022-MS-A09//cuiying scientific and technological innovation program of lanzhou university second hospital/ ; CY2023-MS-A05//cuiying scientific and technological innovation program of lanzhou university second hospital/ ; GZKP2023-36//traditional chinese medicine scientific research project of gansu province, china/ ; CYXZ2024-11//cuiying scientific training program for undergraduates of lanzhou university/ ; },
abstract = {BACKGROUND: Prostate cancer is a major global health challenge, characterized by high morbidity and mortality rates. Traditional treatment options, including androgen deprivation therapy and chemotherapy, often lead to drug resistance. In recent years, natural compounds have garnered attention for their potential therapeutic effects. Evodiamine, a bioactive alkaloid from Evodia rutaecarpa, has demonstrated promising anti-cancer properties in various malignancies, including oral squamous cell carcinoma, breast, colorectal, and ovarian cancers. This study explores the efficacy of evodiamine in prostate cancer cells and investigates the mechanisms underlying evodiamine-induced cell death.<br><br>METHODS: To investigate the effects of evodiamine on prostate cancer cells, various cell lines, including both castration-sensitive and castration-resistant variants, were treated with different concentrations of evodiamine for various durations. Cell viability, proliferation, invasion ability, and colony formation were assessed using the CCK8 assay, EdU assay, 3D matrigel drop invasion assay, and colony formation assay, respectively. The effects of evodiamine on apoptosis were analyzed using FACS, Hoechst staining, and Western blot. To evaluate its effects on ferroptosis, malondialdehyde (MDA) and glutathione (GSH) assay kits, as well as DCFH-DA and the lipid peroxidation sensor BODIPY[&#x2122;] 581/501 C11 fluorescent probes, were employed. The molecular mechanisms through which evodiamine regulates GPX4 protein instability were investigated using Western blot and TRIM26 ectopic expression. Additionally, a mouse xenograft model derived from DU145 cells was established to evaluate the in vivo effects of evodiamine and its molecular mechanisms, utilizing hematoxylin and eosin (H&amp;E) staining, immunohistochemistry (IHC), and Western blot analysis.<br><br>RESULTS: Evodiamine significantly suppressed cell viability, proliferation, invasion, and colony formation in prostate cancer cells. Importantly, evodiamine-induced cell death in the PC3 and DU145 cell lines was independent of apoptosis pathway. Instead, evodiamine increased reactive oxygen species (ROS) production, lipid ROS levels and MDA levels, while decreasing GSH levels, indicating the induction of ferroptosis. The key role of ROS in evodiamine-induced ferroptosis was further confirmed by the partial reversal of cell death upon treatment with the ROS scavenger N-acetylcysteine (NAC). Mechanistically, evodiamine induced ferroptosis by destabilizing GPX4 protein in a TRIM26-dependent manner. Moreover, in vivo studies demonstrated that evodiamine significantly inhibited tumor growth and induced ferroptosis in tumor cells, highlighting its therapeutic potential.<br><br>CONCLUSION: This study demonstrates that evodiamine exerts potent antitumor effects against prostate cancer through inhibiting TRIM26-mediated stabilization of GPX4 protein and triggering ferroptosis. These findings suggest that evodiamine, a natural product derived from traditional Chinese medicine, could be a promising therapeutic agent for prostate cancer.},
}
@article {pmid40418638,
year = {2025},
author = {Maxwell, MN and Murphy, BT and McDonald, FB and O'Halloran, KD},
title = {Exploring the respiratory efficacy of combined chronic glucocorticoid and antioxidant interventions in the mdx mouse: The PREDNAC trial.},
journal = {Experimental physiology},
volume = {110},
number = {12},
pages = {2019-2035},
pmid = {40418638},
issn = {1469-445X},
support = {//Department of Physiology, UCC/ ; SFI 19/FFP/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; },
mesh = {Animals ; Mice, Inbred mdx ; Male ; *Glucocorticoids/pharmacology/administration &amp; dosage/therapeutic use ; *Muscular Dystrophy, Duchenne/drug therapy/physiopathology ; Mice ; *Antioxidants/pharmacology/administration &amp; dosage/therapeutic use ; *Methylprednisolone/pharmacology/administration &amp; dosage ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Mice, Inbred C57BL ; Disease Models, Animal ; Respiratory Muscles/drug effects/physiopathology ; *Respiration/drug effects ; Drug Therapy, Combination ; Diaphragm/drug effects ; },
abstract = {Duchenne muscular dystrophy (DMD) is characterized by respiratory muscle injury and weakness, ultimately leading to respiratory failure. Impaired respiratory muscle performance, fibrosis and inflammation in early disease are evident in the dystrophin-deficient mdx mouse model of DMD. Prednisone or similar treatment is the current standard of care for DMD and exerts its benefits via an anti-inflammatory action, but chronic treatment is associated with side-effects. A recent study demonstrated improved function in mdx limb muscle with weekly glucocorticoid treatment compared with daily treatment. Herein, we investigated the effect of weekly α-methylprednisolone (PRED) treatment alone and the effect of PRED in combination with daily intake of the antioxidant N-acetyl cysteine, NAC (PREDNAC) on respiratory performance. One-month-old male mdx mice received PRED (0.8 mg/kg methylprednisolone i.p. weekly) or PREDNAC (0.8 mg/kg methylprednisolone i.p. weekly and 1% NAC in drinking water daily) for 3 months. At 4 months of age, conscious breathing was measured in vivo by whole-body plethysmography. Under urethane general anaesthesia, respiratory EMG and inspiratory pressure were measured at baseline and during maximal activity. The intrinsic force-generating capacity of the diaphragm was determined ex vivo. Neither PRED nor PREDNAC influenced breathing or diaphragm force-generating capacity in mdx mice. There was a significant increase in diaphragm and parasternal EMG activity, but inspiratory pressure was unchanged with treatment. We conclude that neither PRED nor PREDNAC has a major beneficial effect on respiratory system performance in the mdx mouse model of DMD. Weekly administration of glucocorticoids is inadequate to protect respiratory performance in mdx mice, which might reflect the higher duty cycle of respiratory muscles compared with limb muscles.},
}
@article {pmid40418545,
year = {2025},
author = {Varikasuvu, SR and Manne, M and Kumar, S and Mudgal, SK and Raj, V and Varshney, S and Gupta, P and Grover, A and Goyal, C and Lal, V and Singh, H and Lisa, M and Saransh Workshop Members, },
title = {COVID-19 clinical outcomes and N-acetylcysteine (CoViNAC study): a GRADE compliant meta-analysis of randomized controlled trials with molecular docking and dynamics simulation studies with Mpro of SARS-CoV-2.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {71},
number = {5},
pages = {95-102},
doi = {10.14715/cmb/2025.71.5.13},
pmid = {40418545},
issn = {1165-158X},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Molecular Docking Simulation ; *SARS-CoV-2/enzymology/drug effects ; Randomized Controlled Trials as Topic ; *Coronavirus 3C Proteases/metabolism/chemistry ; *COVID-19 Drug Treatment ; Molecular Dynamics Simulation ; COVID-19/mortality/virology ; Treatment Outcome ; Antiviral Agents/therapeutic use ; },
abstract = {N-acetylcysteine (NAC) has been proposed as an adjuvant therapy for COVID-19, but evidence from randomized controlled trials (RCTs) remains inconclusive. This systematic review and meta-analysis evaluated NAC's efficacy in improving mortality and recovery/discharge rates. Additionally, molecular docking and molecular dynamics simulation (MDMS) studies were conducted to assess NAC's interaction with the SARS-CoV-2 main protease (Mpro), a key enzyme for viral replication. A systematic search identified 12 RCTs, with 11 trials (1125 patients) included in the mortality analysis. NAC significantly reduced mortality (RR=0.59, 95% CI 0.39-0.88, p=0.01; I[2]=62%), indicating a 41% decreased risk of death. Six RCTs (656 patients) showed improved recovery/discharge rates (RR=1.09, 95% CI 1.03-1.14, p=0.003; I[2]=0%). MDMS studies demonstrated stable NAC binding at the Mpro catalytic site, interacting with His41 and Cys145, crucial for enzymatic activity. These findings suggest NAC significantly improves clinical outcomes in COVID-19 and may inhibit viral replication by targeting Mpro. This integrated evidence substantiates NAC's potential as a critical adjuvant therapy.},
}
@article {pmid40414419,
year = {2025},
author = {Chakraborty, S and Shankaranarayana Rao, BS and Tripathi, SJ},
title = {The neuroprotective effects of N-acetylcysteine in psychiatric and neurodegenerative disorders: From modulation of glutamatergic transmission to restoration of synaptic plasticity.},
journal = {Neuropharmacology},
volume = {278},
number = {},
pages = {110527},
doi = {10.1016/j.neuropharm.2025.110527},
pmid = {40414419},
issn = {1873-7064},
mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Humans ; *Neuronal Plasticity/drug effects/physiology ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Mental Disorders/drug therapy/metabolism ; *Synaptic Transmission/drug effects ; Glutamic Acid/metabolism ; },
abstract = {N-acetylcysteine (NAC) is an effective pleiotropic drug with a strong safety profile. It is predominantly used as a mucolytic agent and in the treatment of paracetamol overdose. However, extensive research in the last decade has shown the prominent efficacy of NAC in many neuropsychiatric and neurodegenerative disorders. NAC acts through multiple mechanisms; primarily, it releases cysteine and modulates glutamatergic and monoaminergic transmission. Further, it restores glutathione levels, promotes oxidative balance, reverses decreased synaptic plasticity, reduces neuroinflammation and mitochondrial dysfunction, and provides neurotrophic support. Additionally, it regulates one-carbon metabolism pathways, leading to the production of key metabolites. In this review, we will be discussing in-depth mechanisms of action of NAC and its promising ability to reverse neuropathological changes, cognitive deficits and associated plasticity changes in various psychiatric and neurodegenerative diseases, including depression, bipolar disorders, schizophrenia, Alzheimer's disease, Huntington's disease, traumatic brain injury, aging. Overall, several preclinical studies and clinical trials have demonstrated the efficacy of NAC in reversing regressive plasticity, cognitive deficits, and associated changes in the brain. NAC remains among the strongest candidates with a high safety profile for managing several types of neurological disorders.},
}
@article {pmid40411876,
year = {2025},
author = {Chen, Y and Jiang, G and Huang, Y and Song, S and Fu, H and Du, B and Xiao, Y and Li, P and Shi, K and Huang, Y and Song, Q and Gao, X and Xie, Q},
title = {Lipoprotein-Based Nanocatalyst Enables Targeted Treatment of APAP-Induced Liver Injury via Enhanced Macropinocytosis.},
journal = {Advanced healthcare materials},
volume = {14},
number = {25},
pages = {e2500507},
doi = {10.1002/adhm.202500507},
pmid = {40411876},
issn = {2192-2659},
support = {82270618//National Natural Science Foundation of China/ ; 82070604//National Natural Science Foundation of China/ ; 82171358//National Natural Science Foundation of China/ ; 23S41900100//Shanghai Science and Technology Development Foundation/ ; 22QA1405000//Shanghai Rising-Star Program/ ; 2023ZKZD21//Shanghai Municipal Education Commission/ ; 2022YFC2502800//Key Technologies Research and Development Program/ ; 2018CR005//Ruijin Hospital/ ; shslczdzk01103//Shanghai Municipal Health Commission/ ; },
mesh = {Animals ; Mice ; *Cerium/chemistry/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/pathology ; *Acetaminophen/adverse effects ; *Pinocytosis/drug effects ; Reactive Oxygen Species/metabolism ; Acetylcysteine/pharmacology ; Humans ; Hepatocytes/metabolism/drug effects ; Male ; *Nanoparticles/chemistry ; Mice, Inbred C57BL ; Liver/metabolism/drug effects ; *Lipoproteins, HDL/chemistry/pharmacology ; },
abstract = {Drug-induced liver injury (DILI), predominantly caused by acetaminophen (APAP) overdose, is characterized by excessive reactive oxygen species (ROS) production and subsequent hepatocyte necrosis. Although N-acetylcysteine (NAC) remains the only approved treatment, its effectiveness is limited by a narrow therapeutic time window and reduced efficacy in advanced cases. To address these limitations, an innovative therapeutic approach is developed utilizing ceria's antioxidant properties. In this study, a reconstituted high-density lipoprotein-encapsulated ceria nanocatalyst (CeO2-rHDL) is engineered to overcome the aggregation tendency and targeting limitation of naked ceria nanoparticles. These findings revealed that CeO2-rHDL enters hepatocytes through macropinocytosis, a process synergistically enhanced by both APAP and NAC, facilitating efficient liver targeting. The nanocatalyst demonstrated remarkable therapeutic efficacy by restoring mitochondrial function through ROS reduction. When combined with NAC, CeO2-rHDL significantly improved survival outcomes in DILI mice. This lipoprotein-based nanocatalyst system represents a promising therapeutic strategy for DILI treatment, offering enhanced targeting capabilities and improved therapeutic efficacy.},
}
@article {pmid40409732,
year = {2025},
author = {Kuttikrishnan, S and Suleman, M and Ahmad, F and Mariyam, Z and Habeeba, U and Prabhu, KS and Buddenkotte, J and Steinhoff, M and Uddin, S},
title = {Curcumin induces apoptosis via downregulation of SKP2 and induction of GADD45A/CDKN1A expression through generation of ROS in cutaneous T-cell lymphoma cells.},
journal = {Toxicology and applied pharmacology},
volume = {501},
number = {},
pages = {117403},
doi = {10.1016/j.taap.2025.117403},
pmid = {40409732},
issn = {1096-0333},
mesh = {*Curcumin/pharmacology ; *Reactive Oxygen Species/metabolism ; Humans ; *Apoptosis/drug effects ; *Lymphoma, T-Cell, Cutaneous/drug therapy/pathology/metabolism ; *S-Phase Kinase-Associated Proteins/metabolism/genetics ; Down-Regulation/drug effects ; *Cell Cycle Proteins/genetics/metabolism/biosynthesis ; Cell Line, Tumor ; *Nuclear Proteins/genetics/metabolism/biosynthesis ; Molecular Docking Simulation ; *Skin Neoplasms/drug therapy/pathology/metabolism ; Signal Transduction/drug effects ; GADD45 Proteins ; },
abstract = {Curcumin, a plant derived natural product isolated from Curcuma longa. The aim of this study is to investigate the anti-proliferative effects and the underlying mechanisms of curcumin in Cutaneous T cell lymphoma (CTCL), a type of non-Hodgkin lymphoma that primarily affects the skin. The study found that curcumin induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases leading to growth inhibition. Furthermore, Curcumin treatment downregulated the expression of S-phase kinase protein (SKP2) with concomitant upregulation of GADD45A, CDKN1A and CDKN1B. Curcumin also suppresses the expression of anti-apoptotic molecules including XIAP and cIAPs. Curcumin treatment of CTCL cells generates reactive oxygen species (ROS) and depletion of glutathione. Pretreatment of CTCL with N-acetyl cysteine prevented curcumin-mediated generation of ROS and prevention caspase activity. Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action. Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action. Molecular docking studies revealed a strong binding affinity of curcumin to the active site of SKP2, primarily involving key residues crucial for its activity. Altogether, our results suggest that targeting SKP2 and GADD45A signaling by curcumin could be an attractive strategy for the treatment of CTCL.},
}
@article {pmid40409588,
year = {2025},
author = {Ebrahimi Medisah, M and Badiee, MS and Mahdavinia, M and Motamed, H and Rahmani, AH},
title = {Lactate is a prognostic marker of acute liver failure in early identification of patients susceptible to liver transplantation following acute acetaminophen poisoning.},
journal = {Annales pharmaceutiques francaises},
volume = {83},
number = {6},
pages = {1139-1149},
doi = {10.1016/j.pharma.2025.05.007},
pmid = {40409588},
issn = {2772-803X},
mesh = {Humans ; *Acetaminophen/poisoning ; Female ; Male ; Adult ; *Liver Transplantation ; *Liver Failure, Acute/chemically induced/blood/surgery/diagnosis ; Prospective Studies ; Biomarkers/blood ; Prognosis ; Cross-Sectional Studies ; *Lactic Acid/blood ; Middle Aged ; *Analgesics, Non-Narcotic/poisoning ; Young Adult ; Drug Overdose ; Chemical and Drug Induced Liver Injury/blood ; Acetylcysteine/therapeutic use ; },
abstract = {BACKGROUND: Acetaminophen (APAP) is the most commonly used analgesic and antipyretic drug, and its intentional or accidental overdose can lead to acute liver failure (ALF). Rapid prognosis and the selection of appropriate patients for transplantation in ALF are crucial. Lactate is the end product of anaerobic glycolysis and an indicator for determining the oxygen status in cells. The aim of this study was to investigate the relationship between serum lactate level and the prognosis of ALF due to acute APAP poisoning in patients referred to Razi Hospital, Ahvaz.<br><br>METHODS: This cross-sectional and prospective study was conducted on 34 healthy individuals (as controls) and 34 patients diagnosed with acute APAP poisoning. Serum levels of APAP, lactate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (T.bil), direct bilirubin (D.bil), and gamma-glutamyl transferase (GGT) were measured in healthy individuals and patients with acute APAP poisoning within 24hours of admission. The relationship between the dose of APAP consumed, the amount of N-acetylcysteine (NAC) received, and the age and gender of the patients with lactate level was also evaluated.<br><br>RESULTS: The mean dose of APAP in the patients was 10.75g. A total of 85% of the patients received NAC. The mean volume of NAC injection was 4.4mmol/L. The number of women with APAP overdose was higher than men. Lactate level increased with increasing APAP doses. The mean serum lactate level significantly reduced after 24hours compared to the initial admission, and the levels of liver markers increased significantly after 24hours.<br><br>CONCLUSION: In order to accept lactate as an international criterion in early identification of liver transplant candidate patients and reduce their mortality, clinical validity studies including definition and validation of clinical conditions related to lactate level and reliability tests are necessary. Therefore, early and periodic determination of serum lactate level seems to be essential as a promising biomarker for the prognosis of ALF caused by acute APAP poisoning.},
}
@article {pmid40404947,
year = {2025},
author = {Bai, H and Du, S and Qiu, D and Li, S and Gao, R and Zhang, Z},
title = {GPX4 Inhibition Contributes to NLRP3-Mediated Pyroptosis and Cognitive Impairment in Ketamine-Exposed Neonatal Rats.},
journal = {Molecular neurobiology},
volume = {62},
number = {9},
pages = {12360-12370},
pmid = {40404947},
issn = {1559-1182},
support = {NDYB2022-4//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; NDYB2022-7//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; 31572580//National Natural Science Foundation of China/ ; SYKJYB202301//Discipline Project of College of Veterinary Medicine/ ; },
mesh = {Animals ; *Ketamine/toxicity ; *Pyroptosis/drug effects ; *Cognitive Dysfunction/metabolism/chemically induced/pathology ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/antagonists &amp; inhibitors ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; Animals, Newborn ; Hippocampus/pathology/drug effects/metabolism ; Rats, Sprague-Dawley ; Male ; PC12 Cells ; },
abstract = {Increasing evidence reveals that multiple or prolonged exposure to ketamine causes hippocampal damage and cognitive dysfunction. However, the critical mechanisms underlying ketamine-induced neurotoxicity in the developing brain remain elusive. The present study was designed to investigate the role of GPX4 in ketamine-induced pyroptosis and cognitive dysfunction in the developing rat hippocampus. To achieve this goal, we conducted Western blotting, ELISA tests, histopathological analysis, Morris water maze tests, cell viability assays, and biochemical analyses on PC12 cells, HAPI cells, and 7-day-old rats. Additionally, N-acetylcysteine (NAC) and RSL3 were administered prior to continuous ketamine exposure. Our findings indicate that GPX4 inhibition by RSL3 enhances lipid peroxidation and mitochondrial damage, activates NLRP3/caspase-1 axis-dependent pyroptosis, and exacerbates hippocampal damage and cognitive dysfunction following ketamine exposure, while NAC effectively mitigates the effects of RSL3. Collectively, our in vivo and in vitro results support the notion that GPX4 may serve as a negative regulator of pyroptosis in ketamine-induced hippocampal damage and cognitive dysfunction. Our study proposes a novel strategy for treating ketamine-induced neurotoxicity through upregulating GPX4 expression.},
}
@article {pmid40403956,
year = {2025},
author = {Hu, LJ and Li, CY and Xing, T and Wang, Y and Jiang, Q and Jiang, H and Wang, J and Tang, FF and Chang, YJ and Zhang, XH and Kong, Y and Huang, XJ},
title = {N-acetyl-L-cysteine promoted hematopoietic recovery in patients with acute myeloid leukemia after complete remission--A pilot study.},
journal = {Cancer letters},
volume = {625},
number = {},
pages = {217812},
doi = {10.1016/j.canlet.2025.217812},
pmid = {40403956},
issn = {1872-7980},
mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acetylcysteine/therapeutic use/administration &amp; dosage/adverse effects ; *Hematopoiesis/drug effects ; *Leukemia, Myeloid, Acute/drug therapy/blood/pathology ; Pilot Projects ; Reactive Oxygen Species/metabolism ; Remission Induction ; Treatment Outcome ; Cohort Studies ; },
abstract = {Chemotherapy is a cornerstone treatment for acute leukemia (AL), but it often results in bone marrow (BM) failure, leading to infections, anemia, and bleeding, which significantly impact patient survival. Endothelial progenitor cells (EPCs) are critical elements of the BM microenvironment and are essential for hematopoiesis. Our previous research using in vitro and AML mouse models indicated that BM EPC dysfunction, characterized by impaired angiogenesis and elevated reactive oxygen species (ROS) levels in AML patients, could be partially reversed after complete remission (CR) and further improved with N-acetyl-L-cysteine (NAC) treatment. This pilot cohort study (NCT06024031, www.clinicaltrials.gov) evaluated the effects of NAC on hematopoietic recovery in 30 newly diagnosed AML patients after induction chemotherapy, compared to a propensity-matched control group of 60 patients. Patients received oral NAC (400 mg, three times daily) for 28 days post-chemotherapy alongside standard supportive care. NAC treatment did not affect CR rates (90 % vs. 80 %, P = 0.23), but significantly shortened platelet recovery time (19 vs. 22 days, P = 0.0001) among CR patients. NAC improved EPC percentages, reduced ROS, and enhanced EPC hematopoiesis-supporting functions in patients who achieved CR. NAC was safe and effective in promoting normal hematopoiesis recovery in AML patients in CR following chemotherapy.},
}
@article {pmid40401298,
year = {2024},
author = {Thomas, MC and Edwards, CJ and Dunlap, A},
title = {Practice Patterns for N-acetylcysteine Dosing for Acetaminophen Toxicity in the United States.},
journal = {Innovations in pharmacy},
volume = {15},
number = {4},
pages = {},
pmid = {40401298},
issn = {2155-0417},
abstract = {Background: Although the FDA approved acetaminophen toxicity dosing regimen for intravenous n-acetylcysteine (NAC) is a three-bag regimen, alternate regimens have been published which are generally simpler, and decrease errors and adverse effects. It is not clear how pervasive alternative regimens are used in hospitals in the US and reasons for a change from the FDA regimen. Objective: Characterize practice patterns for treating acetaminophen toxicity. Methods: A pilot-tested, electronic survey containing demographic and practice pattern questions for acetaminophen toxicity management was sent to residency program directors. The survey was open for 4 weeks with several reminder e-mails sent to non-responders. Descriptive statistics were used to summarize the data. Results: There were 119 responses (9.2% response rate). Responses were representative of all geographic areas in the US and were most commonly from community hospitals (67.2%) and those with 300 or more beds (72.2%). Nearly two-thirds used the FDA approved NAC regimen, whereas others used an alternate regimen. Reasons for making the change were for simplicity, to decrease errors or adverse events, or based on local poison center recommendations. More than one-third of respondents reported not using a maximum dosing weight. Conclusions: N-acetylcysteine is usually administered intravenously using the FDA approved regimen for acetaminophen toxicity. The weight for dosing was commonly capped at 100 kg, but some institutions did not use a maximum. Alternative intravenous regimens have been implemented at some institutions with the impetus for change being safety and simplicity.},
}
@article {pmid40400197,
year = {2025},
author = {Naseem, S and Xuan, MF and Hua, H and Park, S and Manzoor, A and Teng, H and Jin, H and Li, X and Li, Q},
title = {Vitamin C and N-acetylcysteine promote bovine adipose-derived mesenchymal stem cell proliferation and differentiation via Akt/mTOR/P70S6K signalling pathway for cultured meat production.},
journal = {Animal bioscience},
volume = {38},
number = {10},
pages = {2250-2265},
pmid = {40400197},
issn = {2765-0189},
support = {YDZJ202101ZYTS105//Science and Technology Development Project in Jilin Province/ ; //Engineering Research Center of North-East Cold Region Beef Cattle Science and Technology Innovation/ ; D20034//Ministry of Education/ ; },
abstract = {OBJECTIVE: Traditional meat production is insufficient to meet the increasing protein requirements, necessitating cultured meat, which is safe, worthwhile, and scalable. Fat is essential for making cultured meat more acceptable to consumers by enhancing flavour and providing a natural appearance. Mesenchymal stem cells from adipose tissue are a promising source for this purpose, but in vitro expansion of cells decreases their proliferation ability and increases cellular senescence. The objective of this study was to improve the proliferation and differentiation abilities of adipose-derived mesenchymal stem cells (AD-MSCs).<br><br>METHODS: In this study, vitamin C (VC) and N-acetylcysteine (NAC) antioxidants were used to treat AD-MSCs from Yanbian cattle testicles. Cell counting kit, 5-ethynyl-2'-deoxyuridine staining, reverse transcription quantitative polymerase chain reaction, and western blot were used to test the cell viability and proliferation ability of AD-MSCs, ORO staining, triglycerides assay, and adipogenic specific markers expression were determined to analyse the adipogenic differentiation ability. Furthermore, oxidative stress parameters and activation of the Akt/mTOR/P70S6K signaling pathway were also studied.<br><br>RESULTS: Results showed that VC and NAC both increased proliferation and differentiation ability of AD-MSCs by increasing the expression of cell cycle regulatory and differentiation genes and proteins expression, and decreasing the expression of cell cycle inhibitory factors, and up-regulating stemness markers expression, while co-treatment showed enhanced effect. Oxidative stress was reduced by decreased reactive oxygen species production, malondialdehyde content, and enhanced glutathione activity, as well as declined cellular senescence. Subsequently, the Akt/mTOR/P70S6K signaling pathway was activated by VC and NAC+VC treatment in AD-MSCs, while NAC only activated Akt expression, indicating its role in controlled cell growth.<br><br>CONCLUSION: This research concludes that NAC (2 mM) and VC (200 &#x3bc;M) improved the proliferation, differentiation potential, and stemness by decreasing oxidative stress and senescence, parallelly activating Akt/mTOR/P70S6K signaling pathway, while combined treatment (NAC+VC) enhanced these effects, providing bases for their utilisation to culture fat in cultivated meat production.},
}
@article {pmid40398509,
year = {2025},
author = {Chen, SJ and Wu, CL and Lin, LY and Horng, JL},
title = {Evaluating N-acetylcysteine for mitigating cisplatin-induced oxidative stress and ionocyte damage in a zebrafish model.},
journal = {Toxicology and applied pharmacology},
volume = {501},
number = {},
pages = {117401},
doi = {10.1016/j.taap.2025.117401},
pmid = {40398509},
issn = {1096-0333},
mesh = {Animals ; *Cisplatin/toxicity ; *Acetylcysteine/pharmacology ; Zebrafish/embryology ; *Oxidative Stress/drug effects ; *Antineoplastic Agents/toxicity ; Embryo, Nonmammalian/drug effects/metabolism ; },
abstract = {In this study, we examined the protective effects of N-acetylcysteine (NAC) against cisplatin-induced toxicity in zebrafish embryos. Cisplatin (cis-diamminedichloroplatinum II), a widely used anticancer drug, is associated with significant cytotoxic effects toward non-target tissues, including renal and ototoxic damage. Using zebrafish embryos exposed to cisplatin, we evaluated survival rates, hatching rates, ionocyte densities, oxidative stress, and platinum accumulation. NAC co-treatment significantly enhanced survival and hatching rates, preserved ionocyte density, mitigated oxidative stress, and reduced platinum accumulation. These findings highlight ionocytes as an effective model for assessing non-renal toxicity due to their high metabolic activity and mitochondrial abundance. The results suggest that NAC might serve as a co-therapeutic agent to alleviate cisplatin-induced toxicity during chemotherapy.},
}
@article {pmid40397293,
year = {2025},
author = {Zheng, Y and Zou, X and Li, Q and Jiang, D and Zhu, F and Wu, Y},
title = {Exosomes derived from umbilical cord blood NK cells inhibit the progression of pancreatic cancer by targeting ROS-mediated mitochondrial dysfunction.},
journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society},
volume = {33},
number = {1-2},
pages = {8},
pmid = {40397293},
issn = {1319-0164},
support = {JYHL2022MS20//TaiShan Industrial Experts Programme/ ; 2023TSGC0549//Small and Medium Sized Enterprise Innovation Capability Enhancement Project of Shandong Province/ ; 2023ZDYF010144//Key Research and Development Program of Rizhao City/ ; JYSJ2022B04//the Practical Teaching Education Research Project Plan of Jining Medical University/ ; 202410443016//College Students' Innovative Entrepreneurial Training Plan Program/ ; },
abstract = {Emerging research indicates that natural killer (NK) cell-derived exosomes (NK-exo) play a significant role in cancer development. However, their regulatory mechanisms, particularly in pancreatic cancer, remain poorly elucidated. This study employed an in vitro co-culture system and an in vivo subcutaneous tumor model to evaluate the anti-tumor effect of NK-exo on pancreatic cancer. Umbilical cord blood (UCB)-derived NK-exo displayed characteristic exosomal morphology, size, and marker expression and was internalized by PANC- 1 cells. NK-exo significantly and dose-dependently reduce cell proliferation, migration, and invasion (P < 0.01). Further analysis demonstrated that NK-exo induced mitochondrial apoptosis in PANC- 1 cells by altering reactive oxygen species (ROS, P < 0.0001) and mitochondrial membrane potential (MPP) levels (P < 0.0001), effects that were significantly diminished with N-acetylcysteine (NAC) treatment (P < 0.0001). Furthermore, NK-exo treated PANC- 1 cells showed upregulation of the apoptotic markers Caspase3 (P < 0.0001) and Caspase9 (P = 0.0086) and reduced the release of PGC- 1α (P = 0.0064), TFAM (P < 0.0001), and SOD2 (P = 0.0021) as demonstrated by qRT-PCR. Western blot analyses revealed a dose dependent significant elevation of total Caspase3, Caspase9, Bax, and cytochrome c level and depression in the anti-apoptotic Bcl- 2. Animal experiments further confirmed that NK-exo treatment significantly reduced tumor volume and weight and increased Bax protein expression relative to the tumor model group. These findings indicate that NK-exo can enter PANC- 1 cells via endocytosis, induce mitochondrial oxidative damage, and suppress PANC- 1 cell progression, thereby demonstrating a robust anti-pancreatic cancer effect.},
}
@article {pmid40394754,
year = {2025},
author = {Sun, Y and Zhou, Y and Huang, D and Zhao, Z and Shao, Q and Li, J and Zhao, X and Liu, X},
title = {Erk1/2 Orchestrates SSPH I-Induced Oxidative Stress, Mitochondrial Dysfunction and Ferroptosis in Hepatocellular Carcinoma.},
journal = {Journal of cellular and molecular medicine},
volume = {29},
number = {10},
pages = {e70609},
pmid = {40394754},
issn = {1582-4934},
support = {82060793//National Natural Science Foundation of China/ ; 2021JJB140005//Natural Science Foundation of Guangxi Province/ ; 2022C043//Young talents in Gui Pai Xing lin of Guangxi University of Chinese Medicine/ ; 2021007//Qihuang Project Team of Guangxi University of Chinese Medicine/ ; },
mesh = {*Ferroptosis/drug effects ; *Carcinoma, Hepatocellular/metabolism/pathology/drug therapy ; Humans ; *Liver Neoplasms/metabolism/pathology/drug therapy ; *Oxidative Stress/drug effects ; Animals ; *Mitochondria/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Mice ; *MAP Kinase Signaling System/drug effects ; *Saponins/pharmacology ; Cell Line, Tumor ; Mice, Nude ; Iron/metabolism ; Cell Survival/drug effects ; Xenograft Model Antitumor Assays ; Butadienes ; Nitriles ; },
abstract = {Although Erk1/2 has been linked to oxidative stress regulation in hepatocellular carcinoma (HCC), the interplay among Erk1/2, reactive oxygen species (ROS), and iron metabolism remains poorly characterised. The steroidal saponin SSPH I, a recognised ferroptosis inducer, exerts dual pharmacological effects via Erk1/2 and ROS-dependent pathways. This study aimed to investigate the regulatory mechanisms of Erk1/2 in ferroptosis and oxidative stress and analyse their feedback regulatory effects on Erk1/2 in HCC using SSPH I as a pharmacological probe, and further elucidate the anti-HCC effects and mechanisms of SSPH I in vitro and in vivo. Mechanistic studies utilised three inhibitors: U0126 (Erk1/2 phosphorylation inhibitor), Ferrostatin-1 (ferroptosis inhibitor), and N-acetyl cysteine (ROS scavenger), combined with SSPH I to delineate its effects on cell viability, mitochondrial dynamics, ferroptosis induction and oxidative stress. Mechanistically, SSPH I disrupted mitochondrial function and suppressed HCC cell survival through iron accumulation and ROS generation, while concurrently activating Erk1/2 signalling. Pharmacological inhibition of ROS or iron pathways partially attenuated SSPH I-induced ferroptosis and ROS generation, but failed to abrogate these effects. Erk1/2 inhibition completely abolished SSPH I-mediated regulation of the Nrf1/2-HO-1 axis and ferroptosis-related protein expression in cellular and animal models, identifying Erk1/2 as the upstream regulatory node. Notably, while both SSPH I and U0126 monotherapies inhibited xenograft growth, their combined use resulted in antagonistic effects. These findings establish Erk1/2 activation as the central molecular mechanism orchestrating SSPH I-driven oxidative stress amplification, mitochondrial dysfunction and ferroptosis execution in HCC.},
}
@article {pmid40394693,
year = {2025},
author = {Chen, Y and Nan, Y and Xu, L and Dai, A and Orteg, RMM and Ma, M and Zeng, Y and Li, J},
title = {Polystyrene nanoplastics exposure induces cognitive impairment in mice via induction of oxidative stress and ERK/MAPK-mediated neuronal cuproptosis.},
journal = {Particle and fibre toxicology},
volume = {22},
number = {1},
pages = {13},
pmid = {40394693},
issn = {1743-8977},
support = {2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; Male ; Mice, Inbred C57BL ; *Polystyrenes/toxicity ; *Copper/metabolism/toxicity ; *Neurons/drug effects/pathology ; *Cognitive Dysfunction/chemically induced ; MAP Kinase Signaling System/drug effects ; Humans ; Mice ; *Nanoparticles/toxicity ; *Microplastics/toxicity ; Cell Line, Tumor ; },
abstract = {BACKGROUND: Recent studies emphasize the significance of copper dyshomeostasis in neurodegenerative diseases, such as Alzheimer's and Parkinson's, thereby highlighting the role of copper in neurotoxicity. Cuproptosis, a novel mechanism of copper-dependent cell death, remains underexplored, particularly concerning environmental pollutants like polystyrene nanoplastics (PS-NPs). While PS-NPs are recognized for inducing neurotoxicity through various forms of cell death, including apoptosis and ferroptosis, their potential to trigger neuronal cuproptosis has not yet been investigated. This study aims to determine whether exposure to PS-NPs induces neurotoxicity via cuproptosis and to explore the preliminary molecular mechanisms involved, thereby addressing this significant knowledge gap.<br><br>METHODS: Seven-week-old male C57BL/6 mice were exposed to PS-NPs at dose of 12.5&#xa0;mg/kg, and were co-treated with the antioxidant N-acetylcysteine (NAC). Complementary in vitro experiments were conducted using SH-SY5Y neuronal cells exposed to PS-NPs at a concentration of 0.75&#xa0;mg/mL, with interventions that included the copper chelator tetrathiomolybdate (TTM), NAC, and the MAPK inhibitor PD98059.<br><br>RESULTS: Exposure to PS-NPs significantly increased cerebral copper accumulation (P&#x2009;<&#x2009;0.05) and induced cuproptosis, characterized by lipid-acylated DLAT oligomerization, dysregulation of cuproptosis regulators (FDX1, LIAS, HSP70), and mitochondrial damage. In murine models, PS-NPs elicited neurotoxicity, as evidenced by neuronal loss, decreased Nissl body density, impaired synaptic plasticity, and suppressed oxidative stress markers (GSH, SOD, Nrf2), alongside activation of the ERK-MAPK pathway, ultimately resulting in deficits in learning and memory. Treatment with NAC alleviated these adverse effects. In SH-SY5Y cells, exposure to PS-NPs resulted in reduced cell viability (p&#x2009;<&#x2009;0.01), an effect that was mitigated by TTM. Furthermore, NAC and PD98059 were found to reverse elevated copper levels, cuproptosis markers, and mitochondrial anomalies (p&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: This study presents preliminary evidence indicating that PS-NPs may induce neuronal cuproptosis, potentially through the oxidative stress-mediated activation of the ERK-MAPK pathway, which contributes to cognitive dysfunction in mice. These findings provide insights into the potential mechanisms underlying PS-NPs neurotoxicity and highlight possible therapeutic targets, such as copper chelation or MAPK inhibition, for mitigating the neurological risks associated with nanoplastic exposure, pending further validation in human-relevant models.},
}
@article {pmid40389439,
year = {2025},
author = {Zhang, YH and Dai, CS and Wang, YJ and Wang, WY and Qi, TT and Xia, MC and Zhou, G and Cui, YM},
title = {Intestinal permeability of N-acetylcysteine is driven by gut microbiota-dependent cysteine palmitoylation.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {4623},
pmid = {40389439},
issn = {2041-1723},
support = {82204515//National Natural Science Foundation of China (National Science Foundation of China)/ ; 7232262//Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)/ ; },
mesh = {*Gastrointestinal Microbiome/physiology ; *Acetylcysteine/metabolism/pharmacokinetics ; Animals ; Humans ; Rats ; Male ; Permeability ; *Cysteine/metabolism ; Lipoylation ; *Intestinal Mucosa/metabolism ; Rats, Sprague-Dawley ; Female ; Specific Pathogen-Free Organisms ; Germ-Free Life ; Intestinal Barrier Function ; },
abstract = {Trillions of intestinal microbiota are essential to the permeability of orally administered drugs. However, identifying microbial-drug interactions remains challenging due to the highly variable composition of intestinal flora among individuals. Using single-pass intestinal perfusion (SPIP) platform, we establish the microbiota-based permeability screening framework involving germ-free (GF) and specific-pathogen-free (SPF) rats to compare in-situ Peff-values and metabolomic profiles of 32 orally administered drugs with disputable classifications of permeability, prior to the verifications of bioorthogonal chemistry and LC-MS/MS. In contrast with SPF controls, N-Acetylcysteine (NAC) exhibits significantly increased permeability in GF rats, which is inversely related to reduced cysteine-3-ketosphinganine by Bacteroides. To further validate these microbiome features, we integrate clinical descriptors from a prospective cohort of 319 participants to optimize a 15-feature eXtreme Gradient Boosting (XGB) model, which reveal that cysteine palmitoylation by intestinal microbiota has significantly affected NAC permeability. By comparison of net reclassification improvement (NRI) index, this machine learning (ML) model of clinical prediction model encompassing intestinal microbial features outperforms other three commercial models in predicting NAC permeability. Here we have developed an intestinal microbiota-based strategy to evaluate uncharacterized NAC permeability, thus accounting for its discordant biopharmaceutics classification.},
}
@article {pmid40387057,
year = {2025},
author = {Zhang, Y and Chen, M and Niu, R and Guo, D and Sun, Z},
title = {Mechanistic Insights into T-2 Toxin-Induced Thymic Epithelial Cell Injury and Immunotoxicity via the ROS-NF-κB-NLRP3 Signaling Axis.},
journal = {Journal of agricultural and food chemistry},
volume = {73},
number = {21},
pages = {12961-12977},
doi = {10.1021/acs.jafc.5c00355},
pmid = {40387057},
issn = {1520-5118},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/genetics/immunology ; *NF-kappa B/genetics/immunology ; *Reactive Oxygen Species/immunology/metabolism ; *Epithelial Cells/drug effects/immunology/metabolism ; Signal Transduction/drug effects ; *T-2 Toxin/toxicity ; Animals ; Mice ; *Thymus Gland/drug effects/immunology/cytology/injuries ; Inflammasomes/immunology/genetics ; Apoptosis/drug effects ; Humans ; Mice, Inbred C57BL ; Male ; },
abstract = {Thymic epithelial cells (TECs) are critical for thymic structure and function, yet the impact of T-2 toxin (T-2) on TECs and related molecular pathways remains unclear. This study sheds light on the mechanisms of T-2-induced TEC damage, focusing on the ROS-NF-κB-NLRP3 signaling axis. The in vivo and in vitro analyses suggest that T-2 induces TEC injury through ROS-driven NLRP3 inflammasome activation, NF-κB signaling, inflammation, and apoptosis. Molecular docking analysis verified the binding of T-2 to critical components involved in oxidative stress, inflammatory signaling pathways, and apoptosis. These findings were further supported by therapeutic interventions targeting ROS and NLRP3. N-acetylcysteine (NAC) effectively reduced ROS levels, suppressed NF-κB signaling, inhibited NLRP3 activation, and mitigated inflammation and apoptosis, effects mirrored by the NLRP3 inhibitor MCC950, emphasizing the critical role of ROS-mediated NLRP3 inflammasome activation through NF-κB signaling in T-2-induced TEC damage. Concurrently, inhibition of the NF-κB signaling further suppressed ROS levels, NLRP3 inflammasome activation, and apoptosis in MTEC1 cells, emphasizing the pivotal function of the ROS-NF-κB-NLRP3 axis in the pathogenesis of T-2-induced thymic injury. Our study offers an in-depth insight into the mechanisms driving T-2-induced immunotoxicity and identifies potential therapeutic strategies targeting these pathways to mitigate thymic injury and preserve immune function.},
}
@article {pmid40384860,
year = {2025},
author = {Gallego-Rentero, M and Botella, LM and Mascaraque, M and Nicolás-Morala, J and Albiñana, V and Abarca-Lachen, E and Gilaberte, Y and González, S and Juarranz, &#xc1; and Carrasco, E},
title = {N-acetylcysteine and raloxifene boost photodynamic therapy against cutaneous squamous cell carcinoma by decreasing TGFβ1 secreted by cancer-associated fibroblasts.},
journal = {International journal of biological sciences},
volume = {21},
number = {7},
pages = {3164-3182},
pmid = {40384860},
issn = {1449-2288},
mesh = {*Photochemotherapy/methods ; *Raloxifene Hydrochloride/therapeutic use/pharmacology ; Animals ; *Carcinoma, Squamous Cell/drug therapy/metabolism ; *Acetylcysteine/therapeutic use/pharmacology ; Mice ; *Transforming Growth Factor beta1/metabolism ; *Skin Neoplasms/drug therapy/metabolism ; Humans ; Cell Line, Tumor ; *Cancer-Associated Fibroblasts/metabolism/drug effects ; },
abstract = {Cutaneous squamous cell carcinoma (cSCC) is a highly prevalent skin cancer. While surgery remains the gold standard treatment, non-invasive methods like photodynamic therapy (PDT) stand out for their high efficacy and minimal cosmetic impact. However, resistance to PDT is still a challenge. Numerous cellular processes involved in cancer biology and therapy resistance are regulated by the TGFβ1/SMAD pathway. Using in vitro bidimensional and tridimensional cultures of cSCC cell lines, we studied the development of resistance to PDT in response to TGFβ1 secreted by cancer associated fibroblasts. Our results highlight the TGFβ1 co-receptor endoglin as a key molecular player in the process. Importantly, targeting endoglin expression with N-acetylcysteine (NAC) or raloxifene significantly reduced TGFβ1 levels and effectively prevented resistance. In addition, the combination of PDT with NAC resulted in an improved therapeutic outcome in vivo in SKH-1 mice with cSCC photogenerated by chronic exposition to ultraviolet light. In conclusion, the combination of PDT with NAC or raloxifene enhances PDT efficacy by mitigating resistance mechanisms, which can open new avenues for the treatment of cSCC.},
}
@article {pmid40381462,
year = {2025},
author = {Liu, M and Ding, C and Yi, Q and Quan, H and Li, W and Wang, Y and Lin, X and Wang, M and Wang, J},
title = {Carboxylesterase-activated hepatocyte-targeting fluorescent probe for drug-induced liver injury diagnosis.},
journal = {Bioorganic chemistry},
volume = {162},
number = {},
pages = {108587},
doi = {10.1016/j.bioorg.2025.108587},
pmid = {40381462},
issn = {1090-2120},
mesh = {Humans ; *Fluorescent Dyes/chemistry/metabolism/chemical synthesis ; *Hepatocytes/metabolism ; *Chemical and Drug Induced Liver Injury/diagnosis/metabolism/diagnostic imaging ; *Carboxylesterase/metabolism ; Molecular Structure ; Animals ; Optical Imaging ; Dose-Response Relationship, Drug ; Hep G2 Cells ; Structure-Activity Relationship ; },
abstract = {In this study, a novel fluorescent probe DCI-Gal-Bz toward CEs was developed. DCI-Gal-Bz exhibits excellent sensitivity and selectivity toward CEs, which is not disturbed by physiologically relevant interferences. DCI-Gal-Bz could specifically distinguish hepatocytes from A549, HeLa, and SGC-7901 cells, showing good hepatocyte-targeting potential, which is because the terminal galactose of DCI-Gal-Bz can be selectively recognized by HepG2 cells overexpressing ASGPR. DCI-Gal-Bz could effectively monitor CEs activity in APAP-induced liver injury (DILI), and reveal the upregulation of CEs during N-acetylcysteine (NAC) hepatoprotective therapy. In other words, DCI-Gal-Bz can clearly distinguish between healthy, injured and repaired states, being a powerful tool for exploring liver CEs-related diseases.},
}
@article {pmid40381010,
year = {2025},
author = {Li, J and Zheng, Q and Wang, F},
title = {Fabrication of N-acetylcysteine-loaded chitosan-cloaked polyphenol nanoparticles for treatment of pediatric pneumonia and acute lung injury.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {398},
number = {11},
pages = {15775-15789},
pmid = {40381010},
issn = {1432-1912},
mesh = {*Chitosan/chemistry/administration &amp; dosage ; *Acetylcysteine/administration &amp; dosage/chemistry/pharmacology ; Humans ; *Acute Lung Injury/drug therapy ; *Nanoparticles/chemistry/administration &amp; dosage ; Animals ; *Polyphenols/administration &amp; dosage/chemistry ; A549 Cells ; *Anti-Bacterial Agents/administration &amp; dosage/chemistry/pharmacology ; Cell Survival/drug effects ; Antioxidants/administration &amp; dosage/chemistry/pharmacology ; *Pneumonia/drug therapy ; Male ; Tannins/chemistry/administration &amp; dosage ; Lung/drug effects/metabolism ; Rats, Sprague-Dawley ; },
abstract = {Bacterial infectious acute pneumonia has long presented a significant barrier to human health and the fast elimination of antibacterial in lung tissue. Engineering nanoformulations that are easily prepared and possess mucoadhesive characteristics for administering antibacterial drugs are crucial for addressing pneumonia and lung injury. This investigation utilized FDA-approved tannic acid (TA) to develop a nanocomplex by cloaking chitosan (CH) to attain prolonged anti-infection efficacy against acute pneumonia. The flash nanocomplexation (FNC) process was employed for developing chitosan-cloaked poly(vinyl alcohol)/TA/N-acetylcysteine (NAC) nanoparticles (CPTN NPs) using NAC as the model drug, relying on non-covalent interactions between the components. The investigation of pneumonia revealed that the robust electrostatic interaction between negatively charged mucin and positively charged chitosan in the trachea facilitated the retention of NAC in the lungs for a minimum of 24 h post-inhalation of CPTN NPs, effectively constraining pneumonia within 3 days. The DPPH values of 97.42 ± 5.1 for CPTN NPs reveal excellent antioxidant ability. The cell viability of NCI-H441 and A549 cells remained above 90% of 100 μg/mL for NAC and CPTN NPs. The antibacterial efficacy of CPTN NPs exhibited a 99.9% reduction compared to the untreated group. The mucoadhesive CPTN NPs, characterized by excellent biocompatibility and produced using a simple and reproducible method, may offer a novel approach to administering CPTN NPs to address acute pediatric pneumonia and lung injury.},
}
@article {pmid40380998,
year = {2025},
author = {Sun, S and Wang, Y and Shen, Y and Li, W and Hu, Z and Peng, Y and Zheng, J},
title = {Metabolic activation and cytotoxicity of carvedilol mediated by cytochrome P450s in vitro and in vivo.},
journal = {Archives of toxicology},
volume = {99},
number = {7},
pages = {2855-2875},
pmid = {40380998},
issn = {1432-0738},
mesh = {Animals ; *Carvedilol/toxicity/metabolism ; Male ; Microsomes, Liver/drug effects/metabolism/enzymology ; Rats, Sprague-Dawley ; Activation, Metabolic ; Rats ; Glutathione/metabolism ; Humans ; Cytochrome P-450 CYP3A/metabolism ; *Chemical and Drug Induced Liver Injury/etiology/pathology/metabolism ; Hepatocytes/drug effects ; Cell Survival/drug effects ; Acetylcysteine/metabolism ; Liver/drug effects/metabolism ; *Antihypertensive Agents/toxicity/metabolism ; *Cytochrome P-450 Enzyme System/metabolism ; },
abstract = {Carvedilol (CAR) is commonly administered in the treatment of essential hypertension. Current reports suggest that CAR therapy may elevate the risk of hepatotoxicity, occasionally progressing to liver injury. However, the underlying mechanisms of the toxicity remain poor understood. This study investigated CAR-associated hepatotoxicity through reactive metabolites formation. In the microsomal incubation mixture containing CAR (50 μM), four phase I metabolites (M1-M4) were detected. Upon the addition of glutathione (GSH), N-acetylcysteine (NAC), or cysteine as trapping agents, four GSH conjugates (M5-M8), four NAC conjugates (M9-M12), and four cysteine conjugates (M13-M16) were also detected. Chemical synthesis of 8-hydroxy CAR identified M1 as the primary oxidative metabolite of CAR. Following the administration of CAR (25 mg/kg), we detected GSH conjugate (M5) in bile, NAC conjugate (M9) in urine, and cysteine adduct (M13) in proteolytic mixture of liver tissues of rat. Furthermore, it was found that CYP3A4 dominated the metabolic activation of CAR. Additionally, CAR exhibited time-course changes and dose-dependent (0, 25, 50, and 100 mg/kg) protein adduction in rat liver tissues, as well as time- and concentration-dependent (0, 10, 25, 50 and 100 μM) inhibition of hepatocyte viability. Ketoconazole (KTZ) significantly decreased the susceptibility of hepatocytes to CAR-induced cytotoxicity. Collectively, these findings offer new insight into the hepatotoxicity mechanism associated with the metabolic activation of CAR.},
}
@article {pmid40375363,
year = {2025},
author = {Edzeamey, FJ and Ramchunder, Z and Valle Gómez, A and Ge, H and Marobbio, CMT and Pourzand, C and Virmouni, SA},
title = {Therapeutic combination of L-ascorbic acid, N-acetylcysteine, and dimethyl fumarate in Friedreich's ataxia: insights from in vitro models.},
journal = {Redox report : communications in free radical research},
volume = {30},
number = {1},
pages = {2505303},
pmid = {40375363},
issn = {1743-2928},
mesh = {*Acetylcysteine/pharmacology/therapeutic use ; *Dimethyl Fumarate/pharmacology/therapeutic use ; *Friedreich Ataxia/drug therapy/metabolism ; *Ascorbic Acid/pharmacology/therapeutic use ; Humans ; Reactive Oxygen Species/metabolism ; Mitochondria/drug effects/metabolism ; Fibroblasts/metabolism/drug effects ; Frataxin ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; Membrane Potential, Mitochondrial/drug effects ; Iron-Binding Proteins/metabolism/genetics ; NF-E2-Related Factor 2/metabolism ; Cell Survival/drug effects ; },
abstract = {Friedreich's Ataxia (FRDA) is a rare neurological disorder caused by an abnormal expansion of Guanine-Adenine-Adenine (GAA) repeat in intron 1 of the FXN gene, which encodes frataxin, leading to reduced expression of frataxin, a mitochondrial protein essential for cellular homeostasis. Frataxin deficiency results in oxidative stress and mitochondrial dysfunction and impaired redox balance. Currently, there is no cure for FRDA. This study aimed to evaluate the therapeutic potential of antioxidants dimethyl fumarate (DMF), N-acetylcysteine (NAC), and L-ascorbic acid (LAA) in restoring mitochondrial redox homeostasis and frataxin levels in FRDA patient-derived fibroblasts and 2D sensory neurons. We assessed cell viability, mitochondrial and cellular reactive oxygen species (ROS) levels, mitochondrial DNA copy number, mitochondrial membrane potential, and frataxin and NRF2 expression at both mRNA and protein levels following antioxidant treatment, either individually or in combination. Treatment with LAA, NAC, and DMF resulted in significant reductions in mitochondrial and cellular ROS, along with increased FXN and NRF2 expression, and enhanced NRF2 nuclear translocation. Furthermore, these compounds improved aconitase/citrate synthase activity, GSH/GSSG ratios, and mitochondrial membrane potential. Notably, the combination of LAA and NAC consistently alleviated multiple disease-associated defects in FRDA cells, suggesting its potential as a promising therapeutic approach.},
}
@article {pmid40374378,
year = {2025},
author = {Li, K and Wang, YJ and Wei, K and Li, WL and Liu, YB and Hu, JN and Chang, WG and Zhang, WX and Chen, L and Li, W},
title = {Ginsenoside Rg2 Alleviates HFD/STZ-Induced Diabetic Nephropathy by Inhibiting Pyroptosis via NF-κB/NLRP3 Signaling Pathways.},
journal = {The American journal of Chinese medicine},
volume = {53},
number = {3},
pages = {909-930},
doi = {10.1142/S0192415X2550034X},
pmid = {40374378},
issn = {1793-6853},
mesh = {*Ginsenosides/pharmacology/therapeutic use/administration &amp; dosage ; Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Diabetic Nephropathies/drug therapy/etiology/genetics/metabolism ; *Pyroptosis/drug effects/genetics ; *Signal Transduction/drug effects/genetics ; *NF-kappa B/metabolism ; Diet, High-Fat/adverse effects ; Male ; Mice, Inbred C57BL ; Humans ; *Diabetes Mellitus, Experimental/drug therapy ; *Phytotherapy ; Streptozocin/adverse effects ; Mice ; Inflammasomes/metabolism ; Cell Line ; Panax/chemistry ; },
abstract = {Diabetes mellitus (DM) is considered to be the most widespread epidemic worldwide, and diabetic nephropathy (DN) is one of the most serious diabetic complications. Its complex pathogenesis makes treatment of DN an ongoing medical challenge. Ginseng (Panax ginseng. C. A Meyer) is a valuable medicinal herb with a long medicinal and culinary history. Ginsenoside Rg2 (Rg2), an important active component in ginseng, has effective inhibitory effects on lipogenesis and hepatic glucose production. However, the potential effect and mechanism of Rg2 on DN remain unclear. In this study, we investigated the effect of Rg2 on DN in high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic mice and high glucose (HG)-induced human kidney 2 (HK-2) cells. The results demonstrated that Rg2 significantly improved the levels of FBG, dyslipidemia and impaired kidney function in DN mice. Additionally, Rg2 decreased the phosphorylation levels of IKKβ, IκBα, and NF-κB p65, inhibited the activation of NLRP3 inflammasomes (NLRP3, ASC, and Caspase 1), and restrained release of inflammatory factors (IL-18 and IL-1[Formula: see text]. In HG-induced HK-2 cells, Rg2 showed similar inhibitory effects on pyroptosis via NF-κB/NLRP3 signaling pathways. Moreover, the effect of Rg2 on inhibiting the activation of NF-κB/NLRP3 signaling pathways may have a relationship to reducing the overproduction of reactive oxygen species (ROS), which is further supported by the ROS inhibitor N-acetylcysteine (NAC). In conclusion, our findings clearly indicated that Rg2 could prevent the progress of DN by inhibiting the activation of pyroptosis-related NF-κB/NLRP3 signaling pathways in vivo and in vitro, suggesting that Rg2 may be a novel and promising therapeutic agent in the treatment of DN.},
}
@article {pmid40362589,
year = {2025},
author = {Ontawong, A and Nehra, G and Maloney, BJ and Vaddhanaphuti, CS and Bauer, B and Hartz, AMS},
title = {N-Acetylcysteine Attenuates Aβ-Mediated Oxidative Stress, Blood-Brain Barrier Leakage, and Renal Dysfunction in 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
pmid = {40362589},
issn = {1422-0067},
support = {R01 AG075583/AG/NIA NIH HHS/United States ; R01 NS133250/NS/NINDS NIH HHS/United States ; 1R01NS133250-24A1/NH/NIH HHS/United States ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *Blood-Brain Barrier/drug effects/metabolism ; *Acetylcysteine/pharmacology ; *Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/metabolism/drug therapy ; Mice, Transgenic ; Disease Models, Animal ; Aldehydes/metabolism ; Male ; Antioxidants/pharmacology ; Brain/metabolism/drug effects ; Kidney/drug effects/metabolism ; S100 Calcium Binding Protein beta Subunit/blood ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) pathology and is closely linked to oxidative stress, which contributes to blood-brain barrier leakage, renal dysfunction, and cognitive decline. We investigated the effects of N-acetyl cysteine (NAC), an FDA-approved antioxidant, on oxidative stress, brain Aβ levels, barrier leakage, renal function, and cognition in 5xFAD mice. Eight-week-old 5xFAD mice were fed a rodent diet supplemented with 600 mg/kgDiet NAC for 4 weeks; wild-type (WT) mice and control 5xFAD mice were fed a regular rodent diet. We detected elevated brain and renal 4-hydroxynonenal(4-HNE) levels, reduced creatinine clearance, and increased plasma S100β levels in untreated 5xFAD mice compared to WT controls. Untreated 5xFAD mice also had higher capillary leakage, reduced P-gp activity, and impaired cognition compared to WT. NAC treatment of 5xFAD mice reduced brain Aβ40 levels, normalized 4-HNE levels to control levels, improved creatinine clearance, decreased capillary leakage, and lowered S100β plasma levels. NAC improved cognitive performance in 5xFAD mice, as shown by Y-maze. Our findings indicate that Aβ-induced oxidative stress contributes to barrier dysfunction, renal impairment, and cognitive deficits in 5xFAD mice. Notably, NAC treatment mitigates these effects, suggesting its potential as an adjunct therapy for AD and other Aβ-related pathologies by reducing oxidative stress.},
}
@article {pmid40359441,
year = {2026},
author = {Goldin, D and Salani, DA and Valdes, B},
title = {N-Acetylcysteine (NAC) for Trichotillomania and Excoriation Disorder: An Overview.},
journal = {Journal of psychosocial nursing and mental health services},
volume = {64},
number = {1},
pages = {15-23},
doi = {10.3928/02793695-20250506-04},
pmid = {40359441},
issn = {0279-3695},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Trichotillomania/drug therapy ; Excoriation Disorder ; },
abstract = {Trichotillomania and excoriation/skin-picking disorder involve repetitive behaviors, such as hair pulling leading to hair loss or skin picking leading to skin lesions, that cause physical complications, significant mental distress, and functional impairment despite attempts to stop. Currently, no first-line pharmacological treatments are approved for these disorders, although glutamatergic agents, select antidepressants, and other medications have demonstrated some benefit. The therapeutic potential of N-acetylcysteine (NAC) is promising. NAC helps maintain glutamate homeostasis in the brain, thereby reducing compulsive and habitual behaviors. In addition, NAC is recognized as a low-risk, well-tolerated, and accessible dietary supplement with valuable therapeutic potential. Deficiencies in pharmacological protocols and lack of government controls place individuals at risk; therefore, health care providers are well positioned to provide reliable information and educate individuals to make informed decisions about their health.},
}
@article {pmid40356978,
year = {2025},
author = {Zhang, M and Yuan, W and Li, C and Chen, C and Liu, X and Ma, Z and Xiang, Y and Chen, G and Wang, C and Li, L and Wang, L and Xu, Z and Xu, C},
title = {Resveratrol and N-acetylcystein reduce hepatic steatosis but enhance initiation and progression of hepatocellular carcinoma by inhibiting GST-pi-MAPK axis in mice.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1574039},
pmid = {40356978},
issn = {1663-9812},
abstract = {INTRODUCTION: Accumulating evidence indicates that antioxidants promote tumor growth and metastasis after tumor onset in several cancer types. However, whether antioxidants prevent or accelerate hepatic tumorigenesis during steatosis remains unknown. Therefore, we investigated the effects of resveratrol (RES) and N-acetylcysteine (NAC) on hepatocellular carcinoma (HCC) development using two fatty liver mouse models.<br><br>METHODS: High-fat diet (HFD) plus diethylnitrosamine (DEN)- and AKT/Ras-induced primary HCC mouse models were used. The weight, liver weight ratio and the number of HCC tumors were calculated and histological features of mouse HCC tissues were analyzed using immumohistochemical staining such as hematoxylin and eosin staining. Proteomic analysis was used to screen for differences in liver cancer progression between antioxidant-treated HCC and models. Protein inhibitor recovery experiments in mice and in vitro cells validate the targets screened by proteomic analysis. The expression of GST-pi, p-JNK and p-p38 signaling molecules in HCC were investigated using Western blotting.<br><br>RESULTS: RES and NAC enhance HCC formation in both DEN/HFD and AKT/Ras mice. RES and NAC alleviate hepatosteatosis, and reduce ROS and DNA damage in mice. Proteomic analysis and protein inhibitor recovery assay demonstrated that GST-pi is a therapeutic target for antioxidant-induced hepatocellular carcinoma growth. Mechanistically, RES and NAC decreased p-JNK and p-p38, the two major mitogen-activated protein kinases, in HCC cells. Blockade of GST-pi abrogated the reduction in p-JNK and p-p38 levels and increased apoptosis of HCC cells.<br><br>CONCLUSION: Antioxidants may increase the incidence of HCC in a population with fatty liver, despite reduction in ROS production, by inhibiting GST-pi-MAPK axis.},
}
@article {pmid40352229,
year = {2025},
author = {Nasrun, MW and Ginting, TT and Siste, K and Pandelaki, J and Kekalih, A and Louisa, M and Susanto, AD and Utami, DS and Tarigan, IN and Trishna, AR and Halim, K},
title = {Efficacy of N-acetylcysteine and motivational enhancement therapy for nicotine addiction: A randomized clinical trial.},
journal = {Narra J},
volume = {5},
number = {1},
pages = {e2178},
pmid = {40352229},
issn = {2807-2618},
mesh = {Humans ; *Acetylcysteine/therapeutic use/pharmacology ; Male ; Female ; Adult ; *Tobacco Use Disorder/drug therapy/therapy ; Middle Aged ; Magnetic Resonance Spectroscopy ; Motivation ; Treatment Outcome ; Brain/metabolism/drug effects ; Creatine/metabolism ; Glutamine ; Prefrontal Cortex ; Aspartic Acid/analogs &amp; derivatives ; },
abstract = {N-acetylcysteine (NAC) is known to enhance neuroplasticity and help reduce smoking addiction by modulating brain metabolites. The use of magnetic resonance spectroscopy (MRS) in smokers receiving NAC as an adjuvant to motivational enhancement therapy (MET) represents a novel approach to understanding how this combination therapy influences brain chemistry. By utilizing MRS, the effectiveness of NAC can be quantitatively assessed by analyzing changes in smoking-affected brain metabolites. The aim of this study was to evaluate the efficacy of NAC combined with MET for nicotine addiction, using MRS to assess neurochemical alterations associated with treatment response. A stratified, randomized, parallel-group clinical trial was conducted, comparing NAC and MET combination to MET only among smokers. The study analyzed the effectiveness of NAC by evaluating glutamate-glutamine (Glx) to creatine ratio (Glx/creatine ratio) and N-acetylaspartate (NAA) to creatine ratio (NAA/creatine ratio) in the nucleus accumbens, bilateral cerebellum, medial prefrontal cortex, ventromedial prefrontal cortex, and bilateral precuneus. Our data indicated that the Glx/creatine ratios for the intervention versus control groups were as follows: nucleus accumbens (0.68 vs 0. 43), bilateral cerebellum (0.68 vs 0.43), left medial prefrontal cortex (1.11 vs 0.82), ventromedial prefrontal cortex (0.32 vs 0.86), and bilateral precuneus (0.75 vs 0.58). The NAA/creatine ratios for the intervention versus control groups were as follows: nucleus accumbens (3.55 vs 8.35), bilateral cerebellum (7.82 vs 4.02), left medial prefrontal cortex (5.47 vs 5.20), ventromedial prefrontal cortex (3.55 vs 7.46), and bilateral precuneus (4.73 vs 4.00). Our analysis indicated that the Glx/creatine ratio was higher in the intervention group than in the control group in the medial prefrontal cortex (p = 0.02), while the NAA/creatine ratio was higher in the intervention group than in the control group in the bilateral cerebellum (p < 0.001). The reported side effects were mild to moderate discomfort and well-tolerated across both groups. These findings highlight the potential of NAC and MET combination in promoting neuroplasticity and supporting nicotine addiction treatment.},
}
@article {pmid40350672,
year = {2025},
author = {Ma, X and Yang, Y and Liu, S and Cui, Y and Wu, J},
title = {Meta-analysis of the efficacy and safety of L-carnitine and N-acetylcysteine monotherapy for male idiopathic infertility.},
journal = {Revista internacional de andrologia},
volume = {23},
number = {1},
pages = {1-12},
doi = {10.22514/j.androl.2025.004},
pmid = {40350672},
issn = {1698-0409},
support = {82370690, 82303813//National Natural Science Foundation of China/ ; ZR2023MH241, ZR2023QH271//Shandong Science and Technology Program/ ; tsqn201909199, tsqn202306403//Taishan Scholars Program of Shandong Province/ ; },
mesh = {Male ; *Acetylcysteine/therapeutic use/adverse effects ; Humans ; *Infertility, Male/drug therapy ; *Carnitine/therapeutic use/adverse effects ; Sperm Motility/drug effects ; Randomized Controlled Trials as Topic ; *Antioxidants/therapeutic use/adverse effects/administration &amp; dosage ; Sperm Count ; Testosterone/blood ; Treatment Outcome ; Ejaculation/drug effects ; },
abstract = {BACKGROUND: Oral antioxidants especially L-carnitine (LC) and N-Acetylcysteine (NAC) are commonly used as the drug treatment method for idiopathic male infertility (IMI).<br><br>METHODS: Randomized controlled trials (RCTs) of LC and NAC monotherapy for IMI were searched systematically by using MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of retrieved studies were also perused. We analyzed the sperm concentration, normal morphology, sperm motility, and ejaculation volume.<br><br>RESULTS: Seven Randomized controlled trials were included. Four trials compared the efficacy of LC with placebo, and three trials compared the efficacy of NAC with placebo. In the efficacy analysis, LC increased sperm concentration (p < 0.001), normal morphology (p = 0.03), and sperm motility (p = 0.02); NAC improved the first three indicators while also increasing ejaculation volume (p = 0.002). In hormone level analysis, LC increased serum testosterone levels (p < 0.001), but the changes in other hormone levels were not statistically significant.<br><br>CONCLUSIONS: Both LC and NAC can improve sperm motility, sperm concentration, and normal morphology, and increase serum testosterone concentration, but have no significant effect on other serum hormones.<br><br>THE PROSPERO REGISTRATION: CRD42024552120.},
}
@article {pmid40348944,
year = {2025},
author = {Kosonen, JP and Eskelinen, ASA and Orozco, GA and Coleman, MC and Goetz, JE and Anderson, DD and Grodzinsky, AJ and Tanska, P and Korhonen, RK},
title = {Mechanobiochemical finite element model to analyze impact-loading-induced cell damage, subsequent proteoglycan loss, and anti-oxidative treatment effects in articular cartilage.},
journal = {Biomechanics and modeling in mechanobiology},
volume = {24},
number = {4},
pages = {1191-1206},
pmid = {40348944},
issn = {1617-7940},
support = {240098//Sigrid Juselius Foundation/ ; 354916//Strategic funding of the University of Eastern Finland, Academy of Finland/ ; 363459//Strategic funding of the University of Eastern Finland, Academy of Finland/ ; 240074//P&#xe4;ivikki and Sakari Sohlberg Foundation/ ; NNF21OC0065373//Novo Nordisk Foundation (the Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA))/ ; },
mesh = {*Proteoglycans/metabolism ; *Cartilage, Articular/pathology/drug effects/metabolism ; *Finite Element Analysis ; *Antioxidants/pharmacology ; Animals ; Acetylcysteine/pharmacology ; Oxidative Stress/drug effects ; *Models, Biological ; Cell Death/drug effects ; Weight-Bearing ; Stress, Mechanical ; Computer Simulation ; Biomechanical Phenomena ; Chondrocytes/drug effects ; },
abstract = {Joint trauma often leads to articular cartilage degeneration and post-traumatic osteoarthritis (PTOA). Pivotal determinants include trauma-induced excessive tissue strains that damage cartilage cells. As a downstream effect, these damaged cells can trigger cartilage degeneration via oxidative stress, cell death, and proteolytic tissue degeneration. N-acetylcysteine (NAC) has emerged as an antioxidant capable of inhibiting oxidative stress, cell death, and cartilage degeneration post-impact. However, the temporal effects of NAC are not fully understood and remain difficult to assess solely by physical experiments. Thus, we developed a computational finite element analysis framework to simulate a drop-tower impact of cartilage in Abaqus, and subsequent oxidative stress-related cell damage, and NAC treatment upon cartilage proteoglycan content in Comsol Multiphysics, based on prior ex vivo experiments. Model results provide evidence that immediate NAC treatment can reduce proteoglycan loss by mitigating oxidative stress, cell death (improved proteoglycan biosynthesis), and enzymatic proteoglycan depletion. Our simulations also indicate that delayed NAC treatment may not inhibit cartilage proteoglycan loss despite reduced cell death after impact. These results enhance understanding of the temporal effects of impact-related cell damage and treatment that are critical for the development of effective treatments for PTOA. In the future, our modeling framework could increase understanding of time-dependent mechanisms of oxidative stress and downstream effects in injured cartilage and aid in developing better treatments to mitigate PTOA progression.},
}
@article {pmid40348128,
year = {2025},
author = {Modanlo, N and Yan, X and Bourgeois, JA},
title = {Pharmacologic Management of Skin-Picking Disorder: An Updated Review.},
journal = {Journal of the Academy of Consultation-Liaison Psychiatry},
volume = {66},
number = {5},
pages = {417-428},
doi = {10.1016/j.jaclp.2025.05.002},
pmid = {40348128},
issn = {2667-2960},
mesh = {Humans ; *Antipsychotic Agents/therapeutic use ; *Skin/injuries ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; *Self-Injurious Behavior/drug therapy ; *Disruptive, Impulse Control, and Conduct Disorders/drug therapy ; Excoriation Disorder ; },
abstract = {INTRODUCTION: Skin-picking disorder (SPD), defined as a psychocutaneous condition that involves excessive picking at the skin causing marked impairment in quality of life, is commonly seen in both dermatology and psychiatry. As such, therapeutic intervention-both nonpharmacologic and pharmacologic-is essential. Given the rising prevalence of SPD and the tremendous impact it can have on quality of life, an updated review, specifically on pharmacologic options, is very much needed.<br><br>OBJECTIVE: The aim of this scoping review is to provide a detailed compilation of updated pharmacologic treatments for SPD based on evidence from recent studies and trials.<br><br>METHODS: A search through PubMed was conducted using the key words "treatment" and "skin picking" or "excoriation" in November 2024. Articles were limited to those that solely address pharmacologic treatments in skin-picking for individuals older than 18 years, were published in the last 20 years, in the English language, and can be classified as a clinical trial, case report/series, or cohort study.<br><br>FINDINGS: Of the 192 articles extracted from PubMed, 13 studies (289 patients) met the inclusion criteria. These articles consist of 7 case reports/series and 6 randomized controlled trials. The following medications were evaluated for treatment of SPD: selective serotonin reuptake inhibitors, glutamatergic drugs (N-acetyl cysteine, memantine), antiepileptics (lamotrigine, topiramate), lithium, antipsychotics (olanzapine, aripiprazole), opioid antagonists (naltrexone), and mirtazapine.<br><br>CONCLUSION: Of the medications evaluated for use in SPD, selective serotonin reuptake inhibitors show the most promising results in terms of mitigating the severity and frequency of skin-picking symptoms. Although habit-reversal psychotherapy has traditionally been first-line treatment, selective serotonin reuptake inhibitors are now increasingly being used in combination with psychotherapy when a patient presents with SPD. N-acetyl cysteine has also been well-established in the treatment of SPD. Other classes of medications that have been studied in SPD include the use of antipsychotics (often combined with antidepressants) and naltrexone. Additional studies are indicated to further expand on the current research and definitively establish the role of the less common medications, such as antiepileptics, in SPD.},
}
@article {pmid40347530,
year = {2025},
author = {Chetcuti, L and Uljarević, M and Schuck, RK and Hardan, AY and Gengoux, GW and Trembath, D and Vadgama, Y and Varcin, KJ and Vivanti, G and Whitehouse, AJO and Helton, M and Frazier, TW},
title = {Characterizing predictors of response to behavioral interventions for children with autism spectrum disorder: A meta-analytic approach.},
journal = {Clinical psychology review},
volume = {119},
number = {},
pages = {102588},
doi = {10.1016/j.cpr.2025.102588},
pmid = {40347530},
issn = {1873-7811},
mesh = {Child ; Child, Preschool ; Humans ; *Autism Spectrum Disorder/therapy ; *Behavior Therapy/methods ; *Outcome Assessment, Health Care/statistics &amp; numerical data ; },
abstract = {A comprehensive understanding of specific factors contributing to variability in responsiveness of children with autism to interventions is paramount for making evidence-based clinical and policy decisions. This meta-analysis examined child and family characteristics, as well as intervention design factors, associated with outcomes of behavioral interventions for children with autism. A systematic review identified 95 studies published between 1987 and 2024, encompassing 6780 children on the autism spectrum and 2150 independent effect sizes. Results indicated that stronger post-intervention effects were observed across intervention approaches for children with higher cognitive, language, and other developmental abilities, greater adaptive functioning, and fewer autism-related features. Additionally, interventions of longer duration and greater total hours were associated with stronger post-intervention outcomes. In contrast, intervention approach (Early Intensive Behavioral Intervention, Naturalistic Developmental Behavioral Interventions, or Developmental Interventions), delivery agent, and child age at intervention onset did not significantly predict the strength of post-intervention outcomes. While study methodology and reporting quality were marginally associated with predictive strength, adjusting for these factors had minimal impact on the reported findings. The insights from this meta-analysis have significant implications for the development of personalized intervention models for children with autism. These models have the potential to optimize outcomes and offer critical guidance for decision-making in both the service and policy levels, ensuring efficient and equitable allocation of resources.},
}
@article {pmid40345318,
year = {2025},
author = {Låg, M and Skuland, T and Ballangby, J and Grytting, VS and Jørgensen, RB and Snilsberg, B and Øvrevik, J and Holme, JA and Refsnes, M},
title = {Mechanisms involved in pro-inflammatory responses to traffic-derived particulate matter (PM) in THP-1 macrophages compared to HBEC3-KT bronchial epithelial cells.},
journal = {Toxicology},
volume = {516},
number = {},
pages = {154174},
doi = {10.1016/j.tox.2025.154174},
pmid = {40345318},
issn = {1879-3185},
mesh = {Humans ; *Particulate Matter/toxicity ; *Vehicle Emissions/toxicity ; *Epithelial Cells/drug effects/metabolism/immunology ; *Macrophages/drug effects/metabolism/immunology ; THP-1 Cells ; *Bronchi/drug effects/cytology/metabolism ; Interleukin-8/metabolism ; *Air Pollutants/toxicity ; Cell Line ; *Inflammation/chemically induced/metabolism ; Receptors, Aryl Hydrocarbon/metabolism/antagonists &amp; inhibitors ; Cytochrome P-450 CYP1A1/metabolism/genetics ; Interleukin-1beta/metabolism ; Particle Size ; },
abstract = {The pro-inflammatory responses in THP-1-derived macrophages and human bronchial epithelial cells (HBEC3-KT) were examined after exposure to size-fractioned particulate matter (PM) sampled in two road tunnels. All tunnel PM samples induced release and expression of CXCL8 and IL-1β in THP-1 macrophages (50 µg/mL) and HBEC3-KT cells (100 µg/mL), but the potency of the samples differed between the cell types. The road tunnel PM induced pro-inflammatory responses in the macrophages to a much higher extent than diesel exhaust particles (DEP) and particles derived from the stone materials used in the asphalt. Tunnel PM induced a markedly higher increase in cytochrome P450 (CYP)1A1 expression in HBEC3-KT cells than in THP-1 macrophages. The content of organic carbon (OC) in PM correlated to the release of CXCL8 in HBEC3-KT cells, but not in THP-1 macrophages. Moreover, the aryl hydrocarbon receptor (AhR)-inhibitor CH223191 and the antioxidant N-acetyl cysteine (NAC) reduced the PM-induced cytokine release in the macrophages to a lower extent than in HBEC3-KT. In contrast, a toll-like receptor (TLR)2 antibody markedly reduced the PM-induced responses in THP-1 macrophages, but not in HBEC3-KT. A TLR4 antibody was without effect in both cell types. The levels of the microbial TLR2-ligand β-glucan in the PM samples were in a range that might be sufficient to induce pro-inflammatory responses. However, a microbial-independent mechanism could also be involved. In support of such a mechanism, the pro-inflammatory responses to a sample of α-quartz (Min-U-Sil 5), with low levels of β-glucan, were reduced by anti-TLR2. In conclusion, our results indicate that traffic-derived PM exert pro-inflammatory responses in THP-1 macrophages and HBEC3-KT cells via different PM constituents and mechanisms. OC/AhR-dependent mechanisms appeared to be important for PM-induced CXCL8 responses in HBEC3-KT cells, while the cytokine responses in THP-1 macrophages seemed to involve TLR2-mediated activation, either via β-glucan-dependent or -independent mechanisms.},
}
@article {pmid40342610,
year = {2025},
author = {Ebid, AIM and Mohamed, HS and Mohammed, YMM and Mohamed Abdel Motaleb, SM},
title = {Efficacy, Safety, and Cost-Effectiveness of N-Acetylcysteine in Preventing Amphotericin B Nephrotoxicity in Egyptian Patients with Hematological Malignancies: A Randomized Controlled Trial.},
journal = {Hospital pharmacy},
volume = {},
number = {},
pages = {00185787251337615},
pmid = {40342610},
issn = {0018-5787},
abstract = {Introduction: Amphotericin B (AmB-d) is one of the most common agents for treating fatal systemic fungal infections in patients with hematologic malignancies. However, its severe adverse effects, especially nephrotoxicity, limited its use. This study evaluated the efficacy, safety, and cost-effectiveness of oral N-acetylcysteine (NAC) in preventing AmB-d nephrotoxicity and promoting renal recovery in Egyptian hematological malignancy patients. Methods: A prospective open-label randomized controlled trial was conducted. Patients were randomized to receive AmB-d plus 600 mg NAC twice daily (intervention group) or AmB-d alone (control group). The primary outcome was the incidence of acute kidney injury (AKI), with secondary outcomes including electrolyte imbalances (hypokalemia, hypomagnesemia) and renal recovery from AKI. A cost-effectiveness analysis was performed, supported by one-way and probabilistic sensitivity analyses (PSA). Results: NAC co-treatment significantly reduced AmB-d-induced AKI (odds ratio = 0.415, 95% CI: 0.174-0.992, P = .041). Renal recovery rates were higher in the NAC group (73.33% vs 53.85%), though not statistically significant (P = .322); the number needed to treat (NNT) was 6, indicating clinical relevance. No significant differences were observed in hypokalemia (P = .547) or hypomagnesemia (P = .768). NAC was cost-effective, with an effectiveness gain of 0.22 and cost savings of 2742.678 EGP per patient. Sensitivity analyses confirmed robustness, with NAC being dominant in 942 out of 1000 PSA scenarios. NAC was well-tolerated, with only mild gastrointestinal side effects reported. Conclusion: NAC co-administration with AmB-d effectively prevents nephrotoxicity, reduces costs, and may promote renal recovery in Egyptian hematological malignancy patients. The favorable NNT for renal recovery suggests clinical relevance, warranting further investigation in larger studies. Trial registration: ClinicalTrials.gov identifier, NCT06122311.},
}
@article {pmid40341677,
year = {2025},
author = {Zhao, Y and Zhu, L and Lin, X and Li, B and Miu, B and Qiu, J and Gao, S and Liu, J},
title = {JS-K induces ferroptosis in renal carcinoma cells by regulating the c-Myc-GSTP1 Axis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {15987},
pmid = {40341677},
issn = {2045-2322},
support = {81272833//National Natural Science Funds/ ; },
mesh = {*Ferroptosis/drug effects ; Humans ; Animals ; *Carcinoma, Renal Cell/metabolism/drug therapy/pathology ; *Kidney Neoplasms/metabolism/drug therapy/pathology ; Mice ; *Proto-Oncogene Proteins c-myc/metabolism/genetics ; Cell Line, Tumor ; *Glutathione S-Transferase pi/metabolism/genetics ; Lipid Peroxidation/drug effects ; Mice, Nude ; Glutathione/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Xenograft Model Antitumor Assays ; Piperazines/pharmacology ; },
abstract = {JS-K is a precursor drug of nitric oxide (NO) and inhibits tumor growth through various mechanisms. Ferroptosis, a form of cell death closely related to lipid peroxidation, is increasingly being recognized for its role in cancer biology. However, the relevance of ferroptosis in the anti-tumor effects of JS-K is yet to be defined. The cytotoxic effects of erastin and JS-K were evaluated in various renal cell carcinoma (RCC) cell lines and normal human renal epithelial cells. Cell viability and the intracellular levels of ferrous ions, glutathione (GSH), lipid peroxides, and malondialdehyde (MDA) were measured using standard in vitro assays. The expression levels of specific proteins were analyzed by western blotting. Subcutaneous xenografts of RCC were established in a nude mouse model, and the anti-tumor effects of JS-K were assessed by histological and immunohistochemical methods. Erastin selectively inhibited the growth of RCC cells without affecting normal renal cells. In addition, JS-K induced ferroptosis in RCC cells by reducing cellular GSH levels, increasing lipid peroxidation, and elevating ferrous ion levels, and the effects of JS-K were neutralized by N-acetylcysteine (NAC). At the molecular level, JS-K downregulated GSTP1 by blocking the transcription factor c-Myc. Finally, JS-K inhibited tumor growth in a mouse model by inducing ferroptosis. JS-K induces ferroptosis in RCC cells by depleting glutathione through the inhibition of the c-Myc-GSTP1 axis.},
}
@article {pmid40340690,
year = {2025},
author = {Yang, N and Lai, Y and Yu, G and Zhang, X and Shi, J and Xiang, L and Zhang, J and Wu, Y and Jiang, X and Zhang, X and Yang, L and Gao, W and Ding, J and Wang, X and Xiao, J and Zhou, K},
title = {METTL3-dependent m[6]A modification of SNAP29 induces "autophagy-mitochondrial crisis" in the ischemic microenvironment after soft tissue transplantation.},
journal = {Autophagy},
volume = {21},
number = {10},
pages = {2168-2191},
pmid = {40340690},
issn = {1554-8635},
mesh = {*Autophagy/genetics/physiology ; *Mitochondria/metabolism ; *Methyltransferases/metabolism/genetics ; Animals ; Humans ; *Ischemia/metabolism/pathology ; *Qb-SNARE Proteins/metabolism/genetics ; *Qc-SNARE Proteins/metabolism/genetics ; Mice ; Reactive Oxygen Species/metabolism ; Male ; Methylation ; *Adenosine/analogs &amp; derivatives/metabolism ; },
abstract = {Necrosis at the ischemic distal end of flap transplants increases patients' pain and economic burden. Reactive oxygen species (ROS) and mitochondrial damage are crucial in regulating parthanatos, but the mechanisms linking disrupted macroautophagic/autophagic flux to parthanatos in ischemic flaps remain unclear. The results of western blotting, immunofluorescence staining, and a proteomic analysis revealed that the autophagic protein SNAP29 was deficient in ischemic flaps, resulting in disrupted autophagic flux, increased ROS-induced parthanatos, and aggravated ischemic flap necrosis. The use of AAV vector to restore SNAP29 in vivo mitigated the disruption of autophagic flux and parthanatos. Additionally, quantification of the total m[6]A level and RIP-qPCR, MeRIP-qPCR, and RNA stability assessments were performed to determine differential Snap29 mRNA m[6]A methylation levels and mRNA stability in ischemic flaps. Various in vitro and in vivo tests were conducted to verify the ability of METTL3-mediated m[6]A methylation to promote SNAP29 depletion and disrupt autophagic flux. Finally, we concluded that restoring SNAP29 by inhibiting METTL3 and YTHDF2 reversed the "autophagy-mitochondrial crisis", defined for the first time as disrupted autophagic flux, mitochondrial damage, mitochondrial protein leakage, and the occurrence of parthanatos. The reversal of this crisis ultimately promoted the survival of ischemic flaps.Abbreviations: AAV = adeno-associated virus; ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta; AIFM/AIF = apoptosis-inducing factor, mitochondrion-associated; ALKBH5 = alkB homolog, RNA demythelase; Baf A1 = bafilomycin A1; CQ = chloroquine; DHE = dihydroethidium; ECs = endothelial cells; F-CHP = 5-FAM-conjugated collagen-hybridizing peptide; GO = gene ontology; HUVECs = human umbilical vein endothelial cells; KEGG = Kyoto Encyclopedia of Genes and Genomes; LC-MS/MS = liquid chromatography-tandem mass spectrometry; LDBF = laser doppler blood flow; m[6]A = N6-methyladenosine; MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3; MeRIP = methylated RNA immunoprecipitation; METTL3 = methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit; NAC = N-acetylcysteine; OGD = oxygen glucose deprivation; PAR = poly (ADP-ribose); PARP1 = poly (ADP-ribose) polymerase family, member 1; PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1; ROS = reactive oxygen species; RT-qPCR = reverse transcription quantitative polymerase chain reaction; RIP = RNA immunoprecipitation; SNAP29 = synaptosomal-associated protein 29; SNARE = soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1 = sequestosome 1; SRAMP = sequence-based RNA adenosine methylation site predicting; STX17 = syntaxin 17; TMT = tandem mass tag; TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling; VAMP8 = vesicle-associated membrane protein 8; WTAP = WT1 associating protein; YTHDF2 = YTH N6-methyladenosine RNA binding protein 2; 3' UTR = 3'-untranslated region.},
}
@article {pmid40340419,
year = {2025},
author = {Stutts, J and Clatterbuck, K and Duckworth, C and Pemberton, T and Elkins, A and Patra, P and Stoecker, W and Geria, N and Nosoudi, N},
title = {Synergistic impact of antioxidant combinations on collagen and elastin synthesis in human dermal fibroblasts.},
journal = {Bio-medical materials and engineering},
volume = {36},
number = {5},
pages = {316-323},
doi = {10.1177/09592989251341159},
pmid = {40340419},
issn = {1878-3619},
mesh = {Humans ; *Elastin/biosynthesis ; *Fibroblasts/drug effects/metabolism/cytology ; *Antioxidants/pharmacology/administration &amp; dosage ; Ubiquinone/analogs &amp; derivatives/pharmacology/administration &amp; dosage ; *Skin/cytology/drug effects/metabolism ; Drug Synergism ; Cells, Cultured ; Catechin/analogs &amp; derivatives/pharmacology/administration &amp; dosage ; *Collagen Type I/biosynthesis ; *Collagen/biosynthesis ; Skin Aging/drug effects ; Acetylcysteine/pharmacology ; Vitamin A/pharmacology ; },
abstract = {Background: The restoration of collagen and elastin in human dermal fibroblasts plays a crucial role in anti-aging and skin rejuvenation therapies. Numerous studies have examined the effects of various antioxidants on skin health, but there is limited research comparing their combined effects on collagen and elastin synthesis in human dermal fibroblasts. Objective: The objective of this study was to evaluate the individual and combined effects of N-acetylcysteine (NAC), Coenzyme Q10 (CoQ10), Niacinamide (NIAC), Gamma Cyclodextrin (GAMMA), Retinol (RET), Epigallocatechin Gallate (EGCG), and Ellagic Acid (ELA) on collagen type I and elastin synthesis in human dermal fibroblasts (HDFs). Methods: Human dermal fibroblasts were treated with individual and combined antioxidants. The expression of collagen type I and elastin was measured using mRNA analysis, immunofluorescence staining, and matrix protein assays. The study focused on the effects of EGCG in combination with other antioxidants like RET, CoQ10, and NAC to identify synergistic effects. Results: The combination of EGCG + RET and EGCG + CoQ10 showed the most significant increase in both elastin and collagen type I synthesis, surpassing the effects of individual antioxidants. EGCG demonstrated the highest fold change in elastin mRNA expression, while the combination treatments notably enhanced the extracellular matrix restoration in HDFs. Conclusion: The combination of EGCG with CoQ10, Retinol, or NAC presents a promising strategy for enhancing skin elasticity and firmness by promoting both elastin and collagen synthesis. These findings suggest that antioxidant combinations can be developed for effective anti-aging skincare formulations.},
}
@article {pmid40337403,
year = {2025},
author = {Pasam, SS and Majety, SK and Nayeem, O and Mishra, D and Chakra G, S and Singh, R and Karuchola, MP and Anumolu, A},
title = {Paraquat poisoning: a case series of 15 survivors and narrative review.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {5},
pages = {2537-2546},
pmid = {40337403},
issn = {2049-0801},
abstract = {BACKGROUND: Paraquat (PQ) poisoning is a grave concern in developing countries due to its wide availability. Acute paraquat poisoning can have both systemic and local manifestations, with mortality rates that can reach as high as 90%; pulmonary complications and multiple organ dysfunction syndromes being major causes. This case series is a unique retrospective observational study of 15 survivors from South India.<br><br>CASE PRESENTATION: The case series consists of 15 cases, with a mean age of 24.6&#xa0;years (excluding outliers), that were alleged to have taken varying amounts of paraquat dichloride. Patients exhibited a diverse range of symptoms affecting multiple organ systems, with particular emphasis on kidney, liver, and lung function. Treatments included a combination of hemodialysis, targeted drug therapy in the form of N-acetyl cysteine, anti-inflammatory therapy with corticosteriods and symptomatic therapy. The case descriptions also include the details of the amount of paraquat allegedly ingested, the ingestion to hospitalization time, demographics, etc, that further help in determination of prognosis.<br><br>OVERVIEW: PQ can cause a variety of clinical signs and symptoms, including gastrointestinal, renal, hepatic, and pulmonary problems. Less commonly, it can also affect the neurological and cardiac systems. Treatment is mainly focused on reducing the effective PQ concentration in blood, as no antidote has been named till date. The paper also discusses the various treatments available, drugs and procedures, and their mechanisms. Also prognostic factors like age, amount, ingestion to hospitalization time, etc.<br><br>CONCLUSION: The study underlines the need for defined treatment protocols, prognostic factors, and enforcing restrictions on availability of this deadly poison.},
}
@article {pmid40333203,
year = {2025},
author = {St John, A and Wang, X and Chen, J and Le, J and Ringgold, K and Klug, J and White, N and Stern, S and Chung, D and Lindner, JR and López, J},
title = {N-ACETYLCYSTEINE REDUCES VON WILLEBRAND FACTOR MULTIMER SIZE AND IMPROVES RENAL MICROVASCULAR BLOOD FLOW IN RATS AFTER SEVERE TRAUMA.},
journal = {Shock (Augusta, Ga.)},
volume = {64},
number = {2},
pages = {236-244},
pmid = {40333203},
issn = {1540-0514},
support = {K08 HL146840/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; *von Willebrand Factor/metabolism/chemistry ; Male ; Rats, Sprague-Dawley ; *Acetylcysteine/pharmacology/therapeutic use ; Rats ; *Renal Circulation/drug effects ; *Microcirculation/drug effects ; *Kidney/blood supply ; *Wounds and Injuries/drug therapy ; },
abstract = {Background: Severe injury induces systemic microvascular impairment that reduces microvascular blood flow (MBF), even after resuscitation to normal blood pressure. These changes are associated with organ dysfunction and death, but the underlying causes and potential therapeutic approaches to address them remain unclear. Two possible contributors are hyperadhesive von Willebrand factor (VWF) secretion from an activated endothelium and oxidative modification of hemostatic proteins. N-acetylcysteine has been shown to address both of these processes and increase MBF in other disease states with similar features. Methods: Anesthetized, male Sprague-Dawley rats were subjected to a standardized polytrauma and pressure-targeted catheter hemorrhage. They then received either no treatment (control) or a single bolus of N-acetylcysteince (NAC), followed by autologous whole blood transfusion. Renal MBF was measured using contrast-enhanced ultrasound at prespecified time points. VWF multimer gels and other laboratory studies were performed. Histologic analysis of vascular thrombi was also performed on uninjured tissue from rats undergoing either this trauma protocol or a sham procedure. Results: NAC increased MBF at 3 h after resuscitation. This was accompanied by a decrease in VWF multimer size that was not seen in the control group. Histologic data showed an overall increase in systemic thrombus burden associated with trauma. Conclusions: NAC improves renal MBF, possibly by reducing VWF multimer size and reducing microthrombus burden. This is significant both mechanistically and therapeutically. It sheds light on the possible pathways involved in causing microvascular obstruction after trauma and identifies possible treatment approaches that could be developed further. Ultimately, targeting these pathways could move us closer to resuscitation strategies that optimize vital organ MBF.},
}
@article {pmid40333083,
year = {2025},
author = {Yang, S and Zhang, Y and Xu, J and Chen, Z and Ren, Y and Long, Y and Huang, X and Liu, J and Huang, H and Xie, S and Ma, R and Dong, Y and Fan, X and Hu, Z and Li, F},
title = {N-Acetylcysteine as a Host-Directed Therapy Against Clarithromycin-Resistant Mycobacterium abscessus.},
journal = {Pathogens (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
pmid = {40333083},
issn = {2076-0817},
support = {21Y11901700//Science and Technology Commission of Shanghai Municipality/ ; 20Z11901002//Science and Technology Commission of Shanghai Municipality/ ; ZD2021CY001//Shanghai Municipal Science and Technology Major Project/ ; },
mesh = {*Acetylcysteine/pharmacology/therapeutic use ; *Mycobacterium abscessus/drug effects ; *Clarithromycin/pharmacology ; Animals ; Humans ; *Mycobacterium Infections, Nontuberculous/drug therapy/microbiology/immunology ; Mice ; *Drug Resistance, Bacterial/drug effects ; *Anti-Bacterial Agents/pharmacology ; Disease Models, Animal ; THP-1 Cells ; Signal Transduction/drug effects ; Female ; },
abstract = {(1) Background: The treatment of Mycobacterium abscessus (M. abscessus) infections resistant to clarithromycin (CLR) is highly challenging. Traditional non-tuberculous mycobacteria (NTM) chemotherapy may disturb the immune homeostasis of the host by increasing oxidative stress; therefore, host-directed immunotherapy is an alternative option for infections caused by M. abscessus. (2) Method: A clinical isolate of CLR-resistant M. abscessus was screened, and then the therapeutic effects of N-acetylcysteine (NAC) against CLR-resistant M. abscessus infection were evaluated in Tohoku Hospital Pediatrics-1 (THP-1) cells and murine models. RNA sequencing and Western blot were used to profile the protective immune responses induced by NAC. The contribution of candidate signaling pathways was confirmed by the corresponding inhibitor and agonist. (3) Results: NAC immunotherapy led to a significant reduction in bacterial loads both in THP-1 cells and murine infection models, which was associated with enhanced antioxidant effects and downregulation of apoptosis signal-regulating kinase 1 (ASK1)-mitogen-activated protein ki-nase/extracellular signal-regulated kinase 3/6 (MKK3/6)-p38 mitogen-activated protein kinase (MAPK)-mediated inflammatory immune responses. The inhibitor of p38 signaling mimicked the protective effect of NAC, while the agonist attenuated it, suggesting that the p38 pathway is crucial in NAC-mediated immune protection against M. abscessus infection. (4) Conclusion: Our study suggests that NAC could be used as a host-directed therapy agent against drug-resistant M. abscessus infection.},
}
@article {pmid40328458,
year = {2025},
author = {Pfau, K and Callizo, J and Rossouw, P and Gabrani, C and Holz, F and Charbel Issa, P and Kellner, U and Strauss, R and Kühlewein, L and Stingl, K and Feltgen, N and Pfau, M},
title = {[Correction: N-Acetylcysteine (NAC) for Retinitis pigmentosa].},
journal = {Klinische Monatsblatter fur Augenheilkunde},
volume = {242},
number = {3},
pages = {e2},
doi = {10.1055/a-2587-6864},
pmid = {40328458},
issn = {1439-3999},
}
@article {pmid40327168,
year = {2025},
author = {Zatloukal, J and Page, C and Brat, K and Svoboda, M and Voláková, E and Plutinský, M and Kopecký, M and Koblížek, V},
title = {Effect of Treatment with Mucoactive Drugs on COPD Exacerbations During 5 years of Follow-up in the Czech Republic: A Real-World Study.},
journal = {Lung},
volume = {203},
number = {1},
pages = {61},
pmid = {40327168},
issn = {1432-1750},
support = {FNOl no. 00098892//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky/ ; no. 15/14/NAP//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky/ ; FNOl no. 00098892//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky/ ; FNBr no. 65269705//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky/ ; UHHK no. 00179906//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky/ ; UHHK no. 00179906//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky/ ; Research Area INDI//Cooperatio Charles University, Czechia/ ; Research Area INDI//Cooperatio Charles University, Czechia/ ; },
mesh = {Humans ; *Pulmonary Disease, Chronic Obstructive/drug therapy/physiopathology/diagnosis ; Male ; Czech Republic ; Female ; Aged ; Middle Aged ; Prospective Studies ; Disease Progression ; *Expectorants/therapeutic use ; Follow-Up Studies ; *Acetylcysteine/therapeutic use ; Treatment Outcome ; Forced Expiratory Volume ; Time Factors ; },
abstract = {INTRODUCTION: Studies indicate that chronic treatment with mucoactive drugs may reduce COPD exacerbation rates. This real-world, multicenter, prospective, observational study aimed to determine the effect of long-term mucoactive treatment on exacerbations in patients with COPD in the Czech Republic.<br><br>METHODS: 452 adult patients on the Czech Multicenter Research Database of COPD with post-bronchodilator FEV1&#x2009;&#x2264;&#x2009;60% of predicted value received standard of care and were followed up for 5&#xa0;years. For the first 24&#xa0;months, 81 patients received regular thiol-based mucoactive drugs (77 erdosteine, 4 N-acetylcysteine) at the discretion of the treating physician and 371 patients had no mucoactive treatment (control group). Erdosteine was fully reimbursed, and NAC was partially reimbursed for COPD patients. The annual number/rate of COPD exacerbations over 5&#xa0;years was monitored.<br><br>RESULTS: Patients receiving mucoactive treatment for 24&#xa0;months had a significantly larger reduction from baseline in all exacerbations compared to the control group (-&#xa0;0.61 vs -&#xa0;0.18, p&#x2009;=&#x2009;0.026; -&#xa0;0.54 vs -&#xa0;0.09, p&#x2009;=&#x2009;0.007; -&#xa0;0.55 vs 0.04, p&#x2009;=&#x2009;0.005; -&#xa0;0.67 vs 0.13, p&#x2009;=&#x2009;0.002; -&#xa0;0.53 vs 0.10, p&#x2009;=&#x2009;0.019 in the first to fifth year, respectively). The reduction in moderate exacerbations was also significantly larger in those receiving mucoactive treatment versus no mucoactive treatment. The exacerbation rate was reduced to a greater extent in the subgroups with cough or with stage 3&#x2012;4 COPD who received mucoactive treatment but was independent of the use of inhaled corticosteroids (ICS).<br><br>CONCLUSION: Mucoactive treatment for two years reduced the number of COPD exacerbations (all, moderate) over five years of follow-up. The reduction in exacerbations was more pronounced in patients with cough or with stage 3&#x2012;4 COPD but was independent of the use of ICS.},
}
@article {pmid40324675,
year = {2025},
author = {Li, Y and Li, N and Zhang, J and Liu, X and Xu, Y and Kong, L and Man, R and Li, J},
title = {FKBP51 protects hair cells of utricles from gentamicin-induced toxicity in vitro: possible relation to the activities of NF-κB signaling pathway.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {202},
number = {},
pages = {115513},
doi = {10.1016/j.fct.2025.115513},
pmid = {40324675},
issn = {1873-6351},
mesh = {Animals ; Mice ; *Anti-Bacterial Agents/toxicity ; Apoptosis/drug effects ; *Gentamicins/toxicity ; *Hair Cells, Auditory/drug effects/metabolism ; Mice, Knockout ; *NF-kappa B/metabolism/genetics ; Reactive Oxygen Species/metabolism ; *Saccule and Utricle/drug effects/cytology/metabolism ; *Signal Transduction/drug effects ; *Tacrolimus Binding Proteins/metabolism/genetics ; Acetylcysteine/chemistry/metabolism ; Tacrolimus Binding Protein 5 ; },
abstract = {FK506-binding protein 51 (FKBP51) belongs to the immunophilin family, which is related to regulation of cell growth and apoptosis. The present study was designed to explore the expression of FKBP51 in murine utricle hair cells (HCs) and the possible mechanisms underpinning the actions of FKBP51 relevant to gentamicin-mediated toxicity, with special attention given to nuclear factor-kappa B (NF-κB) activities in vitro. Here, we found, for the first time, that FKBP51 was widely expressed in both cytoplasm and cytomembrane. Moreover, the expression of FKBP51 in cultured HCs of utricle was downregulated after exposure to 1 mM gentamicin for 24 h. Then, the fkbp51 knockout mice were utilized to further investigate the role of FKBP51 in HCs in response to gentamicin. And the absence of FKBP51 led to severe HCs loss, accumulated ROS levels, and increased apoptotic factors, which could be alleviated by 2 mM N-acetyl-l-cysteine (NAC) to certain degree. In addition, mechanistic studies with 10 mM BAY 11-7082 showed that FKBP51 protected HCs against gentamicin-induced damage, at least in part, via blocking the NF-κB pathway activation. Taken together, our new findings suggest that FKBP51 might serve as a new target for the prevention of HCs of utricle from aminoglycoside-induced vestibular toxicity.},
}
@article {pmid40323204,
year = {2025},
author = {Plane, J and Cabral, TDD and Knoll, RM and Conrado, JEP and Vendramini, BDV and Jung, DH},
title = {N-acetylcysteine for the Prevention of Cisplatin-Induced Hearing Loss: A Systematic Review and Meta-analysis.},
journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery},
volume = {173},
number = {2},
pages = {345-359},
doi = {10.1002/ohn.1272},
pmid = {40323204},
issn = {1097-6817},
support = {T32 DC000020/DC/NIDCD NIH HHS/United States ; },
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Antineoplastic Agents/adverse effects ; *Cisplatin/adverse effects ; *Hearing Loss/chemically induced/prevention &amp; control ; Ototoxicity/prevention &amp; control ; },
abstract = {OBJECTIVE: Cisplatin is an effective antineoplastic drug used worldwide in the treatment of various malignancies. However, it is associated with side effects, including cisplatin-induced hearing loss (CIHL). N-acetylcysteine (NAC) has been suggested as a promising drug to prevent or reduce cisplatin-derived ototoxicity. To evaluate the evidence supporting the efficacy of NAC in preventing CIHL, we conducted a systematic review and meta-analysis of the literature.<br><br>DATA SOURCES: A systematic search was conducted on PubMed, Embase, Web of Science, Clinicaltrials.gov, and Cochrane Library.<br><br>REVIEW METHODS: Articles reporting the administration of systemic or transtympanic injection of NAC for CIHL prevention were considered. The outcomes of interest included the presence of hearing loss events and changes in hearing thresholds at 0.5 through 12&#x2009;kHz following cisplatin treatment.<br><br>RESULTS: A total of 7 studies involving 217 patients met inclusion criteria. Of these patients, 175 received systemic administration of NAC, and the remaining received transtympanic injection of NAC. No significant differences were found in CIHL prevention between the use of either systemic or transtympanic NAC administration compared to placebo (risk ratio [RR] 0.80; 95% confidence interval [CI] 0.54-1.19; P&#x2009;=&#x2009;.28, and RR 0.89; 95% CI 0.51-1.54; P&#x2009;=&#x2009;.67, respectively). No significant differences were found at 0.5 to 8&#x2009;kHz between groups. Qualitative analyses suggested a tendency to otoprotection in ultra-high frequencies (10 and 12&#x2009;kHz).<br><br>CONCLUSION: Our findings suggest that, regardless of administration route, current published evidence does not show that NAC is effective in preventing CIHL in the standard clinical audiogram range. Further studies with larger samples are needed to confirm our findings.<br><br>LEVEL OF EVIDENCE: I.},
}
@article {pmid40321407,
year = {2025},
author = {Hosseini, E and Beyranvand, Z and Schoenwaelder, SM and Farhid, F and Ghasemzadeh, M},
title = {The Reactive Oxygen Species Scavenger N-Acetyl-L-Cysteine Reduces Storage-Dependent Decline in Integrin α IIb β 3-Mediated Platelet Function, Inhibiting Pre-Activation of Integrin and Its β 3 Subunit Cleavage.},
journal = {Oxidative medicine and cellular longevity},
volume = {2025},
number = {},
pages = {7499648},
pmid = {40321407},
issn = {1942-0994},
mesh = {*Acetylcysteine/pharmacology ; Humans ; *Reactive Oxygen Species/metabolism ; *Blood Platelets/metabolism/drug effects/cytology ; *Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; *Integrin beta3/metabolism ; Platelet Activation/drug effects ; *Free Radical Scavengers/pharmacology ; Platelet Adhesiveness/drug effects ; },
abstract = {Background: Premature activation of integrin α IIb β 3 plays a central role in the induction and development of the platelet storage lesion (PSL) characterized by an exhausted platelet phenotype that affects adhesion and spreading on fibrinogen. Given the role of reactive oxygen species (ROS) in regulating platelet activation per se, we investigated the effects of a ROS scavenger on reducing the functional decline of platelet integrin α IIb β 3 during storage. Methods: Platelet-rich plasma-platelet concentrates (PRP-PCs) were either treated with ROS-reducing agents (1 mM N-acetyl-L-cysteine [NAC] or 30 μM NADPH oxidase [NOX] inhibitor, VAS2870) or kept untreated during storage. CD41/CD61 (total integrin α IIb β 3) expression and PAC-1 binding (specific to active integrin α IIb β 3 conformation) were analyzed by flow cytometry over a 5 day storage period. Molecular changes in integrin β 3 subunit were evaluated by western blotting. Platelet adhesion/spreading to fibrinogen in the presence of ROS inhibitors was also investigated during storage using fluorescence microscopy. Results: A decrease in the molecular weight of integrin β 3 subunit was observed during platelet storage, and was significantly reduced by NAC but not VAS2870, suggesting proteolytic cleavage of β 3 during storage. Further to this, ROS inhibitors decreased integrin activation and increased platelet adhesion to fibrinogen from day 3 of storage, while NAC but not VAS2870 improved platelet spreading. Conclusion: This is the first report of increasing β 3 cleavage of integrin during storage that was inversely correlated with integrin α IIb β 3-mediated platelet function. In this regard, as a generic ROS scavenger, NAC was shown to reduce defects in platelet spreading through inhibition of β 3 cleavage. This is in contrast to VAS2870 which selectively inhibits cytosolic NOX alone, suggesting that the reduced platelet function observed during storage may be due to cumulative effects of mitochondrial ROS. Taken together, these studies suggest that adding NAC to platelets may significantly preserve optimal integrin α IIb β 3 and platelet function during storage. Moreover, as a reversible scavenger, its inhibitory effect can be readily compensated after transfusion.},
}
@article {pmid40319292,
year = {2025},
author = {Eswaran, S and Mascarenhas, R and Kabekkodu, SP},
title = {The ester derivative Palmitoylcarnitine abrogates cervical cancer cell survival by enhancing lipotoxicity and mitochondrial dysfunction.},
journal = {Cell communication and signaling : CCS},
volume = {23},
number = {1},
pages = {213},
pmid = {40319292},
issn = {1478-811X},
support = {6242-P8/RGCB/PMD/DBT/ SPDK/2015//Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology, Ministry of Science and Technology, India/ ; },
mesh = {Humans ; *Uterine Cervical Neoplasms/pathology/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Female ; Cell Survival/drug effects ; HeLa Cells ; *Carnitine/analogs &amp; derivatives/pharmacology ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Apoptosis/drug effects ; Extracellular Vesicles/metabolism/drug effects ; Esters ; },
abstract = {BACKGROUND: In cervical cancer (CC), Double C2 Like Domain Beta (DOC2B) functions as a metastatic suppressor. The present study aims to determine whether ectopic expression of DOC2B causes global metabolomic changes in extracellular vesicles (EVs) and corresponds with its tumor suppressive properties.<br><br>METHODS: Using a retroviral method, we first ectopically expressed DOC2B in SiHa cells, which do not normally express DOC2B.<br><br>RESULTS: We observed that ectopically expressed DOC2B significantly altered the global metabolite profile of EVs. Metabolomics identified significant enrichment of palmitoylcarnitine (PC) in EVs upon ectopic expression of DOC2B. We identified that SiHa and HeLa cells exhibited greater cytotoxicity to PC than gingival fibroblast, HaCaT, Cal27, and MCF7. PC treatment reduced the growth, proliferation, and migration of SiHa and HeLa cells, via increasing apoptosis and decreasing S-Phase cells. PC treatment resulted in morphological alterations, decreased length and number of filopodia, and expression of proteins related to cell cycle progression, proliferation, and the epithelial-to-mesenchymal transition. Further, PC treatment caused mitochondrial morphological changes, increased mitochondrial membrane potential, and decreased mtDNA content. The decreased GSH activity, glucose consumption rate, and lactate production upon PC treatment suggest that PC can induce metabolic reprogramming in CC cells. Increased oxidative stress, calcium overload, lipid droplet accumulation, mitochondrial lipotoxicity, and mitophagy suggest that PC can cause mitochondrial dysfunction. N-acetyl cysteine (NAC) treatment reversed the cytotoxic effect of PC, via decreasing lipid peroxidation rate and increasing GSH activity. PC treatment enhanced the cytotoxic effect of cisplatin in CC.<br><br>CONCLUSION: DOC2B restoration or the use of PC may be employed as a novel therapeutic approach for CC.},
}
@article {pmid40318637,
year = {2025},
author = {Paul, B and Merta, H and Ugrankar-Banerjee, R and Hensley, MR and Tran, S and do Vale, GD and Zacherias, L and Hewett, CK and McDonald, JG and Font-Burgada, J and Mathews, TP and Farber, SA and Henne, WM},
title = {Paraoxonase-like APMAP maintains endoplasmic-reticulum-associated lipid and lipoprotein homeostasis.},
journal = {Developmental cell},
volume = {60},
number = {17},
pages = {2313-2330.e10},
pmid = {40318637},
issn = {1878-1551},
support = {R01 CA289703/CA/NCI NIH HHS/United States ; DP2 CA258224/CA/NCI NIH HHS/United States ; R01 DK093399/DK/NIDDK NIH HHS/United States ; R01 DK116079/DK/NIDDK NIH HHS/United States ; R00 CA191152/CA/NCI NIH HHS/United States ; K99 CA191152/CA/NCI NIH HHS/United States ; R01 DK126887/DK/NIDDK NIH HHS/United States ; R35 GM119768/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Homeostasis ; *Endoplasmic Reticulum/metabolism ; Zebrafish/metabolism ; Endoplasmic Reticulum Stress ; Humans ; *Lipid Metabolism ; *Lipoproteins/metabolism ; Lipid Peroxidation ; Oxidative Stress ; *Membrane Proteins/metabolism/genetics ; Hepatocytes/metabolism ; *Aryldialkylphosphatase/metabolism ; Antioxidants/metabolism ; Drosophila melanogaster/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Oxidative stress perturbs lipid homeostasis and contributes to metabolic diseases. Though ignored when compared with mitochondrial oxidation, the endoplasmic reticulum (ER) generates reactive oxygen species requiring antioxidant quality control. Using multi-organismal profiling featuring Drosophila, zebrafish, and mammalian hepatocytes, here we characterize the paraoxonase-like C20orf3/adipocyte plasma-membrane-associated protein (APMAP) as an ER-localized antioxidant that suppresses ER lipid oxidation to safeguard ER function. APMAP-depleted cells exhibit defective ER morphology, ER stress, and lipid peroxidation dependent on ER-oxidoreductase 1α (ERO1A), as well as sensitivity to ferroptosis and defects in ApoB-lipoprotein homeostasis. Similarly, organismal APMAP depletion in Drosophila and zebrafish perturbs ApoB-lipoprotein homeostasis. Strikingly, APMAP loss is rescued with chemical antioxidant N-acetyl-cysteine (NAC). Lipidomics identifies that APMAP loss elevates phospholipid peroxidation and boosts ceramides-signatures of lipid stress. Collectively, we propose that APMAP is an ER-localized antioxidant that promotes lipid and lipoprotein homeostasis in the ER network.},
}
@article {pmid40316146,
year = {2025},
author = {Rogóż, Z and Kamińska, K and Wąsik, A},
title = {N-acetylcysteine enhances the antipsychotic effect of aripiprazole in the neurodevelopmental rat model of schizophrenia.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {252},
number = {},
pages = {174028},
doi = {10.1016/j.pbb.2025.174028},
pmid = {40316146},
issn = {1873-5177},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage/therapeutic use ; *Aripiprazole/pharmacology/administration &amp; dosage/therapeutic use ; *Schizophrenia/drug therapy ; *Antipsychotic Agents/pharmacology/therapeutic use/administration &amp; dosage ; Male ; Rats, Sprague-Dawley ; Rats ; Disease Models, Animal ; Drug Synergism ; Behavior, Animal/drug effects ; },
abstract = {Symptoms of schizophrenia are well characterized, but the mechanism underlying the pathogenesis of the disease still remains unknown. In addition, therapy of negative symptoms and cognitive deficits in schizophrenic patients is a serious clinical problem. Some clinical studies have shown that the atypical antipsychotic drug aripiprazole (ARI), and the antioxidant N-acetylcysteine (NAC) are effective in reducing positive and negative symptoms of schizophrenia in patients. The aim of the present study was to evaluate the influence of repeated co-treatment with low doses of ARI and NAC on the schizophrenia-like behavior in adult rats. The schizophrenia-like behavior was induced in Sprague-Dawley male pups in the neonatal days p5-p16 by repeated administration of the glutathione synthesis inhibitor L-butionine-(S,R)-sulfoximine (BSO) given together with the dopamine reuptake inhibitor 1-[2-[Bis-4(fluorophenyl)methoxy]ethyl]-4-3-(3-phenylpropyl) (GBR 12909). Adult rats received repeated co-treatment with ARI (0.1 mg/kg) and NAC (10 mg/kg) for 21 days, and their effects on schizophrenia-like behavior were assessed (on p90-91) using the social interaction test and novel object recognition test. The present data indicated that the studied drugs at higher doses: ARI (0.3 mg/kg but not 0.1 mg/kg) and NAC (30 mg/kg but not 10 mg/kg) reversed schizophrenia-like symptoms in the tested model. Moreover, repeated co-treatment with low doses of ARI with NAC also reversed schizophrenia-like behavior in the neurodevelopmental rat model of schizophrenia. The above results indicated that NAC enhanced the action of ARI in the used neurodevelopmental rat model of schizophrenia, and the mechanism of action of the used drugs in this model is discussed.},
}
@article {pmid40312270,
year = {2025},
author = {Ji, R and Yang, Y and Bian, B and Zhang, Y and Wang, F and Jia, Y},
title = {Exposure to Polyethylene Terephthalate Microplastic Induces Mouse Liver Fibrosis Through Oxidative Stress and p38 MAPK/p65 NF-κB Signaling Pathway.},
journal = {Journal of applied toxicology : JAT},
volume = {45},
number = {9},
pages = {1694-1704},
doi = {10.1002/jat.4797},
pmid = {40312270},
issn = {1099-1263},
support = {42377430//National Natural Science Foundation of China/ ; 202201382//Inner Mongolia Autonomous Region Health Science and Technology Plan project/ ; HLJH202418//Bud Plan of Baotou Medical College/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; Male ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Polyethylene Terephthalates/toxicity ; *Microplastics/toxicity ; Mice ; Signal Transduction/drug effects ; *Liver Cirrhosis/chemically induced/pathology/metabolism ; Liver/drug effects/pathology/metabolism ; *Transcription Factor RelA/metabolism ; },
abstract = {Microplastic (MP) pollution has garnered attention due to its potential impact on living organisms. Among these, polyethylene terephthalate microplastics (PET-MPs) are frequently detected in both environmental samples and human tissues. Despite this, the effects of PET-MPs on liver damage and fibrosis in mammals remain insufficiently understood. This study demonstrated that oral exposure to PET-MPs at doses of 1 mg/day (with a diameter of 1 μm) over 42 days resulted in inhibited weight gain and altered organ coefficients in male mice, suggesting possible liver damage. Using HE and Masson staining revealed pathological changes in the livers of exposed mice, such as hepatocyte swelling, inflammatory cell infiltration, and collagen deposition. Liver function tests confirmed elevated serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Further, the elevated levels of oxidative stress markers, along with the enhanced expression of proteins related to the p38 MAPK/p65 NF-κB signaling pathway as revealed by western blot analysis, both of which are strongly associated with liver damage and fibrosis. To further elucidate these mechanisms, experiments involving N-acetylcysteine (NAC) to counteract oxidative stress and SB203580 to inhibit p38 MAPK activation demonstrated that both interventions effectively mitigated liver fibrosis. Exposure to PET-MPs may trigger liver injury and fibrosis in mice. During this process, oxidative stress and the p38 MAPK/p65 NF-κB signaling pathway may play significant mediating roles.},
}
@article {pmid40311840,
year = {2025},
author = {Zhang, Z and Zhao, L and Wang, J and Chen, H and Lin, Y and Wang, F and Wang, L and Chen, J and Liu, J and Zhang, X},
title = {Luteolin, as a bidirectional ROS regulator, elevates mouse beige adipocyte browning.},
journal = {Biochimica et biophysica acta. Molecular and cell biology of lipids},
volume = {1870},
number = {5},
pages = {159620},
doi = {10.1016/j.bbalip.2025.159620},
pmid = {40311840},
issn = {1879-2618},
mesh = {Animals ; *Luteolin/pharmacology ; *Reactive Oxygen Species/metabolism ; Mice ; *Adipocytes, Beige/metabolism/drug effects/cytology ; Thermogenesis/drug effects ; Hydrogen Peroxide/pharmacology ; Cell Differentiation/drug effects ; Mast Cells/metabolism/drug effects/cytology ; Mice, Inbred C57BL ; Male ; Cells, Cultured ; },
abstract = {In beige adipocytes, UCP1-dependent thermogenesis can be driven by intracellular reactive oxygen species (ROS) generation. While ROS elevation also induces mast cell activation, serotonin synthesis and release from mast cells inhibits beige progenitor cell proliferation and browning. As a natural antioxidant and mast cell stabilizer, luteolin promotes adipocyte thermogenesis and inhibits mast cell activation. Thus, to activate adipocyte thermogenesis, how luteolin regulates ROS level in beige adipocytes and mast cells needs to be further investigated. In this study, mouse subcutaneous stromal vascular fraction (SVF) cells are induced to differentiate into beige adipocytes, and mouse bone marrow-derived mast cells (BMMCs) are activated with hydrogen peroxide (H2O2). Intracellular ROS level is augmented in differentiated beige adipocytes and H2O2-activated BMMCs, and H2O2-activated BMMCs inhibited brown differentiation of SVF cells and thermogenesis of beige adipocytes. In beige adipocytes, unlike synthetic antioxidant N-acetylcysteine (NAC), luteolin elevates the expression of thermogenic and beige-selective marker genes and intracellular ROS generation. Contrarily, luteolin inhibits H2O2-induced mast cell activation and ROS generation. Further, luteolin partially reverses the inhibitory effects of H2O2-activated BMMCs on the brown differentiation of SVF cells and the thermogenesis of beige adipocytes. Molecular mechanistic studies demonstrate that luteolin regulates intracellular ROS level in beige adipocytes and mast cells via the nuclear factor erythroid 2-related factor 2 (Nrf2)/Catalase pathway. Altogether, as a ROS regulator, luteolin contrarily affects intracellular ROS generation in beige adipocytes and mast cells, and hence elevates adipocyte browning.},
}
@article {pmid40311609,
year = {2025},
author = {Zheng, J and Zhang, W and Ito, J and Henkelmann, B and Xu, C and Mishima, E and Conrad, M},
title = {N-acetyl-l-cysteine averts ferroptosis by fostering glutathione peroxidase 4.},
journal = {Cell chemical biology},
volume = {32},
number = {5},
pages = {767-775.e5},
doi = {10.1016/j.chembiol.2025.04.002},
pmid = {40311609},
issn = {2451-9448},
mesh = {*Ferroptosis/drug effects ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; *Acetylcysteine/pharmacology/chemistry/metabolism ; Humans ; Lipid Peroxidation/drug effects ; },
abstract = {N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc[-], glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis.},
}
@article {pmid40302832,
year = {2025},
author = {Sunny, G and Doddwad, PK and Shenvi, S},
title = {Comparative evaluation of effect of N-acetyl cysteine, maleic acid, and ethylenediaminetetraacetic Acid on the depth of dentinal tubule penetration of an epoxy resin-based root canal sealer: A confocal laser scanning microscopy study.},
journal = {Journal of conservative dentistry and endodontics},
volume = {28},
number = {4},
pages = {309-313},
pmid = {40302832},
issn = {2950-4708},
abstract = {BACKGROUND: Effective root canal irrigation removes the smear layer for optimal sealer penetration. While 17% ethylenediaminetetraacetic Acid (EDTA) is effective, concerns about dentin erosion exist. Alternatives like 7% maleic acid (MA) and 20% N-acetylcysteine (NAC) show promise with fewer adverse effects.<br><br>AIM: To compare the effects of 20% NAC, 7% MA, and 17% EDTA as final irrigating solutions on the depth of sealer penetration into dentinal tubules at coronal, middle, and apical thirds of root canals using confocal laser scanning microscopy (CLSM).<br><br>MATERIALS AND METHODS: Sixty-six single-canal mandibular premolars free of caries, fractures, or prior treatment were selected. The teeth were decoronated to 14 mm root length using a diamond disk under water spray. Working length was determined by inserting a size 10 K-file until visible at the apical foramen, subtracting 1 mm. Root canals were instrumented up to F3 using ProTaper Universal rotary files with 1 mL of 2.5% NaOCl irrigation between files. Based on the final irrigation protocol, samples were divided into three groups (n = 22): Group 1-20% NAC, Group 2-7% MA, and Group 3-17% EDTA. Each group was irrigated with 5 mL of the respective irrigant, followed by a final rinse with 10 mL of distilled water. AH Plus sealer with 0.1% Rhodamine B was applied using a #25 Lentulo, and an F3 gutta-percha cone coated with the sealer was placed to working length, trimmed, and sealed with Cavit. Samples were incubated at 37&#xb0;C and 100% humidity for 7 days to allow sealer setting. Roots were sectioned at 2, 5, and 8 mm from the apex to obtain 1 mm thick sections. Sealer penetration into dentinal tubules was evaluated using CLSM at &#xd7;10 magnification, measuring the penetration depth in micrometers from the canal wall to the point of maximum sealer infiltration using ImageJ software, measuring the longest penetration depth from the canal wall to the point of deepest sealer infiltration.<br><br>RESULTS: Sealer penetration was greatest in the coronal third, followed by the middle, with the least in the apical third (P < 0.0001). NAC demonstrated the highest mean in the coronal region (829.35 &#xb1; 85.36), while MA exhibited superior performance in the middle (522.92 &#xb1; 112.32) and apical (361.76 &#xb1; 49.03) regions. Intergroup comparisons showed superior penetration with 7% MA in the apical region (P < 0.0001). NAC and EDTA demonstrated comparable penetration across regions.<br><br>CONCLUSION: While all irrigants enhanced sealer penetration, 7% MA was most effective in the apical region. Both 7% MA and 20% NAC can serve as alternatives to 17% EDTA for final irrigation.},
}
@article {pmid40302321,
year = {2025},
author = {An, D and Jiang, X and Yang, Y},
title = {Sesamin Exerts Anti-Tumor Activity in Nasopharyngeal Carcinoma Through Inducing Autophagy and Reactive Oxygen Species Production.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {4},
pages = {26038},
doi = {10.31083/FBL26038},
pmid = {40302321},
issn = {2768-6698},
support = {81970864//National Natural Science Foundation of China/ ; Yu Wei (2018) No 2//Chongqing Middle and Youth Medical High-end Talent Studio Project/ ; Yu Wei (2021)//Chongqing Talents Project/ ; },
mesh = {*Reactive Oxygen Species/metabolism ; *Autophagy/drug effects ; Humans ; Animals ; *Lignans/pharmacology ; *Nasopharyngeal Carcinoma/metabolism/drug therapy ; Cell Line, Tumor ; Apoptosis/drug effects ; *Dioxoles/pharmacology/therapeutic use ; *Nasopharyngeal Neoplasms/metabolism/drug therapy/pathology ; Cell Proliferation/drug effects ; Mice ; Xenograft Model Antitumor Assays ; Mice, Nude ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred BALB C ; Cell Movement/drug effects ; *Antineoplastic Agents/pharmacology ; Acetylcysteine/pharmacology ; },
abstract = {BACKGROUND: Sesamin can suppress many cancers, but its effect on nasopharyngeal carcinoma (NPC) is unclear. Herein, we set out to pinpoint the possible changes in NPC due to Sesamin.<br><br>METHODS: The biological function of NPC cells exposed to Sesamin/N-acetyl-L-cysteine (NAC)/3-Methyladenine (3-MA) was detected, followed by evaluation of reactive oxygen species (ROS) production (dichlorodihydrofluorescein diacetate staining) and mitochondrial membrane potential (MMP) (flow cytometry). Proteins pertinent to apoptosis (cleaved caspase-3, cleaved poly (ADP-ribose) polymerase 1 (PARP1)), cell cycle (Cyclin B1), and autophagy (microtubule-associated protein light chain 3 (LC3)-I, LC3-II, Beclin-1, P62) were quantified by Western blot. After the xenografted tumor model in mice was established, the tumor volume and weight were recorded, and Ki-67 and cleaved caspase-3 levels were determined by immunohistochemical analysis.<br><br>RESULTS: Sesamin inhibited viability, proliferation, cell cycle progression and migration, induced apoptosis, increased ROS production, and decreased MMP in NPC cells. Sesamin elevated cleaved caspase-3/caspase-3, cleaved PARP1/PARP1, and Beclin-1 expressions as well as LC3-II/LC3-I ratio, while diminishing Cyclin B1 and P62 levels. NAC and 3-MA abrogated Sesamin-induced changes as above in NPC cells. Sesamin inhibited the increase of the xenografted tumor volume and weight, down-regulated Ki-67, and up-regulated cleaved caspase-3 in xenografted tumors.<br><br>CONCLUSION: Sesamin exerts anti-tumor activity in NPC, as demonstrated by attenuated tumor proliferation and xenografted tumor volume and weight, as well as induced apoptosis in tumor tissues, consequent upon the promotion of autophagy and reactive oxygen species production.},
}
@article {pmid40301453,
year = {2025},
author = {Karakoç, E and Halaçlı, SO and Hanelçi, RH and Ayhan, S and Eylem, CC and Nemutlu, E and Atilla, P},
title = {N-acetylcysteine stimulates organelle malfunction in endometriotic cells via IFN-gamma signaling.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {15120},
pmid = {40301453},
issn = {2045-2322},
support = {#TSA-2021-19011and # THD-2019-18110//Hacettepe University Scientific Research Unit/ ; #TSA-2021-19011and # THD-2019-18110//Hacettepe University Scientific Research Unit/ ; },
mesh = {Humans ; Female ; *Acetylcysteine/pharmacology ; *Endometriosis/metabolism/pathology/drug therapy ; *Interferon-gamma/metabolism ; *Signal Transduction/drug effects ; Endoplasmic Reticulum Stress/drug effects ; *Endometrium/metabolism/drug effects/pathology ; Mitochondria/drug effects/metabolism ; Cell Proliferation/drug effects ; *Organelles/drug effects/metabolism ; Interleukin-6/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {Endometriosis is a chronic inflammatory gynecologic disease characterized by the abnormal implantation of endometrial tissue outside the uterus. The inflammatory microenvironment of endometriosis is dominated by highly migratory endometriotic cells, inflammatory cells, and cytokines. There is no curative treatment other than oral contraceptives, painkillers, and surgery. N-acetyl-L-cysteine (NAC), an anti-inflammatory compound has been identified as a promising agent for endometriosis. However, it is still unclear how NAC interacts with interferon-gamma (IFN-ɣ) and common cytokines in the endometriotic microenvironment. This study aimed to investigate the effects of NAC, alone and in combination with IFN-ɣ and major cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-⍺) on endometriotic cells. For this purpose, we performed a real time-dependent cell impedance assay, Annexin V/PI and ER tracking by flow cytometry, immunofluorescence, western blotting, and metabolomic assays. Our results offered a new insight into the complex relationship between NAC and IFN-ɣ, both of which reduced endometriotic cells' proliferation, induced ER stress and mitochondrial dysfunction. In conclusion, NAC and IFN-ɣ, alter the metabolism of endometriotic cells, leading to endoplasmic reticulum stress and mitochondrial dysfunction. These findings suggest that NAC when combined with IFN-ɣ, has the potential to generate innovative therapeutic modalities for the treatment of endometriosis.},
}
@article {pmid40298799,
year = {2025},
author = {Hu, J and Feng, J and Bai, Y and Yao, ZS and Wu, XY and Hong, XY and Lu, GD and Xue, K},
title = {Sucralose Promotes Benzo(a)Pyrene-Induced Renal Toxicity in Mice by Regulating P-glycoprotein.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
pmid = {40298799},
issn = {2076-3921},
support = {GWVI-11.1-41//Shanghai Municipal Health Commission/ ; GWVI-11.1-41//Shanghai Municipal Health Commission/ ; },
abstract = {BACKGROUND: Sucralose and benzo(a)pyrene (B[a]P) are widespread foodborne substances known to harm human health. However, the effects of their combined exposure on kidney function remain unclear. This study aimed to investigate the mechanisms by which sucralose and B[a]P induce kidney injury through P-glycoprotein (PGP/ABCB1), a crucial protein involved in cellular detoxification.<br><br>METHODS: C57BL/6N mice were co-treated with sucralose and B[a]P for 90 days to evaluate their impact on kidney histopathology and function. In vitro experiments assessed cell viability, reactive oxygen species (ROS) levels, and B[a]P accumulation by flow cytometry. Molecular docking and cellular thermal shift assay (CETSA) were used to determine the binding affinity of sucralose to PGP. Furthermore, PCR, Western blotting, and immunohistochemistry were performed to analyze the expression of PGP and its upstream transcription factors.<br><br>RESULTS: Ninety days of co-exposure to sucralose and B[a]P significantly exacerbated renal dysfunction in mice, as evidenced by the elevated level of serum creatinine and urea nitrogen, which could be reverted by ROS scavenger N-acetyl cysteine (NAC). In vitro, sucralose promoted cellular accumulation of B[a]P, consequently enhancing B[a]P-induced cell growth inhibition and ROS production. Consistently, B[a]P accumulation was enhanced by PGP knockdown in both HK2 and HEK-293 cells. Mechanistically, sucralose can directly bind to PGP, competitively inhibiting its efflux capacity and increasing intracellular B[a]P retention. Prolonged co-exposure further downregulated PGP expression, possibly through the reductions of its transcriptional regulators (PXR, NRF2, and NF-&#x3ba;B).<br><br>CONCLUSIONS: Co-exposure to sucralose and B[a]P exacerbates renal injury by impairing PGP function. Mechanistically, sucralose inhibits PGP activity, resulting in the accumulation of B[a]P within renal cells. This accumulation triggers oxidative stress and inhibits cell growth, which demonstrates that sucralose potentiates B[a]P-induced nephrotoxicity by directly inhibiting PGP-mediated detoxification pathways, thus underscoring the critical need to evaluate toxicity risks associated with combined exposure to these compounds.},
}
@article {pmid40296602,
year = {2025},
author = {Cheng, Y and Chen, HJ and Yang, T},
title = {[Influences of dihydromyricetin on proliferation and apoptosis of chondrocytes in osteoarthritis induced by H2O2 through ROS/p38-MAPK signal pathway].},
journal = {Zhongguo gu shang = China journal of orthopaedics and traumatology},
volume = {38},
number = {4},
pages = {396-402},
doi = {10.12200/j.issn.1003-0034.20230237},
pmid = {40296602},
issn = {1003-0034},
mesh = {Animals ; *Chondrocytes/drug effects/cytology/metabolism ; *Apoptosis/drug effects ; *Hydrogen Peroxide/toxicity ; *Osteoarthritis/metabolism/drug therapy/physiopathology ; Mice, Inbred C57BL ; *Reactive Oxygen Species/metabolism ; Mice ; *Flavonols/pharmacology ; *p38 Mitogen-Activated Protein Kinases/metabolism/genetics ; *Cell Proliferation/drug effects ; Male ; Signal Transduction/drug effects ; *MAP Kinase Signaling System/drug effects ; Cells, Cultured ; },
abstract = {OBJECTIVE: To analyze the influences of dihydromyricetin on the proliferation and apoptosis of chondrocytes in osteoarthritis induced by hydrogen peroxide (H2O2) through reactive oxygen species (ROS)/p38 mitogen activated protein kinase (p38-MAPK) pathway.<br><br>METHODS: Five C57BL/6J mice were euthanized by cervical dislocation after anesthesia. Chondrocytes were extracted and cultured.After passage, the chondrocytes were divided into control group, H2O2 group (0.8 &#x3bc;mol&#xb7;L[-1] H2O2), dihydromyricetin low concentration group (0.8 &#x3bc;mol&#xb7;L[-1] H2O2+20 &#x3bc;mol&#xb7;L[-1] dihydromyricetin), dihydromyricetin high concentration group (0.8 &#x3bc;mol&#xb7;L[-1] H2O2+80 &#x3bc;mol&#xb7;L[-1] dihydromyricetin), and ROS inhibitor N-acetylcysteine (NAC) group (0.8 &#x3bc;mol&#xb7;L[-1] H2O2+5 mmol&#xb7;L[-1] NAC). The activity of chondrocytes was measured by methyl thiazolyl tetrazolium (MTT) assay. The apoptosis rate of chondrocytes was measured by Hoechst 33342 method. The level of ROS in chondrocytes was measured by 2, 7-dichlorofluorescein diacetate (DCFH-DA) fluorescence probe.The level of Type II collagen &#x3b1;1 (Col2&#x3b1;1) mRNA was measured by qRT-PCR.And the expression of Col2&#x3b1;1, p-p38-MAPK/p38-MAPK, B cell lymphoma gene-2 (Bcl-2) and Bcl-2 associated X protein (Bax) proteins was detected by Western blot.<br><br>RESULTS: The chondrocytes showed swirling fibrous mass, and the expression of COL2&#x3b1; was positive. Compared with the control group, the chondrocyte viability, apoptosis rate, ROS fluorescence intensity, p-p38-MAPK/p38-MAPK, and the expression of Bax protein in H2O22 group increased, the level of Col2&#x3b1;1 mRNA, and the expression of Col2&#x3b1;1 and Bcl-2 proteins decreased (P<0.05). Compared with H2O2 group, the chondrocyte viability, apoptosis rate, ROS fluorescence intensity, p-p38-MAPK/p38-MAPK, and the expression of Bax protein in dihydromyricetin low concentration group, dihydromyricetin high concentration group, and NAC group decreased, the level of Col2&#x3b1;1 mRNA, and the expression of Col2&#x3b1;1 and Bcl-2 proteins increased (P<0.05).<br><br>CONCLUSION: Dihydromyricetin may inhibit chondrocyte apoptosis, inflammatory reaction and oxidative stress by inhibiting ROS/p38-MAPK pathway. Dihydromyricetin may be a potential drug for treating osteoarthritis.},
}
@article {pmid40295625,
year = {2025},
author = {Lee, SO and Joo, SH and Lee, NY and Cho, SS and Yoon, G and Kim, KT and Choi, YH and Park, JW and Choi, JS and Shim, JH},
title = {Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPK.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {14912},
pmid = {40295625},
issn = {2045-2322},
support = {RS-2024-00336900//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; Oxaliplatin/pharmacology ; *Apoptosis/drug effects ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Colorectal Neoplasms/metabolism/pathology/drug therapy ; HCT116 Cells ; *Drug Resistance, Neoplasm/drug effects ; Membrane Potential, Mitochondrial/drug effects ; *Antineoplastic Agents/pharmacology ; *JNK Mitogen-Activated Protein Kinases/metabolism ; Cell Survival/drug effects ; Cell Proliferation/drug effects ; Enzyme Activation/drug effects ; Caspases/metabolism ; Sesquiterpenes ; },
abstract = {Treating colorectal cancer (CRC) poses challenges due to the lack of specific molecular targets. Although oxaliplatin (Ox) is commonly used to treat CRC, resistance frequently develops, necessitating the discovery of new therapeutics. This study explored the anticancer effects of Isoalantolactone (IAL) on human CRC cells HCT116 and Ox-resistant HCT116 (HCT116-OxR). Apoptosis, ROS generation, cell cycle distribution, mitochondrial membrane potential (MMP), and caspase activation were assessed through flow cytometry. Protein levels were determined by Western blot analysis. IAL reduced cell viability, measured by MTT assay, and inhibited anchorage-independent colony formation in CRC cells in a time- and concentration-dependent manner. The IC50 values for 48 h of incubation were below 10 µM. Annexin V/7-AAD double staining demonstrated that IAL induced apoptosis in HCT116 and HCT116-OxR cells, and Western blot analysis confirmed increased phosphorylation of JNK and p38 mitogen-activated protein kinase (MAPK). The inhibition of these kinases by SP600125 or SB203580 blocked the antiproliferative effects of IAL. Additionally, IAL triggered ROS generation and disrupted mitochondrial membranes, leading to caspase activation. Pretreatment with N-acetylcysteine (NAC) or Z-VAD-FMK inhibited the antiproliferative effects of IAL, highlighting the crucial roles of ROS generation and caspase activation in IAL-induced apoptosis in CRC cells. In summary, IAL exhibited anticancer effects in CRC cells by inducing apoptosis by elevating ROS level and activating JNK and p38 MAPK. These findings warrant further study to evaluate the therapeutic potential of IAL in treating CRC with various resistances.},
}
@article {pmid40292267,
year = {2025},
author = {Zolfaghari Farajerdi, M and Rajabian, F and Razavi, BM and Ghasemzadeh Rahbarda, M and Khajavi Rad, A and Amoueian, S and Hosseinzadeh, H},
title = {Evaluating the effect of crocin on contrast-induced nephropathy in rats.},
journal = {Avicenna journal of phytomedicine},
volume = {15},
number = {2},
pages = {920-932},
pmid = {40292267},
issn = {2228-7930},
abstract = {OBJECTIVE: Contrast-induced nephropathy (CIN) raises the risk of renal injury, but crocin, a saffron component, may improve kidney function. This study investigated crocin's protective effects against CIN in rats.<br><br>MATERIALS AND METHODS: Male Wistar rats were divided into eight groups: Sham, Control, Contrast medium (diatrizoate), Diatrizoate combined with crocin at 10, 20, or 40 mg/kg/day, Diatrizoate combined with N-acetylcysteine (NAC) at 125 mg/kg/day, and Crocin alone at 40 mg/kg/day. Water deprivation began on day 5 for 48 hr, except for the sham and crocin alone groups. Indomethacin and N(&#x3c9;)-nitro-L-arginine methyl ester were administered after 40 hr of dehydration. Rats were sacrificed on the eighth day, and blood and kidney samples were collected.<br><br>RESULTS: Diatrizoate increased serum creatinine and blood urea nitrogen levels, elevated malondialdehyde levels, and reduced glutathione in renal tissue. Crocin reversed these effects. Diatrizoate caused severe tubular necrosis, proteinaceous casts, medullary congestion, and interstitial edema in kidney tissue. Crocin (20 and 40 mg/kg) significantly reduced tubular necrosis, and doses of 10 and 40 mg/kg reduced interstitial edema. NAC significantly improved histopathological damage, biochemical factors, and oxidative stress. The crocin alone group showed no significant changes.<br><br>CONCLUSION: Diatrizoate induces nephrotoxicity by enhancing oxidative stress in rats, and crocin has a protective effect against it. Crocin mitigates both tissue and biochemical damage inflicted by diatrizoate.},
}
@article {pmid40289970,
year = {2025},
author = {Jiang, L and Lu, Y and Zhao, H and He, W},
title = {Arctigenin Suppresses Melanoma via Mitophagy Activation In vitro and Enhances Dacarbazine Sensitivity In vivo.},
journal = {Current cancer drug targets},
volume = {25},
number = {10},
pages = {1308-1320},
pmid = {40289970},
issn = {1873-5576},
support = {20210178//Science and Technology Committee of Yuzhong District, Chongqing/ ; },
mesh = {Humans ; Animals ; *Melanoma/drug therapy/pathology/metabolism ; *Mitophagy/drug effects ; *Lignans/pharmacology/therapeutic use ; Mice ; *Furans/pharmacology/therapeutic use ; Mice, Nude ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Mitochondria/drug effects/metabolism ; Autophagy/drug effects ; Ubiquitin-Protein Ligases ; },
abstract = {OBJECTIVE: This study aimed to investigate the effect and mechanism of arctigenin (ARG) on the sensitization of dacarbazine (DTIC) via the regulation of mitophagy.<br><br>METHODS: In vitro experiments were conducted to explore the effects of ARG on the biological behavior of melanoma cells, mitochondrial autophagy mediated by PINK1/Parkin, and the role of reactive oxygen species (ROS)-mitochondrial autophagy in the regulation of the biological behavior of melanoma cells by an ROS quenching agent, a mitochondrial autophagy inhibitor, and an activator. The effects of ARG and dacarbazine in nude mice were assessed.<br><br>RESULTS: CCK8 assays revealed that ARG inhibited the proliferation of the human melanoma cell lines A375 and SK-MEL-2. The observation of submicroscopic structures demonstrated mitochondrial damage. Flow cytometry further verified that ARG induced apoptosis. Western blot analysis revealed that the protein expression levels of cleaved caspase 3 and Bax increased, whereas that of Bcl-2 decreased. In addition, ARG increased ROS levels. LC3II/I, PINK1, and Parkin were increased. ARG-induced apoptosis was related to increased mitochondrial oxidative stress and promoted the occurrence of mitochondrial autophagy. After the addition of the autophagy inhibitor Mdivi-1 or the ROS quencher N-acetylcysteine (NAC), the antiproliferative effect of ARG was markedly attenuated. The expression levels of PINK1, Parkin, LC3II/I, cleaved caspase 3, and Bax were increased, whereas that of Bcl-2 was decreased. The formation of mitochondrial autophagosomes was observed by transmission electron microscopy. ARG inhibited the proliferation and induced the apoptosis of melanoma cells in vivo.<br><br>CONCLUSION: Autophagy-mediated cell apoptosis was activated through the PINK1/Parkin pathway by ARG, effectively inhibiting the proliferation of human melanoma cells.},
}
@article {pmid40288286,
year = {2025},
author = {Dai, A and Liu, X and Chen, Y and Wang, Y and Qi, H and Zeng, Y and Li, J},
title = {Co-exposure to ozone and polystyrene nanoplastic exacerbates cognitive impairment and anxiety-like behavior by regulating neuronal pyroptosis in mice.},
journal = {Environment international},
volume = {199},
number = {},
pages = {109501},
doi = {10.1016/j.envint.2025.109501},
pmid = {40288286},
issn = {1873-6750},
mesh = {Animals ; *Pyroptosis/drug effects ; Mice ; *Anxiety/chemically induced ; *Cognitive Dysfunction/chemically induced ; *Ozone/toxicity ; *Polystyrenes/toxicity ; *Nanoparticles/toxicity ; Male ; Neurons/drug effects ; *Microplastics/toxicity ; Mice, Inbred C57BL ; Blood-Brain Barrier/drug effects ; Oxidative Stress/drug effects ; Behavior, Animal/drug effects ; },
abstract = {Ozone (O3) and nanoplastics (NPs) are pervasive environmental pollutants that frequently co-occur in our heavily industrialized era. While it has been documented that exposure to O3 or NPs individually has neurotoxic effects, studies investigating their combined impact and the hazardous mechanisms resulting from co-exposure are limited. In this study, we established a mouse model co-exposure to polystyrene nanoparticles (PS-NPs) and O3, focusing on the prefrontal cortex (PFC), a brain region crucial for cognition and emotion. We examined the effects of O3 and PS-NPs on behavioral changes related to learning, memory, and anxiety, employing transcriptome sequencing alongside molecular and histopathological methods. Our findings indicate that combined exposure to O3 and PS-NPs disrupts the integrity of the blood-brain barrier, reducing Claudin 5 expression and leading to increased accumulation of PS-NPs in the PFC. Transcriptome sequencing demonstrated the involvement of the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and oxidative stress in the pathological changes observed in the PFC. Through immunohistochemical and immunofluorescence analysis, we observed enhanced microglial activation, which correlates with increased production of inflammatory factors. Additionally, western blot and immunofluorescence co-labeling analyses revealed elevated expression levels of GSDMD-N, caspase-1, IL-1β, and IL-18 proteins, which are associated with neuronal pyroptosis. Finally, immunofluorescence co-labeling confirmed that the activation of the p38 MAPK pathway in neurons is involved in co-exposure-induced pyroptosis. Meanwhile, N-Acetylcysteine (NAC), a common antioxidant, can alleviate neuroinflammation and neuronal pyroptosis in the PFC, and it rescued the cognitive deficits and anxiety-like behaviors observed in the co-exposed mice. Our study illustrates that co-exposure to O3 and NPs can aggravate damage to the blood-brain barrier and elevate oxidative stress levels in the PFC, thereby increasing the occurrence of neuroinflammation and may mediate neuronal pyroptosis through activation of the p38 MAPK pathway, ultimately contributing to neurobehavioral toxicity.},
}
@article {pmid40284514,
year = {2025},
author = {Polo-Montalvo, A and Gómez-Cerezo, N and Cicuéndez, M and González, B and Izquierdo-Barba, I and Arcos, D},
title = {Osteogenic and Antibacterial Response of Levofloxacin-Loaded Mesoporous Nanoparticles Functionalized with N-Acetylcysteine.},
journal = {Pharmaceutics},
volume = {17},
number = {4},
pages = {},
pmid = {40284514},
issn = {1999-4923},
support = {PID2020-117091RB-I00, AEI /10.13039/501100011033//Ministerio de Ciencia e Innovaci&#xf3;n/ ; Nano4Infection, FD5/22_01//Fundaci&#xf3;n Ram&#xf3;n Areces, SPAIN/ ; PID2023-149093OB-I00, MCIU/AEI/10.13039/501100011033/FEDER,UE//Ministerio de Ciencia e Innovaci&#xf3;n/ ; },
abstract = {Background/Objectives: Bone infection is one of the most prevalent complications in orthopedic surgery. This pathology is mostly due to bacterial pathogens, among which S. aureus stands out. The formation of a bacterial biofilm makes systemic treatment with antibiotics ineffective. Herein we propose a nanosystem composed of mesoporous bioactive glass nanoparticles (MBGN) loaded with levofloxacin and functionalized with N-acetylcysteine (NAC), aiming to offer an alternative to current treatments. These nanoparticles would present antibacterial activity able to disintegrate the biofilm and regenerate the peri-implantar osseous tissue. Methods: MBGN of composition 82.5 SiO2-17.5 CaO have been synthesized, loaded with levofloxacin, and functionalized with NAC (MBGN-L-NAC). The antimicrobial activity against mature S. aureus biofilms and bioactivity of the nanosystem have been evaluated, as well as its biocompatibility and ability to promote murine pre-osteoblastic MC3T3-E1 differentiation. Results: MBGNs exhibited high surface areas and radial mesoporosity, allowing up to 23.1% (% w/w) of levofloxacin loading. NAC was covalently bound keeping the mucolytic thiol group, SH, available. NAC and levofloxacin combination enhances the activity against S. aureus by disrupting mature biofilm integrity. This nanosystem was biocompatible with pre-osteoblasts, enhanced their differentiation towards a mature osteoblast phenotype, and promoted bio-mimetic mineralization under in vitro conditions. MBGN-L-NAC nanoparticles induced greater osteogenic response of osteoprogenitor cells through increased alkaline phosphatase expression, increased mineralization, and stimulation of pre-osteoblast nodule formation. Conclusions: MBGN-L-NAC exhibits a more efficient antibacterial activity due to the biofilm disaggregation exerted by NAC, which also contributes to enhance the osteoinductive properties of MBGNs, providing a potential alternative to conventional strategies for the management of bone infections.},
}
@article {pmid40284511,
year = {2025},
author = {Meadows, I and Mvungi, H and Salim, K and Kaswaga, O and Mbelele, P and Liyoyo, A and Semvua, H and Ngoma, A and Heysell, SK and Mpagama, SG},
title = {N-Acetylcysteine to Reduce Kidney and Liver Injury Associated with Drug-Resistant Tuberculosis Treatment.},
journal = {Pharmaceutics},
volume = {17},
number = {4},
pages = {},
pmid = {40284511},
issn = {1999-4923},
support = {D43 TW012247/TW/FIC NIH HHS/United States ; T32 AI007046/AI/NIAID NIH HHS/United States ; TMA2016SF-1463//EDCTP/ ; 1T32AI007046-24A44/NH/NIH HHS/United States ; },
abstract = {Background: New drug classes and regimens have shortened the treatment duration for drug-resistant tuberculosis, but adverse events (AEs) and organ toxicity remain unacceptably common. N-acetylcysteine (NAC) has demonstrated potential in reducing kidney and liver toxicity in other clinical settings, but efficacy in drug-resistant tuberculosis treatment has not been rigorously evaluated. Method: A randomized controlled trial was conducted at Kibong'oto Infectious Diseases Hospital in Tanzania to assess the efficacy of NAC in reducing AEs in patients undergoing rifampin-resistant pulmonary tuberculosis treatment. Participants received an all-oral standardized rifampin-resistant regimen alone, with NAC 900 mg daily, or NAC 900 mg twice daily for 6 months. AEs, severe AEs, and renal and liver toxicity were monitored monthly and classified according to the Risk, Injury, Failure, Loss, and End-stage kidney disease criteria and National Cancer Institute Common Terminology Criteria for Adverse Events. Incident ratios and Kaplan-Meier curves were employed to compare group event occurrences. Results: A total of 66 patients (mean age 47 ± 12 years; 80% male) were randomized into three groups of 22. One hundred and fifty-eight AEs were recorded: 52 (33%) in the standard treatment group, 55 (35%) in the NAC 900 mg daily group, and 51 (32%) in the NAC 900 mg twice-daily group (p > 0.99). Severe AEs were observed in four patients in the standard group, two in the NAC 900 mg daily group, and three in the NAC 900 mg twice-daily group. Renal toxicity was more prevalent in the standard treatment group compared to those that received NAC (45% vs. 23%; p = 0.058), with a shorter onset of time to toxicity (χ[2] = 3.199; p = 0.074). Liver injury events were rare across all groups. Conclusion: Among Tanzanian adults receiving rifampin-resistant tuberculosis treatment, NAC did not significantly reduce overall AEs but demonstrated important trends in reducing renal toxicity.},
}
@article {pmid40277294,
year = {2025},
author = {Li, F and Gao, S and Ma, R and Zhang, Y and Li, Y and Wu, D and Han, Z and Li, Q and He, Q and Li, J and Dai, Q and Xu, AD and Zhang, L and Liu, C and Lu, Y},
title = {Polymer-Encapsulated Catalase for Targeted Redox Regulation in Acute Liver Injury.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {21},
number = {23},
pages = {e2412349},
doi = {10.1002/smll.202412349},
pmid = {40277294},
issn = {1613-6829},
support = {YDZJSX2024B011//Shanxi Province Central Government Guidance Fund for Local Science and Technology Development/ ; 2024AOXIANG02//Project for Scientific Breakthroughs at Shanxi Bethune/ ; 2022YFC2104800//Key Technologies Research and Development Program/ ; L234016//National Natural Science Foundation of China-Nuclear Technology Innovation Joint Fund/ ; },
mesh = {*Catalase/chemistry/therapeutic use/metabolism/administration &amp; dosage ; Animals ; Oxidation-Reduction ; *Polymers/chemistry ; Liver/pathology/drug effects ; Mice ; Oxidative Stress/drug effects ; Male ; Antioxidants ; },
abstract = {The liver plays a critical role in maintaining homeostasis, and its dysfunction can lead to severe conditions like acute liver injury (ALI), which is primarily caused by viral infections, toxins, and oxidative stress. Reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), significantly drive hepatocyte injury, initiating oxidative stress and inflammation. Current antioxidants, such as N-acetylcysteine (NAC) and superoxide dismutase (SOD), show limited clinical efficacy due to poor targeting, instability, and toxicity. Catalase (CAT), an essential enzyme for H2O2 decomposition, represents a promising therapeutic for ALI; however, its clinical application faces challenges in stability, rapid degradation, and insufficient targeting. Here, a novel nanocapsule-based CAT delivery system (n(CAT)) is presented, formed through in situ radical polymerization using 2-methacryloyloxyethyl phosphorylcholine (MPC) and N-(3-aminopropyl)-methacrylamide hydrochloride (APM). This strategy significantly enhances CAT's stability, retains enzyme activity, and improves selective liver accumulation, particularly at inflammation sites. The results demonstrate that n(CAT) effectively reduces oxidative stress, minimizes inflammation, and facilitates liver repair in ALI and ischemia-reperfusion injury (IRI) models. These findings highlight the potential of n(CAT) as a promising platform for advanced antioxidant therapies targeting liver diseases, including hepatitis.},
}
@article {pmid40277148,
year = {2025},
author = {Tuset, MP and Cooper, JN and Ebode, D and Mittal, J and Garnham, C and Melchionna, T and Hessler, R and Schilp, S and Godur, D and McKenna, K and Mittal, R and Eshraghi, AA},
title = {Intracochlear Drug Delivery Using a Catheter and Dexamethasone-Eluting Electrode Preserves Residual Hearing Post-Cochlear Implantation.},
journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery},
volume = {173},
number = {1},
pages = {208-217},
doi = {10.1002/ohn.1252},
pmid = {40277148},
issn = {1097-6817},
mesh = {Animals ; *Dexamethasone/administration &amp; dosage ; *Cochlear Implantation/methods ; *Cochlear Implants ; *Drug Delivery Systems ; *Acetylcysteine/administration &amp; dosage ; *Catheters ; Cochlea ; *Hearing/drug effects ; Evoked Potentials, Auditory, Brain Stem ; Disease Models, Animal ; Feasibility Studies ; Electrodes, Implanted ; },
abstract = {OBJECTIVES: This study aims to assess the feasibility and safety of a cochlear catheter (cannula) for inner ear drug delivery during cochlear implantation. We evaluated the otoprotective effect of L-N-acetylcysteine (L-NAC) administered via a cannula in combination with a dexamethasone-eluting cochlear implant (CI).<br><br>STUDY DESIGN: An animal model study.<br><br>SETTING: Animal facility of an academic institution.<br><br>METHODS: Animals were divided into 8 groups: (1) implantation with a CI; (2) implantation with a dexamethasone-eluting CI (CIDexel); (3) cannula injection of artificial perilymph (Can+AP); (4) cannula injection of Ringer (Can+R); (5) cannula injection of R and CI (Can+CI); (6) cannula injection of R and Dexel (Can+Dexel); (7) cannula injection of 2&#x2009;mM L-NAC and CI (Can L-NAC 2&#x2009;mM+CI); or (8) cannula injection of 2mM L-NAC and Dexel (Can L-NAC 2&#x2009;mM++Dexel). The contralateral ear served as the control group. Hearing thresholds were determined preoperatively, and at postoperative day (POD 7) and POD 30 post-cochlear implantation, using auditory brainstem responses (ABRs). The organ of Corti dissections were performed at POD 30 for hair cell (HC) viability, and oxidative stress assessment using immunostaining.<br><br>RESULTS: The L-NAC (2&#x2009;mM) and dexamethasone-eluting electrode group had significantly lower hearing thresholds than the standard CI, Can L-NAC 2&#x2009;mM, and Dexel groups. The animal group treated with L-NAC (2&#x2009;mM) and dexamethasone-eluting electrode showed higher HC viability and reduced oxidative stress.<br><br>CONCLUSION: An intracochlear cannula can deliver pharmaceutical interventions without causing additional hearing loss. L-NAC presents strong anti-apoptotic potential and administration through a cannula together with Dexel implantation, and achieves a synergistic effect enhancing the otoprotection.},
}
@article {pmid40275972,
year = {2024},
author = {Keshavarz, S and Reisi, M and Keivanfar, M and Rabbani, F and Sabzghabaee, AM},
title = {Efficacy of Adding Oral N acetyl Cysteine Supplement to the Cystic Fibrosis Treatment Regimen: A Randomized Quasi-Experimental Trial.},
journal = {Journal of research in pharmacy practice},
volume = {13},
number = {3},
pages = {72-77},
pmid = {40275972},
issn = {2319-9644},
abstract = {OBJECTIVE: This study investigated the efficacy of adding the oral N-acetyl cysteine (NAC) supplement to the cystic fibrosis (CF) treatment regimen compared to adding a placebo. It also studied the quality of life and respiratory indicators of patients aged 6-18 with mild-to-moderate pulmonary involvement.<br><br>METHODS: This clinical trial was a randomized, quasi-experimental pilot and add-on therapy controlled with a placebo for 3 months. The case group received 200 mg of oral NAC three times a day. In contrast, the control group had a placebo in the same way. From the 2021 fall to the summer of 2022, 38 CF patients referred to Imam Hossein Children's Hospital Clinic were finally examined. They were clinically stable with a forced expiratory volume in the first second (FEV1) level of more than 50% and no history of underlying cardiovascular and renal diseases.<br><br>FINDINGS: The differences between the groups were not significant. In the placebo group, key measures remained unchanged, whereas the NAC group had an improvement in the CF Questionnaire-Revised score but no notable changes in other indices. Overall, comparisons of forced vital capacity (FVC) between the groups showed no variation.<br><br>CONCLUSION: The indicators of FEV1, FVC, FEV1/FVC, forced expiratory flow between 25% and 75% of vital capacity, and the quality of life of the case group were not significantly different from those of the placebo group, and no significant differences were observed between this medicine and placebo.},
}
@article {pmid40275970,
year = {2024},
author = {Shabani, AM and Alikhani, A and Heydari, F and Hosseinnataj, A and Sohrabi, M and Ramezaninejad, S and Ala, S and Kasgari, HA},
title = {Evaluation of the Effect of N-acetylcysteine in the Prevention of Colistin Nephrotoxicity in Critically Ill Patients: A Randomized Controlled Trial.},
journal = {Journal of research in pharmacy practice},
volume = {13},
number = {3},
pages = {85-91},
pmid = {40275970},
issn = {2319-9644},
abstract = {OBJECTIVE: The present study aimed to evaluate the efficacy of N-acetylcysteine (NAC) in preventing nephrotoxicity in critically ill patients receiving colistin.<br><br>METHODS: In a randomized, controlled clinical trial, eligible participants receiving colistin were divided into two groups: the drug group (n = 24) and the control group (n = 24). In the drug group, 2 g of NAC was administered intravenously daily for 5 days, simultaneously with colistin. The patients in the control group received only colistin. Serum creatinine (SCr), blood urea nitrogen (BUN), and creatinine clearance (CrCl) at baseline and on each day, and the number of cases of acute kidney injury during the study were recorded. Urinary N-acetyl-beta-D-glucosaminidase (NAG) was determined before the start of treatment and on day 5. The study outcomes were the mortality rate, length of intensive care unit (ICU) stay, and NAG levels. Finally, the values were compared between the groups.<br><br>FINDINGS: It was found that the 28-day mortality rate (P = 0.540) and length of ICU stay (P = 0.699) were not significantly improved by coadministration of intravenous N-acetylcysteine with colistin. SCr and BUN showed no significant reduction, and there were no changes in CrCl at the end of treatment. The changes in urinary NAG levels did not differ significantly between the two groups. There was also no difference in the stages of the RIFLE criteria (P = 0.641), and most patients were in the normal stage (58.3%).<br><br>CONCLUSION: Concomitant administration of intravenous NAC at a dose of 2 g daily does not prevent colistin-induced nephrotoxicity, 28-day mortality, and length of ICU stay in critically ill patients.},
}
@article {pmid40269590,
year = {2025},
author = {Liu, N and Liu, Y and Wang, X and Liu, M and Wang, Y and Feng, C and Piao, M},
title = {N-Acety-L-Cysteine Alleviates Isoflurane-Triggered Neuronal Cell Parthanatos by Suppressing Reactive Oxygen Species Accumulation Through the Induction of c-Jun N-Terminal Kinase Signaling Pathway Inhibition.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {5},
pages = {e70268},
pmid = {40269590},
issn = {1099-0461},
support = {//This investigation was supported by grants from the National Natural Science Foundation of China (Grant No. 81771141 and 82471221 to C. F.) and the Science and Technology Development Project of Jilin Province (Grant No. 20210101304JC to C. F.)./ ; },
mesh = {Animals ; *Isoflurane/adverse effects/pharmacology ; *Reactive Oxygen Species/metabolism ; Rats ; *Neurons/metabolism/drug effects/pathology ; *Acetylcysteine/pharmacology ; *JNK Mitogen-Activated Protein Kinases/metabolism ; *MAP Kinase Signaling System/drug effects ; Humans ; Hippocampus/metabolism/pathology ; *Parthanatos/drug effects ; *Anesthetics, Inhalation/adverse effects ; Rats, Sprague-Dawley ; Cell Line, Tumor ; Oxidative Stress/drug effects ; },
abstract = {In recent years, the potential neurotoxicity of inhaled anesthetics on the developing brain has increasingly garnered attention, yet its mechanism remains unclear. Parthanatos is a newly discovered form of programmed cell death dependent on PARP-1, and it is believed to be closely associated with cellular oxidative stress response. However, it is still to be proven whether isoflurane, a commonly used clinical anesthetic, can induce parthanatos in developing brain neurons and whether it activates the oxidative stress signaling pathway in neuronal cells. In this study, we treated SH-SY5Y cells and rat hippocampus neuron cells (RN-h) with isoflurane, measured cell viability using the MTT assay, examined the activation of the parthanatos-related PARP-1/AIF/PAR signaling pathway using western blot analysis, detected the accumulation of ROS using DCFH-DA, detected mitochondrial membrane potential (Δψm) by a JC-1 assay, and assessed the activation of the oxidative stress-related JNK signaling pathway using western blot. In vivo, we examined the damaging effects of inhaled isoflurane on neonatal rat hippocampal neurons using HE staining. The results showed that 2% and 4% concentrations of isoflurane significantly inhibited cell survival and upregulated the expression levels of PARP-1, AIF, and PAR in both types of neuronal cells. Moreover, isoflurane significantly enhanced ROS levels and decreased Δψm, and activated the JNK signaling pathway in both cell types. Importantly, we found that pretreatment with N-Acetylcysteine (NAC) could inhibit isoflurane-induced parthanatos and the accumulation of ROS in cells, as well as the activation of the JNK pathway. The experimental results in neonatal rats also demonstrated that isoflurane led to significant neuronal death in the hippocampal CA1 region. However, pretreatment with NAC significantly increased the survival rate of pyramidal neurons in this region. In summary, through our experiments, we confirmed that isoflurane can induce parthanatos in neuronal cells, and NAC can decrease ROS accumulation in neuronal cells and thus mitigate the damage isoflurane causes to neuronal cells.},
}
@article {pmid40269151,
year = {2025},
author = {Liu, F and Lv, R and Qiao, X and Lv, G and Yuan, H and Han, J and Wang, X and Wan, J and Wang, M},
title = {Salinomycin and oxaliplatin synergistically enhances cytotoxic effect on human colorectal cancer cells in vitro and in vivo.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {14056},
pmid = {40269151},
issn = {2045-2322},
support = {SDYWZGKCJHLH2023095//Shandong Province Medical Staff Science and Technology Innovation Plan Project/ ; 2020NS160 and 2022NS319//Taian science and technology innovation and development project/ ; 2020NS160 and 2022NS319//Taian science and technology innovation and development project/ ; 2022MPM03//Nursery Project of the Affiliated Taian City Central Hospital of Qingdao University/ ; ZR2020MH239//Natural Science Foundation of Shandong Province, China/ ; },
mesh = {*Oxaliplatin/pharmacology ; Humans ; *Colorectal Neoplasms/drug therapy/metabolism/pathology ; *Pyrans/pharmacology/administration &amp; dosage ; Drug Synergism ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Animals ; Cell Proliferation/drug effects ; Mice ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Cell Movement/drug effects ; *Antineoplastic Agents/pharmacology ; *Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Mice, Nude ; Polyether Polyketides ; },
abstract = {Oxaliplatin (OXA) is widely used for colorectal cancer (CRC) as a first-line chemotherapy. However, drug resistance and peripheral neurotoxicity prevail in colorectal cancer therapy. Salinomycin (SAL) makes cancer cells sensitive to ionizing radiation and chemotherapeutic drugs. Chemotherapy regimens that combine more than two drugs can improve the outcome of patients. In the present study, we detected apoptosis and mitochondrial function in CRC cells through MTT assays, Annexin V-FITC/PI staining, colony-forming assays, intracellular reactive oxygen species (ROS) measurements, western blotting and so on. We used CompuSyn software to calculate combination index (CI). The effect of SAL and OXA was synergistic. The combination treatment inhibited cell proliferation, migration and colony formation but increased the expression of proapoptotic proteins and promoted cell apoptosis of CRC cells. In vitro experiments demonstrated that the SAL and OXA cotreatment increased intracellular ROS levels in CRC cell lines, decreased the MMP and activated the mitogen-activated protein kinase (MAPK) pathway, thus inhibiting the proliferation of CRC cells and promoting the apoptosis of CRC cells. Pretreatment with N-acetylcysteine (NAC) reversed this effect. Cotreatment with SAL and OXA increases the apoptotic effects in OXA-treated CRC cell lines. In vivo, combined treatment of SAL and OXA markedly inhibited the tumor growth compared to either drug alone. SAL enhances OXA-induced antitumor effects in CRC both in vitro and in vivo by ROS-mediated mitochondrial apoptosis and activation of the MAPK pathway. These results may provide a rationale for combining SAL with OXA for CRC treatment.},
}
@article {pmid40267072,
year = {2025},
author = {Oike, H and Yamasaki, K and Hashiguchi, K and Uehira, H},
title = {Evaluation of intake of aged garlic extract and organosulfur compounds on progressive hearing loss in DBA/2J mice.},
journal = {PloS one},
volume = {20},
number = {4},
pages = {e0322105},
pmid = {40267072},
issn = {1932-6203},
mesh = {Animals ; *Garlic/chemistry ; Mice ; *Hearing Loss/drug therapy/physiopathology ; Mice, Inbred DBA ; *Plant Extracts/pharmacology/administration &amp; dosage/chemistry/therapeutic use ; *Cysteine/analogs &amp; derivatives/pharmacology/administration &amp; dosage ; Male ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Acetylcysteine/pharmacology ; *Sulfur Compounds/pharmacology/administration &amp; dosage ; },
abstract = {Garlic is rich in organosulfur compounds with high antioxidant capacity and is known to have various health benefits. Aged garlic is a particularly effective source of these active compounds because it contains fewer toxic components. This study evaluated the effects of S-allyl cysteine (SAC), a major functional organosulfur compound in garlic, and aged garlic extract (AGE) on the suppression of progressive hearing loss. SAC and AGE were dissolved in drinking water at 1% (w/w) and administered to DBA/2J mice, a model of early progressive hearing loss, for 12 weeks, starting at 4 weeks of age. While the results revealed a trend toward weight loss in the SAC group, the weight of the AGE group was comparable to that of the control group, and no adverse events were observed in either group. The hearing ability of the mice was measured using auditory brainstem responses at 4, 8, 12, and 16 weeks of age. Hearing loss at 8 and 16 kHz progressed over the 12-week period, with neither sample inhibiting hearing loss. In contrast, another organosulfur compound, N-acetylcysteine (NAC), administered in 1% w/w drinking water and evaluated for hearing loss over time, significantly suppressed hearing loss progression in DBA/2J mice. These results indicate that the NAC and SAC differ in their ability to prevent hearing loss and demonstrate that the inhibitory effects of functional food components on hearing loss can be evaluated over a short period in DBA/2J mice.},
}
@article {pmid40266430,
year = {2025},
author = {Chen, KL and Lu, HI and Yen, CY and Chen, CY and Chien, TM and Jeng, JH and Chen, BH and Chang, HW},
title = {Antioral cancer effects of ginger derivative 3-HDM exert oxidative stress-associated apoptosis and DNA damage.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {414},
pmid = {40266430},
issn = {1573-4978},
support = {112CM-KMU-05//Chimei-KMU jointed project/ ; MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology, Taiwan/ ; KMU-TC113A04//Kaohsiung Medical University Research Center/ ; KMU-DK(A)113003 and KMU-TB114009//Kaohsiung Medical University/ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Zingiber officinale/chemistry ; *DNA Damage/drug effects ; *Mouth Neoplasms/drug therapy/metabolism/genetics/pathology ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Cell Proliferation/drug effects ; Acetylcysteine/pharmacology ; },
abstract = {BACKGROUND: 3-Hydroxy-1-(3',5'-dimethoxy-4'-hydroxy-phenyl)-hexan-5-one (3-HDM), a novel ginger Zingiber officinale-derived compound, lacks anti-cancer investigation, especially for oral cancer. This study addresses the antioral function and mechanism of 3-HDM against oral cancer cells (Ca9-22 and CAL 27).<br><br>METHOD: MTS, flow cytometry, and western blotting were used to determine cell viability and antioral function and mechanism.<br><br>RESULTS: 3-HDM inhibits oral cancer cell viability without normal cell (S-G) toxicity. This selective antiproliferation relies on oxidative stress validated by N-acetylcysteine (NAC), a reactive oxygen species (ROS) remover. 3-HDM upregulates subG1 and annexin V proportions, enhances caspases 3 and 8 activation to a greater extent in oral cancer than in normal cells, reverted by NAC. This process demonstrates the ROS-dependent selective apoptotic character of 3-HDM. 3-HDM also upregulates more ROS and mitochondrial superoxide and downregulates the mitochondrial membrane potential and glutathione in oral cancer than in normal cells in a ROS-dependent manner. Moreover, 3-HDM suppresses antioxidant signaling mRNA expressions such as NFE2L2, NQO1, and TXN and inhibits NFE2L2 phosphorylation in oral cancer cells compared to normal cells. NAC also downregulates the 3-HDM-induced &#x3b3;H2AX and 8-hydroxy-2-deoxyguanosine DNA damage markers.<br><br>CONCLUSION: 3-HDM shows selective antioral cancer effects and mechanisms without toxicity to normal cells via oxidative stress regulation.},
}
@article {pmid40262667,
year = {2025},
author = {Liu, R and Dai, L and Jia, S and Geng, S and Niu, Y and Chen, J and Dong, C and Li, C and Shi, Y and Wang, X and Zhang, J and Zhao, N and Gao, Z and Yang, X and Gao, S},
title = {Fut8 regulated Unc5b hyperfucosylation reduces macrophage emigration and accelerates atherosclerosis development via the ferroptosis pathway.},
journal = {Free radical biology &amp; medicine},
volume = {235},
number = {},
pages = {1-14},
doi = {10.1016/j.freeradbiomed.2025.04.025},
pmid = {40262667},
issn = {1873-4596},
mesh = {Animals ; *Atherosclerosis/pathology/metabolism/genetics ; Mice ; *Ferroptosis/genetics ; Cell Movement ; *Fucosyltransferases/metabolism/genetics ; Lipoproteins, LDL/metabolism ; Foam Cells/metabolism/pathology ; Oxidative Stress ; *Macrophages/metabolism/pathology ; Tumor Suppressor Protein p53/genetics/metabolism ; *Receptors, Cell Surface/metabolism/genetics ; Humans ; Apolipoproteins E/genetics ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics/metabolism ; Mitochondria/metabolism ; Mice, Inbred C57BL ; Male ; Mice, Knockout ; },
abstract = {The accumulation of foam cells in the arterial walls is a defining characteristic of atherosclerosis. Enhancing their migration from plaques may represent a key strategy for slowing disease progression. Recent studies suggest that fucosyltransferase 8 (Fut8) impairs macrophage migration from the intima by modifying the Unc5b membrane receptor, thereby influencing the development of atherosclerosis. This study investigated the roles of Fut8 and Unc5b in foam cell migration using ApoE[-/-] mouse and foam cell models, employing techniques such as western blotting, mitochondrial function assays, wound healing experiments, and immunofluorescence staining. The findings indicate that Fut8 upregulation increases P53 expression and reduces SLC7A11 and GPX4 levels, leading to altered intracellular concentrations of GSH and Fe[2+], impaired mitochondrial function, and reduced migration capacity, all of which promote atherosclerosis. These mechanisms are closely associated with ferroptosis. Intervention with N-acetylcysteine (NAC) and buthionine sulfoximine (BSO) demonstrated that NAC mitigates oxidative stress and migration inhibition, induced by oxidized low-density lipoprotein (ox-LDL). Additionally, inhibiting ferroptosis slowed the progression of atherosclerosis in ApoE[-/-] mice. Together, these results highlight that Fut8 exacerbates atherosclerosis through a P53/SLC7A11-mediated enhancement of ferroptosis in foam cells, offering a novel perspective on the pathophysiology of atherosclerosis.},
}
@article {pmid40257108,
year = {2025},
author = {He, W and Xu, L and Jiang, W and Yao, S and Fu, Y and Cheng, Z and Zhang, D and Huang, L},
title = {miR-223-3p Mitigates Mitochondrial Dysfunction and Cementoblast Apoptosis in Orthodontic Root Resorption via FoxO3.},
journal = {Journal of periodontal research},
volume = {60},
number = {9},
pages = {923-936},
doi = {10.1111/jre.13384},
pmid = {40257108},
issn = {1600-0765},
support = {82170989//National Natural Science Foundation of China/ ; KQY202307//the Scientific Research and Innovation Project for Postgraduates of the Affiliated Stomatological Hospital of Chongqing Medical University/ ; CSTB2022NSCQ-MSX0794//Natural Science Foundation of Chongqing Municipality/ ; },
mesh = {*MicroRNAs/metabolism/genetics/physiology ; *Apoptosis/genetics ; *Forkhead Box Protein O3/metabolism/genetics ; Oxidative Stress ; *Mitochondria/metabolism ; *Dental Cementum/metabolism/cytology/pathology ; Reactive Oxygen Species/metabolism ; Animals ; Mice ; Membrane Potential, Mitochondrial ; Cell Line ; Tooth Movement Techniques/adverse effects ; },
abstract = {AIM: The aim of this study was to elucidate the roles of miR-223-3p in orthodontically induced inflammatory root resorption (OIIRR).<br><br>METHODS: We used high-throughput miRNA sequencing and transcriptome sequencing to analyze the differentially expressed miRNAs and mRNAs in OCCM-30 cells under hypoxia. Real-time quantitative PCR (RT-qPCR) and Western blotting were used to assess the expression of genes and proteins related to apoptosis, oxidative stress, and mitochondrial dysfunction. Fluorescence staining was employed to detect changes in cellular ROS (reactive oxygen species), MMP (mitochondrial membrane potential), and mtROS (mitochondrial ROS) expression.<br><br>RESULTS: We found that miR-223-3p targeted FoxO3 to regulate apoptosis in cementoblasts under hypoxic conditions. Moreover, hypoxia-induced FoxO3 increased oxidative stress and induced mitochondrial dysfunction in cementoblasts, resulting in cell apoptosis. Administration of the ROS inhibitor NAC (N-acetyl cysteine) effectively reversed FoxO3-induced oxidative stress and mitochondrial dysfunction, thereby rescuing cell apoptosis.<br><br>CONCLUSIONS: miR-223-3p targets FoxO3 and regulates the apoptosis of cementoblasts by improving oxidative stress and mitochondrial dysfunction. These findings may offer new insights into the mechanism of OIIRR.},
}
@article {pmid40256695,
year = {2025},
author = {Narvekar, PS and Shivanand, S and Patil, S and Raikar, S and Mallick, A and Doddwad, PK},
title = {Dentinal tubule penetration of a silicone-based endodontic sealer following N-acetyl cysteine intracanal medicament removal using ultrasonic agitation and laser activated irrigation - An in vitro study.},
journal = {Journal of conservative dentistry and endodontics},
volume = {28},
number = {3},
pages = {231-236},
pmid = {40256695},
issn = {2950-4708},
abstract = {CONTEXT: The removal of intracanal medicament is essential for sealer penetration and the success of endodontic therapy.<br><br>AIMS: To evaluate and compare the dentinal tubule penetration of a silicone-based endodontic sealer following N-acetyl cysteine (NAC) intracanal medicament removal using ultrasonic agitation and laser-activated irrigation.<br><br>MATERIALS AND METHODS: Eighty-one extracted single-rooted mandibular premolars were decoronated and prepared with ProTaper Universal rotary files up to MAF F3. To prepare medicament, NAC powder was mixed with propylene glycol in the ratio of 1:1, placed using a size #30 Lentulospiral, and specimens stored in an incubator for 14 days. The specimens were then instrumented with #30 Hedstr&#xf6;m and divided into three groups according to final irrigant activation techniques: Group I: Diode laser activation, Group II: Passive Ultrasonic agitation, Group III: No agitation (positive control). Canals were obturated with GuttaFlow bioseal sealer mixed with 0.1% Rhodamine B dye and gutta-percha cones and incubated for 7 days. The specimens were sectioned horizontally to obtain 1 mm thick sections from 2, 5, and 8 mm from the apex. Sections were examined under Confocal Laser Scanning Microscope to measure the depth of sealer penetration (in &#xb5;m).<br><br>STATISTICAL ANALYSIS: One-way analysis of variance and Tukeys multiple post hoc test.<br><br>RESULTS: The highest mean depth of penetration of 728.52 &#xb5;m was seen with Group I, followed by Group II and least was seen in Group III.<br><br>CONCLUSIONS: Diode laser activation group was most effective in the removal of NAC intracanal medicament from all the three regions of the root canal.},
}
@article {pmid40253238,
year = {2025},
author = {Zhou, Q and Lin, J and Li, Q},
title = {Study of high-strength, low-shrinkage dental resin composites with bifunctional polysilsesquioxane.},
journal = {Dental materials : official publication of the Academy of Dental Materials},
volume = {41},
number = {6},
pages = {755-767},
doi = {10.1016/j.dental.2025.03.012},
pmid = {40253238},
issn = {1879-0097},
mesh = {*Composite Resins/chemistry/chemical synthesis ; *Organosilicon Compounds/chemistry/chemical synthesis ; Materials Testing ; Polymerization ; Hardness ; Acrylic Resins/chemistry ; Acetylcysteine/chemistry ; Surface Properties ; *Polyurethanes/chemistry ; },
abstract = {OBJECTIVES: The aim of this study was to develop a new composite resin to solve the problem of volume shrinkage of conventional dental restorative composite resins during the curing process in order to improve their mechanical properties and reduce the risk of restoration failure.<br><br>METHODS: We synthesized the mercapto-alkenyl click chemical reaction product (MN-POSS) of acrylate-based POSS (MAP-POSS) with N-Acetylcysteine (NAC) using a bifunctional polysilsesquioxane modification technique and improved its dispersion in the resin matrix by physicochemical methods. In addition, methacrylate-based epoxy POSS (ME-POSS) was further synthesized and used to modify acrylate dental resins to form a free radical-cation hybrid light-curing system.<br><br>RESULTS: The results showed that the composites modified with MN-POSS significantly improved mechanical strength, while the application of ME-POSS effectively reduced polymerization shrinkage, improved the water absorption and dissolution properties of the materials, and enhanced mechanical properties and hardness. This study provides new ideas and material solutions to improve the performance of dental restorative materials.<br><br>SIGNIFICANCE: Both of these improved solutions demonstrate the potential of bifunctional POSS as a modified filler, providing new ideas and methods for the design of future dental restorative materials.},
}
@article {pmid40252905,
year = {2025},
author = {Ricardi, LL and Zecchinati, F and Perdomo, VG and Basiglio, CL and García, F and Arana, MR and Villanueva, SSM},
title = {Oxidative stress promotes post-translational down-regulation of MRP2 in Caco-2 cells: Involvement of proteasomal degradation and toxicological implications.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {201},
number = {},
pages = {115459},
doi = {10.1016/j.fct.2025.115459},
pmid = {40252905},
issn = {1873-6351},
mesh = {Humans ; Caco-2 Cells ; *Oxidative Stress/drug effects ; Multidrug Resistance-Associated Protein 2 ; *Down-Regulation/drug effects ; *Proteasome Endopeptidase Complex/metabolism ; *ATP-Binding Cassette, Sub-Family C Proteins/metabolism/genetics ; tert-Butylhydroperoxide/toxicity/pharmacology ; Reactive Oxygen Species/metabolism ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; *Protein Processing, Post-Translational ; },
abstract = {The intestinal tract is highly susceptible to oxidative stress (OS), which impairs gut barrier function. Multidrug Resistance-Associated Protein 2 (MRP2) is a key efflux pump in the intestinal transcellular barrier, regulating toxicant and drug disposition. We here evaluated the effects of OS on MRP2 in Caco-2 cells treated with tert-butyl hydroperoxide (TBH). After 24 h, TBH 250 μM increased ROS production and lipid peroxidation while decreasing GSH content and SOD activity, confirming OS induction. Under these conditions, total MRP2 protein levels decreased, while P-gp levels remained unchanged. Correspondingly, MRP2 efflux activity decreased, impairing barrier function against ochratoxin A (OTA), a substrate of MRP2, and exacerbating OTA toxicity. Localization analysis revealed reduced apical MRP2 signal in TBH 250 group, with unchanged mRNA levels, indicating post-transcriptional regulation. Mechanistically, TBH induced rapid MRP2 internalization (30 min), mediated by cPKC and clathrin, without microtubule involvement, followed by proteasomal degradation at 24 h. Both processes were dependent on GSH depletion, as treatment with N-Acetyl-l-Cysteine (NAC) restored GSH levels, MRP2 localization, and activity. We provide here the first evidence that human intestinal MRP2 is post-translationally downregulated under specific OS conditions, highlighting its potential role in exacerbating xenobiotic absorption and toxicity in OS-related human diseases.},
}
@article {pmid40251236,
year = {2025},
author = {Poojary, KK and Kunhiraman, JP and Madhvacharya, VV and Kumari, S and Krishna, N and S, SP and K, RG and Mutalik, S and Ghani, NK and Kabekkodu, SP and Prasad, TSK and Adiga, SK and Kalthur, G},
title = {Bromodomain and extraterminal protein inhibitor JQ1 induces maturation arrest and disrupts the cytoplasmic organization in mouse oocytes under in vitro conditions.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13448},
pmid = {40251236},
issn = {2045-2322},
mesh = {Animals ; *Oocytes/drug effects/metabolism/cytology ; Mice ; *Azepines/pharmacology ; *Triazoles/pharmacology ; Female ; Endoplasmic Reticulum Chaperone BiP ; *Cytoplasm/drug effects/metabolism ; In Vitro Oocyte Maturation Techniques ; Oxidative Stress/drug effects ; Oogenesis/drug effects ; },
abstract = {JQ1, a small cell-permeable molecule is known for its potent inhibitory action on bromodomain and extraterminal (BET) proteins. Although earlier studies have shown its inhibitory effect on male gametogenesis, limited information is available about its influence on oocyte development. Since BET genes are known to exhibit regulatory functions on oocyte development and maturation, the present study aimed to investigate the effect of JQ1 on oocyte developmental competence under in vitro conditions. Germinal vesicle (GV) stage oocytes were collected from adult Swiss albino mice and subjected to in vitro maturation (IVM) in the presence of various concentrations of JQ1 (25, 50, and 100 μM). The metaphase II (MII) stage oocytes were assessed for cytoplasmic organization and functional competence at 24 h after IVM. A significant decrease in nuclear maturation (at 50 and 100 μM), symmetric cytokinesis, altered distribution of mitochondria and cortical granules, poorly organized actin and meiotic spindle, misaligned chromosomes, and elevated endoplasmic reticulum (ER) stress and oxidative stress was observed in JQ1-exposed oocytes. Presence of N-acetyl cysteine (NAC), in IVM medium resulted in significant reduction in JQ1-induced oxidative stress and symmetric cytokinesis. Administration of JQ1 (50 mg/kg, intra peritoneal) to adult Swiss albino mice primed with pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) did not affect the ovulation. However, a high degree of oocyte degeneration, elevated intracellular reactive oxygen species (ROS), and GRP78 expression was observed in JQ1-administered mice. In conclusion, our study reveals that BET inhibitor JQ1 has detrimental effects on oocyte function and development.},
}
@article {pmid40243461,
year = {2025},
author = {Bilski, R and Nuszkiewicz, J},
title = {Antioxidant Therapies as Emerging Adjuncts in Rheumatoid Arthritis: Targeting Oxidative Stress to Enhance Treatment Outcomes.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
pmid = {40243461},
issn = {1422-0067},
mesh = {Humans ; *Arthritis, Rheumatoid/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *Antioxidants/therapeutic use/pharmacology ; Animals ; Reactive Oxygen Species/metabolism ; Antirheumatic Agents/therapeutic use/pharmacology ; Treatment Outcome ; },
abstract = {Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammation and progressive joint destruction. Recent data underscore oxidative stress as a primary factor in the pathophysiology of rheumatoid arthritis, intensifying inflammatory processes and tissue damage via the overproduction of reactive oxygen species (ROS) and compromised antioxidant defenses. Current therapies, including disease-modifying antirheumatic drugs (DMARDs), primarily target immune dysregulation but fail to address oxidative stress, necessitating novel adjunctive treatment strategies. This review explores the potential of antioxidant-based therapies as complementary approaches to RA management. Natural compounds such as curcumin, resveratrol, sulforaphane, and propolis exhibit strong anti-inflammatory and antioxidative properties by modulating redox-sensitive pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase (HO-1). N-acetylcysteine (NAC) replenishes intracellular glutathione, enhancing cellular resilience against oxidative stress. Additionally, molecular hydrogen (H2) selectively neutralizes harmful ROS, reducing oxidative damage and inflammation. The role of vitamin supplementation (D, B12, C, and K) in regulating immune responses and protecting joint structures is also discussed. This review aims to evaluate the efficacy and potential clinical applications of antioxidant therapies in RA, emphasizing their role in mitigating oxidative damage and improving treatment outcomes. While preliminary findings are promising, further clinical trials are needed to establish standardized dosing, long-term safety, and their integration into current RA treatment protocols.},
}
@article {pmid40243112,
year = {2025},
author = {She, Z and Zeng, F and Wu, S},
title = {A zwitterionic chromophore as both a biomarker-activatable optical imaging probe and a therapeutic agent for the detection and treatment of acute lung injury with bacterial infection.},
journal = {Biomaterials science},
volume = {13},
number = {11},
pages = {3006-3015},
doi = {10.1039/d5bm00419e},
pmid = {40243112},
issn = {2047-4849},
mesh = {Animals ; *Acute Lung Injury/drug therapy/diagnostic imaging/microbiology ; *Optical Imaging/methods ; *Fluorescent Dyes/chemistry/pharmacology ; Biomarkers/metabolism ; *Bacterial Infections/drug therapy/diagnostic imaging ; Humans ; Mice ; *Anti-Bacterial Agents/chemistry/pharmacology/therapeutic use ; Acetylcysteine/pharmacology/therapeutic use/chemistry ; },
abstract = {Acute lung injury (ALI), often complicated by bacterial infection, poses significant challenges in diagnosis and treatment. Nitric oxide (NO) plays a key role in the pathophysiology of ALI, making it an ideal biomarker for early detection. In this study, we developed a zwitterionic chromophore, ZW-N, designed as both a biomarker-activatable imaging probe and a therapeutic agent for ALI with bacterial infection. The chromophore ZW-N integrates quaternary ammonium groups for antimicrobial activity and zwitterionic sulfonate groups to enhance biocompatibility and water solubility. Built on a flexible propanyl linker that couples two heptamethine cyanine dyes, ZW-N enables biomarker-responsive dual-modal imaging via optoacoustic (OA) imaging and near-infrared second-window (NIR-II) fluorescence imaging. Moreover, the chromophore ZW-N demonstrates therapeutic efficacy when combined with the clinically used antioxidant N-acetylcysteine (NAC) to treat ALI with bacterial infection. This dual-functional chromophore offers a promising platform for non-invasive, real-time monitoring of ALI, providing significant potential for improved detection and a more effective treatment strategy.},
}
@article {pmid40240934,
year = {2025},
author = {Kim, JH and Lee, JH and Koo, YJ and Song, JW},
title = {N-actylcysteine inhibits diethyl phthalate-induced inflammation via JNK and STAT pathway in RAW264.7 macrophages.},
journal = {BMC molecular and cell biology},
volume = {26},
number = {1},
pages = {12},
pmid = {40240934},
issn = {2661-8850},
support = {2022R1I1A1A01068466//National Research Foundation of Korea/ ; 2022R1A2C1011500//National Research Foundation of Korea/ ; 2022R1F1A1075191//National Research Foundation of Korea/ ; },
mesh = {Animals ; Mice ; RAW 264.7 Cells ; *Phthalic Acids/toxicity ; *Macrophages/drug effects/metabolism ; *Inflammation/chemically induced/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; Cyclooxygenase 2/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Glutathione/metabolism ; Dinoprostone/metabolism ; *MAP Kinase Signaling System/drug effects ; Nitric Oxide/metabolism ; Signal Transduction/drug effects ; *STAT Transcription Factors/metabolism ; STAT3 Transcription Factor/metabolism ; *Acetylcysteine/pharmacology ; },
abstract = {BACKGROUND: Phthalates are plasticizers that cause inflammation in several cell types and adversely affect the health of humans and animals. Nacetylcysteine (NAC) has been shown to exert antioxidant effects in various diseases. However, the effect of NAC on diethyl phthalate (DEP)-induced toxicity in macrophages has not yet been elucidated. In this study, we investigated the effect and underlying mechanisms of NAC on DEP-induced inflammation in RAW264.7 macrophages. RAW264.7 macrophages were pretreated with NAC for 2 h followed by exposure to DEP. We investigated the effect of NAC on NO, reactive oxygen species (ROS), prostaglandin E2 (PGE2), and glutathione (GSH) levels following DEP exposure. In addition, pathway-related genes including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription (STAT) were evaluated using western blot.<br><br>RESULTS: Treatment with 100 and 300 &#xb5;M DEHP, DBP, and DEP significantly increased the protein levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) compared with those in the control group. However, NAC pretreatment downregulated the levels of NO, PGE2, and ROS, elevated GSH levels, and suppressed the mRNA levels of inflammatory cytokines such as interleukin (IL)-1&#x3b2;, IL-6, COX-2, and iNOS compared with those in the DEP-treated group. In addition, NAC significantly reduced the levels of p-JNK and p-STAT1/3 in RAW264.7 macrophages treated with DEP.<br><br>CONCLUSIONS: NAC pretreatment inhibits DEP-induced inflammation via the MAPK/JNK and STAT1/3 pathways in macrophages.},
}
@article {pmid40235406,
year = {2025},
author = {Yildirim, B and Erturk, C and Buyukdogan, H and Saritas, TB and Yildirim Erdogan, N and Ertem, F},
title = {Effect of N-acetylcysteine on fracture healing in rat femoral diaphysis: A histopathological, radiological, and biomechanical analysis.},
journal = {Joint diseases and related surgery},
volume = {36},
number = {2},
pages = {283-292},
pmid = {40235406},
issn = {2687-4792},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Male ; Rats, Wistar ; *Fracture Healing/drug effects ; *Femoral Fractures/diagnostic imaging/pathology/physiopathology/drug therapy/surgery ; Rats ; Diaphyses/diagnostic imaging/drug effects/pathology/injuries ; Biomechanical Phenomena ; Disease Models, Animal ; *Antioxidants/pharmacology ; *Femur/diagnostic imaging/drug effects/pathology/physiopathology ; Radiography ; },
abstract = {OBJECTIVES: The aim of this study was to examine the effect of N-acetylcysteine (NAC), which has antioxidant properties, on healing in a rat femoral diaphysis fracture model.<br><br>MATERIALS AND METHODS: Twenty-four male Wistar-Hannover rats were randomly divided into two groups: experimental (n=12) and control groups (n=12). An open femur fracture model (osteotomy) was applied to the right femora of both groups. Fixation was performed with Kirschner wire. While intraperitoneal NAC treatment was given to the experimental group for 21 days after surgery, an equal volume of intraperitoneal saline injection was administered to the control group. At the end of this period, the femurs obtained from the sacrificed animals were examined histopathologically, radiologically, and biomechanically. Huo scoring was used for histopathological examination. The samples were examined radiologically according to the Radiographic Union Scale in Tibial Fractures (RUST) scoring system. The three-point bending test was used for the biomechanical examination.<br><br>RESULTS: According to the third-week results, NAC could histopathologically contribute positively to fracture healing in rats (p=0.003 and p<0.05, respectively). Considering radiological and biomechanical parameters, no significant difference was observed between the groups in terms of healing (p>0.05). However, a positive significant correlation (67.7%) was found between histopathological results and radiological findings (p=0.016 and p<0.05, respectively).<br><br>CONCLUSION: Our study results indicate that NAC may have a histopathologically positive effect on the healing process in rat traumatic fractures. Based on these findings, NAC preparations may be used as a supportive agent in the treatment of fractures. Further clinical studies are needed.},
}
@article {pmid40229128,
year = {2025},
author = {Li, P and Meng, X and Lu, T and Sun, C and Song, G},
title = {Synergistic Effect of ROS and p38 MAPK in Apoptosis of TM4 Cells Induced by Titanium Dioxide Nanoparticles.},
journal = {Journal of applied toxicology : JAT},
volume = {45},
number = {8},
pages = {1521-1534},
doi = {10.1002/jat.4789},
pmid = {40229128},
issn = {1099-1263},
support = {82460651//National Natural Science Foundation of China/ ; 21966027//National Natural Science Foundation of China/ ; 2023AB049//Science and Technology Planning Project of Xinjiang Production and Construction Corps/ ; },
mesh = {*Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; *Titanium/toxicity ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Animals ; Cell Line ; Cell Survival/drug effects ; Mice ; Male ; *Nanoparticles/toxicity ; *Metal Nanoparticles/toxicity ; MAP Kinase Signaling System/drug effects ; },
abstract = {The adverse effects of titanium dioxide nanoparticles (TiO2 NPs) on the integrity of the blood-testis barrier (BTB) are widely recognized. However, the underlying mechanisms remain incompletely understood. The integrity of the BTB is imperative for the preservation of male reproductive health. TM4 cells, which are major component of the BTB, play a critical role in its integrity. The apoptosis of TM4 cells is closely associated with the disruption of the BTB. Therefore, we selected TM4 cells as experimental models to investigate the apoptosis induced by TiO2 NPs and the underlying mechanisms. Cell viability, excessive production of reactive oxygen species (ROS), activation of p38 mitogen-activated protein kinase (MAPK) pathway, and apoptosis-related protein expression levels were determined under various concentrations (50, 100, 150, and 200 μg/mL) of TiO2 NPs exposure. The results indicate that TiO2 NPs induced the overproduction of ROS and activated the p38 MAPK signaling pathway, which subsequently led to apoptosis. The ROS scavenger N-acetylcysteine (NAC) was able to suppress the activation of p38 MAPK pathway induced by TiO2 NPs, while the p38 MAPK inhibitor SB203580 mitigated TiO2 NPs-induced ROS overproduction and subsequent apoptosis, suggesting an interplay between ROS overproduction and p38 MAPK pathway activation. In summary, TiO2 NPs induced mitochondrial apoptosis via the ROS-p38 MAPK axis. A positive feedback regulatory mechanism exists between the two processes, promoting apoptosis in TM4 cells through a synergistic effect.},
}
@article {pmid40227392,
year = {2025},
author = {Amador-Martínez, I and Aparicio-Trejo, OE and Aranda-Rivera, AK and Bernabe-Yepes, B and Medina-Campos, ON and Tapia, E and Cortés-González, CC and Silva-Palacios, A and Roldán, FJ and León-Contreras, JC and Hernández-Pando, R and Saavedra, E and Gonzaga-Sánchez, JG and Ceja-Galicia, ZA and Sánchez-Lozada, LG and Pedraza-Chaverri, J},
title = {Effect of N-Acetylcysteine in Mitochondrial Function, Redox Signaling, and Sirtuin 3 Levels in the Heart During Cardiorenal Syndrome Type 4 Development.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {3},
pages = {},
pmid = {40227392},
issn = {2076-3921},
support = {CBF2023-2024-190//CONAHCYT/ ; IN200922 and IN202725//PAPIIT-UNAM/ ; 21-1250//Instituto Nacional de Cardiolog&#xed;a Ignacio Ch&#xe1;vez/ ; },
abstract = {Type 4 cardiorenal syndrome (CRS-4) is a pathology in which chronic kidney disease (CKD) triggers the development of cardiovascular disease. CKD pathophysiology produces alterations that can affect the bioenergetics of heart mitochondria, causing oxidative stress and reducing antioxidant glutathione (GSH) levels. GSH depletion alters protein function by affecting post-translational modifications such as S-glutathionylation (RS-SG), exacerbating oxidative stress, and mitochondrial dysfunction. On the other hand, N-acetylcysteine (NAC) is an antioxidant GSH precursor that modulates oxidative stress and RS-SG. Moreover, recent studies have found that NAC can activate the Sirtuin 3 (SIRT3) deacetylase in diseases. However, the role of NAC and its effects on mitochondrial function, redox signaling, and SIRT3 modifications in the heart during CRS-4 have not been studied. This study aimed to investigate the role of NAC in mitochondrial function, redox signaling, and SIRT3 in the hearts of animals with CRS-4 at two months of follow-up. Our results showed that the oral administration of NAC (600 mg/kg/day) improved blood pressure and reduced cardiac fibrosis. NACs' protective effect was associated with preserving cardiac mitochondrial bioenergetics and decreasing these organelles' hydrogen peroxide (H2O2) production. Additionally, NAC increased GSH levels in heart mitochondria and regulated the redox state, which coincided with an increase in nicotinamide adenine dinucleotide oxidized (NAD[+]) levels and a decrease in mitochondrial acetylated lysines. Finally, NAC increased SIRT3 levels and the activity of superoxide dismutase 2 (SOD-2) in the heart. Thus, treatment with NAC decreases mitochondrial alterations, restores redox signaling, and decreases SIRT3 disturbances during CRS-4 through an antioxidant defense mechanism.},
}
@article {pmid40220949,
year = {2025},
author = {Sztolsztener, K and Michalak, D and Chabowski, A},
title = {N-acetylcysteine influence on PI3K/Akt/mTOR and sphingolipid pathways in rats with MASLD induced by HFD: a promising new therapeutic purpose.},
journal = {Molecular and cellular endocrinology},
volume = {603},
number = {},
pages = {112545},
doi = {10.1016/j.mce.2025.112545},
pmid = {40220949},
issn = {1872-8057},
mesh = {Animals ; *Proto-Oncogene Proteins c-akt/metabolism ; *Sphingolipids/metabolism ; *TOR Serine-Threonine Kinases/metabolism ; Male ; *Acetylcysteine/pharmacology/therapeutic use ; *Phosphatidylinositol 3-Kinases/metabolism ; *Signal Transduction/drug effects ; *Diet, High-Fat/adverse effects ; Molecular Docking Simulation ; Rats ; Liver/metabolism/pathology/drug effects ; *Fatty Liver/drug therapy/metabolism/etiology/pathology ; Phosphorylation/drug effects ; Insulin/metabolism ; Rats, Sprague-Dawley ; Rats, Wistar ; },
abstract = {Sphingolipid and glucose metabolism play important roles in the induction and progression of severe liver disorders like metabolic dysfunction-associated steatotic liver disease (MASLD). The perturbation in sphingolipid formation may improve the liver structure and functioning and may constitute the potential therapeutic options for the development of simple steatosis and its progression to steatohepatitis. This study aims to assess the influence of N-acetylcysteine (NAC) on the sphingolipid and insulin signaling pathways in rats subjected to standard or high-fat diets. Sphingolipid level was measured using high-performance liquid chromatography (HPLC). A multiplex assay kit determined the level of phosphorylated form of proteins included in the PI3K/Akt/mTOR pathway. The immunoblotting estimated the expression of proteins from sphingolipid and insulin transduction pathways. A histological Oil red O staining was used to assess the hepatic accumulation of lipid droplets. Molecular docking was applied to showcase NAC interaction with PI3K/Akt/mTOR pathway proteins. NAC decreased dihydroceramide and ceramide levels and increased phosphorylation of sphingosine and sphinganine. This antioxidant also enhanced phosphorylated Akt, GSK3α/β, and P70 S6 kinase and decreased phosphorylated S6RP. In silico docking analysis of insulin signaling molecules evidenced the higher binding affinity of NAC with all tested proteins, i.e., IRS1, PTEN, Akt, GSK3α/β, P70 S6 kinase, and S6RP, suggesting a potential protective influence on insulin resistance development, which is one of the criteria for MASLD diagnosing. Based on these data, NAC improved the hepatic insulin sensitivity and sphingolipid synthesis and storage, improving and restoring glucose homeostasis.},
}
@article {pmid40220169,
year = {2025},
author = {Ciftel, E and Mercantepe, T and Ciftel, S and Karakas, SM and Aktepe, R and Yilmaz, A and Mercantepe, F},
title = {Somatostatin and N-acetylcysteine on testicular damage triggered by ischemia reperfusion: cellular protection and antioxidant effects.},
journal = {Hormones (Athens, Greece)},
volume = {24},
number = {3},
pages = {727-742},
pmid = {40220169},
issn = {2520-8721},
mesh = {Male ; Animals ; *Acetylcysteine/pharmacology ; *Reperfusion Injury/pathology/drug therapy/metabolism ; *Somatostatin/pharmacology ; *Testis/drug effects/pathology/metabolism ; *Antioxidants/pharmacology ; Rats ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Testosterone/blood ; *Testicular Diseases/pathology/metabolism ; Rats, Sprague-Dawley ; },
abstract = {Ischemia-reperfusion (I/R) injury is a significant cause of testicular damage, leading to infertility and other reproductive dysfunctions. Antioxidant therapies have emerged as a potential intervention to mitigate oxidative stress and cellular damage. This study investigates the effects of somatostatin (SST) and N-acetylcysteine (NAC) on testicular damage induced by I/R, focusing on their antioxidant and cellular protective effects. Twenty-four male rats were divided into four groups, as follows: sham operated, I/R injury, I/R + somatostatin treatment, and I/R + NAC treatment. A testicular I/R injury was induced surgically, followed by either SST or NAC administration. Testicular tissues were assessed histopathologically using hematoxylin and eosin staining and employing Johnson's biopsy scoring. Immunohistochemical analyses were performed for caspase- 3, 8-hydroxy- 2'-deoxyguanosine (8-OHdG), testis-specific histone 2B, and testosterone to evaluate apoptosis, oxidative DNA damage, cellular proliferation, and steroidogenesis, respectively. Serum levels of testosterone and follicle-stimulating hormone (FSH) were measured by biochemical analysis. The results showed that both SST and NAC treatments significantly ameliorated histopathological damage and reduced the levels of caspase- 3 and 8-OHdG, indicating reduced apoptosis and oxidative DNA damage. Furthermore, increased testis-specific histone 2B positivity suggested enhanced cellular proliferation. Notably, administration of SST decreased testosterone positivity in the testis, whereas NAC treatment increased it. However, no significant differences in serum testosterone levels were observed between the NAC and SST groups. In addition, serum FSH levels of the I/R + SST group were found to be significantly higher than those of the control group. SST and NAC exhibit protective effects against testicular damage induced by I/R, as evidenced by their antioxidant and anti-apoptotic properties. The differential impact on testosterone positivity in the testis tissue highlights distinct underlying mechanisms, warranting further investigation. Despite these promising findings, the lack of significant changes in serum hormone levels calls for additional studies to fully elucidate the therapeutic potential and mechanistic pathways of SST and NAC in the context of testicular I/R injury.},
}
@article {pmid40218498,
year = {2025},
author = {Jensch, H and Setford, S and Thomé, N and Srikanthamoorthy, G and Weingärtner, L and Grady, M and Holt, E and Pfützner, A},
title = {Dynamic Interference Testing-Unexpected Results Obtained with the Abbott Libre 2 and Dexcom G6 Continuous Glucose Monitoring Devices.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {7},
pages = {},
pmid = {40218498},
issn = {1424-8220},
support = {951933 (ForgetDiabetes)//European Union's Horizon 2020 research and innovation program/ ; Unrestricted grant//Lifescan Global Corp./ ; },
mesh = {*Blood Glucose Self-Monitoring/instrumentation/methods ; Humans ; *Blood Glucose/analysis ; *Biosensing Techniques/methods ; Continuous Glucose Monitoring ; },
abstract = {BACKGROUND: Sensors for continuous glucose monitoring (CGM) are now commonly used by people with type 1 and type 2 diabetes. However, the response of these devices to potentially interfering nutritional, pharmaceutical, or endogenous substances is barely explored. We previously developed an in vitro test method for continuous and dynamic CGM interference testing and herein explore the sensitivity of the Abbott Libre2 (L2) and Dexcom G6 (G6) sensors to a panel of 68 individual substances.<br><br>METHODS: In each interference experiment, L2 and G6 sensors were exposed in triplicate to substance gradients from zero to supraphysiological concentrations at a stable glucose concentration of 200 mg/dL. YSI Stat 2300 Plus was used as the glucose reference method. Interference was presumed if the CGM sensors showed a mean bias of at least &#xb1;10% from baseline with a tested substance at any given substance concentration.<br><br>RESULTS: Both L2 and G6 sensors showed interference with the following substances: dithiothreitol (maximal bias from baseline: L2/G6: +46%/-18%), galactose (>+100%/+17%), mannose (>+100%/+20%), and N-acetyl-cysteine (+11%/+18%). The following substances were found to interfere with L2 sensors only: ascorbic acid (+48%), ibuprofen (+14%), icodextrin (+10%), methyldopa (+16%), red wine (+12%), and xylose (>+100%). On the other hand, the following substances were found to interfere with G6 sensors only: acetaminophen (>+100%), ethyl alcohol (+12%), gentisic acid (+18%), hydroxyurea (>+100%), l-cysteine (-25%), l-Dopa (+11%), and uric acid (+33%). Additionally, G6 sensors could subsequently not be calibrated for use after exposure to dithiothreitol, gentisic acid, l-cysteine, and mesalazine (sensor fouling).<br><br>CONCLUSIONS: Our standardized dynamic interference testing protocol identified several nutritional, pharmaceutical and endogenous substances that substantially influenced L2 and G6 sensor signals. Clinical trials are now necessary to investigate whether our findings are of relevance during routine care.},
}
@article {pmid40207512,
year = {2025},
author = {Zhou, Y and Sha, J and Xu, B and Zhang, K and Wang, Y and Jiang, S and Zhang, H and Xu, S},
title = {Identification and Characterization of Dacomitinib Metabolites in Rats by Liquid Chromatography Combined With Q-Exactive-Orbitrap High Resolution Mass Spectrometry.},
journal = {Biomedical chromatography : BMC},
volume = {39},
number = {5},
pages = {e70075},
doi = {10.1002/bmc.70075},
pmid = {40207512},
issn = {1099-0801},
mesh = {Animals ; Rats ; Microsomes, Liver/metabolism ; Rats, Sprague-Dawley ; Chromatography, Liquid/methods ; *Quinazolinones/metabolism/analysis/chemistry/urine/pharmacokinetics ; Male ; *Mass Spectrometry/methods ; Tandem Mass Spectrometry/methods ; },
abstract = {Dacomitinib is an irreversible inhibitor targeting epidermal growth factor receptor, which has been developed for the treatment of metastatic non-small cell lung cancer (NSCLC). The aim of this study was to establish a reliable liquid chromatography combined with high resolution mass spectrometric method to identify and characterize the metabolites of dacomitinib in rats. In vitro metabolism was investigated through 60-min incubation with rat liver microsomes, while in vivo analysis involved bile and urine sample collection following a single oral 10 mg/kg dose. A total of 18 metabolites, were structurally elucidated through accurate MS measurements, MS[2] spectral interpretation, and fragmentation pattern analysis, including two GSH conjugates and two N-acetyl-cysteine conjugates. Among these metabolites, a total of 12 metabolites were first reported, i.e., M1, M2, M3, M7, M9, M10, M11, M13, M14, M15, M16, and M17. The parent drug remained the predominant species across all metrices. The primary metabolic pathways included: oxidative defluorination, O-demethylation, N-dealkylation, oxidative deamination, piperidin ring opening, N-oxygenation, lactam formation, dehydrogenation, and hydroxylation. Phase II biotransformation pathways included GSH conjugation and N-acetyl-cysteine conjugation. These findings enhance understanding of dacomitinib's metabolic fate, providing critical insights into its elimination mechanisms, and supporting subsequent evaluation of therapeutic efficacy and safety profiles.},
}
@article {pmid40207489,
year = {2025},
author = {Efati, M and Sahebkar, A and Tavallaei, S and Alidadi, S and Hosseini, H and Hamidi-Alamdari, D},
title = {Protective effect of Leuco-methylene blue against acetaminophen-induced liver injury: an experimental study.},
journal = {Drug and chemical toxicology},
volume = {48},
number = {4},
pages = {888-900},
doi = {10.1080/01480545.2025.2485347},
pmid = {40207489},
issn = {1525-6014},
mesh = {Animals ; *Acetaminophen/toxicity ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/pathology/etiology ; *Methylene Blue/pharmacology/analogs &amp; derivatives ; Male ; Rats ; Oxidative Stress/drug effects ; *Analgesics, Non-Narcotic/toxicity ; Liver/drug effects/pathology/metabolism ; Antioxidants/pharmacology ; Rats, Wistar ; Disease Models, Animal ; },
abstract = {Acetaminophen is a commonly used drug for mild to moderate pain relief; however, acetaminophen toxicity due to the formation of toxic metabolites is a major cause of drug-induced liver injury. Methylene blue is an FDA-approved drug for the treatment of methemoglobinemia and has potential applications in the treatment of carbon monoxide and cyanide poisoning. Leuco-methylene blue, a colorless form of methylene blue, is more effective in entering cells and counteracting oxidative stress, making it a valuable option in regulating mitochondrial function and ATP production. In this study, we aimed to evaluate the effect of LMB on liver damage caused by acetaminophen toxicity. Thirty-six rats were divided into six groups: control, APAP, NAC, LMB, MB, and NAC+LMB. All groups except the control received acetaminophen (1500 mg/kg), followed by treatments with NAC (100 mg/kg), LMB (5 mg/kg), MB (5 mg/kg), and NAC+LMB after 3 hours. The rats were sacrificed 24 hours post-acetaminophen administration. LMB significantly reduced serum levels of liver enzymes (ALT, AST, and ALP) and increased the expression of genes involved in mitochondrial biogenesis and antioxidant defense (PGC-1, Nrf2, and Tfam). Additionally, LMB significantly increased total antioxidant capacity and glutathione reductase levels, decreased the prooxidant-antioxidant balance (PAB), and reduced the expression of inflammatory cytokines (IL-6 and TNF-α) in the liver tissue. LMB effectively reduced the severity of acetaminophen-induced liver damage through antioxidant and anti-inflammatory effects. LMB can effectively ameliorate APAP-induced toxicity in rats, with comparable efficacy to N-acetylcysteine with respect to most complications of acetaminophen-induced toxicity in rats.},
}
@article {pmid40205270,
year = {2025},
author = {Gouda, AR and El-Bassiouny, NA and Salahuddin, A and Hamouda, EH and Kassem, AB},
title = {Repurposing of high-dose N-acetylcysteine as anti-inflammatory, antioxidant and neuroprotective agent in moderate to severe traumatic brain injury patients: a randomized controlled trial.},
journal = {Inflammopharmacology},
volume = {33},
number = {6},
pages = {3307-3316},
pmid = {40205270},
issn = {1568-5608},
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Acetylcysteine/administration &amp; dosage/pharmacology/therapeutic use ; *Anti-Inflammatory Agents/administration &amp; dosage/pharmacology/therapeutic use ; *Antioxidants/administration &amp; dosage/pharmacology/therapeutic use ; Biomarkers/blood ; *Brain Injuries, Traumatic/drug therapy ; Glasgow Coma Scale ; Interleukin-6/blood ; Malondialdehyde/blood ; *Neuroprotective Agents/administration &amp; dosage/pharmacology/therapeutic use ; Phosphopyruvate Hydratase/blood ; S100 Calcium Binding Protein beta Subunit/blood ; Drug Repositioning ; },
abstract = {INTRODUCTION: Traumatic brain injury (TBI) refers to an impact of the brain within the skull resulting in an altered mental state. The study aim is to determine the effect of a high dose of N-acetylcysteine (NAC) on biochemical and inflammatory markers of neuronal damage and clinical outcomes in patients with moderate to severe TBI.<br><br>METHODS: A randomized open label-controlled trial was conducted on 40 patients with moderate to severe TBI patients presented to the emergency unit within&#x2009;<&#x2009;24&#xa0;h since the trauma occurred and randomized into NAC and control groups 20 patients each. Serum samples for evaluation of biomarkers: malondialdehyde (MDA), interleukin-6 (IL-6), neuron-specific enolase (NSE), and S100B were withdrawn at baseline and on day 7. The patients were followed for 7 days and evaluated clinically by the Glasgow Coma Scale (GCS).<br><br>RESULTS: There was a significant decrease in NSE and MDA levels on day 7 from baseline in NAC group (p&#x2009;<&#x2009;0.001 and p&#x2009;<&#x2009;0.001). Also, S100B and IL-6 decreased significantly in NAC group on day 7 from baseline (p&#x2009;=&#x2009;0.003 and p&#x2009;<&#x2009;0.001 consequently) compared to control group. Moreover, patients in NAC group showed a significantly shorter length of stay at intensive care unit (ICU) (p&#x2009;=&#x2009;0.038). There was a significant increase in GCS in NAC group on&#xa0;day 7 from baseline (p&#x2009;=&#x2009;0.001).<br><br>CONCLUSION: Adjunctive early use of high-dose NAC significantly reduced inflammatory and oxidative markers and had neuroprotective effect which may be a novel treatment option for moderate to severe TBI patients.<br><br>TRIAL REGISTRATION: Pactr.org identifier: (PACTR202209548995270) on 14 September 2022.},
}
@article {pmid40202448,
year = {2025},
author = {Ommi, NB and Mattocks, DAL and Kalecký, K and Bottiglieri, T and Nichenametla, SN},
title = {Pharmacological recapitulation of the lean phenotype induced by the lifespan-extending sulfur amino acid-restricted diet.},
journal = {Aging},
volume = {17},
number = {4},
pages = {960-981},
pmid = {40202448},
issn = {1945-4589},
mesh = {Animals ; Male ; Mice ; *Amino Acids, Sulfur/administration &amp; dosage ; *Longevity/drug effects ; Glutathione/metabolism ; Mice, Inbred C57BL ; Phenotype ; Liver/metabolism/drug effects ; Buthionine Sulfoximine/pharmacology ; Diet, High-Fat ; Methionine ; Obesity/metabolism ; Acetylcysteine/pharmacology ; },
abstract = {Sulfur amino acid restriction (SAAR), lowering the dietary concentration of sulfur amino acids methionine and cysteine, induces strong anti-obesity effects in rodents. Due to difficulties in formulating the SAAR diet for human consumption, its translation is challenging. Since our previous studies suggest a mechanistic role for low glutathione (GSH) in SAAR-induced anti-obesity effects, we investigated if the pharmacological lowering of GSH recapitulates the lean phenotype in mice on a sulfur amino acid-replete diet. Male obese C57BL6/NTac mice were fed high-fat diets with 0.86% methionine (CD), 0.12% methionine (SAAR), SAAR diet supplemented with a GSH biosynthetic precursor, N-acetylcysteine in water (NAC), and CD supplemented with a GSH biosynthetic inhibitor, DL-buthionine-(S, R)-sulfoximine in water (BSO). The SAAR diet lowered hepatic GSH but increased Nrf2, Phgdh, and serine. These molecular changes culminated in lower hepatic lipid droplet frequency, epididymal fat depot weights, and body fat mass; NAC reversed all these changes. BSO mice exhibited all SAAR-induced changes, with two notable differences, i.e., a smaller effect size than that of the SAAR diet and a higher predilection for molecular changes in kidneys than in the liver. Metabolomics data indicate that BSO and the SAAR diet induce similar changes in the kidney. Unaltered plasma aspartate and alanine transaminases and cystatin-C indicate that long-term continuous administration of BSO is safe. Data demonstrate that BSO recapitulates the SAAR-induced anti-obesity effects and that GSH plays a mechanistic role. BSO dose-response studies in animals and pilot studies in humans to combat obesity are highly warranted.},
}
@article {pmid40201900,
year = {2025},
author = {Hu, X and Wu, JL and He, Q and Xiong, ZQ and Li, N},
title = {Strategy for cysteine-targeting covalent inhibitors screening using in-house database based LC-MS/MS and drug repurposing.},
journal = {Journal of pharmaceutical analysis},
volume = {15},
number = {3},
pages = {101045},
pmid = {40201900},
issn = {2214-0883},
abstract = {Targeted covalent inhibitors, primarily targeting cysteine residues, have attracted great attention as potential drug candidates due to good potency and prolonged duration of action. However, their discovery is challenging. In this research, a database-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy was developed to quickly discover potential cysteine-targeting compounds. First, compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes. And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database. Second, substrate-independent product ions produced from N-acetyl-cysteine moiety were selected. Third, multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds. This strategy showed broad applicability, and covalent compounds with diverse structures were screened out, offering structural resources for covalent inhibitors development. Moreover, the screened compounds, norketamine and hydroxynorketamine, could modify synaptic transmission-related proteins in vivo, indicating their potential as covalent inhibitors. This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.},
}
@article {pmid40200382,
year = {2025},
author = {Kasai, H and Kawai, K and Fujisawa, K},
title = {Formation of the toxic furan metabolite 2-butene-1,4-dial through hemin-induced degradation of 2,4-alkadienals in fried foods.},
journal = {Genes and environment : the official journal of the Japanese Environmental Mutagen Society},
volume = {47},
number = {1},
pages = {8},
pmid = {40200382},
issn = {1880-7046},
abstract = {BACKGROUND: The mechanism of protein modification by 2,4-alkadienals (ADE), lipid peroxidation products prevalent in fried foods, was investigated through model reactions.<br><br>RESULTS: A mixture of 2,4-heptadienal (HDE) and hemin was initially incubated at pH 3.0-7.4, followed by treatment with acetyl-cysteine (AcCys) and acetyl-lysine (AcLys) at pH 7.4. Analysis via HPLC revealed a product with a characteristic UV spectrum as the primary peak. This product was identified as an AcCys-pyrrole-AcLys (CPL) crosslink derived from AcCys, 2-butene-1,4-dial (BDA), and AcLys. Increasing the HDE concentration in the initial reaction led to maximum CPL formation at pH 3.5 in the presence of hemin. Lowering the HDE concentration with a higher Cys/HDE ratio resulted in CPL formation, which was observed at pH 7.4 and 3.5 in the presence of hemin. Upon incubation of ADE and hemin at pH 3.0-3.5, BDA was directly identified as 2,4-dinitrophenylhydrazone. BDA was also detected in the 2,4-decadienal reaction mixture. Additionally, a notable propensity for high BDA-dC adduct formation with hemin under acidic conditions was observed, consistent with the results of CPL assay and BDA-2,4-dinitrophenylhydrazone analysis.<br><br>CONCLUSIONS: 1) BDA is efficiently generated from ADE in the presence of hemin under gastric conditions, and 2) BDA-derived CPL can also form under physiological conditions (pH 7.4) through the interaction of ADE, hemin, Cys, and Lys. BDA is recognized as the primary reactive metabolite of the suspected carcinogen furan (IARC, 2B). Given that human intake of ADE exceeds that of furan and acrylamide (IARC 2A) by several orders of magnitude, and the estimated hemin concentration in the stomach post-meal is comparable to the present study, a substantial amount of BDA may form in the stomach following consumption of fried foods and meat. The risk assessment of ADE warrants a thorough re-evaluation, based on the toxicity mechanism of BDA.},
}
@article {pmid40199136,
year = {2025},
author = {Chuang, YT and Liu, W and Chien, TM and Cheng, YB and Jeng, JH and Chen, CY and Tang, JY and Chang, HW},
title = {Antiproliferative and apoptotic effects of (1R*,12R*)-dolabella-4(16),7,10-triene-3,13-dione (CI-A) in oral cancer cells are mediated by oxidative stress and ERK activation.},
journal = {International immunopharmacology},
volume = {155},
number = {},
pages = {114615},
doi = {10.1016/j.intimp.2025.114615},
pmid = {40199136},
issn = {1878-1705},
mesh = {Humans ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; *Mouth Neoplasms/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Reactive Oxygen Species/metabolism ; *Antineoplastic Agents/pharmacology ; *Extracellular Signal-Regulated MAP Kinases/metabolism ; Glutathione/metabolism ; },
abstract = {The anticancer effects and mechanisms of the main component (CI-A) of methanol extracts of Clavularia inflat have not been reported. This study explores the anti-oral cancer effect and mechanism of (1R*,12R*)-dolabella-4(16),7,10-triene-3,13-dione (CI-A) and compared with normal cells. CI-A shows oxidative-stress-dependent preferential antiproliferation of oral cancer cells without normal cell toxicity. CI-A triggers cell cycle dysregulation, apoptosis/caspase activation, cellular/mitochondrial ROS induction, glutathione depletion, and oxidative DNA damage in oral cancer but not normal cells. After testing with three MAPK (p38, JNK, and ERK) inhibitors, only the ERK inhibitor (PD98059) protects against CI-A-induced antiproliferation in oral cancer cells. CI-A upregulates phosphorylated ERK in oral cancer cells compared to normal cells. Notably, a ROS inhibitor, N-acetylcysteine (NAC), attenuates all CI-A-modulated changes. Moreover, the CI-A-triggered annexin V-detected apoptosis and caspase 3/8/9 activations of oral cancer cells were downregulated by PD98059. In conclusion, CI-A induces the oxidative-stress- and ERK-dependent antiproliferative and apoptotic mechanism in oral cancer cells and shows the benefit of non-cytotoxicity to normal cells.},
}
@article {pmid40199010,
year = {2025},
author = {Ashraf, R and Khalid, Z and Qin, QP and Iqbal, MA and Taskin-Tok, T and Bayil, &#x130; and Quah, CK and Daud, NAM and Alqahtany, FZ and Amin, MA and El-Bahy, SM},
title = {Synthesis of N-heterocyclic carbene‑selenium complexes modulating apoptosis and autophagy in cancer cells: Probing the interactions with biomolecules and enzymes.},
journal = {Bioorganic chemistry},
volume = {160},
number = {},
pages = {108435},
doi = {10.1016/j.bioorg.2025.108435},
pmid = {40199010},
issn = {1090-2120},
mesh = {Humans ; *Apoptosis/drug effects ; *Methane/analogs &amp; derivatives/chemistry/pharmacology ; *Antineoplastic Agents/pharmacology/chemical synthesis/chemistry ; *Autophagy/drug effects ; *Heterocyclic Compounds/chemistry/pharmacology/chemical synthesis ; Drug Screening Assays, Antitumor ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; *Selenium/chemistry/pharmacology ; HeLa Cells ; Cell Proliferation/drug effects ; *Coordination Complexes/pharmacology/chemical synthesis/chemistry ; },
abstract = {Growing cancer resistance is a global threat that calls for development of newer chemotherapeutic analogues especially targeted based therapy to enhance efficacy and selectivity. In this contribution, herein, we report synthesis of selenium incorporated N-heterocyclic carbene (NHC) compounds to explore their potential cytotoxicity against HeLa cells. Test compounds were assured for suitability as drug candidates through physiochemical properties that showed lipophilicity logP 0.85-1.45 for C1-C3 and found stable in biological media (DMEM), whereas, least reactive with N-acetyl cysteine (NAC) and L-glutathione. All the studied compounds showed good cytotoxicity against various cancer strains while compound C1 [3,3-(hexane-1,6-diyl)bis(1-phenethyl-1H-imidazole-2(3H)-selenone)] and C2 [3,3-(hexane-1,6-diyl)bis(1-decyl-1H-imidazole-2(3H)-selenone)] showed promising results with IC50 values of 14.65 ± 0.66 and 8.05 ± 0.35 μg/mL respectively as compared to positive control 21.5 ± 0.05 μg/mL against HeLa cell lines. These compounds showed six-fold higher apoptosis than control with higher accumulation of Ca[+] ions intracellularly that alters the expression level of autophagy proteins and increased capase-9 activity. Cell cycle analysis indicated an arrest of cycle in G1 phase of HeLa cells when treated with C1 &amp; C2. Test compounds showed prominent affinity for binding with DNA and inhibiting thioredoxin reductase enzymes in time dependent manners. These findings indicate that Selenium NHC compounds are promising drug candidates to induce cytotoxicity via apoptosis, autophagy and mitochondrial membrane disruptions to manage tumor growth.},
}
@article {pmid40188524,
year = {2025},
author = {Yang, W and Wang, F and Liu, J and Wang, X and Zhang, H and Gao, D and Wang, A and Jin, Y and Chen, H},
title = {β-Hydroxybutyrate aggravates LPS-induced inflammatory response in bovine endometrial epithelial cells by activating the oxidative stress/NF-κB signaling pathway.},
journal = {International immunopharmacology},
volume = {154},
number = {},
pages = {114609},
doi = {10.1016/j.intimp.2025.114609},
pmid = {40188524},
issn = {1878-1705},
mesh = {Animals ; Cattle ; Female ; *3-Hydroxybutyric Acid/metabolism ; Oxidative Stress/drug effects ; Lipopolysaccharides/immunology ; *Epithelial Cells/drug effects/immunology ; Signal Transduction/drug effects ; *Endometrium/pathology/cytology ; NF-kappa B/metabolism ; Cell Line ; *Endometritis/immunology/metabolism ; Inflammation ; Cytokines/metabolism ; Ketosis ; *Cattle Diseases/immunology ; },
abstract = {Ketosis, a metabolic disorder characterized by elevated levels of ketone bodies in the blood or urine, is known to impair the health and productivity of dairy cows, leading to substantial economic losses in the dairy industry. When ketosis occurs in dairy cows, the levels of β-hydroxybutyrate (BHBA), an abundant form of ketone bodies, in the blood increase significantly. Elevated BHBA levels have been shown to negatively impact reproductive performance and increase the incidence of periparturient diseases in dairy cows, including mastitis and endometritis. However, the role of BHBA in the development of endometritis in dairy cows and its underlying mechanisms remain largely unclear. The present study was designed to investigate the specific role of BHBA in the development of endometritis using an inflammatory response model of the bovine endometrial epithelial cell line (BENDs). Escherichia coli lipopolysaccharide (LPS) treatment (1 μg/mL) significantly increased the expression levels of interleukin (IL)-6 and IL-1β, as well as the phosphorylation of p65 and IκB in BENDs. In addition, co-treatment with BHBA (2.4 mM) and LPS (1 μg/mL) significantly increased the expression levels of proinflammatory cytokines (IL-6, IL-1β, and IL-8), as well as the phosphorylation of p65 and IκB, compared to the LPS-only treatment group. Immunofluorescence staining showed that the addition of LPS altered the nuclear localization of p65, and co-treatment with BHBA and LPS further promoted the translocation of p65 to the nucleus. Additionally, the addition of BHBA significantly increased the levels of oxidation indicators (MDA), whereas the levels of antioxidative indicators, including heme oxygenase-1 (HO-1) and catalase (CAT), were markedly decreased in BENDs. As a representative antioxidant, N-acetylcysteine (NAC) treatment significantly reduced the phosphorylation of p65 and IκB in the BHBA and LPS co-treatment group. SC75741, an NF-κB signaling pathway inhibitor, significantly decreased the expression levels of proinflammatory cytokines (IL-6, IL-1β, IL-8, and CCL5) in the BHBA and LPS co-treatment group. In summary, the current study demonstrates that BHBA aggravates LPS-induced inflammatory response in BENDs through the activation of oxidative stress/NF-κB signaling pathway, unravelling the mechanism by which BHBA exacerbates the inflammatory response in the BENDs of dairy cattle. This study elucidates the role of ketosis and its key metabolite BHBA in the pathogenesis of endometritis in dairy cows, providing valuable insights for understanding this pathological process.},
}
@article {pmid40187375,
year = {2025},
author = {Bruschi, M and Masini, S and Biancucci, F and Piersanti, G and Canonico, B and Menotta, M and Magnani, M and Fraternale, A},
title = {Redox modulation via a synthetic thiol compound reshapes energy metabolism in endothelial cells and ameliorates angiogenic expression in a co-culture study with activated macrophages.},
journal = {Biochimica et biophysica acta. General subjects},
volume = {1869},
number = {6},
pages = {130803},
doi = {10.1016/j.bbagen.2025.130803},
pmid = {40187375},
issn = {1872-8006},
mesh = {Humans ; *Energy Metabolism/drug effects ; Oxidation-Reduction/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism/drug effects ; Coculture Techniques ; *Sulfhydryl Compounds/pharmacology ; *Macrophages/metabolism/drug effects ; Glutathione/metabolism ; Cysteamine/pharmacology ; Acetylcysteine/pharmacology ; *Neovascularization, Physiologic/drug effects ; Oxidative Stress/drug effects ; Cysteine/metabolism ; Endothelial Cells/metabolism/drug effects ; Macrophage Activation/drug effects ; Animals ; },
abstract = {The vascular endothelium is the first interface exposed to circulating compounds and oxidative as well as pro-inflammatory stimuli. Nowadays, cysteine pro-drugs are emerging as new and potential therapies in cardiovascular and inflammatory diseases due to their cytoprotective effects. In this study, the effects of redox modulation by a synthetic thiol compound, i.e., I-152, a precursor of N-acetylcysteine (NAC) and cysteamine (MEA), were evaluated after 6 h and 24 h treatment on human umbilical cord endothelial cell (HUVECs) energy metabolism. Following I-152 treatment, higher cysteine and glutathione (GSH) content were detected via HPLC, in concomitance with I-152 derivatives, i.e., NAC and MEA. Untargeted metabolomics confirmed GSH upregulation and NAC presence in addition to I-152 itself and other metabolites, such as dithiol compound (NACMEAA) and triacetylated I-152. Mass spectrometry revealed that I-152 boosted ATP production, specifically through the mitochondrial OXPHOS, as determined via Seahorse assay without inducing oxidative stress. Additionally, I-152 treatment of HUVECs before co-culture with LPS-stimulated macrophages provided GSH and cysteine sustainment and attenuated the transcription of adhesion molecules as well as iNOS expression. Identifying the impact of redox regulation in physiological conditions and the possible metabolic targets could aid the application of novel thiol-based therapeutics.},
}
@article {pmid40186271,
year = {2025},
author = {Zhang, J and Liu, T and Wu, H and Wei, J and Qu, Q},
title = {Target oxidative stress-induced disulfidptosis: novel therapeutic avenues in Parkinson's disease.},
journal = {Molecular brain},
volume = {18},
number = {1},
pages = {29},
pmid = {40186271},
issn = {1756-6606},
support = {2021ZD0201808//Scientific and technological innovation 2030/ ; },
mesh = {*Oxidative Stress/genetics/drug effects ; *Parkinson Disease/genetics/pathology/drug therapy/therapy ; Animals ; Molecular Docking Simulation ; Humans ; Gene Expression Profiling ; Gene Regulatory Networks ; Mice ; *Molecular Targeted Therapy ; Gene Expression Regulation ; Reproducibility of Results ; Transcriptome/genetics ; Disulfidptosis ; },
abstract = {BACKGROUND: Parkinson's disease (PD), a globally prevalent neurodegenerative disorder, has been implicated with oxidative stress (OS) as a central pathomechanism. Excessive reactive oxygen species (ROS) trigger neuronal damage and may induce disulfidptosis-a novel cell death modality not yet characterized in PD pathogenesis.<br><br>METHOD: Integrated bioinformatics analyses were conducted using GEO datasets to identify PD-associated differentially expressed genes (DEGs). These datasets were subjected to: immune infiltration analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), intersection analysis of oxidative stress-related genes (ORGs) and disulfidptosis-related genes (DRGs) for functional enrichment annotation. Following hub gene identification, diagnostic performance was validated using independent cohorts. LASSO regression was applied for feature selection, with subsequent experimental validation in MPTP-induced PD mouse models. Single-cell transcriptomic profiling and molecular docking studies were performed to map target gene expression and assess drug-target interactions.<br><br>RESULT: A total of 1615 PD DEGs and 200 WGCNA DEGs were obtained, and the intersection with ORGs and DRGs resulted in 202 DEORGs, 11 DEDRGs, and 5 DED-ORGs (NDUFS2, LRPPRC, NDUFS1, GLUD1, and MYH6). These genes are mainly associated with oxidative stress, the respiratory electron transport chain, the ATP metabolic process, oxidative phosphorylation, mitochondrial respiration, and the TCA cycle. 10 hub genes have good diagnostic value, including in the validation dataset (AUC&#x2009;&#x2265;&#x2009;0.507). LASSO analysis of hub genes yielded a total of 6 target genes, ACO2, CYCS, HSPA9, SNCA, SDHA, and VDAC1. In the MPTP-induced PD mice model, the expression of ACO2, HSPA9, and SDHA was decreased while the expression of CYCS, SNCA, and VDAC1 was increased, and the expression of the 5 DED-ORGs was decreased. Additionally, it was discovered that N-Acetylcysteine (NAC) could inhibit the occurrence of disulfidptosis in the MPTP-induced PD model. Subsequently, the distribution of target genes with AUC&#x2009;>&#x2009;0.7 in different cell types of the brain was analyzed. Finally, molecular docking was performed between the anti-PD drugs entering clinical phase IV and the target genes. LRPPRC has low binding energy and strong affinity with duloxetine and donepezil, with binding energies of -7.6&#xa0;kcal/mol and -&#x2009;8.7&#xa0;kcal/mol, respectively.<br><br>CONCLUSION: This study elucidates the pathogenic role of OS-induced disulfidptosis in PD progression. By identifying novel diagnostic biomarkers (e.g., DED-ORGs) and therapeutic targets (e.g., LRPPRC), our findings provide a mechanistic framework for PD management and lay the groundwork for future therapeutic development.},
}
@article {pmid40183046,
year = {2025},
author = {Song, J and Qiao, J and Chen, M and Li, J and Wang, J and Yu, D and Zheng, H and Shi, L},
title = {Chaetoglobosin A induces apoptosis in T-24 human bladder cancer cells through oxidative stress and MAPK/PI3K-AKT-mTOR pathway.},
journal = {PeerJ},
volume = {13},
number = {},
pages = {e19085},
pmid = {40183046},
issn = {2167-8359},
mesh = {Humans ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; *Urinary Bladder Neoplasms/drug therapy/metabolism/pathology ; TOR Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Cell Line, Tumor ; Phosphatidylinositol 3-Kinases/metabolism ; *Indole Alkaloids/pharmacology ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Cell Proliferation/drug effects ; Cell Movement/drug effects ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; *Antineoplastic Agents/pharmacology ; },
abstract = {Chaetoglobosin A (ChA) is an antitumor compound produced by Chaetomium globosum. However, the mechanism of its antitumor effect has been rarely reported. In this study, we evaluated the anti-proliferative effect of ChA on T-24 human bladder cancer cells and explored its mechanism of action. ChA was found to have a good inhibitory effect on T-24 cells by MTT assay with an IC50 value of 48.14 ± 10.25 μΜ. Moreover, it was found to have a migration inhibitory ability and a sustained proliferation inhibitory effect on tumor cells by cell aggregation assay and cell migration assay. The cells morphological changes were determined by Hoechst33342 assay. While Annexin V-FITC/PI double-staining assay also demonstrated that the number of apoptotic cells increased with the increase of drug concentration. Flow cytometry results showed that ChA treatment increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) in T-24 cells and inhibited cell mitosis, resulting in an increase in the number of sub-G1 phase cells. Further western blot experiments demonstrated that MAPK and PI3K-AKT-mTOR pathways were activated after drug treatment in addition to endogenous and exogenous apoptotic pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) upregulated the expression level of Bcl-2 protein, decreased p38 phosphorylation, increased ERK phosphorylation and restored the levels of PI3K and p-mTOR after ChA treatment. These suggest that ChA induces apoptosis by regulating oxidative stress, MAPK, and PI3K-AKT-mTOR signaling pathways in T-24 cells.},
}
@article {pmid40180519,
year = {2025},
author = {Oscullo, G and Méndez, R and Olveira, C and Girón, R and García-Clemente, M and Máiz, L and Sibila, O and Golpe, R and Rodríguez-Hermosa, J and Barreiro, E and Prados, C and Rodríguez-López, JL and de la Rosa-Carrillo, D and Martinez-García, M&#xc1;},
title = {Effect of N-Acetylcysteine on Bronchiectasis in a Real-life Study. Data From the Spanish RIBRON Registry.},
journal = {Archivos de bronconeumologia},
volume = {61},
number = {4},
pages = {196-202},
doi = {10.1016/j.arbres.2025.02.015},
pmid = {40180519},
issn = {1579-2129},
mesh = {Humans ; *Bronchiectasis/drug therapy ; *Acetylcysteine/therapeutic use ; Male ; Female ; Middle Aged ; Aged ; Registries ; Spain ; *Expectorants/therapeutic use ; Longitudinal Studies ; Pseudomonas Infections/drug therapy/prevention &amp; control ; Hospitalization/statistics &amp; numerical data ; Sputum/metabolism ; Treatment Outcome ; Adult ; Pseudomonas aeruginosa/isolation &amp; purification ; },
abstract = {INTRODUCTION: There is scarce information about the most used mucolytic drug in bronchiectasis N-acetylcysteine (N-AC). Our objective was to analyze the effect of N-AC with respect to some outcomes in bronchiectasis.<br><br>METHODS: Ambispective, longitudinal, observational, multi-center (43 centers) study of a cohort of 2461 adult patients diagnosed with bronchiectasis. Those patients treated in a stable situation with at least 600mg/d of N-AC (368; 15%) for at least 6 months were compared with patients not receiving this treatment. The variables analyzed and compared were those available two years before and after treatment. ANCOVA analysis was used to analyze the effect of N-AC as the inter-group difference of the basal intra-group difference for each variable, adjusted for relevant covariables.<br><br>RESULTS: The N-AC group showed a full adjusted improvement of 27% in exacerbations, 17% in hospitalizations, and 31% in total exacerbation rates compared with the no-N-AC group. Moreover, a decrease in the volume of sputum production of 59.7% was observed as well as a decrease of 12% of patients with bronchial infection by Pseudomonas aeruginosa (PA). The use of 1200mg/d (n=116) resulted in only a mild, albeit significative improvement in the exacerbation rate compared with the use of 600mg/d (-11% in absolute number). Both doses were well tolerated.<br><br>CONCLUSION: N-AC (in most cases at a dose of 600mg/d) is safe and effective and sufficient to reduce both the number of exacerbations and hospitalizations and the purulence and volume of sputum, as well as the isolation rate of PA in patients with bronchiectasis.},
}
@article {pmid40177701,
year = {2025},
author = {Kamboj, SS and Sharma, SP and Mohamed, WMY and Sandhir, R},
title = {N-acetyl-L-cysteine mitigates diabetes-induced impairments in sciatic nerve.},
journal = {IBRO neuroscience reports},
volume = {18},
number = {},
pages = {512-519},
pmid = {40177701},
issn = {2667-2421},
abstract = {Diabetic neuropathy is a consequence of long-term hyperglycemia. The emergence of neuronal condition is a result of hyperglycemia-induced oxidative stress. In the present study, streptozotocin-induced diabetes exhibited notable decrease in the levels of phospholipids, glycolipids, gangliosides, and triglycerides in the sciatic nerve. The alterations in lipids resulted in increase in cholesterol to phospholipid ratio in sciatic nerve of diabetic animals. This ratio is crucial and determines the rheological properties of membranes and resulted in substantial reduction in the activity of membrane-bound enzymes; Ca[2 +] ATPase and acetylcholinesterase. Histological examination of the cross-section of the sciatic nerve in diabetic mice revealed axonal atrophy and disarrayed myelin sheath. The potential therapeutic impact of N-acetyl Cysteine (NAC), a powerful antioxidant, on a rat model of diabetic neuropathy was evaluated. NAC was administered to rats in drinking water for a period of 8 weeks. The results indicate that administration of NAC restored lipid composition; ratio of cholesterol to phospholipids, the activity of membrane linked enzymes, and improved the structural defects in sciatic nerve. NAC plays protective role against diabetes-induced alterations in lipid composition in sciatic nerve membranes leading to improvement in structure and function of membranes. Overall, the findings suggest NAC as a potential therapeutic strategy in preventing diabetic neuropathy and other diabetic complications.},
}
@article {pmid40170426,
year = {2025},
author = {Tang, H and Li, L},
title = {Effects of detergent component sodium dodecyl sulfate on growth hormone secretion in GH3 cells: Implications for pediatric exposure and accidental ingestion.},
journal = {Human &amp; experimental toxicology},
volume = {44},
number = {},
pages = {9603271251332255},
doi = {10.1177/09603271251332255},
pmid = {40170426},
issn = {1477-0903},
mesh = {*Sodium Dodecyl Sulfate/toxicity ; Cell Survival/drug effects ; Oxidative Stress/drug effects ; *Growth Hormone/metabolism ; Humans ; *Detergents/toxicity ; Cell Line ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; Animals ; Rats ; *Human Growth Hormone/metabolism ; *Surface-Active Agents/toxicity ; },
abstract = {IntroductionSodium dodecyl sulfate (SDS), a widely used surfactant in detergents, has raised concerns due to its potential health risks, particularly in children. This study evaluates the impact of SDS exposure on GH secretion in GH3 cells, focusing on oxidative stress as a key mechanism.MethodsGH3 cells were treated with varying concentrations of SDS (0.001-10 mM) for 24 or 48 h. Cell viability was assessed using the MTT assay, while GH secretion was quantified via ELISA. Oxidative stress levels were evaluated through ROS fluorescence assays, and gene expression of Nrf2, IL-6, TNF-α, and caspase-3 was analyzed using qPCR. Additionally, the antioxidant N-acetylcysteine (NAC) was used to determine its protective effects against SDS-induced oxidative stress.ResultsSDS exposure led to a dose-dependent decrease in GH secretion and cell viability, with oxidative stress identified as a primary driver. Nrf2 exhibited a biphasic response, showing transient upregulation at low doses but suppression at higher concentrations, exacerbating oxidative damage. NAC treatment reduced ROS levels and partially restored GH secretion, confirming the role of oxidative stress in SDS-induced toxicity.DiscussionThese findings suggest that SDS exposure may disrupt endocrine function, warranting further risk assessment of its safety in consumer products. Given SDS's prevalence in household products, future research should focus on the long-term effects of SDS exposure to children and potential therapeutic interventions to mitigate oxidative damage.},
}
@article {pmid40169142,
year = {2025},
author = {Kawaguchi, M and Yoshino, K and Ida, T and Moriyama, H and Ieda, N and Ohta, Y and Kasamatsu, S and Ihara, H and Nakagawa, H},
title = {Serendipitous Discovery of Photolytic Thiosulfoxide Formation: Application for Visible-Light-Inducible Manipulation of Supersulfide Level in Biological Systems.},
journal = {Journal of the American Chemical Society},
volume = {147},
number = {15},
pages = {12627-12634},
pmid = {40169142},
issn = {1520-5126},
mesh = {*Light ; *Sulfides/chemistry/metabolism ; Humans ; Photolysis ; *Acetylcysteine/chemistry/analogs &amp; derivatives ; Coumarins/chemistry ; Molecular Structure ; },
abstract = {Tools to enable spatiotemporally controlled upregulation of supersulfides, which are highly reactive, unstable sulfur species, are needed to study the pathophysiological roles of post-translational protein modification with catenated sulfur atoms. Here, we set out to design N,N-diethylaminocoumarin (DEAC)-based visible-light-responsive N-acetylcysteine persulfide donors (NAC-SS-DEAC), and serendipitously found that upon visible light irradiation, they donate a sulfane sulfur (S[0]) atom to nucleophiles, including thiols and cyanate. Light-assisted tautomerization of the disulfide moiety of NAC-SS-DEAC to transiently afford unstable thiosulfoxide plays a key role in the S[0] donation. We show that this reaction can be utilized to achieve visible-light-inducible manipulation of supersulfide levels in living cells.},
}
@article {pmid40166462,
year = {2025},
author = {Zhang, Z and Yan, Z and Yuan, T and Zhao, X and Wang, M and Liu, G and Gan, L and Qin, W},
title = {PD-1 inhibition disrupts collagen homeostasis and aggravates cardiac dysfunction through endothelial-fibroblast crosstalk and EndMT.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1549487},
pmid = {40166462},
issn = {1663-9812},
abstract = {INTRODUCTION: Cardiac immune-related adverse events (irAEs) from PD-1-targeting immune check-point inhibitors (ICIs) are an increasing concern due to their high mortality rate. Collagen plays a crucial role in maintaining cardiac structure, elasticity, and signal transduction; however, the effects and mechanisms of PD-1 inhibitor on cardiac collagen remodeling remain poorly understood.<br><br>METHODS: C57BL/6 mice were injected with anti-mouse PD-1 antibody to create a PD-1 inhibitor-treated model. Cardiac function was measured by echocardiography, and collagen distribution was analyzed with Masson's trichrome staining and Sirius Red staining. Single-nucleus RNA sequencing was performed to examine the effects of PD-1 inhibition on gene expression in cardiac fibroblasts (CFs) and endothelial cells (ECs). EC-CF crosstalk was assessed using co-culture experiments and ELISA. ChIP assay was performed to analyze the regulation of TCF12 on TGF-&#x3b2;1 promoter. Western blot, qRT-PCR, and immunofluorescence staining were used to detect the expression of TCF12, TGF-&#x3b2;1, and endothelial-to-mesenchymal transition (EndMT) markers. Reactive oxygen species (ROS) levels were evaluated by DHE staining, MDA content, and SOD activity assays.<br><br>RESULTS: We report a newly discovered cardiotoxic effect of PD-1 inhibitor, which causes aberrant collagen distribution in the heart, marked by a decrease in interstitial collagen and an increase in perivascular collagen deposition. Mechanistically, PD-1 inhibitor does not directly affect CFs but instead impact them through EC-CF crosstalk. PD-1 inhibitor reduces TGF-&#x3b2;1 secretion in ECs by downregulating TCF12, which we identify as a transcriptional promoter of TGF-&#x3b2;1. This subsequently decreases CF activity, leading to reduced interstitial collagen deposition. Additionally, PD-1 inhibitor induces EndMT, increasing perivascular collagen deposition. The endothelial dysfunction induced by PD-1 inhibitor results from ROS accumulation in ECs. Inhibiting ROS with N-acetylcysteine (NAC) preserves normal collagen distribution and cardiac function in PD-1 inhibitor-treated mice by reversing TCF12 downregulation and EndMT in ECs.<br><br>CONCLUSION: Our results suggest that PD-1 inhibitor causes ROS accumulation in cardiac ECs, leading to imbalanced collagen distribution (decrease in interstitial collagen and increase in perivascular collagen) in the heart by modulating TCF12/TGF-&#x3b2;1-mediated EC-CF crosstalk and EndMT. NAC supplementation could be an effective clinical strategy to mitigate PD-1 inhibitor-induced imbalanced collagen distribution and cardiac dysfunction.},
}
@article {pmid40163767,
year = {2025},
author = {Kruse, LD and Holte, C and Zapotoczny, B and Struck, EC and Schürstedt, J and Hübner, W and Huser, T and Szafranska, K},
title = {Hydrogen peroxide damage to rat liver sinusoidal endothelial cells is prevented by n-acetyl-cysteine but not GSH.},
journal = {Hepatology communications},
volume = {9},
number = {2},
pages = {},
pmid = {40163767},
issn = {2471-254X},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Hydrogen Peroxide/toxicity ; *Glutathione/pharmacology ; *Endothelial Cells/drug effects/metabolism ; Rats ; *Liver/drug effects/cytology/blood supply/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; Male ; Cells, Cultured ; Dose-Response Relationship, Drug ; },
abstract = {BACKGROUND: Reactive oxygen species (ROS) are prevalent in the liver during intoxication, infection, inflammation, and aging. Changes in liver sinusoidal endothelial cells (LSEC) are associated with various liver diseases.<br><br>METHODS: Isolated rat LSEC were studied under oxidative stress induced by H2O2 at different concentrations (0.5-1000&#xa0;&#xb5;M) and exposure times (10-120&#xa0;min). LSEC functions were tested in a dose-dependent and time-dependent manner.<br><br>RESULTS: (1) Cell viability, reducing potential, and scavenging function decreased as H2O2 concentration and exposure time increased; (2) intracellular ROS levels rose with higher H2O2 concentrations; (3) fenestrations exhibited a dynamic response, initially closing but partially reopening at H2O2 concentrations above 100&#xa0;&#xb5;M after about 1 hour; (4) scavenging function was affected after just 10 minutes of exposure, with the impact being irreversible and primarily affecting degradation rather than receptor-mediated uptake; (5) the tubulin network was disrupted in high H2O2 concentration while the actin cytoskeleton appears to remain largely intact. Finally, we found that reducing agents and thiol donors such as n-acetyl cysteine and glutathione (GSH) could protect cells from ROS-induced damage but could not reverse existing damage as pretreatment with n-acetyl cysteine, but not GSH, reduced the negative effects of ROS exposure.<br><br>CONCLUSIONS: The results suggest that LSEC does not store an excess amount of GSH but rather can readily produce it in the occurrence of oxidative stress conditions. Moreover, the observed thresholds in dose-dependent and time-dependent changes, as well as the treatments with n-acetyl cysteine/GSH, confirm the existence of a ROS-depleting system in LSEC.},
}
@article {pmid40163489,
year = {2025},
author = {Bao, Q and Wang, Z and Yang, T and Su, X and Chen, Y and Liu, L and Deng, Q and Liu, Q and Shao, C and Zhu, W},
title = {Curcumin induces mitochondrial dysfunction-associated oxidative DNA damage in ovarian cancer cells.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0319846},
pmid = {40163489},
issn = {1932-6203},
mesh = {*Curcumin/pharmacology/therapeutic use ; *Oxidative Stress/drug effects ; *Ovarian Neoplasms/pathology ; Cell Line, Tumor ; Mice, Nude ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; *DNA Damage/drug effects ; *Mitochondria/drug effects ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/therapeutic use ; Humans ; Animals ; Mice ; Xenograft Model Antitumor Assays ; },
abstract = {Resistance to chemotherapeutic agents is a critical challenge for the clinical management of ovarian cancer. While curcumin has been reported to possess anti-cancer properties, how it exerts its anti-neoplastic effect on ovarian cancer cells remains to be explored. We here characterized the fate of human ovarian cancer cell lines HO8910 and OVCAR3 treated with curcumin. Cell proliferation, cell death, mitochondrial function, oxidative damage and tumor formation in nude mice were examined. Significant inhibition of proliferation and induction of apoptosis were observed in ovarian cells treated with curcumin. The cancer cells exhibit cell cycle arrest at G2/M phase, mitochondrial accumulation, mitochondrial oxidative stress and high level of DNA damage after curcumin treatment. This effect of curcumin is independent of the BRCA mutation status. Curcumin-induced proliferation inhibition and apoptosis were effectively attenuated by the application of antioxidant N-acetylcysteine (NAC), suggesting that curcumin exerts its anti-cancer effect by inflicting oxidative stress. Curcumin applied at 200 mg/kg intraperitoneal infusion daily also inhibited the growth, oxidative damage, and mitochondrial accumulation of tumor xenografts in vivo. Together, the results indicate that curcumin can exert its anti-tumor effect via inducing mitochondrial dysfunction-associated oxidative DNA damage and can be potentially used in combination with other DNA repair-interfering therapeutics, such as PARP inhibitor, in the treatment of ovarian cancer.},
}
@article {pmid40163249,
year = {2025},
author = {Snorradottir, AO and Gutierrez-Uzquiza, A and Bragado, P and March, ME and Kao, C and Arkink, EB and Jonsdottir, S and Sigurdardottir, A and Isaksson, HJ and Mariasdóttir, HL and Bjorgvinsdottir, OY and Kowal, NM and Heimisdottir, HL and Sverrisdottir, A and Palsdottir, A and Bjornsson, HT and Hakonarson, H},
title = {N-Acetylcysteine for Hereditary Cystatin C Amyloid Angiopathy: A Nonrandomized Clinical Trial.},
journal = {JAMA neurology},
volume = {82},
number = {5},
pages = {486-494},
pmid = {40163249},
issn = {2168-6157},
mesh = {Humans ; Male ; Female ; *Cystatin C/genetics ; *Acetylcysteine/therapeutic use/administration &amp; dosage/adverse effects ; Adult ; Middle Aged ; *Cerebral Amyloid Angiopathy, Familial/drug therapy/genetics ; Biomarkers/blood ; *Cerebral Amyloid Angiopathy/drug therapy/genetics ; },
abstract = {IMPORTANCE: Hereditary cystatin C amyloid angiopathy (HCCAA) is a lethal, dominantly inherited disease primarily affecting Icelandic young adults that leads to severe cerebral amyloid angiopathy, with no effective therapy.<br><br>OBJECTIVE: To investigate safety, tolerance, and therapeutic potential of N-acetylcysteine (NAC) in lowering disease-associated biomarkers in sequence variation carriers.<br><br>This phase 2a open-label clinical trial was conducted from March 2019 to December 2021 at a single study center at Landspitali University Hospital in Reykjavik, Iceland, and included 17 confirmed carriers of the L68Q-CST3 sequence variation.<br><br>INTERVENTION: High-dose NAC treatment was administered at 2400 mg daily for 9 months. Participants underwent regular monitoring for hemorrhages and disease progression, including blood and skin biopsy samples obtained every 3 months for biomarker testing.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcomes were drug tolerability and safety, cognitive status, and reduction in disease-associated biomarkers in skin biopsies. Secondary outcomes included changes in blood and plasma biomarker levels.<br><br>RESULTS: Of 17 carriers treated, 6 were male and 11 were female, and mean (SD) participant age was 40.0 (4.2) years. Analysis of the primary outcomes showed that NAC was safe and well tolerated. Five cerebral bleeds occurred during the treatment period without permanent neurological sequela; no death occurred. There was significant reduction in median (IQR) disease-specific biomarker levels in skin after treatment, including collagen IV (baseline: 3.69% [2.48%-5.16%]; after treatment: 2.60% [1.99%-2.97%]; P&#x2009;<&#x2009;.001), fibronectin (baseline: 3.17% [2.09%-5.05%]; after treatment: 2.37% [1.87%-3.42%]; P&#x2009;=&#x2009;.01), vimentin (baseline: 1.60% [1.24%-2.37%]; after treatment: 1.31% [0.97%-1.68%]; P&#x2009;<&#x2009;.001), and SMAD (baseline: 2.25% [0.55%-4.36%]; after treatment: 1.56% [0.20%-2.54%]; P&#x2009;<&#x2009;.001) via Wilcoxon matched-pairs signed rank test. Secondary outcomes included a significant increase in reduced glutathione levels and decreased high-molecular-weight cystatin C aggregate levels in plasma after NAC treatment.<br><br>CONCLUSIONS AND RELEVANCE: In this single-center nonrandomized clinical trial, NAC was safe and well tolerated and decreased disease-associated biomarker and amyloid deposition, suggesting NAC may offer a preventive strategy against HCCAA.<br><br>TRIAL REGISTRATION: ClinicalTrialsRegister.eu Identifier: 2017-004776-56.},
}
@article {pmid40159744,
year = {2025},
author = {Adamczuk, P and Jamka, K and Bojar, H and Szala-Rycaj, J and Szewczyk, A and Sawicki, KB and Raszewski, G},
title = {The effect of the antioxidant N-acetylcysteine on cholinesterase activity in the brain and blood during Pirimiphos methyl poisoning in the course of treatment with atropine alone, and with atropine and obidoxime.},
journal = {Annals of agricultural and environmental medicine : AAEM},
volume = {32},
number = {1},
pages = {116-121},
doi = {10.26444/aaem/199716},
pmid = {40159744},
issn = {1898-2263},
mesh = {Animals ; Male ; Mice ; *Brain/drug effects/enzymology ; *Organothiophosphorus Compounds/toxicity/poisoning ; *Acetylcysteine/administration &amp; dosage ; *Obidoxime Chloride/administration &amp; dosage ; Acetylcholinesterase/metabolism/blood ; *Atropine/administration &amp; dosage/therapeutic use ; Butyrylcholinesterase/blood/metabolism ; *Antioxidants/administration &amp; dosage ; *Organophosphate Poisoning/drug therapy/enzymology ; *Antidotes/administration &amp; dosage ; *Insecticides/toxicity/poisoning ; Cholinesterase Inhibitors ; },
abstract = {INTRODUCTION AND OBJECTIVE: The antioxidant N-acetylcysteine (NAC) may help in the treatment of organophosphates poisoning, including Pirymiphos methyl (PM). However, there is no information on the effect of NAC on target cholinesterases during the core treatment with atropine and obidoxime after acute and chronic exposure to PM. The impact was investigated of NAC on the functional status of target cholinesterases in the brain and blood during treatment with atropine (ATR) and/or obidoxime (OBID) in PM-induced toxicity.<br><br>MATERIAL AND METHODS: All experiments were performed on Male Swiss mice. The animals were intoxicated with PM and treated with OBID and/or ATR with or without and NAC, in various combinations (with 2-3 drugs) used simultaneously after intoxication. Total acetylcholinesterase activity (AChE) in brain and blood and plasma butyrylcholinesterase activity (BChE) were monitored at 2 and 72 h after intoxication. Enzyme activity was determined using Ellman's colorimetric method.<br><br>RESULTS: The applied therapies with OBID, ATR and NAC in various configurations significantly reactivated PM-inhibited AChE in the brain and erythrocytes and the BChE in the plasma. The benefits of NAC administration in combination with ATR and/or OBID therapy have also been reported to restore AChE activity in the brain. NAC may reduce the dose of ATR in the treatment of PM poisoning.<br><br>CONCLUSIONS: Adjunctive treatment offered by NAC can reduce or prevent the deleterious effects against PM-induced toxicity. Therefore, NAC remains a strong candidate for adjunct treatment for OP-poisoning, including PM, although additional preclinical and clinical studies are needed.},
}
@article {pmid40159690,
year = {2025},
author = {Chen, H and Wang, J and Zhao, B and Yang, Y and Yang, C and Zhao, Z and Ding, X and Li, Y and Zhang, T and Yingpai, Z and Huo, S},
title = {N-Acetylcysteine relieving hydrogen peroxide-induced damage in granulosa cells of sheep.},
journal = {Cell adhesion &amp; migration},
volume = {19},
number = {1},
pages = {2484182},
pmid = {40159690},
issn = {1933-6926},
mesh = {Animals ; Female ; *Granulosa Cells/drug effects/metabolism/pathology ; *Hydrogen Peroxide/toxicity ; Oxidative Stress/drug effects ; NF-E2-Related Factor 2/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; *Acetylcysteine/pharmacology ; Sheep ; Apoptosis/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Cell Proliferation/drug effects ; },
abstract = {Sheep ovarian granulosa cells (GCs) play a unique role in the ovary. Damage to GCs can affect the normal development of oocytes. The oxidative stress model was constructed by H2O2to study the biological changes. Specifically, pathological characteristic was assessed by immunohistochemistry (IHC), while signaling pathway was studied using western blot, quantitative RT-PCR, and immunofluorescence. Theresults showed that the oxidative damage model was successfully constructed by 200 μmol/LH2O2 for 12 h. NAC can protect the proliferation of GCs under H2O2-induced oxidative stress and reduce apoptosis. It can also promote the secretion of E2 and P4 by GCs and reduce the inflammatory response of GCs. NAC can enhance the expression of NRF2, PI3K and Akt. These findings suggest that NAC alleviates H2O2-induced oxidative stress injury through NRF2/PI3K/AKT signaling pathways. Provide ideas for studying the poor quality of mammalian oocytes.},
}
@article {pmid40156629,
year = {2025},
author = {Xu, Y and You, J and Yao, J and Hou, B and Wang, W and Hao, Z},
title = {Klotho alleviates oxidative stress and mitochondrial dysfunction through the Nrf2/HO-1 pathway, thereby reducing renal senescence induced by calcium oxalate crystals.},
journal = {Urolithiasis},
volume = {53},
number = {1},
pages = {61},
pmid = {40156629},
issn = {2194-7236},
support = {82070724//the National Natural Science Foundation of China/ ; },
mesh = {*Calcium Oxalate ; Klotho Proteins ; *Oxidative Stress/drug effects ; Animals ; *NF-E2-Related Factor 2/metabolism ; Mice ; Mitochondria/metabolism ; Signal Transduction ; *Glucuronidase/metabolism/genetics ; Humans ; Cell Line ; Heme Oxygenase-1/metabolism ; Disease Models, Animal ; Cellular Senescence/drug effects ; *Kidney/metabolism/drug effects/pathology ; Male ; Glyoxylates ; },
abstract = {Klotho is an antiaging protein that is primarily secreted by the kidneys. This study aimed to explore the protective effects of Klotho against calcium oxalate (CaOx) crystal-induced renal aging and the underlying mechanisms involved. We established a mouse model of CaOx crystal deposition via the intraperitoneal injection of glyoxylate (Gly) and constructed an in vitro model by stimulating HK2 cells with calcium oxalate monohydrate (COM). Renal aging levels were assessed through β-galactosidase (SA-β-gal) staining and the detection of senescence-associated markers. By overexpressing Klotho both in vitro and in vivo, we examined oxidative stress, mitochondrial function, and renal aging levels. We then evaluated the role of Nrf2/HO-1 signalling pathway-mediated oxidative stress in CaOx crystal-induced renal aging by applying the oxidative stress scavenger N-acetylcysteine (NAC) and overexpressing or inhibiting Nrf2 in HK2 cells. We subsequently overexpressed Klotho while inhibiting Nrf2 to confirm that Klotho exerts its protective effects through the Nrf2/HO-1 pathway. Finally, we measured the methylation levels of the Klotho promoter and assessed the degree of renal aging induced by CaOx crystals after the inhibition of Klotho DNA methylation. We found that the overexpression of Klotho alleviated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, thereby reducing renal aging. NAC mitigated CaOx crystal-induced renal aging. The overexpression of Nrf2 alleviated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, thus reducing renal aging, whereas the knockdown of Nrf2 exacerbated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, leading to more severe renal aging. The combination of Klotho overexpression and Nrf2 knockdown reversed the protective effects of Klotho. CaOx crystals induced an increase in the DNA methylation levels of Klotho in the kidneys, and the inhibition of DNA methylation alleviated CaOx-induced renal aging. This study revealed that Klotho plays a crucial role in calcium oxalate crystal-induced kidney senescence by influencing kidney oxidative stress and mitochondrial function through the Nrf2/HO-1 pathway.},
}
@article {pmid40155786,
year = {2025},
author = {Nasiri, MJ and Khoshdel, N and Venketaraman, V},
title = {Glutathione and N-acetylcysteine in TB management.},
journal = {The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease},
volume = {29},
number = {4},
pages = {171-177},
doi = {10.5588/ijtld.24.0604},
pmid = {40155786},
issn = {1815-7920},
support = {R15 HL143545/HL/NHLBI NIH HHS/United States ; },
mesh = {*Acetylcysteine/therapeutic use/adverse effects/administration &amp; dosage/pharmacology ; Humans ; *Glutathione/therapeutic use/adverse effects/administration &amp; dosage ; *Antitubercular Agents/therapeutic use ; *Tuberculosis/drug therapy ; Sputum/microbiology ; Oxidative Stress/drug effects ; Treatment Outcome ; },
abstract = {<sec><title>BACKGROUND</title>TB remains a major global health challenge. Glutathione (GSH) and N-acetylcysteine (NAC) have been proposed as adjunctive therapies with potential clinical and immunomodulatory benefits. This systematic review aims to evaluate the efficacy, safety, and immunomodulatory effects of GSH and NAC as adjunctive therapies in TB management.</sec><sec><title>METHODS</title>PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched until October 15, 2024. We included studies assessing the efficacy of GSH and NAC in TB management, focusing on clinical outcomes such as lung function recovery, sputum conversion, hepatoprotection, and immune response modulation. The quality of the studies was assessed using the Cochrane Risk of Bias tool.</sec><sec><title>RESULTS</title>Eight controlled trials were included. GSH and NAC significantly improved lung function accelerated sputum conversion, and provided hepatoprotective effects. GSH, particularly in its liposomal form, enhanced immune responses by modulating cytokine levels and reducing oxidative stress. Most adverse effects reported were mild and manageable, indicating a favourable safety profile for both agents.</sec><sec><title>CONCLUSIONS</title>GSH and NAC show promise as adjunctive therapies in TB management, demonstrating improvements in lung function, sputum conversion, and hepatoprotection while also enhancing immune responses.</sec>.},
}
@article {pmid40153160,
year = {2025},
author = {Borovskaya, TG and Vychuzhanina, AV and Schemerova, YA and Stremlina, LA and Goldberg, VE and Dygai, AM and Zhdanov, VV},
title = {Genoprotective Properties of para-Tyrosol against Doxorubicin-Induced DNA Damage in Sperm and Testicular Tissue Cells of Rats.},
journal = {Bulletin of experimental biology and medicine},
volume = {178},
number = {4},
pages = {567-570},
pmid = {40153160},
issn = {1573-8221},
mesh = {Animals ; Male ; *Doxorubicin/toxicity/pharmacology ; *Testis/drug effects/cytology/metabolism ; Rats ; *Spermatozoa/drug effects/metabolism ; *DNA Damage/drug effects ; Comet Assay ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Rats, Wistar ; Antibiotics, Antineoplastic/toxicity ; *Antimutagenic Agents/pharmacology ; },
abstract = {The effect of para-tyrosol (PT), a hydroxyalkylphenol exhibiting antioxidant properties, on the level of DNA damage in testicular tissue cells and sperm of rats treated with doxorubicin was studied using the DNA comet assay. N-acetylcysteine (NAC) was used as a reference drug. It was found that both drugs reduced the number of DNA breaks in rat testicular tissue cells (by 46-48%). The antigenotoxic effect, judging by %DNA in tail, in relation to spermatozoa was detected only in PT. The number of DNA damage in male germ cells after treatment with PT was reduced by 52% from the control (administration of doxorubicin alone). The results suggest that it is advisable to use PT in order to reduce the genotoxicity of doxorubicin, in the therapy of Hodgkin lymphoma (HL) in treatment regimens containing this anthracycline antibiotic.},
}
@article {pmid40143181,
year = {2025},
author = {Alhaddad, A and Mosalam, EM and AboShabaan, HS and Sallam, AS and Mahfouz, MM and Elhosary, E and Mohammed, AA and Metwally, EM and Shaldam, MA and Ghoneim, ME},
title = {Mechanistic and Molecular Insights into Empagliflozin's Role in Ferroptosis and Inflammation Trajectories in Acetaminophen-Induced Hepatotoxicity.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {3},
pages = {},
pmid = {40143181},
issn = {1424-8247},
abstract = {Background: Acetaminophen (APAP)-induced acute liver injury (ALI) is increasingly becoming a public health issue with high rate of morbidity and mortality. Therefore, there is a critical demand for finding protective modalities by understanding the underlying proposed mechanisms including, but not limited to, ferroptosis and inflammation. Objectives: This study seeks to investigate the possible hepatoprotective effect of empagliflozin (EMPA) against APAP-induced ALI through modulation of ferroptosis and inflammatory cascades. Methods: Mice were allocated into the following five groups: vehicle control, APAP, EMPA 10, EMPA 20 (10 and 20 mg/kg/day, respectively, P.O.), and N-acetylcysteine (NAC, hepatoprotective agent against APAP-induced ALI). The hepatic injury was detected by determining liver enzymes and by histopathological examination. Inflammation, oxidative stress, apoptosis, and ferroptosis were also evaluated. Results: The APAP group showed an elevated level of hepatic enzymes with disrupted hepatic architecture. This toxicity was promoted by inflammation, oxidative stress, apoptosis, and ferroptosis, as indicated by elevated cytokines, lipid peroxidation, reduced antioxidants, increased caspase-3, decreased Bcl-2, and activation of the NF-κB/STAT3/hepcidin pathway. Pretreatment with EMPA remarkably reversed these features, which was reflected by restoration of the histoarchitecture of hepatic tissue, but the higher dose of EMPA was more efficient. Conclusions: APAP can induce ALI through initiation of inflammatory and oxidative conditions, which favor ferroptosis. EMPA hindered these unfavorable consequences; an outcome which indicates its anti-inflammatory, antioxidant, anti-apoptotic, and anti-ferroptotic effects. This modulatory action advocated EMPA as a potential hepatoprotective agent.},
}
@article {pmid40143066,
year = {2025},
author = {Liu, Y and Yao, L and Liu, Y and Yang, Y and Liang, A and He, H and Lei, Y and Cao, W and Chen, Z},
title = {Micheliolide Alleviates Hepatic Fibrosis by Inhibiting Autophagy in Hepatic Stellate Cells via the TrxR1/2-Mediated ROS/MEK/ERK Pathway.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {3},
pages = {},
pmid = {40143066},
issn = {1424-8247},
support = {82100131, 82004168//National Natural Science Foundation of China/ ; CSTB2023NSCQ-MSX0136//Natural Science Foundation Project of Chongqing/ ; KJQN202215101, KJZD-K202315101//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; W0066//CQMU Program for Youth Innovation in Future Medicine/ ; },
abstract = {Background: Hepatic fibrosis is a major global health issue without an optimal drug treatment, highlighting the urgent need to find effective therapies. This study aimed to clarify the role and mechanism of micheliolide in treating hepatic fibrosis. Methods: The efficacy of MCL was evaluated in a mouse model of CCl4-induced hepatic fibrosis. LX-2 cells were subjected to MCL treatment, and subsequent changes in fibrosis markers, autophagy, and the MEK/ERK pathway were analyzed using transcriptomics and Western blotting. The interaction between MCL and TrxR1 or TrxR2 were validated using cellular thermal shift assays (CETSA) and drug affinity responsive target stability (DARTS) assays. Results: Our findings indicated that MCL significantly alleviated CCl4-induced hepatic fibrosis, improved liver function, and downregulated the expression of fibrosis markers. Additionally, MCL significantly inhibited LX-2 cell activation by suppressing cell proliferation, extracellular matrix (ECM) production, and autophagy, while activating the MEK/ERK pathway. Moreover, MCL elevated intracellular and mitochondrial reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential, and altered mitochondrial morphology. The ROS scavenger N-acetylcysteine (NAC) attenuated MCL-induced MEK/ERK pathway activation and increased collagen type I alpha 1 (COL1A1) and fibronectin (FN) expression. Further analysis confirmed that MCL directly interacts with TrxR1 and TrxR2, leading to the inhibition of their enzymatic activities and the induction of ROS generation. Ultimately, MCL attenuated the fibrotic process and autophagic flux in LX-2 cells. Conclusions: The findings of our study confirmed that MCL has the potential to alleviate hepatic fibrosis, thereby introducing a novel candidate drug and therapeutic strategy for management of this condition.},
}
@article {pmid40141299,
year = {2025},
author = {Mokra, D and Porvaznik, I and Mokry, J},
title = {N-Acetylcysteine in the Treatment of Acute Lung Injury: Perspectives and Limitations.},
journal = {International journal of molecular sciences},
volume = {26},
number = {6},
pages = {},
pmid = {40141299},
issn = {1422-0067},
support = {APVV-15-0075//Slovak Research and Development Agency/ ; APVV-18-0084//Slovak Research and Development Agency/ ; APVV-22-0342//Slovak Research and Development Agency/ ; VEGA 1/0131/22//Ministry of Education, Science, Research and Sport of the Slovak Republic/ ; VEGA 1/0093/22//Ministry of Education, Science, Research and Sport of the Slovak Republic/ ; },
mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Acute Lung Injury/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; Respiratory Distress Syndrome/drug therapy ; COVID-19 ; Antioxidants/therapeutic use ; COVID-19 Drug Treatment ; SARS-CoV-2 ; Anti-Inflammatory Agents/therapeutic use ; },
abstract = {N-acetylcysteine (NAC) can take part in the treatment of chronic respiratory diseases because of the potent mucolytic, antioxidant, and anti-inflammatory effects of NAC. However, less is known about its use in the treatment of acute lung injury. Nowadays, an increasing number of studies indicates that early administration of NAC may reduce markers of oxidative stress and alleviate inflammation in animal models of acute lung injury (ALI) and in patients suffering from distinct forms of acute respiratory distress syndrome (ARDS) or pulmonary infections including community-acquired pneumonia or Coronavirus Disease (COVID)-19. Besides low costs, easy accessibility, low toxicity, and rare side effects, NAC can also be combined with other drugs. This article provides a review of knowledge on the mechanisms of inflammation and oxidative stress in various forms of ALI/ARDS and critically discusses experience with the use of NAC in these disorders. For preparing the review, articles published in the English language from the PubMed database were used.},
}
@article {pmid40139162,
year = {2025},
author = {Megan, L and Sanchez-Migallon Guzman, D and Knych, H and Beaufrère, H},
title = {Pharmacokinetics of single-dose oral acetaminophen with and without concurrent administration of silymarin or N-acetylcysteine in orange-winged Amazon parrots (Amazona amazonica).},
journal = {American journal of veterinary research},
volume = {86},
number = {6},
pages = {},
doi = {10.2460/ajvr.24.12.0402},
pmid = {40139162},
issn = {1943-5681},
mesh = {Animals ; *Acetaminophen/pharmacokinetics/administration &amp; dosage/blood/analogs &amp; derivatives ; *Acetylcysteine/administration &amp; dosage/pharmacology/pharmacokinetics ; *Silymarin/administration &amp; dosage/pharmacology/pharmacokinetics ; *Amazona/metabolism/blood ; Administration, Oral ; Male ; Half-Life ; Area Under Curve ; *Analgesics, Non-Narcotic/pharmacokinetics/administration &amp; dosage/blood ; Female ; },
abstract = {OBJECTIVE: To determine the pharmacokinetics of acetaminophen (N-acetyl-para-aminophenol [APAP]) and its metabolites after oral administration of a single dose of APAP, with or without silymarin or N-acetylcysteine (NAC), to orange-winged Amazon parrots (Amazona amazonica).<br><br>METHODS: Eight parrots received, in 3 separate studies, 1 of the following oral treatments: (1) APAP (100 mg/kg) with silymarin (50 mg/kg, twice, q 12 h); (2) APAP (100 mg/kg) with NAC (400 mg/kg); or (3) APAP (100 mg/kg) alone. For each study, blood samples were collected over 24 hours after drug administration to evaluate plasma concentrations of APAP, APAP-glucuronide, and APAP-sulfate. Pharmacokinetic parameters were calculated. Plasma biochemistry panels were performed before and after each study. In a fourth study, a single oral dose of APAP (100 mg/kg) was administered to 8 additional parrots for adverse effects evaluation alone.<br><br>RESULTS: Pharmacokinetic parameters for APAP, APAP-glucuronide, and APAP-sulfate were established. The APAP maximum plasma concentration, time of maximal plasma concentration, and half-life across studies ranged from 2,016.9 to 2,917.2 ng/mL, 1.13 to 2.1 hours, and 1.3 to 1.45 hours, respectively. Acetaminophen had marked metabolism to APAP-glucuronide and negligible to APAP-sulfate. Concurrent administration of APAP with silymarin resulted in a mild but significant elevation in glutamate dehydrogenase.<br><br>CONCLUSIONS: Acetaminophen plasma concentrations were lower than in other avian species despite a relatively high dose. Acetaminophen has fast absorption, short half-life, and marked glucuronidation. Single oral dose administration of APAP, alone or with NAC, appears safe based on plasma biochemistries. Multidose and pharmacodynamic studies are needed.<br><br>CLINICAL RELEVANCE: This is the first pharmacokinetic study of APAP in psittacines, which has the potential to be an effective and safe component of multimodal analgesia in these species.},
}
@article {pmid40136229,
year = {2025},
author = {Sinigaglia, G and Fortunato, LM and Grillo, ML and Partata, WA},
title = {Potential of N-acetylcysteine in the management of low back pain: a scoping review of studies in humans and animal models.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {58},
number = {},
pages = {e14382},
doi = {10.1590/1414-431X2025e14382},
pmid = {40136229},
issn = {1414-431X},
mesh = {*Acetylcysteine/therapeutic use ; *Low Back Pain/drug therapy ; Humans ; Animals ; Disease Models, Animal ; Acetaminophen ; Treatment Outcome ; },
abstract = {Low back pain (LBP) is a common type of pain that causes disability and impairs cognitive function. With over 80% of adults estimated to experience LBP during their lifetime, this type of pain not only has a significant impact on the individual, but also on public health systems and national economies. Unfortunately, there is no single standard of care for patients with LBP. N-acetylcysteine (NAC), which is used clinically to treat acetaminophen overdose, has recently been tested as a potential treatment for LBP. NAC is inexpensive and commercially available, and it has an established tolerance and safety profile. However, NAC's efficacy in LBP has not been established. This scoping review presents a summary of studies investigating the effects of NAC and the potential benefits in LBP treatment, and highlights its potential molecular mechanisms and side effects. A systematic literature search in Pubmed/MEDLINE, Embase, Scopus, Science Direct, Web of Science, Cinahl, and Lilacs databases was conducted. The PRISMA-ScR checklist was used to ensure integrity of the review. The scoping review protocol was registered in the Open Science Framework. No limit was set on study language and publication date. In total, 2357 articles were located, of which 16 were included. The studies show that NAC has potential for LBP treatment, but data are derived only from a few clinical trials and preclinical studies. Thus, there is much to learn and more clinical studies should be performed before NAC can be clinically recommended for the treatment of LBP.},
}
@article {pmid40136129,
year = {2024},
author = {Hardt, M and Mayr, A and Kutschera, E and Marciniak, J and Küchler, EC and Kirschneck, C and Deschner, J and Jäger, A and Beisel-Memmert, S},
title = {Rho Kinases and Reactive Oxygen Species in Autophagy Regulation by Pressure in Periodontal Ligament Cells.},
journal = {Brazilian dental journal},
volume = {35},
number = {},
pages = {e245944},
pmid = {40136129},
issn = {1806-4760},
mesh = {*Periodontal Ligament/cytology/metabolism ; Humans ; *Reactive Oxygen Species/metabolism ; *Autophagy/physiology/drug effects ; *rho-Associated Kinases/metabolism/antagonists &amp; inhibitors ; Pyridines/pharmacology ; Pressure ; Amides/pharmacology ; Cells, Cultured ; Acetylcysteine/pharmacology ; },
abstract = {Autophagy is a self-digestion mechanism of cells, which is related to cell stress. It enables cell survival by maintaining cellular homeostasis or initiates cell death. This study aimed to investigate the intracellular signaling of pressure-induced autophagy regulation in human periodontal ligament (PDL) cells and to analyze the involvement of Rho kinases (ROCK) and reactive oxygen species (ROS) in particular. Human PDL cells were treated with the ROCK inhibitor Y-27632 and the ROS scavenger N-acetylcysteine (NAC) in combination with pressure magnitudes of 2, 6, and 8 g/cm2 over 16 hours. Cells treated with rapamycin served as a positive control and untreated cells as a control group. The Cyto-ID® Autophagy Detection Kit was used for flow cytometric analysis. Statistical analysis was performed using ANOVA and post-hoc tests. The results show that the pressure-induced autophagy was affected differently by the two inhibitors (p<0.05). The application of Y-27632 led to a significant reduction in autophagy in all pressure groups. The application of NAC led to reduced autophagy at pressures of 2 g/cm2 and 6 g/cm2. At 8 g/cm2, this effect was no longer present. In the control group, autophagy was significantly reduced by Y-27632 and significantly increased by NAC. Our data suggest that both Rho-kinase and reactive oxygen species could influence pressure-induced autophagy regulation in PDL cells.},
}
@article {pmid40133146,
year = {2025},
author = {Xu, R and Zhang, G and Huang, H and Zhao, Y and Tan, WS and Cai, H},
title = {Polyvinyl alcohol, N-acetylcysteine, and methyl-β-cyclodextrin exhibit albumin functions in natural killer cell culture.},
journal = {Journal of bioscience and bioengineering},
volume = {139},
number = {6},
pages = {436-444},
doi = {10.1016/j.jbiosc.2025.02.008},
pmid = {40133146},
issn = {1347-4421},
mesh = {*beta-Cyclodextrins/pharmacology/chemistry ; *Polyvinyl Alcohol/pharmacology/chemistry ; *Killer Cells, Natural/cytology/drug effects/metabolism ; *Acetylcysteine/pharmacology/chemistry ; Animals ; *Cell Culture Techniques/methods ; *Albumins/pharmacology ; Cell Line ; Serum Albumin, Bovine ; Mice ; Cattle ; Culture Media/chemistry ; Cholesterol/metabolism ; Cell Proliferation/drug effects ; },
abstract = {Albumin is a crucial component of serum-free media, playing a significant role in ex vivo cell culture as a lipid carrier and antioxidant. However, purified albumin contains undefined substances, making it challenging to achieve clinical application standards for effector cell culture. This study used natural killer (NK)-92 cells as a model to investigate the effects of the albumin substitute replacing bovine serum albumin (BSA) on cell expansion and metabolism in an in-house-designed, chemically defined, serum-free medium. We selected polyvinyl alcohol (PVA), N-acetylcysteine (NAC), and methyl-β-cyclodextrin (M-β-CD) as an albumin substitute combination and optimized their concentrations by using response surface methodology. The optimized albumin substitute was named PVA-NAC-M-β-CD (PNM). After 8 days of culture, NK-92 cells cultured with the PNM exhibited phenotype and cytotoxic function comparable to cells cultured with different concentrations of BSA. The expansion fold was 89.22 ± 3.55, significantly higher than the 51.23 ± 6.57 observed in the 0.75 g/L BSA group (p < 0.05). Further verification of functions of PNM showed that intracellular fatty acid levels, cholesterol consumption rates, and the pSTAT5 level in the PNM group were significantly higher than those in the 0.75 g/L BSA group (p < 0.05). Reactive oxygen species levels remained controlled, and mitochondrial membrane potential was similar. These findings suggested that the PNM can effectively replace the functions of BSA as a fatty acid carrier, antioxidant, and, to some extent, a cholesterol carrier. This study provides insights for developing chemically defined media to prepare clinical-grade NK cells efficiently.},
}
@article {pmid40133121,
year = {2025},
author = {Lucas-Herald, AK and Hussain, S and McGinley, K and Alves-Lopes, R and Amjad, SB and Flett, M and Lee, B and Steven, M and O'Toole, S and Ahmed, SF},
title = {ROS scavengers and genital skin healing in boys with hypospadias.},
journal = {Journal of pediatric urology},
volume = {21},
number = {5},
pages = {1170-1178},
doi = {10.1016/j.jpurol.2025.02.023},
pmid = {40133121},
issn = {1873-4898},
mesh = {Humans ; Male ; *Hypospadias/surgery/metabolism ; *Wound Healing/drug effects/physiology ; *Reactive Oxygen Species/metabolism ; Infant ; Child, Preschool ; Child ; *Free Radical Scavengers/pharmacology ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Fibroblasts/drug effects ; Cyclic N-Oxides/pharmacology ; Case-Control Studies ; Skin ; Antioxidants/pharmacology ; Cells, Cultured ; *Acetylcysteine/pharmacology ; Spin Labels ; Genitalia, Male ; },
abstract = {INTRODUCTION: Hypospadias repair is associated with high complication rates. Vascular cells from boys with hypospadias have increased reactive oxygen species (ROS) compared to controls. It is not clear if ROS affects wound healing in hypospadias.<br><br>OBJECTIVES: The aim of this study is to identify if cell migration and proliferation in genital skin is altered in hypospadias, and whether this is altered by antioxidants.<br><br>STUDY DESIGN: Genital skin fibroblasts (GSFs) were grown from boys undergoing hypospadias repair or routine circumcision. Cells were imaged immediately after creating a wound scratch and 48 h later, in the presence/absence of ROS scavengers, N-acetylcysteine (NAC) or Tempol. Cell migration was determined using ImageJ software. Cell proliferation was measured using a Cell Count Kit-8 (Abcam, UK).<br><br>RESULTS: Twenty-four cases (median age (range) 1.8 (1.2, 6.3) years) and 28 controls (1.6 (1.2, 6.1) years) were recruited. Boys with hypospadias had impaired cell migration with reduced wound closure at 48 h (2.0 fold, p < 0.0001) and reduced cell proliferation (1.3 fold, p = 0.01). External Masculinisation Score was positively correlated with wound closure (r = 0.5, p < 0.0001) and cell proliferation (r = 0.3, p = 0.002). Exposure to NAC and Tempol improved wound closure (1.9 fold, p = 0.01, and 1.5 fold, p = 0.02 respectively) and cell proliferation (1.5 fold, p = 0.02 and 1.4 fold, p = 0.05 respectively).<br><br>DISCUSSION: There is an association between wound healing and virilisation of the external genitalia in boys. ROS scavengers increase cell migration and proliferation in GSFs from boys with hypospadias.<br><br>CONCLUSION: Translational studies are required to confirm whether ROS scavengers may represent a therapeutic option for improving surgical outcome in boys with hypospadias.},
}
@article {pmid40126496,
year = {2025},
author = {Syarif, S and Makkaraka, MAG and Zainal, ATF and Birowo, P and Atmoko, W},
title = {Unlocking the potential of antioxidant supplementation with n-acetylcysteine to improve seminal parameters and analysis of its safety: a systematic review and meta-analysis of randomized controlled trials.},
journal = {Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica},
volume = {97},
number = {1},
pages = {13750},
doi = {10.4081/aiua.2025.13750},
pmid = {40126496},
issn = {2282-4197},
mesh = {Humans ; *Acetylcysteine/adverse effects/therapeutic use/administration &amp; dosage ; Male ; Randomized Controlled Trials as Topic ; *Antioxidants/adverse effects/administration &amp; dosage/therapeutic use ; *Infertility, Male/drug therapy ; Semen Analysis ; Dietary Supplements ; Sperm Motility/drug effects ; Semen/drug effects ; },
abstract = {INTRODUCTION AND OBJECTIVES: N-acetyl-cysteine (NAC) is one of the oldest and most powerful antioxidants used to treat various diseases. It plays an important role in protecting cells against oxidative damage and has the potential to improve seminal parameters in male with infertility. This systematic review and meta-analysis aim to comprehensively evaluate the efficacy and safety profile of antioxidant supplementation with NAC in male with infertility or impaired semen parameters.<br><br>MATERIALS AND METHODS: This systematic review and meta-analysis adhered to Cochrane Handbook guidelines. A literature search across PubMed, ScienceDirect, Cochrane Library and Scopus on February 21, 2024 of studies evaluating NAC supplementation for male infertility or impaired semen parameters was conducted. Study quality was assessed using Revised Cochrane's risk of bias (RoB 2.0) and RevMan 5.4 was used for meta-analysis.<br><br>RESULTS: Search yielded 1.106 articles and 5 studies were included in this meta-analysis. Our study showed that patients who received NAC had statistically significant results in improving sperm volume [MD: 0.69 (0.26-1.12), P = 0.002], sperm concentration [MD: 4.43 1.50-7.36), P = 0.003], sperm total motility [MD: 9.69 (6.61-12.77), P < 0.00001], and normal sperm morphology [MD: 1.36 (0.70-2.03), P < 0.0001] compared to control. Additionally, patients given NAC had no reported side effects based on our included studies.<br><br>CONCLUSIONS: We found NAC supplementation significantly improves seminal parameters and has a favorable safety profile. These findings highlight the potential role of NAC as a safe supplementation for male with infertility or in male with impaired semen parameters.},
}
@article {pmid40125296,
year = {2025},
author = {El-Sarnagawy, GN and Abd Eldayem, YB and Sobeeh, FG},
title = {Pattern and impact of antidotal administration in an Egyptian tertiary poison control center: A three-year retrospective study (2021-2023).},
journal = {Toxicology reports},
volume = {14},
number = {},
pages = {101973},
pmid = {40125296},
issn = {2214-7500},
abstract = {Timely antidote administration is a critical step in acute poisoning management. Awareness of poisoning patterns and the essential antidotal requirement could improve patient care with better hospital resource allocation. This study investigates the pattern and impact of antidotal administration on patient outcomes in an Egyptian tertiary poison control center, providing insights to optimize the antidote stocking of essential antidotes. A three-year cross-sectional study was conducted at Tanta University Poison Control Center from January 2021 to December 2023. Demographic data, poisoning characteristics, causative agents, and administered antidotal data were retrieved. The initial Poisoning Severity Score (PSS), total hospitalization period, and patient outcomes were also recorded. The included 447 antidote-treated poisoned patients showed near equal gender distribution and median age of 25 years. Atropine, oximes, N-acetylcysteine (NAC), and naloxone were the top administered antidotes among patients (48.3 %, 25.7 %, 19.9 %, and 11.2 %, respectively). Mortality and complications were recorded in 5.15 % and 20.8 %, respectively. Administration of atropine, oximes, NAC, and L-carnitine significantly improved all outcomes (p < 0.05). Although HBO therapy significantly improved mortality, it substantially increased intensive care unit admissions (p < 0.001). Despite folic acid administration significantly improved mortality and complication incidences (p < 0.05), its therapeutic efficiency is still questionable. Availability constraints of the digibind and botulinum antitoxin could affect patient outcomes. Administration of atropine, oximes, NAC, naloxone, and sodium bicarbonate was significantly linked to prolonged hospitalization (p < 0.001). Accordingly, the emergency department in each institution should regularly update the antidotal stock based on a review of the list of essential and commonly used antidotes.},
}
@article {pmid40122550,
year = {2025},
author = {Humphries, C and Clarke, E and Eddleston, M and Gillings, M and Irvine, S and Keating, L and Miell, A and Milne, L and Muir, L and O'Brien, R and Oatey, K and Raman, R and Thanacoody, R and Tuck, S and Weir, CJ and Wood, DM and Dear, JW and , },
title = {HiSNAP trial-a multicentre, randomised, open-label, blinded end point, safety and efficacy trial of conventional (300 mg/kg) versus higher doses of acetylcysteine (450 mg/kg and 600 mg/kg) in patients with paracetamol overdose in the UK: study protocol.},
journal = {BMJ open},
volume = {15},
number = {3},
pages = {e097432},
pmid = {40122550},
issn = {2044-6055},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/therapeutic use/adverse effects ; *Acetaminophen/poisoning ; *Drug Overdose/drug therapy ; Multicenter Studies as Topic ; *Analgesics, Non-Narcotic/poisoning ; Randomized Controlled Trials as Topic ; United Kingdom ; *Antidotes/administration &amp; dosage ; *Chemical and Drug Induced Liver Injury/drug therapy ; Male ; Glutathione/metabolism ; Adult ; Female ; },
abstract = {INTRODUCTION: In overdose, a larger proportion of paracetamol (acetaminophen) is converted in the liver to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Glutathione (GSH) is the endogenous antioxidant that protects cells from NAPQI-induced injury. In overdose, GSH stores may become depleted, leaving NAPQI free to produce liver damage. N-Acetylcysteine (NAC) helps prevent paracetamol toxicity by replenishing liver GSH. This protective effect of NAC produces specific metabolites in the circulation. Currently, regardless of the paracetamol dose ingested, patients in the UK receive a dose of NAC based only on their weight. Basic pharmacology, mathematical modelling and observational studies suggest that this dose may be insufficient in some patients (particularly those taking a large overdose).<br><br>METHODS AND ANALYSIS: A multicentre trial, taking place across several hospitals in Scotland, UK, within Emergency Departments and Acute Medical Units. Recruitment commenced on 19 February 2024 and is anticipated to run for approximately 2 years. This is a three-group dose-finding trial, in which participants are assigned in a 1:1:1 ratio to either Standard NAC (300&#x2009;mg/kg) or higher doses of 450&#x2009;mg/kg (Group 1) and 600&#x2009;mg/kg (Group 2). The primary outcome is the proportion of paracetamol metabolites in the circulation that are directly produced by GSH/NAC detoxification of NAPQI. A higher proportion of these metabolites will indicate that the additional NAC is reducing the amount of toxic paracetamol metabolites in the body. The study will first test the primary outcome on the HiSNAP Group 2 against Standard NAC; only if that is significant will HiSNAP Group 1 be tested against Standard NAC.<br><br>ETHICS AND DISSEMINATION: The HiSNAP trial has been approved by the East Midlands (Derby) Research Ethics Committee (reference 23/EM/0129), NHS Lothian Research and Development Department, and the MHRA. Results will be disseminated by peer-reviewed publication, conferences and linked on isrctn.com.<br><br>TRIAL REGISTRATION NUMBER: ISRCTN17516192.},
}
@article {pmid40122511,
year = {2025},
author = {Peerapen, P and Rattananinsruang, P and Putpeerawit, P and Boonmark, W and Thongboonkerd, V},
title = {The direct inhibitory effects of an antioxidant, N-acetylcysteine, against calcium oxalate crystal growth, aggregation and adhesion to MDCK renal cells.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {200},
number = {},
pages = {115403},
doi = {10.1016/j.fct.2025.115403},
pmid = {40122511},
issn = {1873-6351},
mesh = {*Calcium Oxalate/chemistry/metabolism ; Animals ; Dogs ; Madin Darby Canine Kidney Cells ; *Acetylcysteine/pharmacology ; *Antioxidants/pharmacology ; Cell Adhesion/drug effects ; Crystallization ; },
abstract = {N-acetylcysteine (NAC), a potent antioxidant, can reduce nephrolithiatic pathogenesis by diminishing oxidative assault during crystalluria. However, its direct effects on calcium oxalate (CaOx) crystals that affect stone development were unknown. Herein, we examined the direct effects of NAC (at 1, 10 or 100 μM) on CaOx crystal formation, growth, aggregation, adhesion to MDCK renal cells, and internalization into the cells. The findings demonstrated that NAC at all these concentrations did not significantly affect size, number and mass of the newly generated CaOx crystals and their internalization into renal cells. However, NAC dose-dependently inhibited CaOx self-aggregation. Additionally, NAC at all concentrations significantly decreased the enlargement (growth) of the already-formed CaOx crystals and their adhesion to renal cells. Its dose-dependent inhibitory effects on crystal growth and adhesion were demonstrated at lower concentrations (0.01 and 0.1 μM). Measurement of adsorption energy (Eadsorption) between NAC molecule and Ca[2+] ion revealed adsorption or affinity between NAC and Ca[2+]. Their affinity/binding was also confirmed by an ion-selective electrode (ISE)-based titration assay. These data have shown, for the first time, the direct inhibitory effects of NAC against CaOx crystal growth, aggregation and crystal adhesion to renal cells via Ca[2+] binding that may impact the prevention of nephrolithiasis.},
}
@article {pmid40119667,
year = {2025},
author = {Büyükdoğan, H and Ertürk, C and Eren, E and Öztürk, &#xc7; and Yıldırım, B and Sarıtaş, TB and Demirkol, M},
title = {The impact of N-acetylcysteine on early periods of tendon healing: histopathologic, immunohistochemical, and biomechanical analysis in a rat model.},
journal = {Connective tissue research},
volume = {66},
number = {3},
pages = {161-174},
doi = {10.1080/03008207.2025.2479501},
pmid = {40119667},
issn = {1607-8438},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Male ; *Wound Healing/drug effects ; Rats, Wistar ; Rats ; Biomechanical Phenomena/drug effects ; *Achilles Tendon/pathology/drug effects/injuries ; *Tendon Injuries/pathology/drug therapy/metabolism ; Immunohistochemistry ; Disease Models, Animal ; },
abstract = {PURPOSE: This study aimed to evaluate the early effects of N-acetylcysteine, which has antioxidant, inflame-modulatory, and cytoprotective properties, on tendon healing.<br><br>MATERIALS AND METHODS: Thirty-five male Wistar Hannover rats were divided into five groups: first-week treatment (Group 1T), first-week control (Group 1C), third-week treatment (Group 3T), third-week control (Group 3C), and native tendons (Group N). Bilateral Achilles tenotomy was performed on all rats except Group N. After tenotomy, 150&#x2009;mg/kg N-acetylcysteine was administered daily intraperitoneally to treatment groups, while isotonic saline was given to the control groups. Tendons were evaluated histopathologically, immunohistochemically, and biomechanically after sacrifice in the first and third weeks.<br><br>RESULTS: No significant differences were observed in the first week (p&#x2009;>&#x2009;0.05). Movin and Bonar scores (lower scores reflect improved histologic healing) were significantly lower in Group 3T than in Group 3C (p&#x2009;=&#x2009;0.002). Collagen type-I/type-III ratios were higher in Group 3T compared to Group 3C (p&#x2009;=&#x2009;0.001). Fmax (N) values were similar across Group 3T, Group 3C, and Group N (p&#x2009;=&#x2009;0.772). However, cross-sectional areas (mm[2]) were significantly smaller in Group 3T than in Group 3C (p&#x2009;=&#x2009;0.001), with the smallest areas observed in native tendons. Thus, tensile strength (MPa, load per unit area) and toughness (J/10[3]&#xa0;mm[3], energy absorbed per unit volume) were significantly higher in Group 3T than in Group 3C (p&#x2009;=&#x2009;0.001).<br><br>CONCLUSION: N-acetylcysteine supplied some improved results on early markers of tendon healing. Although our findings support the potential of NAC as a therapeutic adjunct in tendon injuries, further studies are needed to evaluate the long-term effects and underlying mechanisms.},
}
@article {pmid40113020,
year = {2025},
author = {Xiong, Z and Ou, Y and Chen, R and Zhou, M and Wang, Z and Wu, G and Che, M and Li, K and Gong, H and Wang, Y and Ling, X and Wang, H and Wang, X and Song, Q and Qi, S and Feng, Z and Peng, J},
title = {Tanycyte proliferation and migration through the sonic hedgehog pathway restores hypothalamic function after ischemic injury.},
journal = {Free radical biology &amp; medicine},
volume = {232},
number = {},
pages = {437-449},
doi = {10.1016/j.freeradbiomed.2025.03.026},
pmid = {40113020},
issn = {1873-4596},
mesh = {Animals ; Mice ; Cell Proliferation ; *Hedgehog Proteins/metabolism/genetics ; *Hypothalamus/metabolism/pathology ; Signal Transduction ; Cell Movement ; *Ependymoglial Cells/metabolism/pathology ; Male ; Endothelin-1 ; *Brain Ischemia/metabolism/pathology ; Disease Models, Animal ; },
abstract = {Tanycytes, a distinct type of glial cell within the hypothalamus, will be investigated in this study to elucidate the intrinsic mechanisms by which they facilitate the restoration of hypothalamic function. We injected endothelin 1 (ET-1) into the third ventricle to establish an ischemic hypothalamic injury model. Nestin CreER[T2] and Rosa26R-CAG:tdTomato mice were crossbred, and viral tracing was used to label and track tanycytes. Functional changes in these cells were observed with calcium imaging. Alterations in tanycytes were assessed with single-cell and transcriptomic sequencing analyses. The involvement of specific pathways was confirmed via intraperitoneal injection of N-acetyl cysteine (NAC) and cycloheximide. Following ischemic injury to the hypothalamus in mice, acute weight loss and impaired activity of Agrp neurons were observed, both of which recovered within 7 days. The fate of tanycytes was traced in Nestin-CreER[T2]: Rosa26R-CAG:Tdtomato mice to confirm their proliferation and migration after hypothalamic injury. Calcium imaging indicated that these proliferating and migrating cells participated in signal transduction, thereby reconstructing the regulatory network of tanycytes. The analysis of single-cell data on postnatal days 8 and 45 identified CDK1 as a marker of proliferative tanycytes. The roles of ROS and the Shh pathway in the proliferation and migration of tanycytes were validated via the intraperitoneal injection of NAC and cycloheximide inhibitors. After inducing ischemic injury to the arcuate nucleus of the hypothalamus, Agrp neuronal activity declined, accompanied by ROS fluctuations within tanycytes. Activation of the Shh pathway prompts the transition of tanycytes from a quiescent state to a proliferative state, thereby leading to their migration to the arcuate nucleus. This process re-establishes the regulatory network of tanycytes and restores metabolic balance. This finding may provide an important target for promoting the recovery of hypothalamic function.},
}
@article {pmid40111652,
year = {2025},
author = {Bai, H and Chen, H and Du, S and Qiu, D and Li, S and Ma, T and Gao, R and Zhang, Z},
title = {N-Acetylcysteine Mitigates Ketamine Neurotoxicity in Young Rats by Modulating ROS-Mediated Pyroptosis and Ferroptosis.},
journal = {Molecular neurobiology},
volume = {62},
number = {7},
pages = {9416-9429},
pmid = {40111652},
issn = {1559-1182},
support = {SYKJYB202302//Discipline Project of College of Veterinary Medicine/ ; NDYB2022-4//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; NDYB2022-7//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; 2023MS03035//Natural Science Foundation of Inner Mongolia Autonomous Region of china/ ; },
mesh = {Animals ; *Ketamine/toxicity ; *Pyroptosis/drug effects ; *Acetylcysteine/pharmacology/therapeutic use ; Rats, Sprague-Dawley ; *Ferroptosis/drug effects ; *Reactive Oxygen Species/metabolism ; Hippocampus/pathology/drug effects/metabolism ; Male ; Rats ; PC12 Cells ; Neuroprotective Agents/pharmacology ; Lipid Peroxidation/drug effects ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; },
abstract = {Ketamine, an N-methyl-D-aspartate receptor antagonist with anesthetic and analgesic properties, is extensively utilized for the induction and maintenance of pediatric perioperative anesthesia. Increasing evidence suggests that prolonged exposure to ketamine may induce neurotoxicity in developing animals, adversely affecting their long-term cognitive function. N-acetylcysteine (NAC) is an organic sulfur compound in the Allium genus; however, the mechanisms through which it alleviates ketamine-induced neurotoxicity during developmental stages remain inadequately understood. Refine the investigation of the mechanisms by which Nac mitigates ketamine-induced neurotoxicity during development via ferroptosis and pyroptosis pathways. Postnatal day 7 in SD rats PC12 cells and HAPI cells were used in this study. The neuroprotective mechanism of Nac was elucidated through pathological, histological, and molecular biological methodologies to assess pyroptosis, ferroptosis, hippocampal tissue damage, and behavioral modifications in adulthood. The results suggest that prior administration of Nac reduced lipid peroxidation and mitochondrial injury, along with pyroptosis activated by the NLRP3/caspase-1 pathway, hippocampal damage, and cognitive deficits after exposure to ketamine. In summary, our findings from both in vivo and in vitro studies indicate that ROS plays a significant regulatory role in the neurotoxic effects of ketamine during development. Furthermore, Nac mitigates hippocampal damage and cognitive deficits associated with ketamine exposure by inhibiting ROS-mediated ferroptosis and pyroptosis.},
}
@article {pmid40108283,
year = {2025},
author = {Charoensappakit, A and Sae-Khow, K and Vutthikraivit, N and Maneesow, P and Sriprasart, T and Pachinburavan, M and Leelahavanichkul, A},
title = {Immune suppressive activities of low-density neutrophils in sepsis and potential use as a novel biomarker of sepsis-induced immune suppression.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {9458},
pmid = {40108283},
issn = {2045-2322},
support = {N41A640076, N34A660583//The National Research Council of Thailand (NRCT)/ ; RA-MF-18/65, RA-MF-15/66, and RA-MF-14/67//Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University/ ; B16F640175//The Program Management Unit for Human Resources, Institutional Development, Research, and Innovation/ ; },
mesh = {Humans ; *Sepsis/immunology/blood ; *Neutrophils/immunology/metabolism ; Biomarkers ; Male ; Female ; Middle Aged ; Aged ; B7-H1 Antigen/metabolism/immunology ; T-Lymphocytes/immunology ; Phagocytosis ; Leukocytes, Mononuclear/immunology ; Antigens, CD/metabolism ; Apoptosis ; Adult ; },
abstract = {Data of low-density neutrophils (LDN), the neutrophils in the peripheral blood mononuclear cells (PBMC) fraction, in sepsis is still less. As such, LDN (CD66b-positive cells in PBMC) was highest in intensive care unit (ICU) patients with sepsis (n=24) compared with non-sepsis (n=10) and healthy control (n=20), with a negative correlation with lymphocyte count and could predict secondary infection and mortality with the area under the curve (AUC) at 0.79 and 0.84, respectively. Compared with sepsis normal-density neutrophils (NDN), sepsis-LDN demonstrated higher expression of CD66b, CD63, CD11b, and CD184, but lower expression of CD62L and CD182 and defects of effector functions, including phagocytosis and apoptosis. The t-distributed stochastic neighbor embedding (t-SNEs) demonstrated high program cell death ligand-1 (PD-L1) in sepsis-LDN. In sepsis samples, the T cell proliferation in PBMC (T cells with LDNs) was lower than that in the isolated T cells (T cells alone) and incubation of anti-PD-L1 neutralizing antibody, but not a reactive oxygen species (ROS) scavenger (N-acetyl cysteine), improved the T cell suppression. Additionally, 30 min lipopolysaccharide (LPS) activation altered healthy control NDN into LPS-LDN (reduced density) and LPS-NDN (maintain density) with similarly elevated CD66b, CD11B, and CD62L. However, LPS-LDN (in vitro LDN) showed lower expression of CD63, CD184, and PD-L1 compared with LDN from patients (sepsis-LDN), suggesting a partial LPS impact on LDN generation. From the microscopic-based method (Wright's staining in PBMC), sepsis-LDN demonstrated a mixed population of mature and immature cells with a good correlation with the flow-based analysis (Bland-Altman analysis and AUC). In conclusion, LDN in sepsis, partly generated by LPS activation, was associated with secondary infection and T cell suppression, mainly through the expression of PD-L1, which might be an immune suppression biomarker, especially with a less expensive microscopic-based method.},
}
@article {pmid40106157,
year = {2025},
author = {Zhang, F and Zhang, C and Sun, W and Xie, S and Wu, P and Zeng, G and Liu, X},
title = {Proteomic Profiling and Therapeutic Targeting of Oxidative Stress in Autoimmune Encephalitis.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {2},
pages = {38},
pmid = {40106157},
issn = {1559-1166},
support = {82360251//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Oxidative Stress ; Mice ; Female ; Mice, Inbred C57BL ; Humans ; Biomarkers/blood ; *Hashimoto Disease/drug therapy/metabolism/blood ; *Encephalomyelitis, Autoimmune, Experimental/drug therapy/metabolism/blood ; Superoxide Dismutase/blood/genetics ; Acetylcysteine/therapeutic use/pharmacology ; *Encephalitis/drug therapy/metabolism/blood ; Adult ; Male ; Glutathione Peroxidase/blood ; Middle Aged ; Antioxidants/therapeutic use/pharmacology ; Apolipoproteins E/blood ; *Proteome/metabolism ; },
abstract = {Autoimmune encephalitis (AE) is an immune-mediated non-infectious disease, and novel and robust biomarkers are needed to improve the diagnosis and prognostic outcomes of AE. Oxidative stress is a ubiquitous cellular process causing damage to various biological molecules. The aim of our study was to understand the clinical implication and mechanism underlying oxidative stress in AE. Liquid chromatography-mass spectrometry analysis was conducted on the serum of eight patients with AE and seven healthy controls, and oxidative stress was characterized. Experimental autoimmune encephalitis (EAE) models were established in C57BL/6 and SJL mice for investigation of the therapeutic effect and mechanism of anti-oxidative stress N-acetylcysteine (NAC). We provided proteomic landscape in the serum of AE and identified antioxidant ALB, APOE, GPX3, and SOD3 as serum diagnostic markers of AE. The antioxidant markers were lowly expressed both in the serum of AE patients and central nervous system (CNS) of EAE mice. NAC administration improved clinical signs and motor function and alleviated nerve injury of EAE mice as well as lowered oxidative stress (decreased MDA content and ROS accumulation and elevated SOD activity and GSH content). ALB, APOE, GPX3, and SOD3 expressions were elevated by NAC in the CNS of EAE mice. Moreover, NAC reduced tissue-resident CD4[+] and CD8[+] T cells and GFAP-marked astrocytes and Iba-1-marked microglia in EAE mice, thus alleviating autoimmunity-mediated damage and neuroinflammation. Our findings facilitate the discovery of novel oxidative stress-related biomarkers for AE and reveal the promise of anti-oxidative stress for AE management.},
}
@article {pmid40106010,
year = {2025},
author = {Yuksel, C and Uz, YH},
title = {Protective effects of N-acetylcysteine against titanium dioxide nanoparticles-induced kidney damage in rats.},
journal = {Journal of molecular histology},
volume = {56},
number = {2},
pages = {112},
pmid = {40106010},
issn = {1567-2387},
support = {Project number: TUBAP 2022/57//Scientific Research Projects Coordination Unit of Trakya University, Turkey/ ; },
mesh = {Animals ; *Titanium/adverse effects/toxicity ; *Acetylcysteine/pharmacology ; Rats ; *Kidney/drug effects/pathology/metabolism ; Male ; *Nanoparticles/chemistry ; *Protective Agents/pharmacology ; *Metal Nanoparticles ; Apoptosis/drug effects ; *Kidney Diseases/chemically induced/pathology ; NF-kappa B/metabolism ; },
abstract = {The objective of this study was to evaluate the potential protective effect of N-acetylcysteine (NAC) against kidney damage induced by titanium dioxide nanoparticles (TiO2NP) through biochemical, histological, and immunohistochemical analyses. Forty rats were randomly divided into four groups of 10 animals each. Saline was administered intragastrically to control group for 14 days. In NAC group, 150 mg/kg NAC was injected intraperitoneally for 21 days. In TiO2NP group, TiO2NP at a dose of 50 mg/kg/day, dissolved in saline, was administered intragastrically for 14 days. TiO2NP + NAC group received 50 mg/kg/day TiO2NP for 14 days and 150 mg/kg NAC for 21 days, starting 7 days before TiO2NP administration. At the end of experiment, rats were anesthetized, serum samples were collected for biochemical analysis, and kidney tissue was removed for histological and immunohistochemical analyses. There was no significant change in body weight, kidney weight, or serum urea-creatinine levels between the groups. TiO2NP caused a significant increase in vacuolization and brush border loss scores in tubular cells, as well as scores for congestion and leukocyte infiltration. However, NAC supplementation significantly ameliorated these impairments. Additionally, TiO2NP significantly increased NF-kB, TNF-α, and caspase-3 immunoreactivities, as well as the number of PCNA-positive and TUNEL-positive cells. NAC treatment decreased all immunoreactivities and TUNEL-positive cells, but did not change the number of PCNA-positive cells after TiO2NP exposure. The results of the study showed that the toxic effects of TiO2NP on the kidneys, commonly encountered in daily life, can be mitigated by the anti-inflammatory and anti-apoptotic properties of NAC.},
}
@article {pmid40097764,
year = {2025},
author = {Li, X and Li, W and Xie, X and Fang, T and Yang, J and Shen, Y and Wang, Y and Wang, H and Tao, L and Zhang, H},
title = {ROS Regulate Rotenone-induced SH-SY5Y Dopamine Neuron Death Through Ferroptosis-mediated Autophagy and Apoptosis.},
journal = {Molecular neurobiology},
volume = {62},
number = {7},
pages = {9271-9289},
pmid = {40097764},
issn = {1559-1182},
mesh = {*Rotenone/toxicity/pharmacology ; *Reactive Oxygen Species/metabolism ; *Autophagy/drug effects ; *Ferroptosis/drug effects ; *Apoptosis/drug effects ; Humans ; *Dopaminergic Neurons/drug effects/metabolism/pathology ; Cell Line, Tumor ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {Rotenone, a plant-derived natural insecticide, is widely used to induce Parkinson's disease (PD) models. However, the mechanisms of rotenone-induced cell death remain unclear. Here, we found that rotenone (0.01, 0.1, or 1 μmol/L) suppressed SH-SY5Y dopamine neuron viability and led to PD-like pathological changes, such as reduced tyrosine hydroxylase (TH) but increased α-synuclein. Rotenone increased the levels of intracellular reactive oxygen species (ROS) and mitochondrial ROS, as well as the levels of the antioxidants nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), ultimately resulting in oxidative stress. Moreover, rotenone significantly downregulated the expression of GPX4 and xCT but upregulated the expression of COX2 and NCOA4, which are markers of ferroptosis. Furthermore, rotenone decreased phosphorylated mTOR level but increased Beclin-1, ATG5, LC3 and p62 expression, suggesting that rotenone enhances autophagy and reduces autophagy flux. Additionally, rotenone reduced Bcl-2 levels and the mitochondrial membrane potential (MMP) while promoting BAX and Caspase-3 expression, thus initiating cell apoptosis. N-acetylcysteine (NAC), a ROS scavenger, and ferrostatin-1 (Fer-1) and deferoxamine (DFO), two ferroptosis inhibitors, significantly eliminated rotenone-induced autophagy and apoptosis. Moreover, ML385, a specific inhibitor of Nrf2, suppressed rotenone-induced ferroptosis. Our results demonstrated that ROS might mediate rotenone-induced PD-like pathological changes by regulating iron death, autophagy, and apoptosis. Inhibiting ferroptosis blocked the rotenone-induced increase in autophagy and apoptosis. Thus, the ability of ROS to regulate rotenone-induced death through autophagy and apoptosis is dependent on ferroptosis. The findings require validation in multiple neuronal cell lines and in vivo.},
}
@article {pmid40094443,
year = {2025},
author = {Smieško, L and Mažerik, J and Gondáš, E and Dohál, M and Jošková, M and Šutovská, M and Fraňová, S},
title = {N-Acetylcysteine and Its Therapeutic Potential in an Animal Model of Allergic Asthma.},
journal = {Journal of aerosol medicine and pulmonary drug delivery},
volume = {38},
number = {3},
pages = {118-126},
doi = {10.1089/jamp.2024.0049},
pmid = {40094443},
issn = {1941-2703},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Asthma/drug therapy/physiopathology/immunology ; Disease Models, Animal ; Cytokines/metabolism ; Guinea Pigs ; Bronchoalveolar Lavage Fluid/immunology/chemistry ; Airway Remodeling/drug effects ; *Lung/drug effects/physiopathology/metabolism/immunology ; *Expectorants/pharmacology/administration &amp; dosage ; Male ; Airway Resistance/drug effects ; Trachea/drug effects/physiopathology/metabolism ; Muscle, Smooth/drug effects/physiopathology/metabolism ; Inflammation Mediators/metabolism ; Dose-Response Relationship, Drug ; Mucociliary Clearance/drug effects ; Cough/drug therapy/physiopathology ; },
abstract = {Background: N-acetylcysteine (NAC) is a classical mucolytic agent that, in addition to its mucolytic activity, also exhibits antioxidant activity. This could be beneficial in treating chronic inflammatory airway diseases, including asthma. Background: We evaluated the ability of NAC to modulate airway defense mechanisms, airway reactivity, inflammation, and remodeling after 10 days of administration [20 and 60 mg/(kg·d)] in an experimental guinea pig model of allergic inflammation. Methods: The concentrations of inflammatory cytokines (interleukins: IL-4, IL-5, IL-10, IL-12, and IL-13), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were measured in bronchoalveolar lavage fluid using a multiplex detection method. The concentration of remodeling marker transforming growth factor beta-1 (TGF-β1) was measured in lung homogenates using enzyme-linked immunosorbent assay. In vivo, changes in specific airway resistance and number of cough efforts were determined. Tracheal smooth muscle reactivity was evaluated in vitro. Ciliary beat frequency (CBF) indicated mucociliary clearance. Results: A 10-day administration of NAC at a higher dosage led to a significant decrease in the regulatory cytokines IL-4, IL-5, and GM-CSF. NAC, in both dosing schedules, decreased the levels of TGF-β1. NAC at a higher dosage reduced the number of chemically induced cough reflexes and CBF. NAC did not affect airway hyperreactivity parameters. Conclusion: NAC is a multifactorial drug, and under our experimental conditions of allergic inflammation, it showed positive effects on the levels of regulatory cytokines and growth factors, which probably led to a reduction in the intensity of airway defense mechanisms.},
}
@article {pmid40094059,
year = {2025},
author = {Yadav, N and Mondal, D and Raja, R and Ma, EL and Singh, KP and Sharma, DK and Das, AK},
title = {N-acetylcysteine enhances bone marrow activity in treating pancytopenia induced by canine hemoprotozoan diseases.},
journal = {Veterinary research forum : an international quarterly journal},
volume = {16},
number = {1},
pages = {1-10},
pmid = {40094059},
issn = {2008-8140},
abstract = {Canine hemoprotozoan diseases viz. ehrlichiosis and babesiosis are mostly associated with critical anemia and thrombocytopenia with pancytopenic changes, leading to multi-organ failure. For faster recovery of patients with complicated hemoprotozoan diseases, whole blood transfusion or bone marrow stimulating agents to produce more red blood cells (RBCs) and platelets might be helpful. Unfortunately, canine specific transfusion procedures are expensive and even not available in many developing countries. Development of alternate therapeutic modality by bone marrow stimulation to augment the production of RBCs and platelets and thus, to treat the critical pancytopenic patients is and an urgent necessity. N-acetylcysteine (NAC), acts as a precursor of reduced glutathione and increases the production of bone marrow B cells. It also improves viability and self-renewal capacity of stem cells and thus, boosts hematopoietic differentiation by protecting induced pluripotent stem cells. This study envisaged to develop alternate therapeutic approach to combat pancytopenia secondary to canine hemoprotozoan diseases. Bone marrow mediated aplastic pancytopenia was induced experimentally by administration of cyclophosphamide in rats. Bone marrow stimulating property of NAC was compared with desmopressin, another bone marrow stimulator, which revealed better in terms of hematobiochemical and histopathological changes. Results of rat model study were extrapolated in clinical canine hemoprotozoan cases having pancytopenia. Dogs treated with hemoprotozoan disease specific therapy along with NAC rendered favorable changes by haltering the progression of critical anemia and thrombocytopenia. Study revealed that supplementation of NAC along with canine hemoprotozoan specific therapy is beneficial to alleviate pancytopenia.},
}
@article {pmid40092853,
year = {2024},
author = {Wahab, A and Ganiger, C and Pawar, R and Phaphe, S and Ronad, Y},
title = {Anti-microbial and micro-leakage properties of orthodontic cement.},
journal = {Bioinformation},
volume = {20},
number = {10},
pages = {1368-1373},
pmid = {40092853},
issn = {0973-2063},
abstract = {Glass Ionomer Cement (GIC) is used for cementing orthodontic bands because of its anti-cariogenic property, which is attributed to the release of fluoride. Therefore, it is of interest to assess the antimicrobial property and micro-leakage of GIC incorporated with different concentration of N-acetylcysteine (N-AC) and copper nanoparticle (Cu-NP). Our study composed of 5 groups i.e. group I is control with different concentration of N-AC and Cu-NP involving each group with 8 samples. We found that, group V showed the highest zone of inhibition; while the micro-leakage was seen highest for group I with a score of 2.2 ± 1.09 and the least score was recorded for Group III (0.8± 0.37). Thus, addition of 2% Cu-NP and 15% N-AC resulted in minimal micro-leakage. We conclude that increase in concentration of N-AC and CU-NP antimicrobial property efficiency also increases; on the other hand, increase in the concentration of N-AC and CU-NP did not decrease the micro-leakage.},
}
@article {pmid40084379,
year = {2025},
author = {Yang, CC and Chen, WM and Shia, BC and Wu, SY},
title = {Impact of long-term N-acetylcysteine use on cancer risk.},
journal = {American journal of cancer research},
volume = {15},
number = {2},
pages = {618-630},
pmid = {40084379},
issn = {2156-6976},
abstract = {Chronic obstructive pulmonary disease (COPD) patients face an increased risk of developing various malignancies due to shared risk factors and underlying systemic inflammation. N-acetylcysteine (NAC) has shown potential anticancer properties in preclinical studies, but clinical evidence in COPD patients is limited. We conducted a nationwide propensity score-matched cohort study using data from Taiwan's National Health Insurance Research Database to evaluate the anticancer effects of NAC in COPD patients. Patients diagnosed with COPD between 2008 and 2019 were included, and those with pre-existing cancer were excluded. NAC use was defined as consistent administration for most days with an average dose exceeding 28 cumulative defined daily doses (cDDDs) annually. Cox regression models were adjusted for various covariates was employed. PSM yielded 91,546 patients, evenly distributed between NAC and non-NAC groups. Multivariate Cox regression analysis revealed a lower cancer risk in patients with long-term NAC use compared to non-users (adjusted hazard ratio [aHR] 0.69, 95% confidence interval [CI] 0.66-0.72; P<0.001). Dose-dependent relationships were observed, with higher daily NAC intake associated with reduced cancer risk. Time-varying Cox regression analysis demonstrated significant reductions in the risk of specific cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer, among NAC users compared to non-users. Our study provides clinical evidence supporting the potential anticancer effects of NAC in COPD patients. These findings highlight the importance of exploring NAC as a chemopreventive agent in high-risk populations and inform clinical practice and future research endeavors.},
}
@article {pmid40083413,
year = {2025},
author = {Hu, QL and Zhong, H and Wang, XR and Han, L and Ma, SS and Li, L and Wang, Y},
title = {Mitochondrial phosphate carrier plays an important role in virulence of Candida albicans.},
journal = {Mycology},
volume = {16},
number = {1},
pages = {369-381},
pmid = {40083413},
issn = {2150-1203},
abstract = {Candida albicans is a common fungal pathogen that can cause life-threatening infections. MIR1 is considered to be a mitochondrial phosphate carrier of C. albicans, while its role in virulence has not been fully elucidated. In this study, we found that mir1Δ/Δ mutant exhibited severe virulence defect in both nematode and murine models. Further mechanism studies revealed that the mir1Δ/Δ mutant grew more slowly than the wild-type strain and showed severe filamentation defects on the hypha-inducing agar media, including YPD + serum, Lee, Spider + glucose, SLAD, SLD, and YPS. Furthermore, the loss of MIR1 resulted in unfermentable carbon utilisation defect, ATP decrease, and reactive oxygen species (ROS) accumulation in C. albicans. Antioxidant proanthocyanidins, vitamin E, and N-acetyl cysteine (NAC) could reduce intracellular ROS levels and partially rescue the filamentation defects of the mir1Δ/Δ mutant. Accordingly, hypha-specific genes, as well as CEK1 and RIM101 were down-regulated in the mir1Δ/Δ mutant, and this down-regulation could be partially rescued by the addition of the antioxidant NAC. Collectively, MIR1 plays an important role in C. albicans mitochondrial function, filamentation and virulence, and would be a promising antifungal target.},
}
@article {pmid40080083,
year = {2025},
author = {Basaran, R and Efendioglu, M and Akça, M and Ceman, D and Demirtaş, C and Sürmeneli, YE and Yildirim, M},
title = {Antihyperalgesic effects of gabapentin and levetiracetam in a model of post-traumatic epilepsy.},
journal = {Physiology international},
volume = {112},
number = {1},
pages = {68-84},
doi = {10.1556/2060.2025.00524},
pmid = {40080083},
issn = {2498-602X},
mesh = {Animals ; *Gabapentin/pharmacology ; *Levetiracetam/pharmacology ; Rats, Sprague-Dawley ; Male ; *Epilepsy, Post-Traumatic/drug therapy/physiopathology/chemically induced ; *Anticonvulsants/pharmacology/therapeutic use ; Rats ; *Analgesics/pharmacology ; Pain Threshold/drug effects ; *Hyperalgesia/drug therapy/physiopathology ; Disease Models, Animal ; *Amines/pharmacology ; Acetylcysteine/pharmacology ; *gamma-Aminobutyric Acid/pharmacology ; *Cyclohexanecarboxylic Acids/pharmacology ; Pentylenetetrazole ; Pain Measurement/methods ; },
abstract = {OBJECTIVE: This study aimed to investigate the role of levetiracetam (LEV) and gabapentin (GBP) on mechanical and thermal pain thresholds, as well as n-acetylcysteine (NAC) as an adjuvant, in the pentylenetetrazol (PTZ)-induced post-traumatic epilepsy (PTE) model after mild-traumatic brain injury (TBI) in male Sprague-Dawley rats.<br><br>METHODS: Animals were randomly divided into 7 groups (Control, PTE, PTE+LEV, PTE+GBP, PTE+NAC, PTE+LEV+NAC and PTE+GBP+NAC). Rats received 50 mg kg-1 LEV, 100 mg kg-1 GBP, and combinations of these antiepileptics with 100 mg kg-1 NAC for 14 days after TBI.<br><br>RESULTS: While the thermal pain threshold decreased significantly in the PTE group (P < 0.05), it&#xa0;increased in the PTE+LEV, PTE+GBP, and PTE+LEV+NAC groups (P < 0.05, P < 0.001 and P < 0.01, respectively). Interestingly, NAC alone did not affect the thermal pain threshold, but the combination of PTE+LEV+NAC increased the thermal pain threshold. Furthermore, PTE+GBP+NAC administration prevented the effect of GBP on the thermal pain threshold.<br><br>CONCLUSIONS: The presented study is the first to examine the effect of LEV and GBP in PTE. It was found that PTE decreased the thermal pain threshold, but LEV and GBP applied for 14 days prevented the decrease in PTE-related pain threshold and increased the thermal pain threshold. NAC, which was used as an adjuvant to support antiepileptic drugs, did not influence the thermal pain threshold alone; however, it increased the pain threshold more by potentiating the effect of LEV. Both LEV and GBP have an antihyperalgesic effect in the PTE model facilitated by PTZ, and NAC further reinforces the antihyperalgesic effect of LEV.},
}
@article {pmid40069676,
year = {2025},
author = {Heydari, B and Aflatonian, M and Bagherizadeh, M and Hoseinzade, F and Saghafi, F},
title = {Evaluating the efficacy of N-acetylcysteine in diminishing the duration and frequency of rotavirus-induced gastroenteritis: a preliminary randomized, placebo-controlled, double-blind clinical trial.},
journal = {BMC pediatrics},
volume = {25},
number = {1},
pages = {186},
pmid = {40069676},
issn = {1471-2431},
support = {85//Shahid Sadoughi University of Medical Sciences/ ; },
mesh = {Humans ; Double-Blind Method ; *Rotavirus Infections/drug therapy/complications ; *Gastroenteritis/drug therapy/virology ; *Acetylcysteine/therapeutic use ; Male ; Female ; Infant ; Child, Preschool ; Diarrhea/virology/drug therapy ; Treatment Outcome ; Feces/virology ; Time Factors ; Rotavirus ; },
abstract = {BACKGROUND: Globally, gastroenteritis stands as a primary contributor to child mortality, annually taking the lives of 3 million children under the age of 5 years. Rotavirus, a major factor in viral diarrhea among children aged 6 months to 2 years, presents with severe symptoms such as watery diarrhea and vomiting. Although mortality rates have decreased due to supportive care and vaccines, promising alternatives like N-acetylcysteine (NAC) show potential benefits in laboratory studies, indicating a possible supplementary strategy for managing rotavirus infections by reducing the duration and antigen excretion in feces.<br><br>METHODS: During this double-blind clinical trial, 71 patients, confirmed to have gastroenteritis resulting from rotavirus using a rapid diagnostic strip, were randomly allocated to two groups. One group was prescribed NAC at a dosage of 60&#xa0;mg/kg/day, while the other received a placebo. The patient's progress was monitored daily until their gastroenteritis improved, and details regarding the duration of diarrhea and the frequency of bowel movements were recorded for each participant.<br><br>RESULTS: The average duration of diarrhea in the NAC group and the placebo group was 2 and 3 days, respectively, with a level of p&#x2009;=&#x2009;0.121. During the diarrhea period, the number of bowel movements in the NAC group was recorded at 28.1&#x2009;&#xb1;&#x2009;21.6 times, whereas in the placebo group, it was 35.3&#x2009;&#xb1;&#x2009;33.1 times, yielding a p-value of 0.409.<br><br>CONCLUSIONS: Even though the effects of NAC were observed in lowering the duration of the period and decreasing the frequency of bowel movements in gastroenteritis, these results did not reach statistical significance. Hence, the data from this study suggest that NAC may not effectively reduce the duration of diarrhea and the frequency of bowel movements linked to gastroenteritis caused by rotavirus.<br><br>TRIAL REGISTRATION: IRCT20181208041882N13, 14-10-2023 (https://irct.behdasht.gov.ir/trial/68259).},
}
@article {pmid40058751,
year = {2025},
author = {Zhao, Y and Lv, R and He, Y and Dong, N and Wang, X and Pu, J and Yu, Q},
title = {The miR-21-5p/DUSP8/MAPK signaling pathway mediates inflammation and apoptosis in vascular endothelial cells induced by intermittent hypoxia and contributes to the protective effects of N-acetylcysteine.},
journal = {European journal of pharmacology},
volume = {997},
number = {},
pages = {177462},
doi = {10.1016/j.ejphar.2025.177462},
pmid = {40058751},
issn = {1879-0712},
mesh = {*Apoptosis/drug effects ; Animals ; *MicroRNAs/genetics/metabolism ; Humans ; *Human Umbilical Vein Endothelial Cells/drug effects/metabolism/pathology ; *Acetylcysteine/pharmacology ; Mice ; *Dual-Specificity Phosphatases/metabolism/genetics ; *MAP Kinase Signaling System/drug effects ; Mice, Inbred C57BL ; Inflammation/pathology/metabolism ; Male ; Cell Hypoxia/drug effects ; Sleep Apnea, Obstructive/drug therapy ; },
abstract = {Obstructive sleep apnoea hypopnea syndrome (OSAHS) is a sleep disorder associated with significant cardiovascular complications, characterized by intermittent hypoxia (IH). IH causes endothelial dysfunction, an early event in cardiovascular disease. We investigated the role of dual-specificity phosphatase 8 (DUSP8), a key negative regulator of the mitogen-activated protein kinase (MAPK) signalling pathway, in IH-induced endothelial cell damage, and the therapeutic effects of N-acetylcysteine (NAC) by establishing IH models in human umbilical vein endothelial cells and C57BL/6 mice. DUSP8 and MAPK signalling pathway-related proteins were analysed by western blotting, and DUSP8 mRNA and miR-21-5p expression was assessed by RT-qPCR. Inflammatory cytokines were detected by an enzyme-linked immunosorbent assay, apoptosis-related proteins were analysed by western blotting, and apoptosis was assessed using flow cytometry. IH stimulation induced inflammation and apoptosis in endothelial cells, downregulated DUSP8 expression, and upregulated the phosphorylation of key molecules involved in the MAPK signalling pathway. However, DUSP8 overexpression alleviated IH-induced inflammation and apoptosis in endothelial cells and reduced the phosphorylation of key molecules in the MAPK signalling pathway. Bioinformatic analysis and dual-luciferase reporter assays confirmed that DUSP8 is a direct target of miR-21-5p. DUSP8 overexpression effectively reversed the damage caused by miR-21-5p upregulation under IH conditions. Furthermore, in cell and animal models of IH, NAC demonstrated protective effects against inflammation, apoptosis, and oxidative stress through a mechanism linked to the miR-21-5p/DUSP8/MAPK signalling pathway. Overall, this study elucidated the protective role of DUSP8 against IH-induced endothelial injury and confirmed the potential of NAC as a therapeutic agent for OSAHS-related diseases.},
}
@article {pmid40057704,
year = {2025},
author = {Qiu, X and Yang, S and Zhang, Y and Wang, Q and Kong, L and Zhou, L},
title = {Effect of N-acetylcysteine on antimicrobials induced nephrotoxicity: a meta-analysis.},
journal = {BMC nephrology},
volume = {26},
number = {1},
pages = {128},
pmid = {40057704},
issn = {1471-2369},
mesh = {*Acetylcysteine/therapeutic use ; Humans ; *Anti-Infective Agents/adverse effects ; *Acute Kidney Injury/chemically induced/prevention &amp; control ; Randomized Controlled Trials as Topic ; Creatinine/blood ; *Antioxidants/therapeutic use ; },
abstract = {OBJECTIVE: N-acetylcysteine (NAC) has antioxidant effects in reducing acute kidney injury. This study systematically reviewed and assessed the efficacy of NAC in preventing antimicrobials induced nephrotoxicity.<br><br>METHODS: Pubmed, Embase, Web of Science, and the Cochrane Library were searched extensively for relevant studies that evaluating NAC on antimicrobials induced nephrotoxicity until June 1, 2024. Eligible records were screened according to the inclusion and exclusion criteria. The odds ratio (OR) was selected to evaluate the effect of NAC on nephrotoxicity. We pooled the extracted data using a random effects model.<br><br>RESULTS: Three randomized controlled trials were included in the analysis. The pooled results showed that NAC could reduce the incidence of antimicrobials induced nephrotoxicity (OR&#x2009;=&#x2009;0.487, 95% CI&#x2009;=&#x2009;0.258, 0.918, P&#x2009;=&#x2009;0.03, I[2]&#x2009;=&#x2009;0%). Serum creatine (Scr) on Day 2 was significantly decreased in the NAC group compared to the placebo group (SMD,&#x2009;-&#x2009;0.298; 95%CI,&#x2009;-&#x2009;0.585 to&#x2009;-&#x2009;0.010; I[2]&#x2009;=&#x2009;23%; P&#x2009;=&#x2009;0.04). No difference was observed in blood urea nitrogen (BUN), and creatinine clearance (CrCl).<br><br>CONCLUSION: In this meta-analysis, NAC was associated with a benefit in the prevention of antimicrobials induced nephrotoxicity. However, large-scaled and well-designed RCTs are required in the future.},
}
@article {pmid40057223,
year = {2025},
author = {Maartens, M and Vlok, M and van de Vyver, M},
title = {Antioxidants improve the viability of diabetic bone marrow MSCs without rescuing their pro-regenerative secretome function.},
journal = {Molecular and cellular endocrinology},
volume = {601},
number = {},
pages = {112519},
doi = {10.1016/j.mce.2025.112519},
pmid = {40057223},
issn = {1872-8057},
mesh = {Animals ; *Mesenchymal Stem Cells/drug effects/metabolism/pathology ; *Antioxidants/pharmacology ; Cell Survival/drug effects ; Ascorbic Acid/pharmacology/analogs &amp; derivatives ; *Secretome/metabolism/drug effects ; Acetylcysteine/pharmacology ; *Diabetes Mellitus, Experimental/pathology/metabolism ; *Bone Marrow Cells/drug effects/metabolism/pathology ; Mice ; *Regeneration/drug effects ; Proteomics ; Proteome/metabolism ; Male ; Mice, Obese ; Cell Proliferation/drug effects ; },
abstract = {Bone marrow mesenchymal stem cell (BM-MSC) dysfunction and poor viability are prominent in diabetes and limit their therapeutic efficacy. A proteomic investigation was performed to assess disease associated alterations and the efficacy of antioxidants to rescue cellular function. BM-MSCs were isolated from obese diabetic mice (B6.Cg-Lep[ob]/J) cultured in the presence or absence of N-acetylcysteine (NAC) and ascorbic acid-2phosphate (AAP). Label free Liquid Chromatography and Mass Spectrometry (LC-MS) analysis detected 5079 proteins with 251 being differentially expressed between treatment groups. NAC/AAP improved cellular growth/viability post isolation by up-regulating proteins involved in redox status, ATP synthesis, Rho-GTPase signaling and modulated the immunophenotype of BM-MSCs. Despite a single application of the secretome not providing any advantage for wound bed regeneration in full thickness excisional diabetic wounds, the intracellular proteome illustrated the potential mechanisms of action by which NAC/AAP targeted the respiratory chain and modulated the immune phenotype of BM-MSCs. Given these observations, antioxidant supplementation might be more effective as prophylactic strategy to protect MSCs against functional decline instead of using it as a restorative agent and warrants further investigation.},
}
@article {pmid40056000,
year = {2025},
author = {Zanganeh, Z and Hezavehei, M and Halvaei, I and Sharafi, M},
title = {Beneficial Effects of N-Acetyl Cysteine in the Different Equilibration Times on Post-Thawed Rooster Sperm Quality.},
journal = {Reproduction in domestic animals = Zuchthygiene},
volume = {60},
number = {3},
pages = {e70035},
doi = {10.1111/rda.70035},
pmid = {40056000},
issn = {1439-0531},
support = {TMU8216//Tarbiat Modares University/ ; },
mesh = {Animals ; Male ; *Acetylcysteine/pharmacology ; *Chickens ; *Semen Preservation/veterinary/methods ; *Cryopreservation/veterinary/methods ; *Spermatozoa/drug effects/physiology ; Semen Analysis/veterinary ; Sperm Motility/drug effects ; Cryoprotective Agents/pharmacology ; Antioxidants/pharmacology ; },
abstract = {Cryopreservation is the best method for preserving rooster sperm, especially in declining indigenous breeds. Cryopreserved semen is significantly compromised due to equilibration time, cold shock and oxidative stress encountered during the freezing-thawing process. To improve the quality and fertility of thawed semen, it is essential to protect sperm cells from peroxidative damage. This study assessed the effects of N-acetyl cysteine (NAC), an antioxidant supplement, on the functional parameters of thawed rooster sperm after pre-freezing equilibration periods of 2 and 4 h. Samples were collected from 10 male Ross 308 broiler breeders and diluted with Beltsville extenders containing different concentrations of NAC (0, 0.1, 1 and 10 mM/mL) during equilibrium periods of 2 and 4 h before freezing. Our findings showed that NAC-0.1 and NAC-1 groups in 2 h increased significantly total and progressive motility (59.85 ± 3.73, 59.67 ± 3.73, 42.85 ± 2.64 and 42.80 ± 2.64, respectively), viability, and plasma membrane functionality (62.45 ± 3.51, 62.36 ± 3.51, 56.81 ± 3.51 and 56.82 ± 3.56, respectively) compared to the control groups. Furthermore, NAC-0.1-2 h and NAC-1-2 h demonstrated the lowest levels of apoptosis and intracellular reactive oxygen species (ROS), as well as the highest mitochondrial membrane potential in comparison to the control groups. These findings indicate that NAC-0.1 and NAC-1 are effective in maintaining the quality of thawed rooster sperm during a 2-h equilibration period.},
}
@article {pmid40051733,
year = {2025},
author = {Asgharzadeh, N and Diziche, AN and Amini-Khoei, H and Yazdanpanahi, N and Korrani, MS},
title = {N-acetyl cysteine through modulation of HDAC2 and GCN5 in the hippocampus mitigates behavioral disorders in the first and second generations of socially isolated mice.},
journal = {IBRO neuroscience reports},
volume = {18},
number = {},
pages = {350-359},
pmid = {40051733},
issn = {2667-2421},
abstract = {OBJECTIVES: Social isolation stress (SIS) in early life can lead to behavioral disorders. N-acetylcysteine (NAC), an antioxidant, may aid treatment. This study explored NAC's impact on behavior in first and second-generation mice after SIS, focusing on HDAC2 and GCN5 expression in the hippocampus.<br><br>MATERIALS AND METHODS: In this study, 24 male and 24 female mice were bred for one generation. The pups were divided into six (3male, 3female) groups (n&#x202f;=&#x202f;20): 1- Control receiving normal saline, 2- SIS with normal saline, 3- SIS with NAC (150&#x202f;mg/kg) IP for four weeks. Eight mice from each group underwent behavioral, histopathological, and molecular tests, while others were mated (4 males + 4 females) to produce second generations. These pups were divided into 9 groups (n&#x202f;=&#x202f;8) for behavioral tests, including elevated plus maze, open field, forced swimming, and histopathological and molecular assessments (HDAC2 and GCN5 expression) in the hippocampus.<br><br>RESULTS: The SIS group showed increased HDAC2 and GCN5 expression. Following SIS, there was a decrease in open arm entries and passes in the open field test, alongside increased immobility in the forced swimming test and reduced CA1 and CA3 hippocampal diameters. NAC mitigated the adverse molecular, behavioral, and histopathological impacts of SIS across both generations.<br><br>CONCLUSION: NAC reduces behavioral disorders after SIS (first and second generation) by reducing the expression of GCN5 and HDAC2 and increasing neuronal diameter in the hippocampus. Future research should investigate the long-term therapeutic effects of NAC for behavioral disorders after SIS.},
}
@article {pmid40050926,
year = {2025},
author = {Tseng, TH and Chang, CH and Chen, CL and Chiang, H and Wang, JH and Young, TH},
title = {Enhanced antibiotic release and biocompatibility with simultaneous addition of N-acetylcysteine and vancomycin to bone cement: a potential replacement for high-dose antibiotic-loaded bone cement.},
journal = {Journal of orthopaedic surgery and research},
volume = {20},
number = {1},
pages = {246},
pmid = {40050926},
issn = {1749-799X},
mesh = {*Vancomycin/administration &amp; dosage ; *Acetylcysteine/administration &amp; dosage ; *Bone Cements/chemistry ; *Anti-Bacterial Agents/administration &amp; dosage ; Polymethyl Methacrylate ; *Drug Liberation/drug effects ; Materials Testing/methods ; Dose-Response Relationship, Drug ; *Biocompatible Materials ; Animals ; Humans ; },
abstract = {BACKGROUND: Antibiotic-loaded bone cement (ALBC) is crucial for treating orthopedic infections, but its use is limited by suboptimal antibiotic release patterns and potential toxicity. This study explores the dual addition of N-acetylcysteine (NAC) and vancomycin to polymethylmethacrylate (PMMA) as a strategy to enhance the antibacterial efficacy and reduce toxicity.<br><br>METHODS: PMMA cement cylinders were loaded with varying combinations of NAC and vancomycin and tested for antibiotic release, cytotoxicity, and antibacterial activity over a 35-day period. Porosity of the cements was also evaluated as a measure of potential antibiotic release enhancement.<br><br>RESULTS: The addition of NAC improved vancomycin release, particularly after the initial burst release phase, and reduced cytotoxicity compared to high-dose vancomycin alone. The optimal combination was found to be 2 gm vancomycin with either 2 gm or 4 gm of NAC, which maintained effective antibacterial activity over 35 days without the toxicity seen with higher doses of vancomycin alone. Moreover, NAC alone did not demonstrate antibacterial properties, indicating its role primarily as a bioenhancer in this context.<br><br>CONCLUSION: Simultaneous inclusion of NAC and vancomycin in PMMA bone cement provides a more favorable release profile and biocompatibility than high-dose vancomycin alone, suggesting a potential strategy for enhancing the therapeutic efficacy of ALBC in treating prosthetic joint infections. This approach allows for lower doses of antibiotics, reducing potential cytotoxicity, systemic toxicity and enhancing the duration of antibacterial activity.<br><br>LEVEL OF EVIDENCE: Laboratory study.},
}
@article {pmid40049439,
year = {2025},
author = {Liu, JM and Lee, KI and Su, CC and Fang, KM and Liu, SH and Fu, SC and Kuo, CY and Chang, KC and Ke, JA and Chen, YW and Yang, CY and Huang, CF},
title = {Chlorpyrifos-oxon results in autophagic flux dysfunction contributing to neuronal apoptosis via a ROS/AMPK/CHOP activation pathway.},
journal = {Chemico-biological interactions},
volume = {412},
number = {},
pages = {111452},
doi = {10.1016/j.cbi.2025.111452},
pmid = {40049439},
issn = {1872-7786},
mesh = {*Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; *Chlorpyrifos/analogs &amp; derivatives/toxicity/pharmacology ; *Autophagy/drug effects ; *AMP-Activated Protein Kinases/metabolism ; Animals ; *Transcription Factor CHOP/metabolism ; *Neurons/drug effects/metabolism/cytology/pathology ; Mice ; *Signal Transduction/drug effects ; Cell Line, Tumor ; Cell Line ; },
abstract = {Chlorpyrifos (CPF) is a widely used organophosphate (OP) pesticide in agriculture and sanitation, known to elicit neurotoxic effects. Chlorpyrifos-oxon (CPO), a metabolite of CPF, is the primary neurotoxic agent, yet its mechanisms are less understood. In this study, we investigated the effects and underlying mechanisms of CPO-induced neurotoxicity. CPO exposure significantly induced cytotoxicity in Neuro-2a cells, alongside the activation of apoptosis, as evidenced by an increase in the apoptotic cell population, caspase-3 activity, and cleavage of caspaspe-3, -7, and PARP proteins. Furthermore, defective autophagy was observed in CPO-treated Neuro-2a cells, indicated by increased expression of Beclin-1, Atg5, LC3-II, and p62 proteins. 3-MA, an autophagy inhibitor, suppressed CPO-activated LC3-II and apoptotic marker proteins expression, but not p62. In contrast, chloroquine and bafilomycin A1, autophagic flux inhibitors, potentiated the CPO-induced elevation of LC3-II, p62, and cleaved caspase-3 and -7 protein levels. CPO exposure also upregulated CHOP protein expression. Transfection with CHOP-specific siRNA markedly reduced CHOP protein expression, autophagic flux dysfunction, and apoptosis. Additionally, CPO exposure significantly increased AMPKα phosphorylation and reactive oxygen species (ROS) generation. Antioxidant N-acetylcysteine (NAC), but not the AMPK inhibitor Compound C, effectively attenuated the CPO-induced ROS generation in neuronal cells, which was accompanied by the prevention of AMPKα activation, downstream CHOP expression, autophagic flux dysfunction, and apoptosis. Collectively, these findings suggest that CPO-induced neurotoxicity arises from autophagic flux dysfunction, contributing to apoptosis via the ROS-activated AMPK pathway, which regulates CHOP expression, ultimately leading to neuronal cell death. Targeting the ROS/AMPK/CHOP axis may offer a promising intervention to against CPO-induced neurotoxicity.},
}
@article {pmid40048297,
year = {2025},
author = {Flaherty, BF and Olsen, CS and Coon, ER and Srivastava, R and Cook, LJ and Keenan, HT},
title = {Patterns of Use of β-2 Agonists, Steroids, and Mucoactive Medications to Treat Bronchiolitis in the PICU: U.S. Pediatric Health Information System 2009-2022 Database Study.},
journal = {Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies},
volume = {26},
number = {3},
pages = {e294-e303},
pmid = {40048297},
issn = {1529-7535},
support = {UM1 TR004409/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Intensive Care Units, Pediatric/statistics &amp; numerical data ; *Bronchiolitis/drug therapy ; Retrospective Studies ; Infant ; Male ; Female ; *Adrenergic beta-2 Receptor Agonists/therapeutic use ; Length of Stay/statistics &amp; numerical data ; United States ; *Expectorants/therapeutic use ; Databases, Factual ; Child, Preschool ; *Steroids/therapeutic use ; *Practice Patterns, Physicians'/statistics &amp; numerical data ; Saline Solution, Hypertonic/therapeutic use ; Infant, Newborn ; },
abstract = {OBJECTIVES: Describe β2-agonists, steroids, hypertonic saline (HTS), n-acetylcysteine (NAC), and dornase alfa (DA) use to treat bronchiolitis, factors associated with use, and associations between use and PICU length of stay (LOS).<br><br>DESIGN: Retrospective, multicenter cohort study.<br><br>SETTING: PICUs in the Pediatric Health Information System database.<br><br>PATIENTS: PICU admitted children 24 months young or younger with bronchiolitis.<br><br>INTERVENTIONS: None.<br><br>MEASUREMENTS AND MAIN RESULTS: We analyzed 47,520 hospitalizations between July 1, 2018, and June 30, 2022. We calculated the rate of medication use overall and the median (range) rate for each hospital: &#x3b2;2-agonist (24,984/47,520 [52.6%]; median hospital, 51.7% [21.4-81.7%]), steroid (15,878/47,520 [33.4%]; median hospital, 33.4% [6.0-54.8%]), HTS (7,041/47,520 [14.8%]; median hospital, 10.5% [0-66.1%]), NAC (1,571/47,520 [3.3%]; median hospital, 0.8% [0-22.0%], and DA (840/47,520 [1.8%]; median hospital, 1.4% [0-13.6%]). Logistic regression using generalized estimating equations (GEEs) identified associations between concurrent asthma and &#x3b2;2-agonist (adjusted odds ratio [aOR], 8.68; 95% CI, 7.08-10.65; p < 0.001) and steroid (aOR, 10.10; 95% CI, 8.84-11.53; p < 0.001) use. Mechanical ventilation was associated with all medications: &#x3b2;2-agonists (aOR, 1.79; 95% CI, 1.57-2.04; p < 0.001), steroids (aOR, 2.33; 95% CI, 1.69-3.21; p < 0.001), HTS (aOR, 1.82; 95% CI, 1.47-2.25; p < 0.001), NAC (aOR, 3.29; 95% CI, 2.15-5.03; p < 0.001), and DA (aOR, 7.65; 95% CI, 4.30-13.61; p < 0.001). No medication was associated with decreased PICU LOS. To assess changes in medication use over time and associations with the 2014 American Academy of Pediatrics bronchiolitis guidelines, we expanded our analysis to 83,820 hospitalizations between July 1, 2009, and June 30, 2022. Logistic regression with GEEs found no change in &#x3b2;2-agonist use; steroid use increased after guideline publication (aOR, 1.05; 95% CI, 1.01-1.10; p = 0.02), HTS use changed from increasing prior to the guidelines (aOR, 1.32; 95% CI, 1.11-1.56; p = 0.001) to stable since guideline publication (aOR, 0.93; 95% CI, 0.81-1.07; p = 0.33).<br><br>CONCLUSIONS: &#x3b2;2-agonists, steroids, and HTS are commonly, but variably used for PICU bronchiolitis treatment. Medication use appears relatively stable over the last decade.},
}
@article {pmid40043915,
year = {2025},
author = {Chen, Y and Yang, X and Li, J and Luo, H and Huang, Q and Yang, W and Lei, T and Lui, S and Gong, Q and Li, H and Wu, H and Gao, H},
title = {A nasally administrated reactive oxygen species-responsive carrier-free gene delivery nanosystem for Alzheimer's disease combination therapy.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {381},
number = {},
pages = {113604},
doi = {10.1016/j.jconrel.2025.113604},
pmid = {40043915},
issn = {1873-4995},
mesh = {Animals ; *Alzheimer Disease/therapy/genetics/metabolism ; *Reactive Oxygen Species/metabolism ; Administration, Intranasal ; *Nanoparticles/administration &amp; dosage/chemistry ; *Gene Transfer Techniques ; Amyloid Precursor Protein Secretases/genetics ; *RNA, Small Interfering/administration &amp; dosage/genetics ; Genetic Therapy/methods ; *Fingolimod Hydrochloride/administration &amp; dosage/chemistry ; Humans ; Mice ; Acetylcysteine/administration &amp; dosage ; Amyloid beta-Peptides/metabolism/genetics ; Male ; Brain/metabolism ; Mice, Inbred C57BL ; Microglia/metabolism/drug effects ; Aspartic Acid Endopeptidases/genetics ; },
abstract = {Combination therapies targeting multiple pathways are needed in order to improve treatment outcomes in Alzheimer's disease (AD) due to its complex pathogenesis. Amyloid-β and microglia-mediated neuroinflammation significantly contribute to AD pathogenesis. Amyloid-β-related nucleic acid drugs have demonstrated considerable potential in AD treatment; however, their clinical translation is limited by complex synthesis processes and carrier toxicity. Herein, an intranasally administrated, reactive oxygen species (ROS)-responsive, carrier-free gene delivery nanosystem (FTBR-NAC) was constructed for re-polarizing microglia and decreasing amyloid-β expression. In this nanosystem, fingolimod was conjugated with biguanide via an ROS-responsive linker to form the carrier for β-secretase 1 siRNA (siBACE1) to form FTBR nanoparticles. The electropositivity of FTBR and mucolytic activity of N-acetylcysteine (NAC) together enhanced the brain entry of FTBR. Upon reaching the brain, FTBR responded to the elevated ROS at the pathological site, releasing siBACE1 and fingolimod. Administration of FTBR-NAC improved cognitive function in AD mice, demonstrating the high therapeutic efficacy of this relatively simple nanosystem.},
}
@article {pmid40038825,
year = {2025},
author = {Emara, SM and Fahmy, SF and AbdelSalam, MM and Wakeel, LME},
title = {Effect of high-dose N-acetyl cysteine on the clinical outcome of patients with diabetic peripheral neuropathy: a randomized controlled study.},
journal = {Diabetology &amp; metabolic syndrome},
volume = {17},
number = {1},
pages = {79},
pmid = {40038825},
issn = {1758-5996},
abstract = {BACKGROUND: Diabetic peripheral neuropathy (DPN) is a vastly common and bothersome disorder with a clinically challenging course of treatment affecting patients with diabetes. This study aimed to evaluate the efficacy and safety of high dose oral N-acetyl cysteine (NAC) as adjuvant therapy on clinical outcome of DPN.<br><br>METHODS: A prospective, randomized, parallel, open label, controlled clinical trial. Ninety eligible DPN patients were randomly assigned to either control group receiving standard of care or NAC group receiving standard of care treatment and NAC at a dose of 2400&#xa0;mg/day for 12&#xa0;weeks. Glutathione peroxidase (GPx), nuclear factor erythoid-2 related factor (NRF-2) and tumor necrosis factor (TNF) were measured at baseline and after 12&#xa0;weeks to assess anti-oxidant and anti-inflammatory properties. Michigan neuropathy screening instrument (MNSI), Toronto clinical neuropathy score (TCNS), Diabetic neuropathy score (DNS), Diabetes-39 quality of life questionnaire (DQOL) and pain score were assessed at baseline and after 12&#xa0;weeks.<br><br>RESULTS: NAC group showed a significant increase (p&#x2009;<&#x2009;0.05) in NRF-2 by 25.3% and GPx by 100% and a decline of 21.45% in TNF-alpha levels versus controls that reported a decline in NRF-2 and GPx and an increase in TNF-alpha. HgbA1C and AST levels significantly decreased in NAC versus controls (7.2&#x2009;&#xb1;&#x2009;1 vs 8&#x2009;&#xb1;&#x2009;1.1, p&#x2009;=&#x2009;0.028 and 29.1 vs 55.4, p&#x2009;=&#x2009;0.012) respectively. NAC administration resulted in a significant decline in MNSA, TCNS, DNS and pain scores versus controls that showed increase in all scores. The QOL total score and the anxiety and energy and mobility domain scores significantly decreased in the NAC group versus controls, p&#x2009;<&#x2009;0.001.<br><br>CONCLUSION: High dose NAC administered for 12&#xa0;weeks modulated inflammation by reducing TNF-alpha and increasing GPx and NRF2 versus controls. NAC improved clinical outcomes of DPN reflected by a decline in neuropathy and pain scores and an improvement in QOL.<br><br>NCT04766450.},
}
@article {pmid40037730,
year = {2025},
author = {Chen, S and Hou, Z and Xiao, M and Wu, P and Yang, Y and Han, S and Xia, J and Hu, J and Zhang, K and Yang, L},
title = {Quaternized chitosan-based photothermal antibacterial hydrogel with pro-vascularization and on-demand degradation properties for enhanced infected wound healing.},
journal = {Carbohydrate polymers},
volume = {355},
number = {},
pages = {123350},
doi = {10.1016/j.carbpol.2025.123350},
pmid = {40037730},
issn = {1879-1344},
mesh = {*Hydrogels/chemistry/pharmacology ; *Chitosan/chemistry/pharmacology ; *Wound Healing/drug effects ; *Anti-Bacterial Agents/pharmacology/chemistry ; Animals ; Humans ; Rats ; Rats, Sprague-Dawley ; Human Umbilical Vein Endothelial Cells/drug effects ; Staphylococcus aureus/drug effects ; Copper/chemistry/pharmacology ; *Wound Infection/drug therapy ; Escherichia coli/drug effects ; Male ; Neovascularization, Physiologic/drug effects ; Methicillin-Resistant Staphylococcus aureus/drug effects ; Photothermal Therapy ; Polymers/chemistry ; Indoles ; },
abstract = {Compromised skin barrier fails to prevent pathogenic bacterial invasion, leading to wound infection and potentially severe tissue damage, for which conventional wound dressings provide inadequate therapeutic outcomes. Herein, we have developed a multifunctional injectable hydrogel (QCS-APA/P@D@C) based on quaternized chitosan (QCS) and aldehyde-modified aliphatic polycarbonate (APA), incorporating Prussian Blue (PB) @Polydopamine (PDA) @Cu (P@D@C) submicron particles (SPs). This novel hydrogel exhibits photothermal antibacterial properties, on-demand removal capability, and Cu[2+]-facilitated wound healing enhancement. The QCS-APA/P@D@C hydrogel, crosslinked via dynamic Schiff-base bonds, exhibits remarkable antibacterial efficacy (>99 %) against various bacteria, including multidrug-resistant (MDR) bacteria, through the synergistic effects of QCS, Cu[2+], and 808 nm near-infrared (NIR) photothermal effect. The hydrogel demonstrates rapid degradation (~12 min) upon exposure to N-acetylcysteine (NAC), facilitating on-demand removal and minimizing secondary trauma during dressing changes. Furthermore, the sustained release of Cu[2+] within 1-10 μM significantly enhances the migration and tube formation of human umbilical vein endothelial cells (HUVECs). In a Staphylococcus aureus (S. aureus)-infected wound model of Sprague-Dawley (SD) rats, the QCS-APA/P@D@C hydrogel demonstrated effectively modulating wound inflammation, promoting collagen deposition and angiogenesis, and accelerating wound closure. These findings demonstrate that the QCS-APA/P@D@C hydrogel can effectively promote the healing of bacterially infected wounds.},
}
@article {pmid40037093,
year = {2025},
author = {Pan, H and Zhai, G and Jing, Q and Fan, Y and Fang, C and Shi, F},
title = {Two-step metabolic activation to ortho-benzoquinone intermediate and its role in 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside-induced liver injury in mice.},
journal = {Drug metabolism and disposition: the biological fate of chemicals},
volume = {53},
number = {3},
pages = {100047},
doi = {10.1016/j.dmd.2025.100047},
pmid = {40037093},
issn = {1521-009X},
mesh = {Animals ; *Stilbenes/metabolism/toxicity ; *Glucosides/metabolism/toxicity ; Mice ; *Chemical and Drug Induced Liver Injury/metabolism/etiology/pathology ; *Benzoquinones/metabolism ; Male ; Liver/metabolism/drug effects/pathology ; Activation, Metabolic ; Humans ; Microsomes, Liver/metabolism ; Fallopia multiflora/chemistry ; },
abstract = {2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is the most abundant constituent of Polygonum multiflorum and is exclusively found in this herb. This renowned herbal medicine has been documented to lead to liver damage in humans. The present study demonstrated that TSG underwent 2-step metabolic activation to generate a reactive metabolite, involving both intestinal and hepatic metabolisms. TSG was hydrolyzed to its aglycone 2,3,5,4'-tetrahydroxystilbene (TS) in the intestine, and then, the 2,3 catechol of 2,3,5,4'-tetrahydroxystilbene was metabolized to an ortho-benzoquinone intermediate in the liver. The reactive metabolite was characterized as the N-acetyl-cysteine conjugate both in vivo and in vitro. Its structure was verified by a combined isotope-labeling strategy using the [14]N/[15]N, H/D, and [79]Br/[81]Br isotope pattern-based mass shifts. Intestinal β-glucosidase and hepatic CYP3A4 and CYP2C9 contributed to the reactive metabolite formation. The reactive intermediate could covalently modify the hepatic proteins through cysteine in mice. Combined with the treatment with β-glucosidase, a single oral administration of 400 mg/kg TSG caused liver centrilobular necrosis and degeneration in mice. Selective CYP3A inhibitor ketoconazole protected TSG-induced liver injury, concurrently attenuating protein adduct formation modified by reactive metabolites. The results indicate that TSG does not exert hepatotoxic effects but that the reactive ortho-benzoquinone metabolite from the oxidation of the 2,3 catechol of aglycone is responsible for TSG-induced liver injury. The study also facilitates a better understanding of the principal hepatotoxic chemicals in Polygonum multiflorum. SIGNIFICANCE STATEMENT: 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) undergoes intestinal deglycosylation to generate its aglycone, and then, the 2,3 catechol of aglycone was metabolized to an ortho-benzoquinone intermediate in the liver. β-glucosidase potentiates TSG-induced liver injury and protein adduction by the reactive metabolite. The results indicate that the reactive metabolite of TSG exerts hepatotoxic effects rather than the parent compound.},
}
@article {pmid40028879,
year = {2025},
author = {Truwit, JD and Fleming, K and Nanchal, RS},
title = {Empowering Respiratory Therapists to Restrict Nebulized 3% Saline and N-Acetylcysteine During Mechanical Ventilation.},
journal = {Respiratory care},
volume = {70},
number = {8},
pages = {937-945},
pmid = {40028879},
issn = {1943-3654},
support = {UL1 TR001436/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage ; Retrospective Studies ; Female ; *Respiration, Artificial/methods ; Male ; Middle Aged ; Nebulizers and Vaporizers ; *Respiratory Therapy/methods/standards ; Aged ; Saline Solution, Hypertonic/administration &amp; dosage ; *Guideline Adherence/statistics &amp; numerical data ; Practice Guidelines as Topic ; Intensive Care Units ; Length of Stay/statistics &amp; numerical data ; },
abstract = {Background: We previously implemented a policy that enabled respiratory therapists to reject orders for nebulized 3% hypertonic saline and/or N-acetylcysteine (HTS/NAC) that did not conform to the American Association for Respiratory Care (AARC) Clinical Practice Guideline. Outcomes of adhering to this more conservative approach are not well studied. We sought to determine if an approach conforming to guidelines is noninferior to a previously practiced more liberal approach. Methods: We performed a retrospective analysis of 2,272 subjects receiving mechanical ventilation ≥48 h within 5 adult ICUs between June 2020 and August 2023. The primary outcome was ventilator-free days at day 28 (VFD28). Secondary outcomes included ventilator days, ICU days, hospital stay, re-intubation rates, and mortality. Analysis was stratified by before and after policy implementation (see intervention) and by receiving HTS/NAC or not (ϕHTS/NAC). The latter was examined before and after propensity matching. The Δ for noninferiority was -0.5 days for VFD28 and +0.5 days for other continuous variables. As outcomes were not normally distributed, we analyzed them using Mann-Whitney U statistics. Results: Two thousand two hundred seventy-two subjects were evaluated. The mean age was 58.70 + 16.13 years and 929 (40.9%) subjects were women. HTS/NAC administration was reduced after policy implementation (40.2% before policy and 8.9% after policy; a reduction of 77.9%). The post-policy group and ϕHTS/NAC before and after propensity matching groups were all noninferior to the comparators. Subjects had significantly more VFD28 in the post-policy group, median (IQR), post 21 (0-25), pre: 20 (0-24), P = .02; and in the ϕHTS/NAC group, before matching ϕHTS/NAC: 21 (0-25), HTS/NAC: 18 (0-23), P < .001 and after propensity matching ϕHTS/NAC: 21 (0-25), HTS/NAC; 18 (0-23), P < .001. Conclusions: Restricting practice to conform to the AARC Clinical Practice Guideline was noninferior to more liberal use. The use of HTS/NAC in mechanically ventilated subjects does not appear efficacious and is both costly and time-consuming.},
}
@article {pmid40023441,
year = {2025},
author = {Yonatan, E and Shukha, ON and Golani, I and Abu-Ata, S and Awad-Igbaria, Y and Khatib, N and Ginsberg, Y and Palzur, E and Beloosesky, R and Shamir, A},
title = {Maternal N-acetylcysteine supplementation in lactation ameliorates metabolic and cognitive deficits in adult offspring exposed to maternal obesity.},
journal = {Neuropharmacology},
volume = {271},
number = {},
pages = {110390},
doi = {10.1016/j.neuropharm.2025.110390},
pmid = {40023441},
issn = {1873-7064},
mesh = {Animals ; Female ; Pregnancy ; *Lactation/drug effects ; Mice ; *Acetylcysteine/administration &amp; dosage/pharmacology ; *Cognitive Dysfunction/prevention &amp; control/etiology/metabolism ; *Prenatal Exposure Delayed Effects/metabolism ; Male ; Diet, High-Fat/adverse effects ; *Pregnancy in Obesity/metabolism ; Mice, Inbred ICR ; Dietary Supplements ; Maze Learning/drug effects ; Microglia/drug effects ; Obesity ; },
abstract = {Maternal obesity in pregnancy and lactation is linked to metabolic disturbances and neurodevelopmental problems in offspring, increasing the risk of psychiatric disorders in adulthood. We proposed that maternal N-acetyl cysteine (NAC) supplementation during lactation, a critical period for neurodevelopment, potentially protects offspring from developing cognitive impairment in adulthood. Fifteen young female ICR mice were randomly allocated to different experimental groups: high-fat diet (HFD; 60.3% fat before mating, during pregnancy and lactation), HFD-NAC of 300 mg/kg/day during lactation, CD (high-fat diet before mating, during pregnancy, and regular chow control diet of 8.2% fat during lactation), CD-NAC of 300 mg/kg/day during lactation and control group consuming regular chow diet. The serum inflammatory markers of the offspring were evaluated post-weaning, while metabolic markers, microglial density, and cognitive performance were assessed in adulthood using the novel Object Recognition and Morris Water Maze tests. Our results demonstrate maternal obesity during gestation and lactation increased body weight, hepatic steatosis, and microglial cell density in the dentate gyrus (DG) and cortex. Furthermore, these offspring exhibited reduced spatial learning abilities in adulthood, regardless of sex. However, maternal NAC administration during lactation and maternal diet intervention significantly reduced brain microglial density and improved both male and female offspring metabolic profiles. More importantly, NAC supplementation during lactation, regardless of maternal diet, enhanced male offspring's learning ability in adulthood. Our findings indicate that administering NAC to obese mothers during the critical lactation period may offer protection against metabolic disturbances and cognitive deficits in adult offspring previously exposed to maternal obesity.},
}
@article {pmid40023202,
year = {2025},
author = {Pangrazzi, L and Cerilli, E and Balasco, L and Khurshid, C and Tobia, C and Dall'O', GM and Chelini, G and Perini, S and Filosi, M and Barbieri, A and Ravizza, T and Vezzani, A and Provenzano, G and Pastore, A and Weinberger, B and Rubert, J and Domenici, E and Bozzi, Y},
title = {The interplay between oxidative stress and inflammation supports autistic-related behaviors in Cntnap2 knockout mice.},
journal = {Brain, behavior, and immunity},
volume = {127},
number = {},
pages = {57-71},
doi = {10.1016/j.bbi.2025.02.030},
pmid = {40023202},
issn = {1090-2139},
mesh = {Animals ; *Oxidative Stress/physiology ; Mice ; Mice, Knockout ; *Membrane Proteins/genetics/metabolism ; *Autism Spectrum Disorder/metabolism/genetics ; *Nerve Tissue Proteins/genetics/metabolism ; Inflammation/metabolism ; Cerebellum/metabolism ; Microglia/metabolism ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; Behavior, Animal/physiology ; Acetylcysteine/pharmacology ; Brain/metabolism ; Autistic Disorder/metabolism ; },
abstract = {Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental condition characterized by social communication deficits and repetitive/restricted behaviors. Several studies showed that oxidative stress and inflammation may contribute to ASD. Indeed, increased levels of oxygen radicals and pro-inflammatory molecules were described in the brain and peripheral blood of persons with ASD and mouse models. Despite this, a potential direct connection between oxidative stress and inflammation within specific brain areas and ASD-related behaviors has not been investigated in detail yet. Here, we used RT-qPCR, RNA sequencing, metabolomics, immunohistochemistry, and flow cytometry to show that pro-inflammatory molecules were increased in the cerebellum and periphery of mice lacking Cntnap2, a robust model of ASD. In parallel, oxidative stress was present in the cerebellum of mutant animals. Systemic treatment with N-acetyl-cysteine (NAC) rescued cerebellar oxidative stress, inflammation, as well as motor and social impairments in Cntnap2[-/-] mice, concomitant with enhanced function of microglia cells in NAC-treated mutants. Intriguingly, social deficits, cerebellar inflammation, and microglia dysfunction were induced by NAC in Cntnap2[+/+] animals. Our findings suggest that the interplay between oxidative stress and inflammation accompanied by genetic vulnerability may underlie ASD-related behaviors in Cntnap2 mutant mice.},
}
@article {pmid40022144,
year = {2025},
author = {Okon, IA and Beshel, JA and Owu, DU and Orie, NN and Jim, AE and Edet, LI},
title = {Moderate aerobic exercise improves haematological indices without altering cardio-metabolic enzyme activities in sedentary healthy young adults.},
journal = {BMC sports science, medicine &amp; rehabilitation},
volume = {17},
number = {1},
pages = {32},
pmid = {40022144},
issn = {2052-1847},
abstract = {BACKGROUND: Regular aerobic exercise regulates cardiorespiratory functions by its effect on specific enzyme activities. This study investigated the immediate effects of moderate aerobic exercise on haematological parameters and cardio-metabolic enzymes activity in healthy young male and female adults.<br><br>METHODS: Forty young healthy sedentary subjects, twenty males (25&#x2009;&#xb1;&#x2009;5.6 years; 65&#x2009;&#xb1;&#x2009;4.0&#xa0;kg; 176.9&#x2009;&#xb1;&#x2009;2.5&#xa0;cm) and twenty females (25&#x2009;&#xb1;&#x2009;4.5 years, 62&#x2009;&#xb1;&#x2009;2.9&#xa0;kg, 175&#x2009;&#xb1;&#x2009;1.3&#xa0;cm) volunteered for the study. The exercise regimen was of moderate intensity lasting for 20&#xa0;min daily on a treadmill at incremental speed of 3&#xa0;km/h to 13&#xa0;km/h for 14 consecutive days. The weight and height of participants were measured. Blood sample was collected via antecubital vein for haematological and biochemical analysis. The haematological parameters namely red blood cell and indices, leukocyte and differential white blood cell count, platelet and platelet indices were assessed. Cardiac troponin-T, creatine kinase, lactate dehydrogenase and N-acetyl-cysteine activated creatine kinase activities were assessed before and after exercise.<br><br>RESULTS: The result showed a significant (p&#x2009;<&#x2009;0.05) increase in RBC (males 7%, females 11%) haemoglobin (males 8%, females 8.3%), haematocrit (males 5%, females 14%) leukocyte (males 54%, females 40%) and monocyte count (males 68%, females 55%) after 14 days of exercise. The enzymatic activities of lactate dehydrogenase, N-acetyl-cysteine activated creatine kinase (CK-NAC), creatine kinase (CK-MB) and cardiac troponin-T showed no significant change after 14 days of exercise.<br><br>CONCLUSION: It is concluded that moderate aerobic exercise increased haematological parameters and maintained cardio-metabolic enzymes activities in young male and female adults.},
}
@article {pmid40021515,
year = {2025},
author = {Dong, L and Hao, X and Liu, M and Zhai, Y and Wang, X and Tian, X and Li, W and Peng, Y and Zheng, J},
title = {Metabolic activation and cytotoxicity of ibudilast mediated by CYP3A4.},
journal = {Archives of toxicology},
volume = {99},
number = {5},
pages = {2023-2038},
pmid = {40021515},
issn = {1432-0738},
mesh = {Animals ; *Cytochrome P-450 CYP3A/metabolism ; Humans ; Microsomes, Liver/drug effects/metabolism/enzymology ; Glutathione/metabolism ; *Pyridines/toxicity/metabolism/pharmacokinetics ; Mice ; Male ; Activation, Metabolic ; *Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology ; Hepatocytes/drug effects/metabolism ; Cysteine/metabolism ; Mice, Inbred C57BL ; Cell Survival/drug effects ; Acetylcysteine/metabolism ; Indolizines ; Pyrazoles ; },
abstract = {Ibudilast (IBD) is a relatively nonselective inhibitor of phosphodiesterase, commonly used for treating asthma, progressive multiple sclerosis and other neuropathological pain conditions. Although IBD was considered safe and harmless to human health, its clinical use might be associated with reported increases of serum AST and ALT as well as liver weight. However, the mechanisms behind such liver injury are still unknown. The purpose of this work was to investigate metabolic activation of IBD and to define correlation between bioactivation and hepatotoxicity of IBD. Two oxidative metabolites, IBD-derived glutathione (GSH) conjugates (M1, M2), N-acetyl-L-cysteine (NAC) conjugates (M3, M4), and cysteine (Cys) conjugates (M5, M6) were detected in mouse liver microsomes fortified with IBD (100 μM) and trapping agents GSH, NAC, or Cys, respectively, and two GSH conjugates (M1 and M2), one NAC conjugate (M4) and one Cys conjugate (M5) were detected. Similar observation was obtained in human liver microsomal incubations. The formation of M1-M6 was NADPH-dependent. Moreover, biliary GSH conjugates and urinary NAC conjugates derived from IBD were detected in mice given IBD intragastrically at 100 mg/kg. The metabolism study suggested the formation of an epoxide intermediate. In addition, the epoxide intermediate was found to react with cysteine residues of hepatic protein in a dose-dependent manner. Further studies indicate that CYP3A4 dominated the metabolic activation of IBD. Exposure of primary hepatocytes to IBD resulted in decreased cell survival. Pretreatment of mice hepatocytes with ketoconazole attenuated the susceptibility to the cytotoxicity of IBD (25-400 μM). The reactive epoxide intermediate might correlate the hepatotoxicity induced by IBD. This work revealed the reactive epoxide intermediate might correlate the hepatotoxicity induced by IBD, and would provide new insights into the mechanisms behind the adverse reactions taking place in clinical use of IBD, especially for the reported liver injury.},
}
@article {pmid40020975,
year = {2025},
author = {Liu, ZH and Zhai, Y and Zhang, J and Huang, W and Li, W and Qin, W},
title = {Mitochondrial iron deficiency mediated inhibition of ecdysone synthesis underlies lead (Pb) induced developmental toxicity in Drosophila melanogaster.},
journal = {Toxicology and applied pharmacology},
volume = {497},
number = {},
pages = {117283},
doi = {10.1016/j.taap.2025.117283},
pmid = {40020975},
issn = {1096-0333},
mesh = {Animals ; *Drosophila melanogaster/drug effects/metabolism ; *Lead/toxicity ; *Mitochondria/metabolism/drug effects ; *Ecdysone/biosynthesis/antagonists &amp; inhibitors ; *Iron/metabolism ; *Iron Deficiencies ; Oxidative Stress/drug effects ; Male ; Female ; Drosophila Proteins/metabolism/genetics ; },
abstract = {Lead (Pb) is a pervasive heavy metal possessing developmental toxicity, at least in part, by disrupting iron homeostasis. In this study, we aimed to elucidate the underlying mechanism of iron deficiency mediated developmental defects in Pb exposed Drosophila melanogaster, mainly focusing on iron-dependent synthesis of ecdysone signaling, which plays a key role in the development of insects. Herein, we found Pb exposure resulted in iron deficiency in mitochondria by inhibiting expression of mitoferrin (evidenced by qPCR assay), the mitochondrial iron importer. Further study demonstrated that biosynthesis of ecdysone, a hormone synthesized with the help of iron-containing cytochrome P450s in mitochondria, was inhibited following Pb exposure. Ecdysone supplementation, to some extent, rescued Pb induced developmental delay and reproductive defects in Drosophila melanogaster. Furthermore, we found that disruption of mitoferrin and ecdysone synthesis was restored by NAC (N-Acetylcysteine, a well-known ROS scavenger), suggesting that oxidative stress plays a key role in Pb mediated mitochondrial iron dys-homeostasis and developmental toxicity. This study therefore revealed that mitochondrial iron deficiency mediated inhibition of ecdysone synthesis is a key event associated with iron dys-homeostasis mediated developmental defects caused by Pb exposure. Meanwhile, our study indicated that mitochondria may act as an important target of Pb, thus providing potential protective strategies against Pb toxicity.},
}
@article {pmid40020837,
year = {2025},
author = {Yaseen, K and Ejaz, S and Imran, M},
title = {Surface engineering of biomedical catheters using N-acetyl cysteine functionalized carboxymethyl chitosan nanosystems to combat biofouling and device-associated infections.},
journal = {International journal of biological macromolecules},
volume = {306},
number = {Pt 2},
pages = {141516},
doi = {10.1016/j.ijbiomac.2025.141516},
pmid = {40020837},
issn = {1879-0003},
mesh = {*Chitosan/chemistry/analogs &amp; derivatives ; *Acetylcysteine/chemistry ; *Biofouling/prevention &amp; control ; Anti-Bacterial Agents/pharmacology/chemistry ; Humans ; *Catheters/microbiology ; Biofilms/drug effects ; Pseudomonas aeruginosa/drug effects ; Escherichia coli/drug effects ; Meropenem/pharmacology/chemistry ; Surface Properties ; },
abstract = {Functionalized anti-biofouling nanosystems were developed to engineer the surface of silicone catheters for mitigating the incidence of device-associated infections (DAIs). These infections are typically a consequence of microbial biofilms and antimicrobial resistance (AMR) which lead to increased hospitalization costs and mortality rates. Covalent coupling of N-acetyl cysteine (NAC) with O-carboxymethyl chitosan (O-CMC) was optimized to develop NAC-functionalized CMC nanosystems (NAC-CMC-NS). The coupling was confirmed by nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy and 4, 6-trinitrobenzene sulfonic acid (TNBS) assay indicating 80 ± 2 % functionalization efficacy. Subsequently, meropenem-loaded NAC-CMC NS exhibited an average particle size of 273 ± 4.2 nm with 0.4 ± 0.03 polydispersity index (PDI), a zeta potential of -9.15 ± 0.5 mV and encapsulation efficiency (EE) of 67 ± 3.2 %. These functionalized NS employing the dual strategy of contact-killing and meropenem-release, exhibited exceptional antimicrobial activity leading to the 76 ± 1.5 % and 60 ± 1 % inhibition of E. coli and P. aeruginosa biofilms, respectively. After the successful grafting of functionalized NS onto silicone catheters, the resulting substrate remarkably reduced the bacterial colonization, offering a promising solution for reducing DAIs like ventilator-associated pneumonia (VAP) and catheter-associated urinary tract infections (CAUTI). Moreover, the excellent hemocompatibility and low cytotoxicity of these nanovesicles highlight their potential applications for clinical use.},
}
@article {pmid40017063,
year = {2025},
author = {Bikal, P and Bhardwaj, JK},
title = {N-Acetyl-L-Cysteine Mediated Attenuation of Cadmium Induced Oxidative Stress and Apoptosis in Ovarian Antral Follicles In Vitro.},
journal = {Environmental toxicology},
volume = {40},
number = {8},
pages = {1102-1112},
doi = {10.1002/tox.24505},
pmid = {40017063},
issn = {1522-7278},
support = {//CSIR (Council of Scientific and Industrial Research)/ ; },
mesh = {Female ; Animals ; *Acetylcysteine/pharmacology ; Apoptosis/drug effects ; *Cadmium/toxicity ; Oxidative Stress/drug effects ; Goats ; *Ovarian Follicle/drug effects/metabolism ; Granulosa Cells/drug effects/metabolism ; *Antioxidants/pharmacology ; Cells, Cultured ; },
abstract = {Female fertility has been demonstrated to be directly correlated with cadmium, a heavy metal contaminant that is widely present in the environment. N-acetyl cysteine (NAC), a powerful antioxidant, has been shown to have therapeutic effects for a number of ailments. NAC's potential to prevent ovarian toxicity caused by Cd is still unknown. Therefore, the objective of the current study was to evaluate the concentration- and time-dependent protective effect of NAC supplementation against Cd-induced granulosa cell toxicity in healthy caprine ovaries. The in vitro cultured ovaries/follicles were subjected to different cytotoxic (ethidium bromide and acridine orange [EB/AO] staining), histomorphological, and biochemical analyses during study. The results revealed that NAC treatment significantly attenuated the Cd-instigated cytotoxicity in granulosa cells, as evidenced by diminished apoptotic attributes in NAC co-supplemented groups compared to only Cd-exposed groups. Moreover, NAC markedly restored the decline in enzymatic activity of antioxidant enzymes (GST, SOD, and CAT), along with ferric reducing antioxidant power, further diminishing the formation of MDA in Cd exposed caprine ovary. The findings of this study indicated that Cd, being an ovarian toxicant, adversely affects the female reproductive system. However, simultaneous NAC administration significantly reduced the Cd-caused ovarian damage, indicating that NAC has therapeutic potential in controlling female gonadotoxicity due to gradually growing environmental Cd pollution.},
}
@article {pmid40013897,
year = {2025},
author = {Nakatsu, L and Lopez, JR and Garcia, CM and Cherian, M and Nash, J and Tofighi, D and Seifert, SA and Smolinske, S and Warrick, BJ},
title = {Comparison of two-bag and three-bag acetylcysteine regimens in the treatment of paracetamol poisoning: a systematic review and meta-analysis.},
journal = {Clinical toxicology (Philadelphia, Pa.)},
volume = {63},
number = {3},
pages = {155-165},
doi = {10.1080/15563650.2025.2456116},
pmid = {40013897},
issn = {1556-9519},
mesh = {*Acetylcysteine/administration &amp; dosage/therapeutic use ; *Acetaminophen/poisoning ; Humans ; *Antidotes/administration &amp; dosage ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/drug therapy ; *Drug Overdose/drug therapy ; *Analgesics, Non-Narcotic/poisoning ; },
abstract = {INTRODUCTION: Worldwide, paracetamol poisoning is a common cause of acute liver failure and referral to transplant centers. Acetylcysteine has long been the mainstay of treatment, but recent literature suggests that a simplification of the "three-bag" method may decrease adverse effects. Our primary hypothesis is that a simplified dosing regimen (two-bag regimen) is non-inferior to the three-bag method in preventing liver injury. Our secondary hypothesis is that a simplified regimen will have lower rates of adverse effects.<br><br>METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched Medline/PubMed, Google, Google Scholar, Cochrane Library, Embase and Toxnet on May 23, 2022. The Medical Subject Headings terms were NAC, acetaminophen toxicity, acetyl-cysteine, N-acetylcysteine, paracetamol, APAP, 2-bag, and 3-bag. The Embase terms were acetylcysteine, NAC, 2-bag, two bag, 3-bag, three bag, simplified dosing, acetaminophen, Tylenol[&#xae;], paracetamol, APAP, drug overdose, poisoning, and overdose. Studies included both non-United States Food and Drug Administration-approved and United States Food and Drug Administration-approved acetylcysteine regimens. Case reports, review articles, and animal studies were excluded. Two authors independently reviewed each study using Rayyan QCRI to determine if the studies met search criteria while blinded to the selections of each other. The two authors discussed until reaching a consensus. We used a primary outcome of non-inferiority of hepatotoxicity. We used secondary outcomes of non-allergic anaphylactoid reactions and adverse events. We conducted a fixed-effect meta-analysis using R package meta. To visually summarize the meta-analysis results, we also produced forest plots. We used Cochran's Q test and I[2] statistical analysis to assess heterogeneity between the studies.<br><br>RESULTS: Our search resulted in 657 total citations, which were reduced to unique citations. Of the 643 studies, 46 met the criteria for full text review, and eight met the study criteria. Of the eight studies investigating a simplified acetylcysteine regimen, four studies utilized some form of a modified two-bag infusion regimen, varying in duration or dosing of infusions, and four studies shared the same "common" two-bag treatment, a regimen that delivers acetylcysteine 200&#x2009;mg/kg over 4&#x2009;h, followed by 100&#x2009;mg/kg acetylcysteine over 16&#x2009;h. The six studies comparing a two-bag dosing regimen to the three-bag technique were utilized for our random effect model meta-analysis. We found no significant heterogeneity amongst the six studies for either hepatotoxicity (Q(5) = 1.11; P&#x2009;=&#x2009;0.95; I[2] = 0%; 95% CI: 0%-74.6%) or non-allergic anaphylactoid reactions and adverse events (Q(5) = 10.15; P&#x2009;=&#x2009;0.07; I[2] = 50.7%; 95% CI: 0%-80.4%). Compared to the traditional three-bag dosing regimen, the two-bag method did not demonstrate a difference in relative risk for hepatotoxicity (OR: 0.88; 95% CI: 0.72-1.08; P&#x2009;=&#x2009;0.23) but did demonstrate a significantly decreased likelihood of non-allergic anaphylactoid reactions and other adverse events (OR: 0.24; 95% CI: 0.17-0.35; P&#x2009;<0.0001).<br><br>DISCUSSION: The two-bag method is a safe and effective treatment for acute paracetamol poisoning. The two-bag regimen is correlated with a significant reduction in non-allergic anaphylactoid reactions, compared to the three-bag method, and is non-inferior with respect to hepatotoxicity. While we feel this information is practice changing for many, further research in the form of a randomized control trial would be beneficial to compare even more abbreviated methods such as a "single bag method."<br><br>CONCLUSION: Two-bag acetylcysteine dosing regimens appear to be non-inferior to the three-bag method with respect to hepatotoxicity, and result in fewer anaphylactoid, cutaneous, and gastrointestinal reactions.},
}
@article {pmid40011998,
year = {2025},
author = {Wu, CH and Chou, WC and Jou, IM and Tu, YK and Ma, CH and Tsai, KL},
title = {Cisplatin-induced oxidative stress, apoptosis, and pro-inflammatory responses in chondrocytes through modulating LOX-1.},
journal = {Journal of orthopaedic surgery and research},
volume = {20},
number = {1},
pages = {206},
pmid = {40011998},
issn = {1749-799X},
mesh = {*Cisplatin/pharmacology/toxicity/adverse effects ; *Chondrocytes/drug effects/metabolism/pathology ; *Scavenger Receptors, Class E/metabolism/genetics ; *Oxidative Stress/drug effects/physiology ; *Apoptosis/drug effects/physiology ; Animals ; *Antineoplastic Agents/toxicity/pharmacology ; Humans ; Inflammation/chemically induced/metabolism ; NF-kappa B/metabolism ; Cells, Cultured ; *Inflammation Mediators/metabolism ; },
abstract = {Cisplatin is a potent and efficacious anticancer medication. In pediatric cancer, the height of the growth plate's proliferating layer is known to be reduced by cisplatin, but researchers have not yet determined the specific mechanism behind this phenomenon. Lectin-like oxidized low-density lipoprotein receptor-1 is known to be involved in the development of osteoarthritis and atherosclerosis. The equilibrium of cartilage is regulated by LOX-1, but the function of LOX-1 in cisplatin-induced chondrocyte impairment remains unknown. Positive regulation of LOX-1 leads to increased cellular oxidative stress and cell damage. Research has shown that blocking of LOX-1 can reduce the chondrocyte damage and oxidative stress in cells induced by oxidized LDL treatment. However, the role of LOX-1 in cisplatin-mediated chondrocyte damage is still unclear. This study found that cisplatin increased ROS concentration and p38, ERK phosphorylation. Cisplatin activated NF-κB in chondrocytes. In addition, LOX-1 small interfering RNA transfection mitigated cisplatin-induced apoptosis in TC28a2 cells. Phosphorylated extracellular signal-regulated kinase and p38 were dose-dependently increased by administration of cisplatin. Silencing LOX-1 or MAPK inhibition reduces cisplatin-caused apoptosis. The findings suggest that cisplatin-induced growth plate dysfunction operates through the LOX-1/p38/NF-κB signaling pathway.},
}
@article {pmid40009511,
year = {2025},
author = {Kandel, H and Cruz, AR and Thom, RP and McDougle, CJ},
title = {N -Acetylcysteine for Nonsuicidal Self-Injurious Behavior in 3 Adults With Williams Syndrome : A Case Series.},
journal = {Journal of clinical psychopharmacology},
volume = {45},
number = {3},
pages = {277-281},
doi = {10.1097/JCP.0000000000001976},
pmid = {40009511},
issn = {1533-712X},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/therapeutic use/pharmacology/adverse effects ; *Self-Injurious Behavior/drug therapy/etiology ; Adult ; *Williams Syndrome/complications/psychology/drug therapy ; Male ; Female ; Young Adult ; },
abstract = {BACKGROUND: Williams syndrome (WS) is a genetic disorder that results from a microdeletion of 25 to 27 genes on chromosome 7q11.23. Individuals with WS often exhibit comorbid neuropsychiatric symptoms, especially anxiety. To our knowledge, nonsuicidal self-injurious behavior (NSSIB) has not been reported in WS. N -acetylcysteine (NAC) is a safe and readily available drug that may modulate glutamate activity in the brain. NAC is effective for treating various neuropsychiatric symptoms and disorders. There are limited reports in the literature where NAC has been used to treat NSSIB effectively, but none in WS.<br><br>METHODS: This report describes using NAC to treat NSSIB in 3 adults with WS.<br><br>FINDINGS: Nonsuicidal self-injurious behavior was successfully treated in 3 adults with WS using NAC in doses ranging from 2400 to 3600 mg a day, resulting in significant improvement in their daily functioning. Additionally, NAC was well tolerated.<br><br>CONCLUSIONS: NAC was effective for treating NSSIB in 3 adults with WS. By addressing these challenging behaviors, NAC offers a promising pharmacological intervention that can significantly improve the quality of life for patients with WS who engage in NSSIB. Further research and clinical trials are necessary.},
}
@article {pmid40007988,
year = {2024},
author = {Habib, M},
title = {Combination of atorvastatin plus N-acetylcysteine versus atorvastatin alone to prevent contrast-induced nephropathy.},
journal = {Archives of medical sciences. Atherosclerotic diseases},
volume = {9},
number = {},
pages = {e207-e211},
pmid = {40007988},
issn = {2451-0629},
abstract = {INTRODUCTION: Contrast-induced acute renal injury is the third leading cause of hospital-acquired acute kidney injury. Our trial aimed to compare high-dose statin versus statin plus N-acetylcysteine (NAC) to prevent contrast-induced nephropathy.<br><br>MATERIAL AND METHODS: Randomized control trial included patients who undergoing elective percutaneous coronary intervention (PCI) at Alshifa Hospital in Gaza, the first group (statin: 50 patients) received 80 mg of atorvastatin orally once daily for 3 days. The second group (statin + NAC: 50 patients) received 80 mg of atorvastatin orally once daily for 3 days, plus NAC 1200 mg orally twice daily every 12 h for 2 days. All patients underwent measurement of serum creatinine and urea level before PCI and 2-3 days after the procedure. The primary endpoint was to compare development of contrast-induced nephropathy between the two groups.<br><br>RESULTS: The total group comprised 100 patients: 71 male patients and 29 female patients. Mean age was 59 &#xb1;9.8 years. After intervention serum creatinine decreased from 1.02 &#xb1;0.27 mg/dl to1.01 &#xb1;0.29 mg/dl in the statin group, while it decreased from 1.08 &#xb1;0.36 mg/dl to 0.92 &#xb1;0.13 mg/dl in the statin + NAC group. The difference between the two groups was significant (p = 0.048). Also, the urea plasma level in the statin group decreased from 34.5 &#xb1;9.7 mmol/l to 30.6 &#xb1;8.7 mmol/l after PCI, while in the statin + NAC group it decreased from 36.4 &#xb1;9.9 mmol/l to 26.2 &#xb1;10.6 mmol/l; the difference between the two groups was significant (p = 0.017). Contrast-induced nephropathy was seen in 9 (18%) patients in the statin group and in 2 (4%) patients in the statin + NAC group (p = 0.025).<br><br>CONCLUSIONS: The combination of high-dose atorvastatin plus NAC compared to atorvastatin alone was associated with a significant reduction of contrast-induced nephropathy in patients undergoing PCI.},
}
@article {pmid40005451,
year = {2025},
author = {Abdelbagi, O and Taha, M and Al-Kushi, AG and Alobaidy, MA and Baokbah, TAS and Sembawa, HA and Azher, ZA and Obaid, R and Babateen, O and Bokhari, BT and Qusty, NF and Malak, HA},
title = {Ameliorative Effect of N-Acetylcysteine Against 5-Fluorouracil-Induced Cardiotoxicity via Targeting TLR4/NF-κB and Nrf2/HO-1 Pathways.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {2},
pages = {},
pmid = {40005451},
issn = {1648-9144},
mesh = {Animals ; *Fluorouracil/adverse effects/therapeutic use ; *Acetylcysteine/pharmacology/therapeutic use ; Rats ; NF-E2-Related Factor 2/drug effects/metabolism ; *Cardiotoxicity/drug therapy/etiology ; NF-kappa B/drug effects/metabolism ; Toll-Like Receptor 4/drug effects/metabolism ; Oxidative Stress/drug effects ; Male ; Signal Transduction/drug effects ; Rats, Wistar ; },
abstract = {Background and Objectives: 5-Fluorouracil (5-FU) is a widely prescribed and effective chemotherapeutic drug, but its cardiotoxic side effects pose a significant challenge to its use. Identifying a protective agent that does not affect its anticancer efficacy is essential. Our study aimed to investigate the cardioprotective effect of N-acetyl cysteine (NAC) against 5-FU-induced cardiac injury and to elucidate the underlying mechanisms. Materials and Methods: This study included four experimental groups, each with eight rats (n = 8): Group I (control group), Group II (NAC group), Group III (5-FU group), and Group IV (combined group 5-FU+NAC). Cardiac enzymes, oxidative stress, inflammatory, and apoptotic markers were investigated, and cardiac sections from the different groups were histologically examined. Results: Co-treatment of 5-FU with NAC resulted in significantly lower levels of cardiac enzymes (alanine transaminase (ALT) by 62.1%, aspartate transaminase (AST) by 73.6%, lactate dehydrogenase (LDH) by 55.8%, and creatine kinase (CK) by 57.3%) compared to the 5-FU group, along with marked improvements in heart tissue histology. Additionally, NAC enhanced the activity of cardiac antioxidant enzymes (superoxide dismutase (SOD) by 295.6%, catalase (CAT) by 181%, and glutathione peroxidase (GPx) by 320.9%) while decreasing malondialdehyde (MDA) by 51.1%, a marker of membranous lipid peroxidation. This might be due to significant upregulation of the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway at the gene and protein levels. The combined treatment significantly decreased the gene expression of the toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) pathway. Furthermore, it downregulated the protein levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α) by 29.9%, interleukin-1 beta (IL-1β) by 21.9%, and interleukin-6 (IL-6) by 49.3%. Moreover, it upregulated the antiapoptotic marker B-cell lymphoma 2 (Bcl-2) protein levels by 269% and decreased apoptotic indicators Bcl-2-associated protein x (Bax) by 57.9% and caspase-3 by 30.6% compared to the 5-FU group. Conclusions: This study confirmed that NAC prevented the cardiotoxic effect of 5-FU through its antioxidant, anti-inflammatory, and antiapoptotic properties, suggesting its potential application as an adjuvant therapy in chemotherapy to alleviate 5-FU-induced cardiotoxicity.},
}
@article {pmid40002497,
year = {2025},
author = {Lomelí Martínez, SM and Pacheco Moisés, FP and Bitzer-Quintero, OK and Ramírez-Jirano, J and Delgado-Lara, DLC and Cortés Trujillo, I and Torres Jasso, JH and Salazar-Flores, J and Torres-Sánchez, ED},
title = {Effect of N-Acetyl Cysteine as an Adjuvant Treatment in Alzheimer's Disease.},
journal = {Brain sciences},
volume = {15},
number = {2},
pages = {},
pmid = {40002497},
issn = {2076-3425},
abstract = {Oxidative stress levels are exacerbated in Alzheimer's disease (AD). This phenomenon feeds back into the overactivation of oxidase enzymes, mitochondrial dysfunction, and the formation of advanced glycation end-products (AGEs), with the stimulation of their receptors (RAGE). These factors stimulate Aβ peptide aggregation and tau hyperphosphorylation through multiple pathways, which are addressed in this paper. The aim of this study was to evaluate the regulatory effect of N-acetyl cysteine (NAC) on oxidant/antioxidant balance as an adjuvant treatment in patients with AD. The results obtained showed that NAC supplementation produced improved cognitive performance, decreased levels of oxidative stress markers, lowered activities of oxidase enzymes, increased antioxidant responses, and attenuated inflammatory and apoptotic markers. Moreover, NAC reversed mitochondrial dysfunction, lowered AGEs-RAGE formation, attenuated Aβ peptide oligomerization, and reduced phosphorylation of tau, thereby halting the formation of neurofibrillary tangles and the progression of AD.},
}
@article {pmid40002335,
year = {2025},
author = {Chien, HJ and Hu, HM and Tsai, SJ and Lin, CL and Yang, SF and Chen, JK and Liu, CJ and Hsieh, YH},
title = {Licochalcone A Induces Uterine Leiomyoma Cell Apoptosis via the ROS-Mediated JNK Activation of the GRP78/NRF2 Pathway In Vitro and In Vivo.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {2},
pages = {},
pmid = {40002335},
issn = {2076-3921},
support = {CSMU-CCH-112-01//Chung Shan Medical University and Changhua Christian Hospital/ ; KMU-TC113A02//Kaohsiung Medical University Research Center Grant/ ; },
abstract = {Licochalcone A (LicoA) possesses anti-tumor properties. However, the potential therapeutic effect of LicoA on uterine leiomyomas (ULs) remains unknown. In this study, the effects of LicoA on the proliferation of ULs and its underlying mechanism were explored. LicoA treatment significantly decreased the viability of uterine smooth muscle cells (UtSMCs) and ELT3 cells in a dose-dependent manner. The induction of ELT3 cell apoptosis by LicoA was accompanied by the increased generation of reactive oxygen species (ROS), elevated endoplasmic reticulum (ER) stress (GRP78/IRE1α/ATF6/CHOP), and the increased expression of proapoptotic proteins (c-caspase-3, c-caspase-9, and c-PARP). The ability of Z-VAD-FMK (a caspase inhibitor) and n-acetylcysteine (NAC; a cell membrane permeable antioxidant) to reverse LicoA-induced ROS-mediated ER stress pathways also observed. Furthermore, GRP78 or JNK knockdown was involved in LicoA-induced ROS-mediated ER stress and apoptosis in ELT3 cells. In immunodeficient mice, LicoA significantly suppressed the growth of ELT3 tumor cells, without toxicity. This study is the first to show that LicoA exerts anti-leiomyoma effects via the modulation of ROS-mediated ER stress-induced apoptosis through the JNK/GRP78/NRF2 signaling pathway.},
}
@article {pmid40002315,
year = {2025},
author = {Ückert, AK and Suciu, I and Land, A and Spreng, AS and Welte, H and Herzog, D and Basler, M and Leist, M},
title = {Chemical and Biological Mechanisms Relevant to the Rescue of MG-132-Treated Neurons by Cysteine.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {2},
pages = {},
pmid = {40002315},
issn = {2076-3921},
support = {TRR353//Deutsche Forschungsgemeinschaft/ ; 161L0243B//Federal Ministry of Education and Research/ ; 016LW0146K//Federal Ministry of Education and Research/ ; 964537//European Union/ ; 964518//European Union/ ; 101057014//European Union/ ; GP/EFSA/ED/2022/01//European Food Safety Authority/ ; },
abstract = {Proteasome dysfunctions are observed in many human pathologies. To study their role and potential treatment strategies, models of proteasome inhibition are widely used in biomedical research. One frequently used tool is the proteasome inhibitor MG-132. It triggers the degeneration of human neurons, and several studies show protection from pathological events by glutathione or its precursors. It has therefore been concluded that glutathione protects cells from proteasome dysfunction. However, an alternative explanation is that MG-132, which is a peptide aldehyde, is chemically inactivated by thiols, and the apparent protection by glutathione from proteasome dysfunction is an artefact. To clarify this issue, we examined the chemical inactivation of MG-132 by thiols and the role of such reactions for neuroprotection. Using mass spectrometry and nuclear magnetic resonance spectroscopy, we found that MG-132 reacted with L-cysteine to form a stable end product and with glutathione to form an unstable intermediate. Using a cell-free proteasome inhibition assay, we found that high concentrations of L-cysteine can scavenge a substantial fraction of MG-132 and thus reduce proteasome inhibition. Glutathione (or N-acetyl-cysteine) did not alter proteasome inhibition (even at high concentrations). In a final step, we studied human neuronal cultures. We exposed them to MG-132, supplemented the culture medium with various thiols, and assessed intracellular L-cysteine concentrations. The transcriptome response pattern also indicated an inhibition of the proteasome by MG-132 in the presence of L-cysteine. We conclude that thiol concentrations that can be reached in cells do not inactivate MG-132 in pathological models. They rather act in a cytoprotective way as antioxidants.},
}
@article {pmid40001479,
year = {2025},
author = {Zhao, M and Han, M and Guo, S and Tang, Z},
title = {CXCL12 as a Potential Hub Gene for N-Acetylcysteine Treatment of T1DM Liver Disease.},
journal = {Biomolecules},
volume = {15},
number = {2},
pages = {},
pmid = {40001479},
issn = {2218-273X},
support = {No. 31572585//National Natural Science Foundation of China/ ; },
mesh = {*Acetylcysteine/pharmacology/therapeutic use ; *Chemokine CXCL12/genetics/metabolism ; Animals ; *Diabetes Mellitus, Type 1/drug therapy/genetics/complications/metabolism ; Humans ; Dogs ; *Liver Diseases/drug therapy/genetics/metabolism ; Male ; Liver/metabolism/drug effects/pathology ; Disease Models, Animal ; },
abstract = {The etiology of type 1 diabetes mellitus (T1DM) is intricate, leading to its classification as an autoimmune metabolic disorder. T1DM often coexists with various visceral diseases. N-acetylcysteine (NAC) is widely acknowledged for its potent antioxidant properties. Studies have demonstrated that the combination of NAC and insulin can effectively alleviate iron-induced nephropathy in T1DM and mitigate oxidative stress injury in skeletal muscle associated with the condition. However, the potential impact of NAC alone on liver disease in individuals with T1DM remains uncertain. In this study, a beagle model was established to simulate T1DM, enabling investigation into the role of NAC in liver disease using RNA-seq biogenic analysis and subsequent validation through molecular biological methods. The findings revealed suppressed expression of CXCL12 chemokine in the livers of individuals with T1DM, while treatment with NAC induced specific activation of CXCL12 within the liver affected by T1DM. These results suggest that CXCL12 may serve as a regulatory factor involved in the therapeutic effects of NAC on liver disease associated with TIDM. This discovery holds significant implications for utilizing NAC as an adjunctive therapy for managing complicated liver diseases accompanying type 1 diabetes mellitus.},
}
@article {pmid40000992,
year = {2025},
author = {Kumar, S and Das, B and Maurya, G and Dey, S and Gupta, P and Sarma, JD},
title = {Limonoid-rich fraction from Azadirachta indica A. Juss. (neem) stem bark triggers ROS-independent ER stress and induces apoptosis in 2D cultured cervical cancer cells and 3D cervical tumor spheroids.},
journal = {BMC cancer},
volume = {25},
number = {1},
pages = {334},
pmid = {40000992},
issn = {1471-2407},
support = {BT/MEDII/NIBMG/SYMEC/2014/Vol.II//Department of Biotechnology, Ministry of Science and Technology, India/ ; },
mesh = {Humans ; *Uterine Cervical Neoplasms/drug therapy/metabolism/pathology ; Female ; *Apoptosis/drug effects ; *Limonins/pharmacology/chemistry ; Reactive Oxygen Species/metabolism ; Plant Bark/chemistry ; Spheroids, Cellular/drug effects ; *Azadirachta/chemistry ; *Plant Extracts/pharmacology/chemistry ; HeLa Cells ; *Endoplasmic Reticulum Stress/drug effects ; Cell Line, Tumor ; *Antineoplastic Agents, Phytogenic/pharmacology ; Cell Survival/drug effects ; Cell Proliferation/drug effects ; },
abstract = {BACKGROUND: The existing anticancer drugs in clinical practice show poor efficacy in cervical cancer patients and are associated with multiple side effects. Our previous study demonstrated the strong antineoplastic activity of crude extract prepared from the stem bark of Azadirachta indica (Neem) against cervical cancer. However, the active phytoconstituents of neem stem bark extract and its underlying anticancer mechanism are yet to be investigated. Thus, the present study aimed to identify the active fraction from crude neem stem bark extract to further dissect its anticancer mechanism and determine the active components.<br><br>METHODS: Dichloromethane (DCM) extract from neem stem bark was prepared and fractionated using thin-layer chromatography. The fractions obtained were screened against HeLa and ME-180 cervical cancer cell lines to identify the most active fraction, which was then selected for further studies. Clonogenic assay, cell cycle analysis, apoptosis assay, and reactive oxygen species (ROS) assay were performed to determine the cytotoxicity of the active fraction. Gene expression was analyzed using real-time PCR and western blot to determine the mechanism. Additionally, the HeLa cells-derived 3D spheroid model was used to determine the antitumor efficacy of the active fraction. Electrospray ionization-mass spectrometry, Fourier-transform infrared spectroscopy, and proton nuclear magnetic resonance were used to identify the phytoconstituents of the fraction.<br><br>RESULTS: Initial screening revealed fraction 2 (F2) as the most active fraction. Additionally, F2 showed the least cytotoxic effect on normal human fibroblast cells. Mechanistically, F2 induced cell cycle arrest and apoptosis in cervical cancer cells. F2 increased ROS levels, induced ER stress, and activated cell survival pathway. Treatment with N-acetyl cysteine revealed that F2 induced ROS-independent ER stress and apoptosis. 3D spheroid viability and growth delay experiments demonstrated the strong antitumor potential of F2. Finally, six compounds, including one flavonoid (nicotiflorin) and five limonoids, were identified in the F2 fraction.<br><br>CONCLUSION: This is the first study to identify the active fraction and its phytoconstituents from neem stem bark and demonstrate the anticancer mechanism against cervical cancer. Our study highlights the importance of investigating neem stem bark-derived limonoids and nicotiflorin as a potential source to develop new anticancer therapeutic agents.},
}
@article {pmid39992072,
year = {2025},
author = {Eid, SY and Koshak, MF and Elzubier, ME and Refaat, B and Almaimani, RA and Althubiti, M and Nour Eldin, EEM and Alahmadi, NH and Fatani, SH and Aslam, A and Khidir, EBA and Abdellatif, AAH and El-Readi, MZ},
title = {Protective effects of oral pharmaceutical solution of fucoxanthin against paracetamol-induced liver injury: modulation of drug-metabolizing enzymes, oxidative stress, and apoptotic pathways in rats.},
journal = {Drug development and industrial pharmacy},
volume = {51},
number = {4},
pages = {332-343},
doi = {10.1080/03639045.2025.2469808},
pmid = {39992072},
issn = {1520-5762},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Acetaminophen/toxicity/adverse effects ; *Xanthophylls/pharmacology/administration &amp; dosage ; *Apoptosis/drug effects ; Male ; Rats, Wistar ; Rats ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/drug therapy/metabolism/pathology ; Liver/drug effects/metabolism/pathology ; Administration, Oral ; *Protective Agents/pharmacology/administration &amp; dosage ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; },
abstract = {BACKGROUND: Paracetamol (PAC) overdose causes acute liver injury through oxidative stress, inflammation, and apoptosis. While N-acetyl cysteine (NAC) is the standard treatment, fucoxanthin (FUC), a carotenoid from brown seaweed, has shown hepatoprotective effects in animal studies, but its role in PAC toxicity is unclear.<br><br>OBJECTIVE: Compared to NAC, this study assessed the hepatoprotective potential of oral FUC solution toward PAC-induced injury to the rat's liver.<br><br>METHOD: FUC was formulated as a pharmaceutical solution and characterized via UV-VIS spectroscopy. Six groups of male Wistar rats each contain five animal which are in total 30 rats: negative control (NC), positive control (PC, 2&#x2009;g/kg PAC), NAC (1200&#x2009;mg/kg), and three oral FUC doses (100, 200, and 500&#x2009;mg/kg) for seven days, with PAC administered on day-8. Liver tissues were analyzed for oxidative stress, gene expression, and histology.<br><br>RESULTS: FUC solution was clear with absorbance at 433&#x2009;nm. PAC caused 30% mortality (p&#x2009;<&#x2009;.01 vs. others). NAC reduced ALT (56%), AST (78%), ALP (28%), and increased TP by 25% (p&#x2009;<&#x2009;.001 vs. PC). FUC at 500&#x2009;mg/kg (F500) was superior, reducing ALT (82%), AST (93%), ALP (40%), and increasing TP (35%) (p&#x2009;<&#x2009;.001 vs. NAC). PAC increased oxidative stress, CYP2E1/CYP3A2 expression, apoptosis markers, and suppressed Nrf2/AMPK/AKT1. F500 improved antioxidants, reduced oxidative stress, and apoptosis, enhanced the Nrf2/AMPK pathway, and downregulated CYP2E1/CYP3A2 (p&#x2009;<&#x2009;.01).<br><br>CONCLUSION: FUC, particularly at 500&#x2009;mg/kg, offers significant hepatoprotection against PAC-induced liver injury by modulating drug metabolizing enzymes and enhancing antioxidant defenses, warranting further research.},
}
@article {pmid39989173,
year = {2025},
author = {Jiang, ZB and He, QH and Kang, LP and Jiang, S and Liu, JN and Xu, C and Wang, WJ and Wang, XR and Wu, QB and Huang, DH},
title = {Rutecarpine Suppresses Non-Small Cell Lung Cancer Progression Through Activating the STING Pathway and Elevating CD8+ T Cells.},
journal = {Chemical biology &amp; drug design},
volume = {105},
number = {2},
pages = {e70070},
doi = {10.1111/cbdd.70070},
pmid = {39989173},
issn = {1747-0285},
support = {//Beijing Science and Technology Innovation Medical Development Foundation: KC2021-JX-0186-4/ ; //Zhuhai Hospital of Integrated Traditional Chinese &amp; Western Medicine (No.202303)/ ; //Guangdong Province-Provincial Chinese Medicine construction special fund named Traditional Chinese Medicine Inheritance Studio construction project Guangdong Chinese Medicine Office Letter [2023] 108/ ; //Guangdong Provincial Administration of Traditional Chinese Medicine (No. 20221361, No. 20251345, No. 20241285)/ ; //Zhuhai Science and Technology Innovation Bureau (No. 2420004000022, No. 2320004000290, No. 2420004000007)/ ; //China Postdoctoral Science Foundation (2022M713652 and 2022M721411)/ ; //Guangdong Basic and Applied Basic Research Foundation of China (2022A1515110790 and 2024A1515012478)/ ; //"Towards a New Horizon" Research Project of the Beijing Chao Enxiang Traditional Chinese Medicine Heritage and Development Foundation in 2023 (No. 2023CX03)/ ; },
mesh = {Animals ; Humans ; Mice ; Antineoplastic Agents/pharmacology/chemistry ; *Apoptosis/drug effects ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology/metabolism ; *CD8-Positive T-Lymphocytes/drug effects/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; *Lung Neoplasms/drug therapy/pathology/metabolism ; Membrane Proteins/metabolism ; Quinazolines/pharmacology/chemistry ; *Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; B7-H1 Antigen/chemistry/metabolism ; },
abstract = {Globally, non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths. Rutecarpine (RUT), a quinazolinocarboline alkaloid that is naturally occurring and present in Chinese medicinal herbs, has been shown to have anticancer properties in several cancer cell lines. However, the specific antitumor mechanisms of RUT in NSCLC remain unclear. This study demonstrates that RUT induces apoptosis and significantly reduces the viability of NSCLC cell lines. This effect is achieved by stimulating intracellular ROS production, leading to mitochondrial dysfunction. The decreased cell viability observed with RUT treatment is attributed to the elimination of ROS and apoptosis through the suppression of ROS by N-acetylcysteine (NAC). Furthermore, RUT therapy elevated the production of CXCL10 and CCL5 in NSCLC cell lines and markedly activated the STING pathway in NSCLC cells. Mechanistically, RUT substantially decreased the levels of PD-L1 protein in NSCLC cells. Notably, in vivo experiments demonstrated that RUT significantly inhibits mouse NSCLC tumor growth in mice, exhibiting anti-tumor activity by elevating CD8[+] T cells. These findings strongly support RUT as a promising anti-cancer drug for NSCLC.},
}
@article {pmid39988222,
year = {2025},
author = {Xu, H and Mao, X and Mo, D and Lv, M},
title = {6PPD impairs growth performance by inducing intestinal oxidative stress and ferroptosis in zebrafish.},
journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP},
volume = {293},
number = {},
pages = {110161},
doi = {10.1016/j.cbpc.2025.110161},
pmid = {39988222},
issn = {1532-0456},
mesh = {Animals ; *Zebrafish/growth &amp; development/metabolism ; *Oxidative Stress/drug effects ; *Ferroptosis/drug effects ; *Phenylenediamines/toxicity ; *Intestines/drug effects ; *Water Pollutants, Chemical/toxicity ; Zebrafish Proteins/metabolism/genetics ; },
abstract = {N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), a tire-derived pollutant, has gained increasing attention due to its potential toxicity to aquatic organisms. Although previous studies have revealed that 6PPD impacts early developmental stages of larval fish, its effects on adult fish, particularly on key organs, remain unclear. In this study, we observed that adult zebrafish exposed to 6PPD exhibited reduced growth performance and increased fecal output. Histological examination with hematoxylin and eosin (H&amp;E) staining revealed damage to the intestinal villi and a reduction in goblet cell numbers, indicating that 6PPD impairs growth performance by disrupting the digestive system. Comparative transcriptomic analysis revealed that 6PPD caused significant changes in the expression of 727 genes in the intestine, of which 280 genes were up-regulated and 447 genes were down-regulated. These genes were primarily associated with nutrient digestion and absorption, energy metabolism, immune response, and redox regulation. Mechanistically, 6PPD induced oxidative stress and triggered ferroptosis in the intestine, leading to structural damage of the intestinal villi. Treatment with the antioxidant N-acetylcysteine (NAC) alleviated 6PPD-induced oxidative stress and ferroptosis, thereby improving intestinal villi structure and promoting fish growth. This study provides insights into the mechanisms by which 6PPD impairs growth in adult zebrafish and highlights NAC as a potential therapeutic strategy to mitigate its toxicity.},
}
@article {pmid39985580,
year = {2025},
author = {Shariati, S and Mohtadi, S and Khodayar, MJ and Salehcheh, M and Azadnasab, R and Mansouri, E and Moosavi, M},
title = {Quinic acid alleviates liver toxicity induced by acetaminophen in mice via anti-oxidative and anti-inflammatory effects.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {398},
number = {8},
pages = {10367-10378},
pmid = {39985580},
issn = {1432-1912},
support = {TRC-9924//Ahvaz Jundishapur University of Medical Sciences/ ; },
mesh = {Animals ; *Acetaminophen/toxicity ; *Chemical and Drug Induced Liver Injury/metabolism/pathology/drug therapy/prevention &amp; control ; *Antioxidants/pharmacology/therapeutic use ; Male ; Oxidative Stress/drug effects ; Mice ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; NF-E2-Related Factor 2/metabolism ; *Liver/drug effects/metabolism/pathology ; Cytochrome P-450 CYP2E1/metabolism ; Tumor Necrosis Factor-alpha/metabolism/blood ; },
abstract = {Acetaminophen (N-acetyl-para-aminophenol: APAP)-induced hepatotoxicity is a common toxicity that is associated with oxidative stress and inflammation. Quinic acid (QA) is a naturally occurring metabolite that exhibits antioxidant and anti-inflammatory properties. In this research, the effect of QA on hepatotoxicity caused by APAP was investigated. The mice were divided into six groups: control, APAP (300 mg/kg, i.p.), QA (100 mg/kg, i.p.), N-acetylcysteine (NAC) (100 mg/kg, i.p.), and treatment groups, which pretreated with QA at two doses of 50 and 100 mg/kg. NAC and QA were injected for 7 days, and APAP was injected on the seventh day. On day 8, mice were euthanized, and serum factors, markers of oxidative stress, tumor necrosis factor-α (TNF-α), and expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and cytochrome P450 2E1 (CYP2E1) proteins were measured. The results showed that the APAP-treated group significantly increased the activity of serum enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase). APAP decreased hepatic total thiol content, as well as catalase, superoxide dismutase, and glutathione peroxidase activities, and increased thiobarbituric acid reactive substances and TNF-α levels. In addition, Nrf2 and CYP2E1 protein expression was upregulated in APAP-induced injury. Moreover, histopathological findings confirmed APAP hepatotoxicity. However, QA protected mice against the detrimental effects resulting from an imbalance in the oxidant/antioxidant system. QA ameliorated APAP-induced inflammation and histopathological changes and was able to upregulate the protein expression of Nrf2, while also reversing the increase in protein expression of CYP2E1 in APAP-intoxicated mice. These findings demonstrate the potential of QA in preventing APAP-induced hepatotoxicity, which is comparable to the effects of NAC.},
}
@article {pmid39983406,
year = {2025},
author = {Zhang, C and Peng, S and Zheng, Z and Chen, Z and Li, M and Huang, N and Liu, Z and Yang, MX and Chen, H},
title = {Novel bis-pocket binding aldose reductase inhibitors sensitize MCF-7/ADR cells to doxorubicin in a dual-role manner.},
journal = {Bioorganic chemistry},
volume = {157},
number = {},
pages = {108286},
doi = {10.1016/j.bioorg.2025.108286},
pmid = {39983406},
issn = {1090-2120},
mesh = {Humans ; *Aldehyde Reductase/antagonists &amp; inhibitors/metabolism ; *Doxorubicin/pharmacology/chemistry ; Structure-Activity Relationship ; Molecular Structure ; *Drug Screening Assays, Antitumor ; *Cell Proliferation/drug effects ; *Dose-Response Relationship, Drug ; *Enzyme Inhibitors/pharmacology/chemistry/chemical synthesis ; MCF-7 Cells ; Antibiotics, Antineoplastic/pharmacology/chemistry/chemical synthesis ; Drug Resistance, Neoplasm/drug effects ; Antineoplastic Agents/pharmacology/chemistry/chemical synthesis ; },
abstract = {Multidrug resistance (MDR) represents a bottleneck in the treatment of breast cancer. Although the potential of aldose reductase inhibitors (ARIs) as sensitizers against MDR has been explored in recent decades, the intrinsic mechanism still needs to be elucidated, and promising agents in the clinic need to be developed. In this study, three novel ARIs (5a-c), characterized by bis-pocket binding, were designed and synthesized. Inhibitory activity is positively correlated with antioxidation and benefits from rigid spacers. Only 5a with less activities in inhibition and antioxidation was demonstrated as a stronger sensitizer against doxorubicin (DOX)-resistant MCF-7 cells (MCF-7/ADR) than epalrestat (EPA). Either 5a or EPA may decrease GSH abundance and increase ROS, Fe[2+], and lipid peroxidation levels. The restorative effects of both ARIs may be blocked by N-acetyl cysteine (NAC). These data suggest that both 5a and EPA may restore the sensitivity of MCF-7/ADR cells to DOX by increasing ferroptosis activity. Furthermore, the inhibition of AKR1B1 by 5a, as well as by EPA, dramatically decreased both p-STAT3 and SLC7A11 expression. Gene knockdown of AKR1B1 has the same effects as AKR1B1 inhibition. This evidence indicates that both ARIs can suppress MCF-7/ADR cell growth via the upregulation of ferroptosis activity via the AKR1B1/STAT3/SLC7A11 axis. Additionally, 5a was found to increase the accumulation of intramolecular DOX by inhibiting ABCB1, but EPA did not. These results support that 5a is a promising sensitizing agent against multidrug resistance in breast cancer.},
}
@article {pmid39981906,
year = {2025},
author = {Chen, J and Cheng, Y and Cui, H and Li, S and Duan, L and Jiao, Z},
title = {N‑acetyl‑L‑cysteine protects rat lungs and RLE‑6TN cells from cigarette smoke‑induced oxidative stress.},
journal = {Molecular medicine reports},
volume = {31},
number = {4},
pages = {},
pmid = {39981906},
issn = {1791-3004},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Oxidative Stress/drug effects ; Rats ; *Lung/metabolism/drug effects/pathology ; Male ; Rats, Wistar ; Apoptosis/drug effects ; Cell Line ; *Smoke/adverse effects ; Alveolar Epithelial Cells/metabolism/drug effects ; Antioxidants/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; *Cigarette Smoking/adverse effects ; Malondialdehyde/blood ; bcl-2-Associated X Protein/metabolism ; Superoxide Dismutase/blood ; Disease Models, Animal ; },
abstract = {Cigarette smoke (CS) is a key contributor of chronic obstructive pulmonary disease (COPD); however, its role in the pathogenesis of COPD has not been fully elucidated. N‑acetyl‑L‑cysteine (NAC), as an antioxidant, has been used in the treatment of COPD; however, the mechanisms of action of NAC are not fully understood. Alveolar epithelial type 2 (ATII) cells serve an essential role in the maintenance of alveolar integrity. The aim of the present study was to identify the effect of CS on rat lungs and ATII cells. A subacute lung injury model of Wistar rats was established using CS exposure for 4 weeks. Interalveolar septa widening, infiltration of inflammatory cells, edema fluid in airspaces and abnormal enlargement of airspaces were observed through H&amp;E staining. ELISA revealed that NAC could protect against CS‑induced increases in serum levels of malondialdehyde and decreases in serum levels of superoxide dismutase. Additionally, 8‑hydroxy‑deoxyguanosine was detected using immunohistochemical staining, and this was also expressed at increased levels in the lung tissue of the CS‑exposed group. In addition, the expression levels of Bcl‑2, BAX and caspase‑3 p12 in lung tissue were detected by western blotting or immunohistochemical staining. The expression levels of Bcl‑2 decreased and those of caspase3 p12 were increased in response to CS exposure when compared with those in the control group. These effects were prevented by treatment with NAC. In vitro, the effect of CS extract (CSE) on rat lung epithelial‑6‑T‑antigen negative (RLE‑6TN) cells was observed, flow cytometry was used to detect intracellular reactive oxygen species (ROS) levels and the occurrence of apoptosis, and the content of glutathione (GSH) was detected using a colorimetric assay. Additionally, the expression levels of heme oxygenase‑1 (HO‑1), p53 and Bcl‑2 were examined by western blotting, and HO‑1 mRNA expression was also examined using reverse transcription‑quantitative PCR. The results of the present study revealed that CSE induced apoptosis of RLE‑6TN cells, accompanied by increased levels of intracellular ROS and exhaustion of GSH. Significantly increased protein levels of HO‑1 and p53, as well as decreased protein levels of Bcl‑2 were also observed. These effects were prevented by administration of NAC. Overall, these findings suggested that CS could promote apoptosis in rat lung tissues and alveolar epithelial cells by inducing intracellular oxidative injury, and NAC may serve an antioxidant role by replenishing the intracellular GSH content.},
}
@article {pmid39980679,
year = {2025},
author = {Natali, PG and Piantelli, M and Sottini, A and Eufemi, M and Banfi, C and Imberti, L},
title = {A step forward in enhancing the health-promoting properties of whole tomato as a functional food to lower the impact of non-communicable diseases.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1519905},
pmid = {39980679},
issn = {2296-861X},
abstract = {Nutritional interventions facilitating the consumption of natural, affordable, and environment-compatible health-promoting functional foods are a promising strategy for controlling non-communicable diseases. Given that the complex of tomato micronutrients produces healthier outcomes than lycopene, its major antioxidant component, new strategies to improve the health-supporting properties of the berry are ongoing. In this context, a whole tomato food supplement (WTFS), enriched by 2% olive wastewater containing a complex of healthy nutrients with converging biologic activities, has recently been developed, which is superior to those present in tomato commodities or obtained with whole tomato conventional processing methods. WTFS equals the antioxidant activity of N-acetyl-cysteine and interferes with multiple inflammation and cellular transformation-sustaining metabolic pathways. In interventional studies, WTFS inhibits prostate experimental tumors and improves benign prostate hypertrophy-associated symptoms with no associated side-effects. Although WTFS may be susceptible to further improvements and clinical scrutiny, its composition embodies the features of advanced functional foods to ease adherence to dietary patterns, that is, the Mediterranean diet, aimed at contrasting and mitigating the low-grade inflammation, thus being interceptive or preventive of non-communicable diseases.},
}
@article {pmid39980567,
year = {2025},
author = {Ahn, CH and Myong, JS and Ahmed, KR and Rahman, MA and Fahim, MMH and Choi, M and Rahman, M and Choi, J and Kim, K and Moon, S and Dalli, M and Syahputra, RA and Shin, SW and Harrath, AH and Park, MN and Kim, B and Yoo, HS},
title = {A pharmacoinformatic approach for studying Atractylodes Lancea DC's anticancer potential and control ROS-mediated apoptosis against prostate cancer cells.},
journal = {Frontiers in oncology},
volume = {15},
number = {},
pages = {1471110},
pmid = {39980567},
issn = {2234-943X},
abstract = {INTRODUCTION: Prostate cancer (PCa) is a malignancy characterized by abnormal cell proliferation in the prostate gland, a critical component of the male reproductive system. Atractylodes lancea DC. (ALD), a medicinal herb commonly used in traditional Asian medicine, is highly regarded for its antioxidant, antidiabetic, and anticancer properties. Virtual docking stud-ies have identified Atractylenolide II and III as active components of ALD, demonstrating strong binding potential to inhibit androgen receptor (AR) activity, with docking scores of -8.9 and -9.3, respectively. These findings suggest that ALD may exert a synergistic effect comparable to or greater than that of enzalutamide (ENZ) in inhibiting AR. How-ever, its specific anticancer and anti-metastatic mechanisms in prostate cancer remain unclear.<br><br>METHODS: The cytotoxic effects of ALD were evaluated on PC3 and DU145 prostate cancer cells, as well as on the normal prostate cell line BPH-1. Cell viability was assessed using the EZ-Cytotoxic kit, while colony formation assays and TUNEL staining were used to meas-ure proliferation and apoptosis, respectively. Apoptosis was further analyzed through an-nexin V-FITC/PI staining and quantified by flow cytometry (FACS). Western blotting was performed to elucidate the underlying molecular mechanisms. Additionally, mito-chondrial membrane potential (&#x394;&#x3a8;m) and intracellular calcium levels were measured to evaluate mitochondrial function, while reactive oxygen species (ROS) generation was assessed with and without pretreatment with N-acetylcysteine (NAC) .<br><br>RESULTS: ALD selectively reduced the viability of PC3 and DU145 prostate cancer cells while spar-ing BPH-1 normal prostate cells, demonstrating cancer-selective cytotoxicity. ALD dis-rupted mitochondrial function by reducing &#x394;&#x3a8;m and increasing intracellular calcium lev-els. A concentration-dependent increase in ROS generation was observed in PC3 and DU145 cells, which was completely inhibited by NAC pretreatment, confirming a ROS-mediated mechanism. Colony formation assays revealed a significant reduction in prolif-eration, while TUNEL and annexin V-FITC/PI staining indicated enhanced apoptosis. Western blot analysis showed that ALD modulates critical survival pathways, leading to apoptotic cell death.<br><br>DISCUSSION: These findings demonstrate that ALD exerts potent anticancer effects against metastatic prostate cancer cells through ROS-mediated apoptosis and mitochondrial dysfunction, while exhibiting minimal cytotoxicity toward normal prostate cells. The presence of ac-tive compounds such as Atractylenolide II and III suggests a synergistic interaction that enhances AR inhibition and promotes apoptosis. ALD's ability to engage multiple path-ways highlights its therapeutic potential as a selective and multifaceted treatment for ag-gressive prostate cancer.},
}
@article {pmid39979946,
year = {2025},
author = {Rahman, FA and Graham, MQ and Adam, AM and Juracic, ES and Tupling, AR and Quadrilatero, J},
title = {Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.},
journal = {Journal of biomedical science},
volume = {32},
number = {1},
pages = {29},
pmid = {39979946},
issn = {1423-0127},
support = {RGPIN 258590//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN 2020-05632//Natural Sciences and Engineering Research Council of Canada/ ; },
mesh = {Animals ; *Muscular Atrophy/physiopathology/etiology ; *Mitophagy ; Mice ; *Hindlimb Suspension/adverse effects ; *Muscle, Skeletal/pathology ; Male ; Immobilization/adverse effects ; Reactive Oxygen Species/metabolism ; },
abstract = {BACKGROUND: Skeletal muscle atrophy involves significant remodeling of fibers and is characterized by deficits in mitochondrial content and function. These changes are intimately connected to shifts in mitochondrial turnover, encompassing processes such as mitophagy and mitochondrial biogenesis. However, the role of these mitochondrial turnover processes in muscle atrophy remains poorly understood.<br><br>METHODS: We used a novel mitophagy reporter model, mt-Keima mice, to perform hindlimb immobilization and accurately measure mitophagy. A comprehensive set of analyses were conducted to investigate biochemical and molecular changes at the muscle and mitochondrial levels. We also performed image analyses to determine mitophagic flux. To further explore the role of mitophagy in immobilization-induced atrophy, we treated animals with N-acetylcysteine (NAC; 150&#xa0;mg/kg/day) to modify reactive oxygen species (ROS) signaling and colchicine (0.4&#xa0;mg/kg/day) to inhibit autophagy.<br><br>RESULTS: Our study revealed that hindlimb immobilization leads to muscle weakness and atrophy of fast-twitch muscle fibers (types IIA, IIX, and IIB), with recovery observed in IIA fibers following remobilization. This atrophy was accompanied by a significant increase in mitophagic flux. Additionally, immobilization induced notable mitochondrial dysfunction, as shown by diminished respiration, increased mitochondrial ROS, and greater whole muscle lipid peroxidation. Treatment of immobilized mice with NAC enhanced mitochondrial respiration and reduced ROS generation but suppressed mitophagic flux and intensified atrophy of type IIX and IIB fibers. Additionally, administration of colchicine to immobilized mice suppressed mitophagic flux, which also exacerbated atrophy of IIX and IIB fibers. Colchicine treatment led to significant reductions in mitochondrial function, accompanied by CASP9 and CASP3 activation.<br><br>CONCLUSION: These findings emphasize the role of mitophagy in limiting excessive muscle atrophy during immobilization. Targeting mitophagy may offer new strategies to preserve muscle function during prolonged periods of immobilization.},
}
@article {pmid39976169,
year = {2025},
author = {Savaliya, BF and Kim, S and Veltman, T and Trott, DJ},
title = {Comparison of the in vitro antibiofilm activities of otic cleansers against canine otitis externa pathogens.},
journal = {Veterinary dermatology},
volume = {36},
number = {2},
pages = {148-158},
pmid = {39976169},
issn = {1365-3164},
support = {//Dermcare-Vet, Australia/ ; //University of Adelaide/ ; },
mesh = {Animals ; *Biofilms/drug effects ; Dogs ; *Otitis Externa/veterinary/microbiology/drug therapy ; *Dog Diseases/microbiology/drug therapy ; Microbial Sensitivity Tests/veterinary ; Edetic Acid/pharmacology ; *Anti-Bacterial Agents/pharmacology ; Biguanides/pharmacology ; Malassezia/drug effects ; Pseudomonas aeruginosa/drug effects ; Bacteria/drug effects ; },
abstract = {BACKGROUND: Biofilm production by canine otitis externa (COE) pathogens and resistance development to multiple antimicrobials are commonly reported problems in veterinary practice. The use of adjuvants to disrupt biofilms may be a viable adjunctive therapy.<br><br>HYPOTHESIS/OBJECTIVES: To compare the in&#xa0;vitro antibiofilm activity against COE pathogens of three otic cleansers: PHMB-EDTA (poly [hexamethylene] biguanide hydrochloride and disodium edetate), N-acetylcysteine (NAC) and Triz-EDTA.<br><br>ANIMALS/ISOLATES: Thirty isolates of each species, including Staphylococcus pseudintermedius, Pseudomonas aeruginosa, Streptococcus canis, Proteus mirabilis, Escherichia coli, and Malassezia pachydermatis, were collected from COE cases and stored at -80&#xb0;C until tested.<br><br>METHODS AND MATERIALS: Biofilm production was determined by Congo-red agar and microtitre plate-assay methods. Ten of the best biofilm-producing isolates per species were selected to determine minimum biofilm eradication concentration (MBEC) values. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were determined to compare MBEC/MIC and MBEC/MBC.<br><br>RESULTS: PHMB-EDTA possessed antibiofilm activity at low concentrations (MBEC range 3.9/2.3-500/300&#x2009;&#x3bc;g/mL) against all tested COE pathogens. NAC demonstrated antibiofilm activity for all tested bacterial COE pathogens (MBEC range 4,925-19,700&#x2009;&#x3bc;g/mL); however, most M.&#x2009;pachydermatis isolates exhibited MBEC values >20,000&#x2009;&#x3bc;g/mL. Triz/EDTA at the highest concentration tested (3,025/19,520&#x2009;&#x3bc;g/mL) did not demonstrate antibiofilm activity against most COE pathogens except for S. canis (94.5/610&#x2009;&#x3bc;g/mL).<br><br>PHMB-EDTA had intrinsic antibiofilm activity at low concentrations against all COE pathogens. Therefore, it is likely to be a very effective adjuvant when used in conjunction with other antimicrobials for the treatment of COE caused by biofilm-producing pathogens.},
}
@article {pmid39974683,
year = {2025},
author = {Shenvi, S and Joshi, SB and Seal, M},
title = {A comparative evaluation of the decalcifying effects of ethylenediaminetetraacetic acid and N-acetyl cysteine on root canal dentin using energy-dispersive X-ray spectroscopy.},
journal = {Journal of conservative dentistry and endodontics},
volume = {28},
number = {1},
pages = {39-43},
pmid = {39974683},
issn = {2950-4708},
abstract = {BACKGROUND: Chelating agents used to remove the inorganic part of the smear layer from prepared canals can alter dentin mineral composition, potentially affecting the adhesion of resin-based root canal cement and sealers.<br><br>AIM: This study aimed to compare the decalcifying effects of 17% ethylenediaminetetraacetic acid (EDTA), 20% N-acetyl cysteine (NAC), and deionized water (control) on root canal dentin using energy-dispersive X-ray spectroscopy (EDXS).<br><br>MATERIALS AND METHODS: Sixty-nine extracted human mandibular premolars were randomly divided into three groups, yielding 138 root halves treated with either 17% EDTA, 20% NAC, or a control solution (n = 46). The mineral content was assessed using EDXS, and statistical analysis was conducted with the Kruskal-Wallis test, using an alpha level of 5%.<br><br>RESULTS: Twenty percent NAC and control groups retained more calcium, magnesium, and phosphorus than 17% EDTA, suggesting better mineral preservation, while 17% EDTA resulted in the lowest mineral content across all elements analyzed.<br><br>CONCLUSION: Twenty percent NAC exhibited milder decalcifying effects compared to EDTA while preserving mineral content. Twenty percent NAC could be a biocompatible alternative to EDTA for smear layer removal in endodontic treatments.},
}
@article {pmid39972374,
year = {2025},
author = {Muthmainah, M and Sketriene, D and Anversa, RG and Harris, E and Griffiths, S and Gogos, A and Sumithran, P and Brown, RM},
title = {Exploring the utility of N-acetylcysteine for loss of control eating: protocol of an open-label single-arm pilot study.},
journal = {Pilot and feasibility studies},
volume = {11},
number = {1},
pages = {19},
pmid = {39972374},
issn = {2055-5784},
abstract = {BACKGROUND: A sense of loss of control over eating, such that eating occurs despite the intent not to, is common in people with obesity and eating disorders such as binge eating disorder and bulimia nervosa. Currently, options for management of loss of control eating are limited. We recently determined that the pro-drug N-acetylcysteine (NAC) reduces compulsive-like eating in a rat model of diet-induced obesity. We will now conduct a single site, open-label pilot study to examine the feasibility of a randomized controlled trial (RCT) of NAC for loss of control eating in humans.<br><br>METHODS: Thirty-six adult volunteers with loss of control eating will be enrolled. All participants will receive NAC at a dose of 1200&#xa0;mg orally twice daily for 12&#xa0;weeks. Eating behaviors and triggers will be assessed before and after the NAC treatment period using questionnaires (Eating Loss of Control Scale, Palatable Eating Motives Scale: Coping Subscale, Food Craving Inventory, Reward-Based Eating Scale, Perceived Stress Scale, and Emotional Eating Scale) and ecological momentary assessment (EMA). The primary outcomes of this feasibility study are recruitment rate, participant retention rate at week 12, and medication adherence. The secondary outcome is change in Eating Loss of Control Scale score from baseline to week 12. Exploratory data will be collected on the change in eating behaviors from baseline to week 12. Although EMA can provide real-time data on eating behaviors compared with retrospective questionnaires, it relies on repeated daily measurement for long periods which can affect participant's adherence to study protocol. Therefore, this feasibility study will assess the performance of EMA versus retrospective questionnaires and will determine which approach suits the purposes of the research.<br><br>DISCUSSION: The results of this study will inform the feasibility of a RCT of NAC for loss of control eating using EMA.<br><br>TRIAL REGISTRATION: This study was prospectively registered with the Australian and New Zealand Clinical Trials Registry in June 2022 (ACTRN12622000902796).},
}
@article {pmid39971251,
year = {2025},
author = {Fu, H and Wang, Y and Huang, B and Liang, Z and Li, Y and Cao, Z and Wu, J and Zhao, Y},
title = {Tannic acid‑cerium nanoenzymes serve as broad-spectrum antioxidants to alleviate acute kidney injury by modulating macrophage polarization, mitophagy and endoplasmic reticulum stress.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {380},
number = {},
pages = {892-909},
doi = {10.1016/j.jconrel.2025.02.038},
pmid = {39971251},
issn = {1873-4995},
mesh = {Animals ; *Acute Kidney Injury/drug therapy/pathology/metabolism ; *Tannins/administration &amp; dosage/chemistry/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; *Antioxidants/administration &amp; dosage/pharmacology/chemistry/therapeutic use ; Mitophagy/drug effects ; Male ; Mice ; *Cerium/chemistry/administration &amp; dosage/pharmacology ; Macrophages/drug effects ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; RAW 264.7 Cells ; Nanoparticles/chemistry/administration &amp; dosage ; Humans ; Polyphenols ; },
abstract = {Acute kidney injury (AKI) is a critical condition marked by a rapid decline in renal function, primarily driven by oxidative stress, mitochondrial dysfunction, and inflammation. Despite extensive research, effective therapeutic strategies addressing the complex pathophysiology of AKI remain limited. In this study, we prepared a tannic acid‑cerium nanoenzyme (TA-Ce) and explored its potential for treating AKI. TA-Ce, synthesized via a one-pot method, demonstrated strong reactive oxygen species (ROS) scavenging, therapeutic efficacy, and biocompatibility in vitro and in vivo. TA-Ce, approximately 25.6 nm in size, was obtained by optimizing the molar ratios of TA to Ce and pH conditions, resulting in effective accumulation in the injured kidney. In addition, TA-Ce exhibited broad-spectrum antioxidant ability, capable of scavenging various ROS and alleviating oxidative stress. Notably, TA-Ce outperformed the conventional anti-inflammatory drug N-acetylcysteine (NAC) in both rhabdomyolysis-induced AKI (RM-AKI) and cisplatin-induced AKI (CP-AKI) mouse models. Mechanistic studies in RM-AKI revealed that TA-Ce disrupted the vicious cycle of oxidative stress, mitochondrial damage, endoplasmic reticulum stress, apoptosis, and inflammation. The nanoenzyme restored mitochondrial autophagic flux by inhibiting the P62-LC3 signaling pathway and alleviated endoplasmic reticulum stress by suppressing the IRE1-XBP1s pathway. Consequently, this prevented the downstream activation of the Bcl-2-Bax-Cyt-c-Cleaved Casp-3 apoptotic pathway and the NF-κB inflammatory pathway, ultimately ameliorating RM-AKI. This study lays a strong foundation for the development of metal-polyphenol nanomaterials as a therapeutic strategy for clinical AKI.},
}
@article {pmid39968425,
year = {2025},
author = {Aiad, M and Bhalala, HJ and Bagshaw, H and Starner, S and Saha, D},
title = {Severe Hepatotoxicity From Capmatinib: A Case Report and Therapeutic Approach.},
journal = {Cureus},
volume = {17},
number = {1},
pages = {e77652},
pmid = {39968425},
issn = {2168-8184},
abstract = {Capmatinib, a selective mesenchymal-epithelial transition (MET)-kinase inhibitor, is approved for treating metastatic non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping mutation. Although a known side effect, not much data is available on the management of capmatinib-induced liver injury. Here, we present a case of a 60-year-old male with MET exon mutated NSCLC who developed grade 4 liver injury after capmatinib initiation, which did not respond to drug discontinuation and eventually responded to N-acetyl cysteine (NAC) and ursodeoxycholic acid (ursodiol) therapy. This case demonstrates that NAC plus ursodiol can be an effective treatment strategy in such patients.},
}
@article {pmid39961200,
year = {2025},
author = {Cp, S and V, A and Tm, MK and S, M and K, B and Singh, ISB and Puthumana, J},
title = {BIF-induced ROS-mediated cytotoxicity and genotoxicity in embryonic cell culture of Daphnia magna.},
journal = {Aquatic toxicology (Amsterdam, Netherlands)},
volume = {280},
number = {},
pages = {107285},
doi = {10.1016/j.aquatox.2025.107285},
pmid = {39961200},
issn = {1879-1514},
mesh = {Animals ; *Daphnia/drug effects/embryology ; *Reactive Oxygen Species/metabolism ; *Pyrethrins/toxicity ; *Water Pollutants, Chemical/toxicity ; *Insecticides/toxicity ; Oxidative Stress/drug effects ; DNA Damage ; Embryo, Nonmammalian/drug effects ; Daphnia magna ; },
abstract = {Bifenthrin (BIF) is a widely used synthetic pyrethroid insecticide that poses significant risks to the environment, particularly to aquatic ecosystems. In the present study, the cytotoxic and genotoxic effects of BIF on Daphnia magna cells were evaluated using in vitro methods. To achieve this, we developed a novel embryonic cell culture system from D.magna using Modified Schneider's Insect Medium (MSIM), which demonstrated remarkable viability for over two months. The lethal concentration 50 (LC50) values of BIF were determined using this cell culture system through XTT (2,3-bis-(2‑methoxy-4-nitro-5-sulphenyl)-(2H)-tetrazolium-5-carboxanilide)assays, yielding values of 7.4 µg/mL and 4.3 µg/mL for 24 h and 48 h exposures, respectively. A fluorometric intracellular reactive oxygen species (ROS) assay was employed to measure ROS production, revealing that BIF exposure induced oxidative stress in a dose-dependent manner. The activities of Glutathione peroxidase (GPx), glutathione (GSH), and glutathione-S-transferase (GST) were significantly reduced, indicating oxidative damage. Co-treatment with N-acetylcysteine(NAC) mitigated these effects, restoring antioxidant enzyme activity and reducing (ROS) levels. Gene expression analysis via quantitative real-time PCR (qPCR) showed upregulation of stress-related genes (hsp70, hsp90) and antioxidant genes (Mn/ZnSod, cat) following exposure to LC50 concentrations of BIF. However, prolonged exposure led to a downregulation of these genes, suggesting cumulative effects over time. The comet assay confirmed that BIF caused genotoxicity, as evidenced by significant increases in comet and tail lengths. Co-treatment with NAC effectively mitigated these genotoxic effects. This study highlighted the cytotoxic and genotoxic potential of BIF in aquatic organisms and suggested the need for environmentally friendly pest control strategies. Also, the findings confirmed the reliability of D. magna embryonic cell cultures for assessing the toxicological effects of environmental pollutants, offering new possibilities for in vitro toxicity testing at cellular and molecular levels.},
}
@article {pmid39960426,
year = {2025},
author = {Roshdy, E and Taniguchi, H and Nakamura, Y and Takahashi, H and Kikuchi, Y and Celik, I and Mohammed, ESI and Ishihara, Y and Morioka, N and Abe, M},
title = {Design, Synthesis, and Biological Evaluation of BODIPY-Caged Resiquimod as a Dual-Acting Phototherapeutic.},
journal = {Journal of medicinal chemistry},
volume = {68},
number = {4},
pages = {4561-4581},
pmid = {39960426},
issn = {1520-4804},
mesh = {Humans ; *Boron Compounds/chemistry/pharmacology/chemical synthesis ; *Imidazoles/chemistry/pharmacology/chemical synthesis ; *Drug Design ; *Photosensitizing Agents/pharmacology/chemical synthesis/chemistry ; *Photochemotherapy ; Animals ; Molecular Docking Simulation ; HeLa Cells ; Mice ; A549 Cells ; Antineoplastic Agents/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; },
abstract = {Resiquimod, an imidazoquinoline scaffold, exhibits potent immunotherapeutic activity but is associated with off-target effects, limiting its clinical utility. To address this limitation, we developed a novel BODIPY-caged resiquimod that is responsive to red light, combining photocaging and photodynamic therapy functionalities. Molecular docking studies guided identification of the optimal caging site for resiquimod, effectively masking its immune activity. BODIPY-caged resiquimod remained inactive under dark conditions, effectively masking resiquimod's immunostimulatory effects. However, red light irradiation precisely uncaged resiquimod, inducing robust immune activation, even in the presence of N-acetyl cysteine as an antioxidant. Notably, the attachment of resiquimod to BODIPY reduced the dark toxicity typically associated with BODIPY as a photosensitizer. In 3D spheroid models of HeLa and A549 cells, BODIPY-caged resiquimod demonstrated spatiotemporal control over cytotoxicity, significantly enhancing cell death only upon irradiation. This dual-function therapeutic approach highlights a "win-win" strategy: precise, red-light-mediated control of immune activation and photodynamic efficacy with reduced collateral toxicity.},
}
@article {pmid39959616,
year = {2025},
author = {Chaves, AS and Ventura, RD and Pacini, MF and Magalhães, NS and Silva, PMRE and Martins, MA and Pérez, AR and Carvalho, VF},
title = {Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands.},
journal = {Frontiers in endocrinology},
volume = {16},
number = {},
pages = {1500630},
pmid = {39959616},
issn = {1664-2392},
mesh = {Animals ; *NF-E2-Related Factor 2/metabolism ; *Hypothalamo-Hypophyseal System/drug effects/metabolism ; *Pituitary-Adrenal System/drug effects/metabolism ; Male ; *Acetylcysteine/pharmacology ; Mice ; *Receptors, Glucocorticoid/metabolism/genetics ; *Pituitary Gland/metabolism/drug effects ; Down-Regulation/drug effects ; Signal Transduction/drug effects ; Feedback, Physiological/drug effects ; *Heme Oxygenase-1/metabolism ; Up-Regulation/drug effects ; Membrane Proteins ; },
abstract = {We previously showed that antioxidants induced an impairment of negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in rats, in parallel to a down-regulation of the glucocorticoid receptor (GR) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the pituitary gland. This study evaluated the role of the Nrf2-heme-oxygenase-1 (HO-1) pathway on the impairment of the negative feedback of the HPA axis induced by N-acetylcysteine (NAC). Male Swiss-Webster mice were orally supplemented with NAC for 5 consecutive days. The Nrf2-HO-1 pathway activator cobalt protoporphyrin IX (CoPPIX) was injected intraperitoneally on days 2 and 5 after the starting of NAC supplementation. NAC reduced the expression of Nrf2 in the pituitary of mice. Furthermore, NAC induced adrenal enlargement and hypercorticoidism, along with a decrease in the GRα expression and an increase of GRβ expression in the pituitary gland. Treatment with CoPPIX reduced adrenal enlargement, systemic corticosterone levels, and GRβ expression in the pituitary gland of mice supplemented with NAC, besides increasing the expression of GRα. CoPPIX treatment also restored the failure in the negative feedback of the HPA axis induced by NAC. In conclusion, these findings showed that NAC reduced the Nrf2-HO-1 pathway activation in the pituitary gland, in a mechanism probably related to a local downregulation of GRα and an up-regulation of GRβ, leading to a failure of negative feedback of the HPA axis and consequently to the hyperactivity of this neuroendocrine axis.},
}
@article {pmid39959017,
year = {2024},
author = {Subiksha, K and Jena, A and Sarangi, P and Mohanty, S and Sahoo, S and Mallick, RR},
title = {Comparative evaluation of antibacterial efficacy of N-acetylcysteine, Aegle marmelos, and chitosan as intracanal medicaments against Enterococcus faecalis biofilm - An in vitro study.},
journal = {Journal of conservative dentistry and endodontics},
volume = {27},
number = {12},
pages = {1246-1250},
pmid = {39959017},
issn = {2950-4708},
abstract = {CONTEXT: The main objective of root canal treatment is the removal of bacteria. Established medicaments and their combinations have been compromised in efficacy against Enterococcus faecalis, causing the need to explore novel intracanal medicaments.<br><br>AIM: The aim of the study was to evaluate the antibacterial efficacy of chitosan, N-acetylcysteine (NAC), and Aegle marmelos as intracanal medicaments against E. faecalis biofilm.<br><br>MATERIALS AND METHODOLOGY: Minimum inhibitory concentration and susceptibility of medicaments determined. Two hundred and forty dentin disc specimens were prepared and inoculated with E. faecalis for 21 days. Samples were divided into four groups (A - N-acetylcysteine; B - Aegle marmelos; C - Chitosan; D -Control) (n = 60), and two subgroups (n = 30) based on the duration of medicament placed (subgroup 1: 24 h, subgroup 2: 7 days). Thereafter, dentinal shavings were retrieved, incubated in agar plate, visible colonies counted, and statistically analyzed.<br><br>RESULTS: At 24 h Group C1 exhibited the lowest CFUs, followed by Group A1, Group B, and Group D1. On the 7[th] day, Group B2 showed the lowest CFUs, followed by Group A2, Group C2, and Group D2.<br><br>CONCLUSIONS: Against E. faecalis, NAC has the highest antimicrobial properties closely followed by Aegle marmelos and both provide promising novel possibilities for use as intracanal medicaments.},
}
@article {pmid39954867,
year = {2025},
author = {Wang, J and Zhao, R and Ma, J and Qin, J and Zhang, H and Guo, J and Chang, X and Zhang, W},
title = {Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia.},
journal = {Free radical biology &amp; medicine},
volume = {230},
number = {},
pages = {248-262},
doi = {10.1016/j.freeradbiomed.2025.02.012},
pmid = {39954867},
issn = {1873-4596},
mesh = {Humans ; Acetylcysteine/pharmacology ; *Ataxia/genetics/pathology/drug therapy ; Cyclohexylamines/pharmacology ; Deferoxamine/pharmacology ; *Ferroptosis/genetics/drug effects ; Lipid Peroxidation ; Mitochondria/pathology/metabolism/genetics/drug effects ; *Mitochondrial Diseases/genetics/pathology/drug therapy ; Mutation ; *Optic Atrophy/genetics/pathology ; Oxidative Stress/drug effects ; Phenylenediamines/pharmacology ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics/metabolism ; Ubiquinone/analogs &amp; derivatives/pharmacology ; *Ferredoxin-NADP Reductase/genetics ; },
abstract = {Biallelic mutations in the FDXR are known to cause rare mitochondrial diseases. However, the underlying pathogenic mechanisms remain elusive. This study investigated a patient affected by optic atrophy, ataxia, and peripheral neuropathy resulting from compound heterozygous mutations in FDXR. Structural abnormalities in mitochondria were observed in muscle and nerve tissues. Lymphoblastic cell lines (LCLs) and muscle samples from the patient exhibited signs of mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation. Dysregulation of the glutathione peroxidase-4 was noted in the LCLs. Furthermore, treatment with deferoxamine, N-acetyl-cysteine, and ferrostatin-1 effectively alleviated oxidative stress and cell death. Cortical neurons demonstrate that FDXR deficiency impacts the morphogenesis of neurites. Collectively, these findings suggest that ferroptosis plays a significant role in the pathogenesis of FDXR-associated diseases. Additionally, idebenone appeared to have protective effects against various cellular injuries induced by FDXR mutations, providing novel insights and therapeutic approaches for the treatment of FDXR-associated diseases.},
}
@article {pmid39954761,
year = {2025},
author = {Kumar, S and D'Souza, LC and Shaikh, FH and Rathor, P and Ratnasekhar, CH and Sharma, A},
title = {Multigenerational immunotoxicity assessment: A three-generation study in Drosophila melanogaster upon developmental exposure to triclosan.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {370},
number = {},
pages = {125860},
doi = {10.1016/j.envpol.2025.125860},
pmid = {39954761},
issn = {1873-6424},
mesh = {Animals ; *Triclosan/toxicity ; *Drosophila melanogaster/immunology/drug effects ; Female ; Hemocytes/drug effects ; Male ; *Environmental Pollutants/toxicity ; },
abstract = {Triclosan (TCS) is widely used as an antibacterial agent, nevertheless, its presence in different environmental matrices and its persistent environmental nature pose a significant threat to the organism, including humans. Numerous studies showed that TCS exposure could lead to multiple toxicities, including immune dysfunction. However, whether parental TCS exposure could impair the offspring's immune response remains limited. Maintaining the immune homeostasis is imperative to neutralize the pathogen and crucial for tissue repair and the organism's survival. Thus, this study aimed to assess the multigenerational immune response of TCS using Drosophila melanogaster. TCS was administered to organisms (1.0, 10, and 100.0 μg/mL) over three generations during their developing phases, and its effect on the immunological response of the unexposed progeny was evaluated. Total circulatory hemocyte (immune cells) count, crystal cell count, phagocytic activity, clotting time, gene expression related to immune response and epigenetics, ROS generation, and cell death were assessed in the offspring. A concentration-dependent decline in total hemocytes, crystal cells, phagocytic activity, and increased clotting time in the subsequent generations was observed. Furthermore, parental TCS exposure enhanced the ROS levels, induced cell death, and altered the expression of antimicrobial peptides drosomycin, diptericin, and inflammatory genes upd1, upd2, and upd3, in the offspring's hemocytes across successive generations. The upregulation of reaper hid, and grim suggests that TCS promotes apoptotic death in the offspring's hemocytes. Notably, the increased mRNA expression of epigenetic regulators dnmt2 and g9a in the hemocytes of the offspring indicates epigenetic modifications. Further, we also observed that the antioxidant N-acetylcysteine (NAC) supplementation to the parents alleviated TCS toxicity and improved immunological functions in the progeny, indicating the role of ROS in the TCS-induced multigenerational immune toxicity. This finding provides valuable insights into the potential immune risk of prenatal TCS exposure to their offspring in the higher organism.},
}
@article {pmid39954094,
year = {2025},
author = {Zhou, Y and Yuan, X and Guo, M},
title = {Unlocking NAC's potential ATF4 and m6A dynamics in rescuing cognitive impairments in PTSD.},
journal = {Metabolic brain disease},
volume = {40},
number = {2},
pages = {129},
pmid = {39954094},
issn = {1573-7365},
support = {ZDYF2022SHFZ110//Key R&amp;D Plan of Hainan Province in 2022/ ; },
mesh = {Animals ; *Stress Disorders, Post-Traumatic/drug therapy/metabolism/psychology ; *Activating Transcription Factor 4/metabolism/genetics ; Mice ; Male ; *Cognitive Dysfunction/drug therapy/metabolism ; *Acetylcysteine/pharmacology/therapeutic use ; Hippocampus/metabolism/drug effects ; Apoptosis/drug effects ; Mice, Inbred C57BL ; Disease Models, Animal ; Neurons/drug effects/metabolism ; },
abstract = {In this study, we investigated the therapeutic potential of N-acetylcysteine (NAC) in a mouse model of post-traumatic stress disorder (PTSD) induced by a single prolonged stress (SPS) protocol. Our findings demonstrate that NAC treatment significantly improved cognitive function and mitigated hippocampal neuronal apoptosis in PTSD model mice. These positive effects were accompanied by a reduction in m6A methylation levels and activating transcription factor 4 (ATF4) expression. Silencing ATF4 further attenuated hippocampal neuronal apoptosis and cognitive dysfunction, while ATF4 overexpression partially reversed the beneficial effects of NAC. It suggests that NAC's efficacy in PTSD may be mediated by its regulation of ATF4 expression and m6A methylation levels. Overall, our study provides valuable insights into the potential mechanism of action for NAC in PTSD treatment, offering promising avenues for future therapeutic strategies.},
}
@article {pmid39954037,
year = {2025},
author = {Zhu, X and Yuan, F and Sun, Q and Yang, C and Jiang, H and Xiang, X and Zhang, X and Sun, Z and Wei, Y and Chen, Q and Cai, L},
title = {N-acetylcysteine remodels the tumor microenvironment of primary and recurrent mouse glioblastoma.},
journal = {Journal of neuro-oncology},
volume = {173},
number = {1},
pages = {131-145},
pmid = {39954037},
issn = {1573-7373},
support = {NO. 82303647//the National Natural Science Foundation of China/ ; NO.82203624//the National Natural Science Foundation of China/ ; NO. 2022CFB635//the Natural Science Foundation of Hubei Province/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Glioblastoma/drug therapy/pathology/metabolism ; *Tumor Microenvironment/drug effects ; *Brain Neoplasms/drug therapy/pathology/metabolism ; Mice ; Humans ; *Neoplasm Recurrence, Local/drug therapy/pathology/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Male ; Oxidative Stress/drug effects ; Glutathione/metabolism ; Female ; },
abstract = {PURPOSE: Glioblastoma (GBM) exhibits a high ROS character, giving rise to an immunosuppressive microenvironment and tumor vascular abnormality. This study investigated the potential effect of N-acetylcysteine (NAC), an antioxidant, on primary and recurrent mouse brain tumors.<br><br>METHODS: We measured reactive oxygen species (ROS)/ glutathione (GSH) levels in human GBM. Additionally, we conducted NAC trials on primary mouse brain tumor models (GL261-Luc, CT2A-Luc) and a recurrent mouse GBM model (GL261-iCasp9-Luc). After brain tumor inoculation, mice received a daily 100&#xa0;mg/kg NAC treatment, and the tumor volume was monitored via IVIS imaging. The efficacy of NAC was evaluated through survival time, tumor volume, ROS/GSH levels, M1/M2 macrophages, immune cells infiltration, and tumor vascularization.<br><br>RESULTS: Human GBM suffered from significant oxidative stress. With NAC treatment, mouse brain tumors exhibited a lower ROS level, more M1-like tumor-associated macrophages/microglia (TAMs), more CD8&#x2009;+&#x2009;T cell infiltration, and a normalized vascular character. NAC inhibited tumor growth and suppressed recurrence in mouse brain tumor models.<br><br>CONCLUSION: NAC is a promising adjunctive drug to remodel the brain tumors microenvironment.},
}
@article {pmid39950481,
year = {2025},
author = {Liu, X and Zhong, D and Tang, CZ and Xu, X and Lan, H and Diao, X},
title = {In vitro and In vivo Drug Metabolism Analysis of BPI-460372 - A Covalent TEAD1/3/4 Inhibitor.},
journal = {Current drug metabolism},
volume = {25},
number = {10},
pages = {754-768},
pmid = {39950481},
issn = {1875-5453},
abstract = {BACKGROUND: BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment of cancers with Hippo pathway alterations.<br><br>OBJECTIVE: This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372.<br><br>METHODS: The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes and rat and dog plasma was analyzed using ultra-high-performance liquid chromatography combined with Orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).<br><br>RESULTS: BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human-unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic site was 2-fluoro-acrylamide, and major metabolic pathways in hepatocytes, and rat and dog plasma involved oxidative defluorination, hydration, glutathione (GSH) conjugation, hydrolysis, cysteine conjugation, and N-acetyl cysteine conjugation. &#x3b2;-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree.<br><br>CONCLUSION: This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, and assessment of clinical co-administration limitations and possible metabolic pathways in humans.},
}
@article {pmid39949804,
year = {2025},
author = {Qian, X and Liu, Y and Chen, W and Zheng, S and Lu, Y and Qiu, P and Ke, X and Tang, H and Zhang, X},
title = {Paris saponin VII induces Caspase-3/GSDME-dependent pyroptosis in pancreatic ductal adenocarcinoma cells by activating ROS/Bax signaling.},
journal = {Chinese herbal medicines},
volume = {17},
number = {1},
pages = {94-107},
pmid = {39949804},
issn = {2589-3610},
abstract = {OBJECTIVE: Paridis Rhizoma (Chonglou in Chinese), a traditional Chinese herbal medicine, has been shown have strong anti-tumor effects. Paris saponin VII (PSVII), an active constituent isolated from Paridis Rhizoma, was demonstrated to significantly suppress the proliferation of BxPC-3 cells in our previous study. Here, we aimed to elucidate the anti-pancreatic ductal adenocarcinoma (PDAC) effect of PSVII and the underlying mechanism.<br><br>METHODS: Cell viability was determined by CCK-8, colony formation, and cell migration assays. Cell apoptosis and reactive oxygen species (ROS) production were measured by flow cytometry with annexin V/propidine iodide (Annexin V/PI) and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), respectively. Pyroptosis was evaluated by morphological features, Hoechst 33342/PI staining assay, and release of lactate dehydrogenase (LDH). JC-1 fluorescent dye was employed to measure mitochondrial membrane potential. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to determine the levels of proteins or mRNAs. The effect in vivo was assessed by a xenograft tumor model.<br><br>RESULTS: PSVII inhibited the viability of PDAC cells (BxPC-3, PANC-1, and Capan-2 cells) and induced gasdermin E (GSDME) cleavage, as well as the simultaneous cleavage of Caspase-3 and poly (ADP-ribose) polymerase 1 (PARP). Knockdown of GSDME shifted PSVII-induced pyroptosis to apoptosis. Additionally, the effect of PSVII was significantly attenuated by Z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone (Z-DEVD-FMK), on the induction of GSDME-dependent pyroptosis. PSVII also elevated intracellular ROS accumulation and stimulated Bax and Caspase-3/GSDME to conduct pyroptosis in PDAC cells. The ROS scavenger N-acetyl cysteine (NAC) suppressed the release of LDH and inhibited Caspase-9, Caspase-3, and GSDME cleavage in PDAC cells, ultimately reversing PSVII-induced pyroptosis. Furthermore, in a xenograft tumor model, PSVII markedly suppressed the growth of PDAC tumors and induced pyroptosis.<br><br>CONCLUSION: These results demonstrated that PSVII exerts therapeutic effects through Caspase-3/GSDME-dependent pyroptosis and may constitute a novel strategy for preventing chemotherapeutic resistance in patients with PDAC in the future.},
}
@article {pmid39947664,
year = {2025},
author = {Lee, SO and Joo, SH and Park, J and Khong, QT and Seo, SY and Yoon, G and Park, JW and Na, M and Shim, JH},
title = {Deoxybouvardin Glucoside Induces Apoptosis in Oxaliplatin-Sensitive and -Resistant Colorectal Cancer Cells via Reactive Oxygen Species-Mediated Activation of JNK and p38 MAPK.},
journal = {Journal of microbiology and biotechnology},
volume = {35},
number = {},
pages = {e2410008},
pmid = {39947664},
issn = {1738-8872},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Oxaliplatin/pharmacology ; *Colorectal Neoplasms/drug therapy/metabolism ; HCT116 Cells ; Membrane Potential, Mitochondrial/drug effects ; *Antineoplastic Agents/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Cell Survival/drug effects ; *Glucosides/pharmacology ; Cell Proliferation/drug effects ; *Organoplatinum Compounds/pharmacology ; *JNK Mitogen-Activated Protein Kinases/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Phosphorylation/drug effects ; },
abstract = {The roots of Rubia spp. (Rubiaceae) have been employed to treat hematemesis, inflammatory disease, and tumor. Cyclohexapeptides derived from Rubia spp. have been reported to have antitumor potential; however, the mechanism of action for their antitumor activity remains unclear. We aimed to examine the antitumor effect of deoxybouvardin glucoside (DBG), a cyclohexapeptide from Rubia spp. on oxaliplatin (Ox)-resistant human HCT116 colorectal cancer (CRC) cells. Cell viability in the presence of DBG was monitored using an MTT viability assay, and flow cytometry was used to analyze changes in apoptosis, cell cycle, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) activity. The antiproliferative activity involved apoptosis and phosphorylation of JNK and p38 MAPK. Inhibition of JNK and p38 MAPK by specific inhibitors prevented DBG-induced apoptosis, underscoring the close involvement of these kinases. Further, DBG induced cell cycle arrest in CRC cells at the G2/M phase by regulating the p21, p27, cyclin B1, and cdc2 proteins. DBG-induced apoptosis was accompanied mitochondrial membrane depolarization, resulting in cytochrome c release into the cytoplasm and caspase activation. Remarkably, DBG induced apoptosis by generating high ROS levels. The mediation of apoptosis by increased ROS generation was confirmed by pretreatment with the ROS scavenger N-acetyl cysteine (NAC). Collectively, DBG exhibited anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting JNK and p38 MAPK, inducing cell cycle arrest, elevating cellular ROS levels, and disrupting MMP. This study suggests that DBG has the potential to be utilized as a therapeutic agent for treating Ox-resistant CRC.},
}
@article {pmid39944180,
year = {2025},
author = {Bellone, S and Siegel, ER and Santin, AD},
title = {N-acetylcysteine (NAC) supplementation improves dyspnea and may normalize von Willebrand plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID.},
journal = {Gynecologic oncology reports},
volume = {57},
number = {},
pages = {101682},
pmid = {39944180},
issn = {2352-5789},
support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; },
abstract = {OBJECTIVES: A subset of COVID-infected cancer patients may develop post-acute sequelae of COVID-19 (PASC), also known as Long COVID (LC). While LC is considered multifactorial in its pathogenesis, growing evidence suggests that persistent microvascular inflammation (ie, spike-induced endotheliosis) causing chronically elevated levels of clotting factors including von Willebrand factor (vWF), clumping/clotting of red blood cells and platelets, and thrombotic complications may be at the root of PASC/LC symptoms. N-Acetylcysteine (NAC), a precursor of glutathione, is an inexpensive FDA-approved drug/supplement endowed with mucolytic, antioxidant, anti-inflammatory and thrombolytic properties. Multiple reports have recently demonstrated the potential clinical activity of NAC in COVID-19 patients. We retrospectively evaluated responses to NAC supplementation in a total of 9 PASC/LC patients, 3 of which reporting regular use of NAC, followed in our Gynecologic Oncology clinic.<br><br>METHODS: Gynecologic patients using NAC supplement (3 patients) vs controls (6 patients) with persistent LC/PASC symptoms and with elevated plasmatic vWF levels were identified in our Gynecologic Oncology clinic database and evaluated for improvement/normalization in LC/PASC symptoms and vWF levels.<br><br>RESULTS: Subjective improvement in shortness of breath, brain fog and fatigue with normalization of vWF levels were noted in 3 out of 3 PASC/LC patients using oral NAC (600-1200&#xa0;mg BID) vs none of the randomly selected cancer control patients with PASC/LC (Fisher's exact P&#xa0;=&#xa0;0.0119).<br><br>CONCLUSIONS: These preliminary results suggest that NAC may represent an inexpensive, safe and potentially effective supplement to improve many PASC/LC-related symptoms. Prospective randomized studies with NAC in PASC/LC patients are needed to confirm these findings.},
}
@article {pmid39942681,
year = {2025},
author = {Iciek, M and Bilska-Wilkosz, A and Górny, M and Bednarski, M and Zygmunt, M and Miller, A and Nicosia, N and Lombardo, GP and Zammit, P and Kotańska, M},
title = {The Effect of Disulfiram and N-Acetylcysteine, Potential Compensators for Sulfur Disorders, on Lipopolysaccharide-Induced Neuroinflammation Leading to Memory Impairment and the Metabolism of L-Cysteine Disturbance.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {3},
pages = {},
pmid = {39942681},
issn = {1420-3049},
support = {N41/DBS/001389.//Jagiellonian University, Medical College Krakow/ ; },
mesh = {Animals ; *Lipopolysaccharides/adverse effects/toxicity ; *Acetylcysteine/pharmacology ; *Memory Disorders/drug therapy/metabolism/chemically induced/etiology ; Rats ; *Disulfiram/pharmacology ; *Neuroinflammatory Diseases/drug therapy/chemically induced/metabolism ; Male ; *Cysteine/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Rats, Wistar ; Cerebral Cortex/metabolism/drug effects ; Reactive Oxygen Species/metabolism ; },
abstract = {BACKGROUND: The role of sulfur-containing drugs, disulfiram (DSF) and N-acetylcysteine (NAC), in alleviating neuroinflammation is poorly understood. The objective of this study was to examine the effect of DSF and NAC on memory and on the metabolism of L-cysteine and inflammation-related parameters in the cerebral cortex of rats in a model of neuroinflammation induced by the administration of lipopolysaccharide (LPS).<br><br>METHODS: All the treatments were administered intraperitoneally for 10 days (LPS at a dose of 0.5 mg/kg b.w., DSF at a dose of 100 mg/kg b.w, and NAC at a dose of 100 mg/kg b.w.). Behavior was evaluated by the novel object recognition (NOR) test and object location (OL) test, and the level of brain-derived neurotrophic factor (BDNF) was assayed to evaluate neuronal functioning. Cerebral cortex homogenates were tested for hydrogen sulfide (H2S), sulfane sulfur, sulfates, non-protein sulfhydryl groups (NPSH), nitric oxide (NO), and reactive oxygen species (ROS) by biochemical analysis.<br><br>RESULTS: Neither DSF nor NAC alleviated LPS-induced memory disorders estimated by the NOR test and OL test. The studied compounds also did not affect significantly the levels of BDNF, ROS, NO, H2S, and sulfane sulfur in the cerebral cortex. However, we observed an increase in sulfate concentration in brain tissues after LPS treatment, while DSF and NAC caused an additional increase in sulfate concentration. On the other hand, our study showed that the administration of DSF or NAC together with LPS significantly enhanced the cortical level of NPSH, of which glutathione is the main component.<br><br>CONCLUSIONS: Our study did not confirm the suggested potential of DSF and NAC to correct memory disorders; however, it corroborated the notion that they reduced oxidative stress induced by LPS by increasing the NPSH level. Additionally, our study showed an increase in sulfate concentration in the brain tissues after LPS treatment, which means the upregulation of sulfite and sulfate production in inflammatory conditions.},
}
@article {pmid39941974,
year = {2025},
author = {Lee, SH and Park, GS and Lee, R and Hong, S and Han, S and Lee, YM and Nah, SY and Han, SG and Oh, JW},
title = {Gintonin-Enriched Panax ginseng Extract Induces Apoptosis in Human Melanoma Cells by Causing Cell Cycle Arrest and Activating Caspases.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {3},
pages = {},
pmid = {39941974},
issn = {2304-8158},
support = {2022//Korean Ginseng Corporation/ ; },
abstract = {Gintonin, a non-saponin glycolipoprotein from Panax ginseng, acts as a lysophosphatidic acid ligand. However, its anticancer effects, especially in melanoma, remain unclear. This study investigated the anti-proliferative effects and intracellular signaling mechanisms of a gintonin-enriched fraction (GEF) from Panax ginseng in human melanoma cell lines. In vitro, GEF treatment significantly inhibited cell proliferation, reduced clonogenic potential, and delayed wound healing in melanoma cells. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining showed that GEF induced apoptosis, as evidenced by increased apoptotic cell populations and nuclear changes. GEF also caused cell cycle arrest in the G1 phase for A375 cells and the G2/M phase for A2058 cells. It triggered apoptotic signaling via activation of caspase-3, -9, poly (ADP-ribose) polymerase cleavage, and downregulation of B cell lymphoma-2 (Bcl-2). GEF treatment also raised intracellular reactive oxygen species (ROS) levels and mitochondrial stress, which were mitigated by N-acetyl cysteine (NAC), an ROS inhibitor. In vivo, GEF suppressed tumor growth in A375- and A2058-xenografted mice without toxicity. These findings suggest that GEF from Panax ginseng has potential antitumor effects in melanoma by inducing apoptosis and cell cycle arrest, presenting a promising therapeutic avenue.},
}
@article {pmid39934594,
year = {2025},
author = {Mishra, AK and Hossain, MM and Sata, TN and Pant, K and Yadav, AK and Sah, AK and Gupta, P and Ismail, M and Nayak, B and Shalimar, and Venugopal, SK},
title = {ALR inhibits HBV replication and autophagosome formation by ameliorating HBV-induced ROS production in hepatic cells.},
journal = {Virus genes},
volume = {61},
number = {2},
pages = {167-178},
pmid = {39934594},
issn = {1572-994X},
mesh = {Humans ; *Hepatitis B virus/physiology/genetics ; *Virus Replication ; *Autophagosomes/metabolism/virology ; *Reactive Oxygen Species/metabolism ; *Hepatocytes/virology/metabolism ; Autophagy ; *Oxidoreductases Acting on Sulfur Group Donors/metabolism/genetics ; *Hepatitis B/virology/metabolism/genetics ; MicroRNAs/genetics ; Hep G2 Cells ; Viral Regulatory and Accessory Proteins ; Cell Line ; Nuclear Proteins ; Trans-Activators ; },
abstract = {HBV has a small genome and thrives in the infected hepatocytes by hijacking the cellular machinery and cellular pathways. HBV induces incomplete autophagy for its replication and survival. This study showed that HBV replication induces Reactive oxygen species (ROS) production, which in turn augments the formation of autophagosomes. Augmenter of liver regeneration (ALR) is a sufhydryl oxidase and has an anti-oxidative property. We sought to determine the interplay between HBV and antioxidant protein ALR. We showed that HBV downregulated ALR expression in hepatic cells. There was increased ROS production in HBV-infected cells while ALR downregulated ROS levels and expression of NADPH oxidase NOX4. N-acetyl cysteine, a ROS scavenger, downregulated ROS level and autophagosome formation in HBV-expressing cells. ALR overexpression in HBV-expressing cells downregulated the expression of autophagy marker proteins while upregulated the expression of p-MTOR. ALR overexpression decreased the expression of HBx, HBsAg, and total HBV load. This study showed that HBx relieved ALR-mediated inhibition by upregulating the miR-181a expression in HBV-infected cells, which in turn downregulated ALR expression.},
}
@article {pmid39933948,
year = {2025},
author = {Kwon, MJ and Raut, PK and Jang, JH and Chun, KS},
title = {Isoliquiritigenin Induces Apoptosis via ROS-Mediated Inhibition of p38/mTOR/STAT3 Pathway in Human Melanoma Cells.},
journal = {Biomolecules &amp; therapeutics},
volume = {33},
number = {2},
pages = {378-387},
pmid = {39933948},
issn = {1976-9148},
abstract = {Isoliquiritigenin (ISL), a phenolic compound derived from licorice, exhibits various biological activities, including anti-inflammatory, anti-viral, anti-tumor, and antioxidant effects. However, the molecular mechanisms underlying its anti-cancer effects are not well understood in SK-MEL-28 melanoma cells. Melanoma, a highly aggressive and treatment-resistant cancer, remains a significant health challenge. This study investigates the anti-cancer effects of ISL, focusing on identifying reactive oxygen species (ROS)-mediated apoptosis mechanisms on SK-MEL-28 melanoma cells. Our results show that ISL treatment induces apoptosis in SK-MEL-28 cells, as evidenced by the cleavage of caspase-9, -7, -3, and PARP. ISL increased Bax expression, decreased Bcl-2 expression, and promoted cytochrome C release into the cytosol. ISL also reduced the expression of cell cycle markers, including cyclin D1, D3, and survivin. Notably, ISL treatment markedly increased intracellular ROS levels and pretreatment with N-acetyl cysteine, a ROS scavenger, abrogated the ISL-induced inhibition of the p38/mTOR/STAT3 pathway and prevented apoptosis. Moreover, ISL significantly diminished the constitutive phosphorylation of mTOR and STAT3 in SK-MEL-28 cells by blocking the phosphorylation of p38 MAPK, an upstream kinase of mTOR. Pharmacological inhibition of mTOR attenuated the STAT3 signaling, indicating that mTOR acts as an upstream kinase of STAT3 in these cells. Collectively, these findings demonstrate that ISL inhibits SK-MEL-28 cell growth by downregulating cell survival proteins and inducing apoptosis through ROS generation.},
}
@article {pmid39933827,
year = {2025},
author = {Lee, SO and Joo, SH and Cho, SS and Yoon, G and Choi, YH and Park, JW and Weon, KY and Shim, JH},
title = {Licochalcone D Exerts Antitumor Activity in Human Colorectal Cancer Cells by Inducing ROS Generation and Phosphorylating JNK and p38 MAPK.},
journal = {Biomolecules &amp; therapeutics},
volume = {33},
number = {2},
pages = {344-354},
pmid = {39933827},
issn = {1976-9148},
abstract = {Anticancer activities of Licochalcone D (LCD) in human colorectal cancer (CRC) cells HCT116 and oxaliplatin-resistant HCT116 (HCT116-OxR) were determined. Cell viability assay and soft agar assay were used to analyze antiproliferative activity of LCD. Flow cytometry was performed to determine effects of LCD on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. Western blot analysis was used to monitor levels of proteins involved in cell cycle and apoptosis signaling pathways. LCD suppressed the growth and anchorageindependent colony formation of both HCT116 and HCT116-OxR cells. Cell cycle analysis by flow cytometry indicated that LCD induced cell cycle arrest and increased cells in sub-G1 phase. In parallel with the antiproliferative effect of LCD, LCD up-regulated levels of p21 and p27 while downregulating cyclin B1 and cdc2. In addition, phosphorylation levels of JNK and p38 mitogen-activated protein kinase (MAPK) were increased by LCD. Inhibition of these kinases somehow prevented the antiproliferative effect of LCD. Moreover, LCD increased ROS and deregulated mitochondrial membrane potential, leading to the activation of multiple caspases. An ROS scavenger N-acetyl-cysteine (NAC) or pan-caspase inhibitor Z-VAD-FMK prevented the antiproliferative effect of LCD, supporting that ROS generation and caspase activation mediated LCD-induced apoptosis in CRC cells. In conclusion, LCD exerted antitumor activity in CRC cells by inducing ROS generation and phosphorylation of JNK and p38 MAPK. These results support that LCD could be further developed as a chemotherapeutic agent for treating CRC.},
}
@article {pmid39923905,
year = {2025},
author = {Kim, YH and Kim, JB and Bae, JE and Park, NY and Kim, SH and Park, D and So, JH and Lee, JM and Jeong, K and Choi, DK and Jo, DS and Cho, DH},
title = {ZLDI-8 facilitates pexophagy by ROS-mediated activation of TFEB and ATM in HeLa cells.},
journal = {Bioorganic &amp; medicinal chemistry letters},
volume = {120},
number = {},
pages = {130130},
doi = {10.1016/j.bmcl.2025.130130},
pmid = {39923905},
issn = {1464-3405},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; HeLa Cells ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; *Ataxia Telangiectasia Mutated Proteins/metabolism/antagonists &amp; inhibitors ; Peroxisomes/metabolism/drug effects ; Autophagy/drug effects ; Molecular Structure ; Dose-Response Relationship, Drug ; Structure-Activity Relationship ; },
abstract = {Autophagy-mediated organelle quality control is vital for cellular homeostasis. However, the mechanisms underlying selective autophagy of peroxisomes, known as pexophagy, are less well understood than those of other organelles, such as mitochondria. In this study, we screened a phosphatase inhibitor library using a cell-based system and identified several potent pexophagy inducers, including ZLDI-8, a known inhibitor of lymphoid-specific tyrosine phosphatase. Notably, treatment with ZLDI-8 selectively induces the loss of peroxisomes without affecting other organelles, such as mitochondria, the endoplasmic reticulum, or the Golgi apparatus. The peroxisome loss induced by ZLDI-8 was significantly blocked in ATG5-knockout HeLa cells, confirming its dependence on autophagy. We further found that ZLDI-8 treatment increases both cellular and peroxisomal reactive oxygen species (ROS), which were effectively scavenged by N-acetylcysteine (NAC). The increase in peroxisomal ROS leads to the activation of ATM kinase and the dephosphorylation of TFEB. Moreover, ROS scavenging prevents all of these processes. Taken together, these findings demonstrate that ZLDI-8 induces pexophagy through a mechanism involving peroxisomal ROS-mediated activation of TFEB and ATM. This study provides valuable insights into the molecular mechanisms regulating selective peroxisome degradation and potential therapeutic strategies for targeting pexophagy.},
}
@article {pmid39921193,
year = {2025},
author = {Lin, KA and Su, CC and Lee, KI and Liu, SH and Fang, KM and Tang, CH and Lia, WC and Kuo, CY and Chang, KC and Huang, CF and Chen, YW and Yang, CY},
title = {The herbicide 2,4-dichlorophenoxyacetic acid induces pancreatic β-cell death via oxidative stress-activated AMPKα signal downstream-regulated apoptotic pathway.},
journal = {Toxicology letters},
volume = {405},
number = {},
pages = {16-29},
doi = {10.1016/j.toxlet.2025.01.009},
pmid = {39921193},
issn = {1879-3169},
mesh = {*2,4-Dichlorophenoxyacetic Acid/toxicity ; *Herbicides/toxicity ; *Apoptosis/drug effects ; *Insulin-Secreting Cells/drug effects/pathology/enzymology/metabolism ; *Oxidative Stress/drug effects ; Animals ; *AMP-Activated Protein Kinases/metabolism/genetics ; Signal Transduction/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Cell Line ; Membrane Potential, Mitochondrial/drug effects ; Cell Survival/drug effects ; Insulin/metabolism ; Mitochondria/drug effects ; Insulin Secretion ; },
abstract = {2,4-Dichlorophenoxyacetic acid (2,4-D) is one of commonly and widely used organic herbicides in agriculture. It has been reported that 2,4-D can induce adverse effects in mammalian cells. Epidemiological and animal studies have indicated that exposure to 2,4-D is associated with poorer glycemic control and impaired pancreatic β-cell function. However, limited information is available on 2,4-D-induced toxicological effects in β-cells, with the underlying toxicological mechanisms remains unclear. Herein, our results showed that 2,4-D exposure (30-500 μg/mL) significantly reduced cell viability, induced mitochondria dysfunction (including the mitochondrial membrane potential (MMP) loss, the increase in cytosolic cytochrome c release, and the change in Bcl-2 and Bax protein expression), and triggered apoptotic events (including the increased population of apoptotic cells, caspase-3 activity, and caspase-3/-7 and PAPR activation) in RIN-m5F β-cells, accompanied with insulin secretion inhibition. Exposure of cells to 2,4-D could also evoke JNK, ERK1/2, p38, and AMP-activated protein kinase (AMPK)α activation as well as reactive oxygen species (ROS) generation. Pretreatment of cells with compound C (an AMPK inhibitor) and the antioxidantN-acetylcysteine (NAC), but not that SP600125/PD98059/SB203580 (the inhibitors of JNK/ERK/p38, respectively), obviously attenuated the 2,4-D-triggered AMPKα phosphorylation, MMP loss, apoptotic events, and insulin secretion dysfunction,as similar effects with the transfection with AMPKα1-specific siRNA. Of note, buffering the ROS production with NAC obviously prevented the 2,4-D-induced ROS generation as well as AMPKα activation, but the either compound C and AMPKα1-specific siRNA transfection could not effectively reduce 2,4-D-induced ROS generation. Collectively, these findings indicate that the induction of oxidative stress-activated AMPKα signaling is a crucial mechanism underlying 2,4-D-triggered mitochondria-dependent apoptosis, ultimately leading to β-cell death.},
}
@article {pmid39920835,
year = {2025},
author = {Roe, T and Talbot, T and Terrington, I and Johal, J and Kemp, I and Saeed, K and Webb, E and Cusack, R and Grocott, MPW and Dushianthan, A},
title = {Physiology and pathophysiology of mucus and mucolytic use in critically ill patients.},
journal = {Critical care (London, England)},
volume = {29},
number = {1},
pages = {68},
pmid = {39920835},
issn = {1466-609X},
mesh = {Humans ; *Mucus/physiology/drug effects/metabolism ; *Expectorants/therapeutic use/pharmacology ; *Critical Illness/therapy ; *Mucociliary Clearance/physiology/drug effects ; },
abstract = {Airway mucus is a highly specialised secretory fluid which functions as a physical and immunological barrier to pathogens whilst lubricating the airways and humifying atmospheric air. Dysfunction is common during critical illness and is characterised by changes in production rate, chemical composition, physical properties, and inflammatory phenotype. Mucociliary clearance, which is determined in part by mucus characteristics and in part by ciliary function, is also dysfunctional in critical illness via disease related and iatrogenic mechanisms. The consequences of mucus dysfunction are potentially devastating, contributing to prolonged ventilator dependency, increased risk of secondary pneumonia, and worsened lung injury. Mucolytic therapies are designed to decrease viscosity, improve expectoration/suctioning, and thereby promote mucus removal. Mucolytics, including hypertonic saline, dornase alfa/rhDNase, nebulised heparin, carbocisteine/N-Acetyl cysteine, are commonly used in critically ill patients. This review summarises the physiology and pathophysiology of mucus and the existing evidence for the use of mucolytics in critically ill patients and speculates on journey to individualised mucolytic therapy.},
}
@article {pmid39917036,
year = {2025},
author = {Henaidy, MF and Ghanem, M and Shehata, SF and Shouair, AM and Mabrouk, RR},
title = {Therapeutic effects of NAC and CoQ10 on aluminium phosphide poisoning as an adjuvant therapy: A Pilot study.},
journal = {Toxicology reports},
volume = {14},
number = {},
pages = {101907},
pmid = {39917036},
issn = {2214-7500},
abstract = {UNLABELLED: In aluminium phosphide (AlP) poisoning, death is mainly due to acute heart failure. There is some evidence showing that N-acetylcysteine (NAC) and coenzyme Q10 have antioxidant and cardioprotective effects. This study investigated a new approach for treating acute AlP poisoning by using NAC and Co-Q10 as adjuvant therapy.<br><br>SUBJECTS AND METHODS: The study design was a retrospective-prospective study. It was conducted in the poisoning unit of Kafer Eldwar General Hospital. Sixty patients with acute aluminium phosphide poisoning were included. The patients were divided into two groups. The first group (standard protocol) considered the control group received the standard supportive care, and their data were collected from the medical records. The second group (new protocol) in addition to the standard supportive care received the NAC and CoQ10 regimen, and all data were collected in a specially designed sheet.<br><br>RESULTS: The results showed that the highest percentage of patients in both groups were aged 18-25, followed by those under 18, and females outnumbered the males. The systolic (SBP) and diastolic (DBP) blood pressure showed significant improvement in the new protocol group. A significant statistical difference was found between the two groups regarding mechanical ventilation (p&#x202f;=&#x202f;0.015), where mechanical ventilation was used in 20&#x202f;% of patients in the new protocol group and 50&#x202f;% in the standard group. Regarding the outcome of patients, the survival rate reached 73.3&#x202f;% upon using the new protocol, compared to 50&#x202f;% who received the standard protocol.<br><br>CONCLUSION: The data imply that further investigation in using the NAC and CoQ10 regimen is warranted. It gave an improvement of the survival rate and decrease the need for mechanical ventilation in AlP.},
}
@article {pmid39912999,
year = {2025},
author = {Li, M and Hu, Y and Wu, X and Tong, J and Tao, J and Tang, A and Ji, Y and Yao, Y and Tao, F and Liang, C},
title = {Placental Ferroptosis May Be Involved in Prenatal Arsenic Exposure Induced Cognitive Impairment in Offspring.},
journal = {Biological trace element research},
volume = {203},
number = {9},
pages = {4543-4560},
doi = {10.1007/s12011-025-04525-0},
pmid = {39912999},
issn = {1559-0720},
support = {U22A20361//the National Natural Science Foundation of China/ ; YJS20230151//Postgraduate Innovation Research and Practice Program of Anhui Medical University/ ; },
mesh = {Pregnancy ; *Ferroptosis/drug effects ; Female ; *Placenta/metabolism/drug effects/pathology ; Humans ; Animals ; Mice ; *Prenatal Exposure Delayed Effects/chemically induced/metabolism ; *Cognitive Dysfunction/chemically induced/metabolism ; *Arsenic/toxicity/blood ; Mice, Inbred C57BL ; Male ; Adult ; },
abstract = {The association between prenatal arsenic (As) exposure and offspring's cognition is still unclear, and the underlying etiology has also not been elucidated. Based on the Ma'anshan Birth Cohort (MABC) study in China, 1814 mother-child pairs were included in this study, and the association of As levels in cord serum with preschoolers' intelligence scores was explored. To validate the results from population study, in vivo models were adopted to observe the association between prenatal As exposure and spatial learning and memory abilities of mice offsprings. The As-exposure induced ferroptosis in the placenta of human beings as well as C57BL/6 J mice and HTR-8/SVneo cells was explored in order to clarify the potential cause of impairment of offspring's cognition related to As exposure, respectively. In the population study, we observed a significant inverse association between natural logarithm transformed (ln) As levels and preschoolers' intelligence scores, especially for the fluid reasoning index (FRI) [(β (95%CI): - 1.07 (- 1.98, - 0.16)] and working memory index (WMI) [β (95%CI): - 1.51 (- 2.76, - 0.25)]. Meanwhile, the data from in vivo models revealed that the learning and memory abilities of offspring mice decreased after prenatal As exposure. The occurrence of ferroptosis-like characteristics in the placenta and HTR-8/SVneo cells after As exposure was observed, accompanying with evident oxidative stress, iron accumulation, mitochondrial damage, and decreased protein levels of GPX4, xCT, and FTH1 (or FPN1). Notably, the ferroptosis-like alterations induced by NaAsO2 can be effectively alleviated by N-acetylcysteine (NAC) and ferrostatin-1 (Fer-1) treatment in HTR-8/SVneo cells, respectively. In conclusion, prenatal As exposure associates with impairment of offspring's cognition, and placental ferroptosis may be involved in the association. Further studies are needed to confirm the findings.},
}
@article {pmid39912676,
year = {2025},
author = {Sui, B and Li, X and Li, N and Tao, Y and Wang, L and Xu, Y and Hou, Y and Hu, B and Tan, D},
title = {Synergistic action of mucoactive drugs and phages against Pseudomonas aeruginosa and Klebsiella pneumoniae.},
journal = {Microbiology spectrum},
volume = {13},
number = {3},
pages = {e0160124},
pmid = {39912676},
issn = {2165-0497},
support = {82072325//MOST | National Natural Science Foundation of China (NSFC)/ ; 42376099//MOST | National Natural Science Foundation of China (NSFC)/ ; 23YF1443700//Shanghai Sailing Program/ ; 20224Y0287//Shanghai Municiapl Health Commission/ ; DUT23YG214//Fundamental Research Funds for the Central Universities/ ; },
mesh = {*Pseudomonas aeruginosa/drug effects/virology ; *Klebsiella pneumoniae/drug effects/virology ; *Acetylcysteine/pharmacology ; *Expectorants/pharmacology ; Phage Therapy/methods ; *Ambroxol/pharmacology ; *Bacteriophages/physiology/drug effects ; Humans ; Pseudomonas Infections/therapy/microbiology ; Anti-Bacterial Agents/pharmacology ; Klebsiella Infections/therapy/microbiology ; Drug Synergism ; },
abstract = {N-acetylcysteine (NAC) and ambroxol hydrochloride (AMB) are commonly prescribed alongside antibiotics to alleviate sputum retention in lower respiratory tract infections, which are often caused by bacterial pathogens. With the rising threat of antibiotic resistance, phage therapy has emerged as a promising alternative alongside. However, no studies have explored the potential interactions between phages and these mucoactive agents despite their frequent concurrent use during phage therapy. Therefore, investigating the potential synergy and its subsequent impact on phage infection dynamics could enhance clinical strategies for treating bacterial infections with phages. Our study utilized Pseudomonas aeruginosa strain ZS-PA-35 and Klebsiella pneumoniae strain Kp36, alongside their respective phages, to investigate their interactions in the presence of NAC or AMB. Our findings indicate that, under specific conditions, these mucoactive agents can function as adjuvants to lytic phages, enhancing bacterial susceptibility to phage infection and facilitating subsequent phage proliferation. Our study revealed that these synergistic interactions are strongly influenced by the physiological characteristics of the phages, the surrounding microenvironments, and the physiology of host tissues, as varying outcomes of phage-host interactions were observed among different phages and across distinct media. Taken together, our results emphasize the complexity of interactions between phages and NAC or AMB, underscoring the need for caution when using combination treatments.IMPORTANCEN-acetylcysteine (NAC) and ambroxol hydrochloride (AMB) are used in medical treatment of patients with acute and chronic bronchitis. Often, the choice of NAC or AMB is empirically determined by physicians. However, the potential impact of combining NAC or AMB with phage therapy remains unclear. To address this gap, a comprehensive understanding of their interplay is crucial to determine any potential synergistic effects. This study aims to elucidate how NAC or AMB influence phages targeting different receptors, thereby affecting their antibacterial activity against Pseudomonas aeruginosa and Klebsiella pneumoniae. Our results suggest that, under certain conditions, NAC or AMB provides an adjuvant effect by rendering the cells more susceptible to phage infection. These results contribute to advancing our understanding of the clinical combination of mucoactive agents and phage therapy, offering insights for optimizing treatment efficacy.},
}
@article {pmid39905500,
year = {2025},
author = {Tawalbeh, M and Ibrahim, RM and Al-Saraireh, T and Khreesha, L and Rawashdeh, BA},
title = {Intratympanic N-acetylcysteine in the prevention of cisplatin-induced ototoxicity: a systematic review and meta-analysis of randomized controlled trials.},
journal = {BMC pharmacology &amp; toxicology},
volume = {26},
number = {1},
pages = {26},
pmid = {39905500},
issn = {2050-6511},
mesh = {*Acetylcysteine/administration &amp; dosage/therapeutic use ; *Cisplatin/adverse effects ; Humans ; *Ototoxicity/prevention &amp; control/etiology ; Randomized Controlled Trials as Topic ; *Antineoplastic Agents/adverse effects ; Hearing Loss/prevention &amp; control/chemically induced ; Injection, Intratympanic ; },
abstract = {OBJECTIVE: To evaluate the efficacy of the otoprotective transtympanic application of N-acetylcysteine in preventing chemotherapy-induced ototoxicity in patients subjected to platinum-based chemotherapy.<br><br>DATA SOURCES: PubMed, Scopus, Web of Science, Cochrane Central, and ClinicalTrials.gov were searched for the following concepts: (("Acetylcysteine" [Mesh]) AND ("Ototoxicity" [Mesh]) AND ("Cisplatin" [Objective: To evaluate the efficacy of otoprotective transtympanic application of N-acetylcysteine in the prevention of chemotherapy-induced ototoxicity in patients subjected to platinum-based chemotherapy. [Mesh]).<br><br>STUDY SELECTION: Inclusion: randomized controlled trials, Exclusion: (1) case reports or case series; (2) thesis; (3) review articles; (4) conference abstracts; (5) animal studies; (6) non-english studies; (7) studies whose population was other than patients on platinum-based chemotherapy.<br><br>DATA EXTRACTION: changes in hearing thresholds measured by pure tone tympanometry, covering high and low frequencies: 250, 500, 1000, 2000, 4000, and 8000&#xa0;Hz. We used RevMan (Review Manager) version 5.3 to conduct the meta-analysis and GRADE to assess the quality of the evidence.<br><br>DATA SYNTHESIS: The literature search yielded 277 unique articles. After reviewing six full-text articles, three RCTs provided data available for meta-analysis. A total of 88 cisplatin-based chemotherapy candidates were included for final analysis. Hearing thresholds showed a significant threshold difference between the ear treated with N-acetylcysteine and the control ear (ear not treated with N-acetylcysteine), especially at high frequencies as high as 8000&#xa0;Hz (pooled effect size -&#x2009;10.67, 95% CI [-12.33, -9.02], P&#x2009;<&#x2009;0.00001). The data favored the Nac group in all frequencies as well, at 4000&#xa0;Hz (pooled effect size -&#x2009;2.13, 95% CI [-3.49, -0.77], P&#x2009;=&#x2009;0.002), at 2000&#xa0;Hz (pooled effect size -&#x2009;1.38, 95% CI [-2.69, -0.06], P&#x2009;=&#x2009;0.04), at 1000&#xa0;Hz (pooled effect size -&#x2009;1.58, 95% CI [-2.63, -0.53], P&#x2009;=&#x2009;0.003), at 500&#xa0;Hz (pooled effect size -&#x2009;1.58, 95% CI [-2.62, -0.54], P&#x2009;=&#x2009;0.003), and at the low frequency of 250 after solving the heterogeneity (pooled effect size -&#x2009;0.96, 95% CI [-2.88, 0.95], P&#x2009;=&#x2009;0.32).<br><br>CONCLUSIONS: Current data justifies the transtympanic administration of N-acetylcysteine for otoprotection in chemotherapy patients, minimizing the enduring consequences of cisplatin-induced ototoxicity and auditory impairment. Given the results' emphasis on the Sarafraz et al. (2018) study, more randomized controlled trials are necessary with an expanded sample size and standardization of N-acetylcysteine concentration, study population, and assessed outcomes.},
}
@article {pmid39903949,
year = {2025},
author = {Sun, M and Lu, Z and Chen, WM and Lv, S and Fu, N and Yang, Y and Wang, Y and Miao, M and Wu, SY and Zhang, J},
title = {N-acetylcysteine therapy reduces major adverse cardiovascular events in patients with type 2 diabetes mellitus.},
journal = {Atherosclerosis},
volume = {402},
number = {},
pages = {119117},
doi = {10.1016/j.atherosclerosis.2025.119117},
pmid = {39903949},
issn = {1879-1484},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Diabetes Mellitus, Type 2/drug therapy/complications/epidemiology/diagnosis ; Male ; Female ; Middle Aged ; *Cardiovascular Diseases/prevention &amp; control/epidemiology/diagnosis ; Taiwan/epidemiology ; Aged ; Incidence ; Databases, Factual ; Risk Assessment ; Time Factors ; Treatment Outcome ; Adult ; },
abstract = {BACKGROUND: Effective preventive strategies for major adverse cardiovascular events (MACE) in T2DM patients are limited. Recent studies have explored the cardiovascular benefits of N-Acetylcysteine (NAC), an antioxidant with endothelial protective properties. This study investigates the long-term effects of NAC on MACE risk in T2DM patients, focusing on its potential as an adjunctive therapy.<br><br>METHODS: This population-based cohort study used data from Taiwan's National Health Insurance Research Database (NHIRD) and included 46,718 T2DM patients diagnosed between 2008 and 2018, with follow-up until December 31, 2021. Propensity score matching (PSM) ensured balanced comparisons between NAC users and non-users. Cox regression and time-dependent Cox hazards models assessed MACE risk, adjusting for multiple covariates.<br><br>RESULTS: In the matched cohort of 23,359 NAC users and 23,359 non-users, NAC users had a significantly lower incidence of MACE (41.74&#xa0;% vs. 46.87&#xa0;%, P&#xa0;<&#xa0;.0001). Adjusted Hazard Ratios (aHRs) indicated a consistent protective effect of NAC against overall MACE (aHR: 0.84; 95&#xa0;% CI: 0.81-0.86, P&#xa0;<&#xa0;.0001). Higher cumulative defined daily doses (cDDD) of NAC correlated with reduced MACE risk, with the highest quartile (Q4) showing an aHR of 0.61 (95&#xa0;% CI: 0.58-0.64, P&#xa0;<&#xa0;.0001).<br><br>CONCLUSION: This study underscores the significant reduction in MACE risk among T2DM patients with long-term NAC therapy. Notably, the findings emphasize NAC's dose-dependent effectiveness in diminishing MACE incidence, indicating its potential as a valuable adjunctive therapy for managing cardiovascular risk in T2DM patients.},
}
@article {pmid39902830,
year = {2025},
author = {Chamberlain, SR and Ioannidis, K and Grant, JE},
title = {Trait Impulsivity Predicts Treatment Response in Gambling Disorder.},
journal = {Clinical neuropharmacology},
volume = {48},
number = {2},
pages = {27-28},
doi = {10.1097/WNF.0000000000000622},
pmid = {39902830},
issn = {1537-162X},
mesh = {Humans ; *Gambling/drug therapy/psychology ; *Impulsive Behavior/drug effects/physiology ; Treatment Outcome ; Male ; *Naltrexone/therapeutic use ; Female ; Adult ; Middle Aged ; *Acetylcysteine/therapeutic use ; Narcotic Antagonists/therapeutic use ; },
abstract = {OBJECTIVES: Impulsivity is thought to be a core feature of gambling disorder, yet little is known as to whether trait impulsivity predicts treatment response.<br><br>METHODS: Data were pooled from 2 previous randomized controlled pharmacological trials using naltrexone and N-acetyl cysteine.<br><br>RESULTS: Trait impulsivity statistically explained variation in medication treatment response (P = 0.0260, R2 = 0.26). Higher baseline motor impulsiveness was associated with greater treatment response (P = 0.009).<br><br>CONCLUSIONS: Measures of impulsivity may thus be important to include in future large-scale datasets, in trial settings but also routine clinical gambling clinic practice, toward building predictive algorithms that may ultimately help to inform optimal treatment choices and improve outcomes.},
}
@article {pmid39901768,
year = {2025},
author = {Lu, YT and Chen, TY and Lin, HH and Chen, YW and Lin, YX and Le, DC and Huang, YH and Wang, AH and Lee, CC and Ling, TY},
title = {Small Extracellular Vesicles Engineered Using Click Chemistry to Express Chimeric Antigen Receptors Show Enhanced Efficacy in Acute Liver Failure.},
journal = {Journal of extracellular vesicles},
volume = {14},
number = {2},
pages = {e70044},
pmid = {39901768},
issn = {2001-3078},
mesh = {*Liver Failure, Acute/therapy/metabolism/chemically induced ; *Extracellular Vesicles/metabolism ; Animals ; Humans ; *Click Chemistry/methods ; *Receptors, Chimeric Antigen/metabolism/genetics ; Mesenchymal Stem Cells/metabolism ; Mice ; Acetaminophen ; Male ; },
abstract = {Acetaminophen (APAP) overdose can cause severe liver injury and life-threatening conditions that may lead to multiple organ failure without proper treatment. N-acetylcysteine (NAC) is the accepted and prescribed treatment for detoxification in cases of APAP overdose. Nonetheless, in acute liver failure (ALF), particularly when the ingestion is substantial, NAC may not fully restore liver function. NAC administration in ALF has limitations and potential adverse effects, including nausea, vomiting, diarrhoea, flatus, gastroesophageal reflux, and anaphylactoid reactions. Mesenchymal stromal cell (MSC)-based therapies using paracrine activity show promise for treating ALF, with preclinical studies demonstrating improvement. Recently, MSC-derived extracellular vesicles (EVs) have emerged as a new therapeutic option for liver injury. MSC-derived EVs can contain various therapeutic cargos depending on the cell of origin, participate in physiological processes, and respond to abnormalities. However, most therapeutic EVs lack a distinct orientation upon entering the body, resulting in a lack of targeting specificity. Therefore, enhancing the precision of natural EV delivery systems is urgently needed. Thus, we developed an advanced targeting technique to deliver modified EVs within the body. Our strategy aims to employ bioorthogonal click chemistry to attach a targeting molecule to the surface of small extracellular vesicles (sEVs), creating exogenous chimeric antigen receptor-modified sEVs (CAR-sEVs) for the treatment. First, we engineered azido-modified sEVs (N3-sEVs) through metabolic glycoengineering by treating MSCs with the azide-containing monosaccharide N-azidoacetyl-mannosamine (Ac4ManNAz). Next, we conjugated N3-sEVs with a dibenzocyclooctyne (DBCO)-tagged single-chain variable fragment (DBCO-scFv) that targets the asialoglycoprotein receptor (ASGR1), thus producing CAR-sEVs for precise liver targeting. The efficacy of CAR-sEV therapy in ALF models by targeting ASGR1 was validated. MSC-derived CAR-sEVs reduced serum liver enzymes, mitigated liver damage, and promoted hepatocyte proliferation in APAP-induced injury. Overall, CAR-sEVs exhibited enhanced hepatocyte specificity and efficacy in ameliorating liver injury, highlighting the significant advancements achievable with cell-free targeted therapy.},
}
@article {pmid39900950,
year = {2025},
author = {El-Abassy, OM and Fawzy, MG and Kamel, EB},
title = {Two chromatographic methods for analyzing paracetamol in spiked human plasma with its toxic metabolite, N-acetyl parabenzoquinone imine and its antidote, N-acetyl-L-cysteine.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {4119},
pmid = {39900950},
issn = {2045-2322},
mesh = {*Acetaminophen/blood ; Humans ; *Acetylcysteine/blood ; *Benzoquinones/blood ; Chromatography, High Pressure Liquid/methods ; *Imines/blood ; *Antidotes ; Chromatography, Thin Layer/methods ; Reproducibility of Results ; },
abstract = {Acetaminophen, also known as paracetamol (APAP), is a highly utilized pharmaceutical agent on a global scale, particularly in the field of pediatrics. Regrettably, an overdose of APAP, resulting from the predominant oxidation, has the potential to trigger acute liver injury. The study's goal was to find an easy, accurate, and selective way to measure APAP, N-acetyl para benzoquinone imine (NAPQI) (an APAP metabolite that is harmful), and N-acetyl-L-cysteine (NAC) (an antidote). Two different chromatographic methods were used. The HPTLC method, which used silica gel 60 F254 as a stationary phase and a developing liquid made up of methanol, ethyl acetate, and glacial acetic acid (8:2:0.2, v/v/v) and a UV detection at 254 nm. The HPLC method was developed using a mobile phase consisting of water, methanol, and formic acid in a proportion of (70:30:0.15, v/v/v). The stationary phase used in the approach was a C18 column. Analytes quantification was established utilizing a UV detector operating at a wavelength of 254 nm. The present methods make it possible to measure the amount of APAP in plasma samples. When it comes to pharmacokinetics or medication levels in children's plasma, for example, this may be also very helpful. The current methods can quantify NAPQI, which is helpful in figuring out drug concentrations in individuals with APAP intoxication diagnoses. Additionally, the current approaches can estimate NAC as an antidote; as a result, this study is a complete study because it can analyse drug, toxic metabolite, and antidote in one analytical run. Using the innovative blue applicability grade index software, which measures the practicality of procedures, both methodologies were compared with a reported methods. Additionally, the achievement of the eco-friendliness profile of the designed procedures was assessed. Both techniques passed the ICH validation tests.},
}
@article {pmid39898945,
year = {2025},
author = {Supervía, A and Gispert, M&#xaa;&#xc0; and Puiguriguer, J and Álvarez Zabala, PB and Martínez Sánchez, L and Olmos, S and Calderón, B and de Paz Picornell, R and Nogué, S and Córdoba, F},
title = {Paracetamol poisoning: a prospective comparison of 2 protocols for N-acetylcysteine treatment.},
journal = {Emergencias : revista de la Sociedad Espanola de Medicina de Emergencias},
volume = {37},
number = {1},
pages = {39-43},
doi = {10.55633/s3me/100.2024},
pmid = {39898945},
issn = {2386-5857},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/therapeutic use/adverse effects ; *Acetaminophen/poisoning ; Female ; Prospective Studies ; Male ; Adult ; *Analgesics, Non-Narcotic/poisoning ; Length of Stay/statistics &amp; numerical data ; *Antidotes/administration &amp; dosage/therapeutic use/adverse effects ; Emergency Service, Hospital/statistics &amp; numerical data ; Young Adult ; Clinical Protocols ; Middle Aged ; Adolescent ; Treatment Outcome ; *Drug Overdose/drug therapy ; },
abstract = {OBJECTIVE: Paracetamol poisoning can be serious and require treatment with N-acetylcysteine (NAC). A dose of 300 mg/kg is usually given in 3 fractions over 21 hours. An alternative regimen, the Scottish and Newcastle Acetylcysteine Protocol (SNAP), specifies the same total dose given in 2 intravenous injections over 12 hours. This study aimed to compare the 2 regimens in terms of effectiveness, adverse events, and lengths of emergency department (ED) and hospital stays.<br><br>METHODS: Prospective multicenter study to compare outcomes associated with the traditional NAC regimen vs SNAP. We enrolled all patients with paracetamol poisoning requiring NAC treatment in the participating hospital EDs from 2021 through 2023. Data related to referrals, poisoning episodes, and discharge destinations were collected. Patients were studied in 2 groups according to the protocol assigned in the EDs.<br><br>RESULTS: A total of 165 patients were treated (SNAP, 103; traditional protocol, 62). The mean (SD) age was 28.1 (19.7) years, and most were female (70.5%). No differences in peak transaminase levels were observed. SNAP-treated patients had significantly fewer adverse effects as well as shorter stays both in the ED (17.8 [15.2] hours vs 25.9 [17.1] hours; P = .001) and on the ward (2.6 [2.3] days vs 4.4 [3.6] days; P = .019).<br><br>CONCLUSIONS: Fewer adverse events occurred with the SNAP approach. The 2 protocols were similarly effective. The SNAP-treated patients spent less time in the ED, and those who were admitted to hospital had shorter stays.},
}
@article {pmid39894191,
year = {2025},
author = {Amini, H and Shirpoor, A and Naderi, R},
title = {Nandrolone decanoate induces heart injury via oxidative damage and mitochondrial apoptotic pathway by regulation of TLR4/NF-κB/NLRP3 axis in male rats: The rescue effect of N-acetylcysteine.},
journal = {Steroids},
volume = {214},
number = {},
pages = {109563},
doi = {10.1016/j.steroids.2025.109563},
pmid = {39894191},
issn = {1878-5867},
mesh = {Animals ; Male ; *Toll-Like Receptor 4/metabolism ; *NF-kappa B/metabolism ; *Apoptosis/drug effects ; *Acetylcysteine/pharmacology ; *Rats, Wistar ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; *Oxidative Stress/drug effects ; *Signal Transduction/drug effects ; *Nandrolone/pharmacology/analogs &amp; derivatives ; Mitochondria/drug effects/metabolism ; },
abstract = {Myocardial apoptosis is a leading cause of damage in cardiac tissues of nandrolone (ND) treatment. However, its molecular mechanism is not fully understood. This study aims to investigate the effect of ND with or without N -acetylcysteine (NAC) treatment on oxidative damage and TLR4/NF-κB /NLRP3 signaling pathway in the heart of male rats. Eighteen male Wistar rats with a weight range of 220 ± 10 g were selected. They were divided into three groups (n = 6): control (C) group, ND group, NAC + ND group. After six weeks of treatment, the TUNEL staining indicated that ND increased the number of apoptotic cells in the hearts of male rats. The molecular analysis demonstrated that ND exposure resulted in increased protein levels of cytochrome c, c-Caspase-3/p-Caspase-3 ratio, p53, TLR4, NF-κB, NLRP3, and 8-OHdG with a concomitant up-regulation of LDH and CK-MB enzymes activity in the heart tissue compared to the C group. Our findings suggested that ND can cause damage to heart tissue via induction of DNA damage, apoptosis, and probably TLR4/NF-κB/NLRP3 signaling pathway plays a crucial role in this process. It also demonstrates that these negative effects of ND can be reduced by using NAC treatment as an antioxidant and anti-inflammatory agent.},
}
@article {pmid39893616,
year = {2025},
author = {Abu Hasna, A and Khoury, RD and Mendes, GV and Carvalho, CAT and Bresciani, E and Valera, MC},
title = {N-acetylcysteine antimicrobial action against endodontic pathogens-systematic review and meta-analysis.},
journal = {Odontology},
volume = {113},
number = {4},
pages = {1354-1364},
pmid = {39893616},
issn = {1618-1255},
mesh = {*Acetylcysteine/pharmacology ; Humans ; *Root Canal Irrigants/pharmacology ; Chlorhexidine/pharmacology ; Sodium Hypochlorite/pharmacology ; Calcium Hydroxide/pharmacology ; *Anti-Infective Agents/pharmacology ; },
abstract = {Effective root canal disinfection is crucial for the success of endodontic treatment. N-acetylcysteine (NAC), known for its antimicrobial properties, has recently been investigated as a potential endodontic irrigant or intracanal medication. This systematic review aims to assess the antimicrobial efficacy of NAC in comparison to sodium hypochlorite, chlorhexidine, and calcium hydroxide against endodontic pathogens. A comprehensive search was conducted in PubMed, Scopus, Web of Science, Cochrane Library, and LILACS databases up to April 2024, without language or date restrictions. The PICO strategy for this review were as follows: population-teeth requiring endodontic treatment; intervention-NAC used as an endodontic irrigant or intracanal medication; comparison-sodium hypochlorite, chlorhexidine, and calcium hydroxide; Outcomes: reduction in microbial load, encompassing clinical and in vitro studies. Risks of bias assessment and data extraction were conducted with two reviewers independently selecting studies, extracting data, and assessing risk of bias. A general meta-analysis was performed across all included studies, with additional meta-analyses evaluating different exposure times, NAC concentrations, control groups and evaluation methods. After removing duplicates, 9170 studies were initially identified, and seven in vitro studies were included in the systematic review, of which five were included in the meta-analysis. Data were compared using standardized mean differences within a random-effects model. No clinical studies using NAC as an antimicrobial agent were identified. The overall meta-analysis demonstrated that NAC effectively reduced Enterococcus faecalis. Further meta-analyses revealed that exposure time, NAC concentration and choice of control group significantly influenced NAC's effectiveness. NAC effectively reduced Enterococcus faecalis, showing comparable antimicrobial activity to CHX and NaOCl, especially at concentrations of 25-50 mg/mL over a 7-day exposure. Despite significant heterogeneity across studies, NAC demonstrated satisfactory antimicrobial effects in vitro. This suggests that NAC merits reconsideration as an effective intracanal medication for clinical use.},
}
@article {pmid39892016,
year = {2025},
author = {Gong, L and Chang, L and Chen, S and Wei, X and Du, H and Cheng, J and Chen, X and Yuan, Z and Zhao, P and Geng, M and Yang, H and Cai, K and Dai, L},
title = {Multifunctional injectable hydrogel with self-supplied H2S release and bacterial inhibition for the wound healing with enhanced macrophages polarization via interfering with PI3K/Akt pathway.},
journal = {Biomaterials},
volume = {318},
number = {},
pages = {123144},
doi = {10.1016/j.biomaterials.2025.123144},
pmid = {39892016},
issn = {1878-5905},
mesh = {Animals ; *Wound Healing/drug effects ; *Hydrogels/chemistry/administration &amp; dosage/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Mice ; *Hydrogen Sulfide/pharmacology/administration &amp; dosage/chemistry ; RAW 264.7 Cells ; *Macrophages/drug effects/cytology/metabolism ; Signal Transduction/drug effects ; Male ; Rats ; Rats, Sprague-Dawley ; Chitosan/chemistry/analogs &amp; derivatives ; Phosphatidylinositol 3-Kinases/metabolism ; Hyaluronic Acid/chemistry ; Injections ; },
abstract = {Hydrogen sulfide (H2S) gas therapy is beneficial for accelerating wound healing and alleviating the inflammatory process, but is seriously hindered by insufficient delivery and unsustainable release in vivo. This study presents a multifunctional injectable hydrogel, OC@ε-PL-SATO, composed of oxidized hyaluronic acid and N-acetylcysteine (NAC) as an initiator, carboxymethyl chitosan and S-aroylthiooxime modified ε-Poly-(l-lysine) (ε-PL-SATO). ε-PL-SATO is a NAC-responsive H2S donor. OC@ε-PL-SATO hydrogel is designed for the desired wound healing process, with rapid gelation (<30 s) and a sustained H2S release. After mixing and gelling, H2S could be long-term released from the hydrogel and effectively drives macrophages toward M2 polarization, thereby ameliorating the inflammatory response. Revealed by transcriptome analysis, the underlying mechanism is that OC@ε-PL-SATO hydrogel releasing H2S inhibits LPS-mediated inflammatory responses in RAW264.7 cells by interfering with phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling and NF-κB activation. Furthermore, the OC@ε-PL-SATO hydrogel effectively eliminates the bacterial burden and alleviates the accompanying inflammation in a rat model of cutaneous wound infection. Importantly, the sustained generation of H2S gas significantly promotes angiogenesis and collagen deposition, ultimately accelerating the wound repair. In conclusion, this study provides a multifunctional injectable hydrogel with rapid gelatinization and continuous H2S release for accelerating the infected wound healing.},
}
@article {pmid39887038,
year = {2025},
author = {Sharma, P and Kumar, R and Bari, A and Singh, SK},
title = {N-Acetyl Cysteine and Vitamin C Modulate the Antibiotic Efficacy Against Escherichia coli Cells.},
journal = {Microbial drug resistance (Larchmont, N.Y.)},
volume = {31},
number = {3},
pages = {87-93},
doi = {10.1089/mdr.2024.0135},
pmid = {39887038},
issn = {1931-8448},
mesh = {*Ascorbic Acid/pharmacology ; *Escherichia coli/drug effects/growth &amp; development ; *Acetylcysteine/pharmacology ; *Anti-Bacterial Agents/pharmacology ; Microbial Sensitivity Tests/methods ; *Antioxidants/pharmacology ; Microbial Viability/drug effects ; Fluoroquinolones/pharmacology ; Aminoglycosides/pharmacology ; },
abstract = {Supplements with their own beneficial effect on hosts are consumed by us. N-acetyl cysteine (NAC) and Vitamin C (Vit C) are antioxidants and supplements, consumed for their beneficial properties. The present investigation evaluates the effect of their antioxidant property on antibiotic efficacy against Escherichia coli cells from different physiological states, including exponential and stationary-phase, cell aggregates, and in-vitro stress-induced persister cells. Survival was measured in cfu/mL by cfu (colony-forming unit) counting, with efficacy determined by log-fold change in survival by comparing CFUs in antibiotics alone and antibiotic + antioxidant combinations. Fluoroquinolones in the presence of NAC reduced ∼1 log CFUs of log-phase and persister cells, while Vit C reduced CFUs (∼1-3-log increase) of cells from all physiological states. Aminoglycosides results were inconclusive; streptomycin's activity declined (∼1-3-log increase in survival), whereas amikacin's activity potentiated (∼1-log reduction in cfu/mL). Rifampicin's showed reduced activity (∼2-3 log increase in survival) with Vit C in all the states and a ∼1-2 log increase with NAC, especially in cell aggregates and persisters. Beta-lactams activity showed variability, with amoxicillin and ampicillin not being influenced, but ceftriaxone showed significant reduction of efficacy (∼2-3-log increase in survival) in all the treatments. The findings suggest that the overall impact of antioxidants on antibiotic efficacy varies depending on the antibiotic class.},
}
@article {pmid39885970,
year = {2025},
author = {Brites, GS and Ferreira, I and Sebastião, AI and Sousa, C and Silva, A and Carrascal, M and Oliveira, RC and Gonçalo, M and Vitorino, C and Neves, BM and Cruz, MT},
title = {Blocking the adverse outcome pathway of skin sensitization through a N-acetyl cysteine and lysine-loaded hydrogel.},
journal = {Journal of pharmaceutical analysis},
volume = {15},
number = {1},
pages = {101071},
pmid = {39885970},
issn = {2214-0883},
abstract = {Image 1.},
}
@article {pmid39884079,
year = {2025},
author = {Chen, K and Li, J and Chen, Z and Shen, C and Li, X and Li, Y and Song, D and Li, X and Wang, X and Xia, Y and Yu, X and Wang, Y and Shen, Y and Tong, J},
title = {Notoginsenoside R1 alleviates blue light-induced corneal injury and wound healing delay by binding to and inhibiting TRIB1.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {138},
number = {},
pages = {156399},
doi = {10.1016/j.phymed.2025.156399},
pmid = {39884079},
issn = {1618-095X},
mesh = {Animals ; *Ginsenosides/pharmacology ; Humans ; *Wound Healing/drug effects ; Mice ; Reactive Oxygen Species/metabolism ; *Corneal Injuries/drug therapy/etiology/metabolism ; Cell Proliferation/drug effects ; Cell Movement/drug effects ; *Protein Serine-Threonine Kinases/metabolism/antagonists &amp; inhibitors ; *Light/adverse effects ; Male ; Cell Survival/drug effects ; Panax notoginseng/chemistry ; *Intracellular Signaling Peptides and Proteins/metabolism/antagonists &amp; inhibitors ; Epithelial Cells/drug effects ; Mice, Inbred C57BL ; Blue Light ; },
abstract = {BACKGROUND: With the escalating use of digital devices, blue light (BL) exposure has emerged as a critical concern due to its potential to cause ocular damage. This study explores the protective effects of notoginsenoside R1 (NR1), a bioactive compound from Panax notoginseng (Burkill) F.H. Chen (Sanqi), against BL-induced corneal epithelial injury.<br><br>PURPOSE: This research aims to investigate the protective effects of NR1 on BL-induced corneal injury and wound healing delay.<br><br>METHODS: Human corneal epithelial cells (hCECs) were pretreated with NR1 (0-50 &#x3bc;M) or N-acetylcysteine (NAC, 10 mM), then exposed to BL (570 &#x3bc;W/cm&#xb2;) for 24 h. Cell viability, proliferation, migration, and ROS levels were assessed using various techniques. In mice, NR1 (25 &#x3bc;M and 50 &#x3bc;M) and NAC (0.3 %) eye drops were administered during BL exposure. Corneal injury, healing rates, cell proliferation, migration, ROS, and inflammation were evaluated. RNA-sequencing, bioinformatics, and molecular binding validation identified tribbles homolog 1 (TRIB1) as a key molecule mitigating BL damage with NR1. Functional studies via gene silencing, overexpression, and pharmacological modulation further explored TRIB1's role in BL exposure.<br><br>RESULTS: NR1 significantly reduced BL-induced inflammation, ROS production, and inhibited migration and proliferation in hCECs and murine corneas. It also alleviated BL-induced corneal injury and delayed healing in mice. NR1 inhibited TRIB1 upregulation, a marker of BL-induced injury and healing delay. Overexpression of TRIB1 negated NR1's therapeutic effects on hCECs, while TRIB1 silencing mitigated functional impairment. In mice, increased Trib1 expression caused corneal injury and delayed healing, reversed by NR1 treatment.<br><br>CONCLUSION: NR1 shows potential as a therapeutic agent by inhibiting TRIB1 elevation in response to BL exposure, providing a novel promising target for corneal injury and wound healing delay induced by BL, and offering a comprehensive strategy for clinical pharmacological intervention.},
}
@article {pmid39882502,
year = {2024},
author = {Biering, V and Bellouard, R and Martin, M and Dailly, &#xc9; and Monteil-Ganière, C and Le Carpentier, EC},
title = {N-acetylcysteine use in a cocaine-induced liver failure: a case report.},
journal = {Frontiers in toxicology},
volume = {6},
number = {},
pages = {1502716},
pmid = {39882502},
issn = {2673-3080},
abstract = {BACKGROUND: Cocaine intoxication and abuse is a worldwide problem that can be the cause of numerous acute medical complications, including severe acute hepatitis. Although these cases are scarce, they are extremely serious and may lead to liver transplantation or death. Management of toxic hepatitis, once the causative agent has been discontinued, is essentially symptomatic, based on clinical and biological monitoring and prevention of complications related to acute hepatitis.<br><br>CASE DETAILS: We present a case of a 28-year-old woman admitted to the emergency department for acute hepatitis due to cocaine intoxication. In addition to a sharp rise in her liver enzymes, the patient also presented metabolic acidosis, renal failure, and rhabdomyolysis. Treatment consisted of administering N-acetylcysteine (NAC), dialysis, and additional supportive measures. An improvement in the liver function with a decrease in transaminases occurred after the NAC administration. The toxicokinetics of major cocaine metabolites and clinical chemistry concentrations were monitored.<br><br>CONCLUSION: In addition to the usual management measures for acute hepatitis, the administration of N-acetylcysteine should be investigated further, although it is currently used only in cases of acetaminophen acute toxic hepatitis.},
}
@article {pmid39877352,
year = {2024},
author = {Ruths, L and Hengge, J and Teixeira, GQ and Haffner-Luntzer, M and Ignatius, A and Riegger, J},
title = {Terminal complement complex deposition on chondrocytes promotes premature senescence in age- and trauma-related osteoarthritis.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1470907},
pmid = {39877352},
issn = {1664-3224},
mesh = {Animals ; *Chondrocytes/immunology/metabolism/pathology ; Humans ; *Osteoarthritis/immunology/pathology/metabolism/etiology ; *Cellular Senescence/immunology ; Mice ; Male ; Mice, Knockout ; Mice, Inbred C57BL ; *Complement Membrane Attack Complex/metabolism/immunology ; Cartilage, Articular/immunology/pathology/metabolism ; *Aging/immunology ; CD59 Antigens/genetics ; Swine ; *Wounds and Injuries/immunology/complications ; Disease Models, Animal ; },
abstract = {BACKGROUND: The complement system is locally activated after joint injuries and leads to the deposition of the terminal complement complex (TCC). Sublytic TCC deposition is associated with phenotypical alterations of human articular chondrocytes (hAC) and enhanced release of inflammatory cytokines. Chronic inflammation is a known driver of chondrosenescence in osteoarthritis (OA). Therefore, we investigated whether TCC deposition contributes to stress-induced premature senescence (SIPS) during aging in vivo and after ex vivo cartilage injury.<br><br>METHODS: Femoral condyles of male 13-week-old and 72-week-old CD59-ko (higher TCC deposition), C6-deficient (insufficient TCC formation), and C57BL/6 (WT) mice were collected to assess age-related OA. Furthermore, macroscopically intact human and porcine cartilage explants were traumatized and cultured with/without 30% human serum (HS) to activate the complement system. Explants were additionally treated with clusterin (CLU, TCC inhibitor), N-acetylcysteine (NAC, antioxidant), Sarilumab (IL-6 receptor inhibitor), STAT3-IN-1 (STAT3 inhibitor), or IL-1 receptor antagonist (IL-1RA) in order to investigate the consequences of TCC deposition. Gene and protein expression of senescence-associated markers such as CDKN1A and CDKN2A was determined.<br><br>RESULTS: In the murine aging model, CD59-ko mice developed after 72 weeks more severe OA compared to C6-deficient and WT mice. mRNA analysis revealed that the expression of Cdkn1a, Cdkn2a, Tp53, Il1b, and Il6 was significantly increased in the cartilage of CD59-ko mice. In human cartilage, trauma and subsequent stimulation with HS increased mRNA levels of CDKN1A, CDKN2A, and IL6, while inhibition of TCC formation by CLU reduced the expression. Antioxidative therapy with NAC had no anti-senescent effect. In porcine tissue, HS exposure and trauma had additive effects on the number of CDKN2A-positive cells, while Sarilumab, STAT-IN-1, and IL-1RA reduced CDKN2A expression by trend.<br><br>CONCLUSION: Our results demonstrate that complement activation and consequent TCC deposition is associated with chondrosenescence in age-related and trauma-induced OA. We provided evidence that the SIPS-like phenotype is more likely induced by TCC-mediated cytokine release rather than oxidative stress. Overall, targeting TCC formation could be a future approach to attenuate OA progression.},
}
@article {pmid39876989,
year = {2025},
author = {Song, M and Han, M and Zhang, H and Yang, Y and Tian, Y and Li, J and Zhao, J},
title = {The Effective Compound Combination of Bufei Yishen Formula III Improves the Mitochondrial Dysfunction via Inhibiting JNK/Sab Pathway in COPD Mice.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {525-538},
pmid = {39876989},
issn = {1177-8881},
mesh = {Animals ; *Pulmonary Disease, Chronic Obstructive/drug therapy/metabolism/pathology ; Mice ; *Mitochondria/drug effects/metabolism ; Mice, Inbred BALB C ; *Drugs, Chinese Herbal/pharmacology/administration &amp; dosage/chemistry ; Male ; Disease Models, Animal ; *MAP Kinase Signaling System/drug effects ; },
abstract = {PURPOSE: The effective compound combination of Bufei Yishen formula III (ECC-BYF III) has shown protective effects against chronic obstructive pulmonary disease (COPD). However, its effect on mitochondrial dysfunction remains unclear. The current study aimed to investigate the effect of ECC-BYF III on mitochondrial dysfunction in COPD mice and elucidate its potential mechanisms.<br><br>METHODS: Twenty-eight BALB/c mice were randomized into four groups: control, model, ECC-BYF III, and NAC (N-acetylcysteine) groups. A COPD model was established using cigarette smoke and Klebsiella pneumoniae for 8&#xa0;weeks. The mice in the ECC-BYF III group were treated with ECC-BYF III (7.7 mg/kg/d), and the NAC group was treated with NAC (78 mg/kg/d) for eight weeks. Mice in the control and model groups were administered with 0.5% sodium carboxymethyl cellulose (25 mL/kg/d) for eight weeks. Then pulmonary function, histopathology, inflammatory factor levels, mitochondrial ultrastructure and function, and immunoblotting analyses were evaluated.<br><br>RESULTS: Compared with the model, ECC-BYF III significantly improved the decline in pulmonary function and histopathological changes. Furthermore, ECC-BYF III ameliorated mitochondrial dysfunction by restoring the mitochondrial membrane potential, increasing mitochondrial complex I activity, and decreasing tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) level and protein expressions of SH3BP5 (Sab), Phospho-JNK (P-JNK), and cleaved CASP3.<br><br>CONCLUSION: The results suggest that the potential therapeutic benefit of ECC-BYF III against mitochondrial dysfunction in COPD is due to the inhibition of the JNK/Sab pathway, which will help to further understand the potential mechanisms of ECC-BYF III in the treatment of COPD.},
}
@article {pmid39873044,
year = {2025},
author = {Komatsu, K and Chao, D and Matsuura, T and Kido, D and Ogawa, T},
title = {Advancing osseointegration research: A dynamic three-dimensional (3D) in vitro culture model for dental implants.},
journal = {Journal of dental sciences},
volume = {20},
number = {1},
pages = {350-360},
pmid = {39873044},
issn = {2213-8862},
abstract = {BACKGROUND/PURPOSE: In-vitro studies are essential for understanding cellular responses, but traditional culture systems often neglect the three-dimensional (3D) structure of real implants, leading to limitations in cellular recruitment and behavior largely governed by gravity. The objective of this study was to pioneer a novel 3D dynamic osteoblastic culture system for assessing the biological capabilities of dental implants in a more clinically and physiologically relevant manner.<br><br>MATERIALS AND METHODS: Rat bone marrow-derived osteoblasts were cultured in a 24-well dish with a vertically positioned dental implant. Controlled rotation using a 3D rotator with 3&#xb0; tilts was applied. Cell attachment, proliferation, and differentiation on implant surfaces were evaluated in response to different surface topographies, physicochemical properties, and local environments.<br><br>RESULTS: Among the tested rotational speeds (0, 10, 30, 50&#xa0;rpm), optimal osteoblast attachment and proliferation were observed at 30&#xa0;rpm. A linear correlation was found between cell attachment and rotation speed up to 30&#xa0;rpm, declining at 50&#xa0;rpm. Alkaline phosphatase (ALP) activity and mineralized matrix formation were elevated on newly acid-etched, hydrophilic surfaces compared to their 4-week-old hydrophobic surfaces. Sandblasted implants showed higher ALP activity and matrix mineralization. Adding N-acetyl cysteine to the culture medium increased ALP activity and mineralization.<br><br>CONCLUSION: Osteoblasts successfully attached, proliferated, and mineralized on dental implants in&#xa0;vitro under optimized dynamic conditions. This system differentiated the biological capabilities of implants with varying surface topographies, wettability, and biochemically modulated environments. These findings support developing a 3D dynamic dental implant culture model, advancing osseointegration research and innovating dental implant designs.},
}
@article {pmid39872815,
year = {2024},
author = {Li, F and Deng, L and Xu, T and Xu, L and Xu, Z and Lai, S and Ai, Y and Wang, Y and Yan, G and Zhu, L},
title = {Getah virus triggers ROS-mediated autophagy in mouse Leydig cells.},
journal = {Frontiers in microbiology},
volume = {15},
number = {},
pages = {1519694},
pmid = {39872815},
issn = {1664-302X},
abstract = {INTRODUCTION: Getah virus (GETV) is a zoonotic virus transmitted via a mosquito-vertebrate cycle. While previous studies have explored the epidemiology and pathogenicity of GETV in various species, its molecular mechanisms remain largely unexplored.<br><br>METHODS: This study investigated the impact of GETV infection and associated molecular mechanisms on reactive oxygen species (ROS) and autophagy levels in mouse Leydig cells both in vivo and in vitro. The male mice and TM3 cells were treatment with N-acetylcysteine (NAC) to reduce cellular ROS levels. Rapamycin (Rapa) and 3-Methyladenine (3- MA) were used to change autophagy in both infected and uninfected TM3 cells.<br><br>RESULTS AND DISCUSSION: The findings revealed that GETV infection in mouse testes speciffcally targeted Leydig cells and induced oxidative stress while enhancing autophagy in testicular tissue. Using TM3 cells as an in vitro model, the study confirmed GETV replication in this cell line, triggering increased ROS and autophagy levels. Treatment with N-acetylcysteine (NAC) to reduce cellular ROS levels markedly reduced autophagy in testicular tissue and TM3 cells infected with GETV. Interestingly, the use of rapamycin (Rapa) and 3-Methyladenine (3- MA) led to autophagy change in both infected and uninfected TM3 cells, with no signiffcant alterations in cellular ROS levels. These results indicate that GETV infection elevates ROS levels, subsequently inducing autophagy in mouse Leydig cells. We also found that autophagy plays an important role in GETV replication. When autophagy levels were reduced using NAC and 3-MA, a corresponding decrease in TCID50 was observed. Conversely, upregulation of autophagy using Rapa resulted in an increase in TCID50 of GETV. Therefore, we speculate that GETV may exploit the autophagy pathway to facilitate its replication. These ffndings illuminate the interplay between GETV and host cells, providing valuable insights for therapeutic strategies targeting autophagy in GETV infections.},
}
@article {pmid39864434,
year = {2025},
author = {Pfau, K and Callizo, J and Rossouw, P and Gabrani, C and Holz, F and Charbel Issa, P and Kellner, U and Strauss, R and Kühlewein, L and Stingl, K and Feltgen, N and Pfau, M},
title = {[N-Acetylcysteine (NAC) for Retinitis pigmentosa].},
journal = {Klinische Monatsblatter fur Augenheilkunde},
volume = {242},
number = {3},
pages = {199-204},
doi = {10.1055/a-2525-4419},
pmid = {39864434},
issn = {1439-3999},
mesh = {*Acetylcysteine/administration &amp; dosage ; *Retinitis Pigmentosa/drug therapy/diagnosis ; Humans ; Treatment Outcome ; Antioxidants/administration &amp; dosage ; Evidence-Based Medicine ; Free Radical Scavengers/administration &amp; dosage ; },
abstract = {Retinitis pigmentosa (RP) is a genetically mediated degenerative retinal disease that leads to progressive photoreceptor degeneration and, ultimately, blindness. Oxidative stress plays a central role in the pathogenesis of RP. This study examines the effect of N-acetylcysteine (NAC), an antioxidant and glutathione precursor, on the disease progression in RP patients. NAC can reduce oxidative stress in the retina and has shown potential neuroprotective effects in preclinical models. Initial clinical studies indicate improvements in visual acuity and macular function with NAC therapy, though no structural changes have yet been demonstrated. The ongoing multicentre Phase III trial "NAC Attack" aims to evaluate the long-term efficacy and safety of NAC in RP.},
}
@article {pmid39861915,
year = {2025},
author = {Nabipur, L and Mouawad, M and Venketaraman, V},
title = {Additive Effects of Glutathione in Improving Antibiotic Efficacy in HIV-M.tb Co-Infection in the Central Nervous System: A Systematic Review.},
journal = {Viruses},
volume = {17},
number = {1},
pages = {},
pmid = {39861915},
issn = {1999-4915},
support = {R15 HL143545/HL/NHLBI NIH HHS/United States ; },
mesh = {*Glutathione/therapeutic use/pharmacology ; Humans ; *Coinfection/drug therapy ; *HIV Infections/drug therapy/complications ; Animals ; Mycobacterium tuberculosis/drug effects ; *Antitubercular Agents/therapeutic use/pharmacology ; *Central Nervous System/microbiology/drug effects ; *Tuberculosis/drug therapy ; *Anti-Bacterial Agents/therapeutic use/pharmacology ; Disease Models, Animal ; Treatment Outcome ; },
abstract = {BACKGROUND: HIV and tuberculosis (TB) co-infection poses a significant health challenge, particularly when involving the central nervous system (CNS), where it leads to severe morbidity and mortality. Current treatments face challenges such as drug resistance, immune reconstitution inflammatory syndrome (IRIS), and persistent inflammation. Glutathione (GSH) has the therapeutic potential to enhance treatment outcomes by improving antibiotic efficacy, reducing inflammation, and mitigating immune dysfunction.<br><br>METHODS: Relevant studies were identified through systematic searches of PubMed, Elsevier, WHO, and related databases. Inclusion criteria focused on preclinical and clinical research examining GSH or its precursors in HIV, TB, or co-infection, with emphasis on microbial control, immune modulation, and CNS-related outcomes.<br><br>RESULTS: Preclinical studies showed that GSH improves macrophage antimicrobial function, reduces oxidative stress, and limits Mycobacterium tuberculosis (M.tb) growth. Animal models demonstrated reduced bacterial burden in the lungs, liver, and spleen with GSH supplementation, along with enhanced granuloma stability. Clinical studies highlighted increased TH1 cytokine production, reduced inflammatory markers, and improved CD4+ T cell counts in HIV-M.tb co-infected patients. N-acetylcysteine (NAC), a GSH precursor, was shown to significantly enhance the efficacy of first-line TB antibiotics and mitigate treatment-associated toxicity.<br><br>DISCUSSION: GSH shows promise as an adjunct therapy for HIV-M.tb co-infection, particularly for cases involving the CNS, where it may improve immune recovery and reduce inflammation. However, evidence is limited by small sample sizes and a lack of randomized trials. Future research should focus on developing CNS-directed GSH formulations and evaluating its integration into current treatment protocols to address the dual burden of HIV and TB, ultimately improving patient outcomes.},
}
@article {pmid39861414,
year = {2025},
author = {Viña, I and Viña, JR and Carranza, M and Mariscal, G},
title = {Efficacy of N-Acetylcysteine in Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis.},
journal = {Nutrients},
volume = {17},
number = {2},
pages = {},
pmid = {39861414},
issn = {2072-6643},
mesh = {Humans ; *Polycystic Ovary Syndrome/drug therapy/blood ; *Acetylcysteine/therapeutic use/pharmacology ; Female ; Metformin/therapeutic use ; Treatment Outcome ; Endometrium/drug effects ; Clomiphene/therapeutic use ; Progesterone/blood ; Luteinizing Hormone/blood ; Adult ; Antioxidants ; },
abstract = {BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age and requires better treatment. N-acetylcysteine (NAC) is known to be beneficial under such conditions owing to its antioxidant potential and insulin-sensitizing properties. The effect of NAC on the reproductive outcomes of PCOS patients was examined in this meta-analysis.<br><br>METHODS: In accordance with PRISMA standards, this meta-analysis included studies that compared N-acetylcysteine, metformin, clomiphene citrate, and a placebo in patients with POCS. The main indicators were follicular growth, endometrial thickness, and hormone level. The risk of bias was evaluated using the Cochrane ROB2 tool.<br><br>RESULTS: Twenty-two studies (n = 2515) were included. NAC was associated with a statistically significant increase in progesterone (SMD 0.95, 95% CI: 0.13-1.77, p = 0.02) and endometrial thickness (SMD 0.58, 95% CI: 0.10-1.06, p = 0.02) compared to the placebo and other drugs (SMD 0.71, 95% CI: 0.48-0.94, p < 0.0001). LH levels were significantly increased by NAC compared to metformin (SMD 0.67, 95% CI: 0.23-1.12, p = 0.003). However, no significant differences were observed in the estradiol, SHBG, or FSH levels.<br><br>CONCLUSIONS: NAC had a major effect on progesterone, endometrial thickness, and LH levels in women with PCOS. Therefore, it may be a potential treatment option.},
}
@article {pmid39860053,
year = {2025},
author = {Sanduzzi Zamparelli, S and Sanduzzi Zamparelli, A and Bocchino, M},
title = {Immune-Boosting and Antiviral Effects of Antioxidants in COVID-19 Pneumonia: A Therapeutic Perspective.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {1},
pages = {},
pmid = {39860053},
issn = {2075-1729},
abstract = {The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has profoundly impacted global health, with pneumonia emerging as a major complication in severe cases. The pathogenesis of COVID-19 is marked by the overproduction of reactive oxygen species (ROS) and an excessive inflammatory response, resulting in oxidative stress and significant tissue damage, particularly in the respiratory system. Antioxidants have garnered considerable attention for their potential role in managing COVID-19 pneumonia by mitigating oxidative stress and modulating immune responses. This review provides a comprehensive overview of the literature on the use of antioxidants in hospitalized patients with mild-to-moderate COVID-19. Studies exploring antioxidants, including vitamins, trace elements, nitric oxide (NO), ozone (O3), glutathione (GSH), L-carnitine, melatonin, bromelain, N-acetylcysteine (NAC), and numerous polyphenols, have yielded promising outcomes. Through their ROS-scavenging properties, these molecules support endothelial function, reduce the thrombosis risk, and may help mitigate the effects of the cytokine storm, a key contributor to COVID-19 morbidity and mortality. Clinical evidence suggests that antioxidant supplementation may improve patient outcomes by decreasing inflammation, supporting immune cell function, and potentially shortening recovery times. Furthermore, these molecules may mitigate the symptoms of COVID-19 by exerting direct antiviral effects that inhibit the infection process and genomic replication of SARS-CoV-2 in host cells. Moreover, antioxidants may work synergistically with standard antiviral treatments to reduce viral-induced oxidative damage. By integrating findings from the literature with real-world data from our clinical experience, we gain a more profound understanding of the role of antioxidants in managing COVID-19 pneumonia. Further research combining comprehensive literature reviews with real-world data analysis is crucial to validate the efficacy of antioxidants and establish evidence-based guidelines for their use in clinical practice.},
}
@article {pmid39857691,
year = {2025},
author = {Vorwerk, J and Liu, L and Stadler, TH and Frank, D and Ahmed, HMM and Patnana, PK and Kebenko, M and Dazert, E and Opalka, B and von Bubnoff, N and Khandanpour, C},
title = {Germline Single-Nucleotide Polymorphism GFI1-36N Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia.},
journal = {Biomedicines},
volume = {13},
number = {1},
pages = {},
pmid = {39857691},
issn = {2227-9059},
support = {17R/2018//Deutsche Jos&#xe9; Carreras Leuk&#xe4;mie-Stiftung/ ; 70112392//German Cancer Aid/ ; KH331/2-3//Deutsche Forschungsgemeinschaft/ ; Kha2/002/20//Interdisziplin&#xe4;res Zentrum f&#xfc;r Klinische Forschung M&#xfc;nster/ ; },
abstract = {Background/Objectives: GFI1-36N represents a single-nucleotide polymorphism (SNP) of the zinc finger protein Growth Factor Independence 1 (GFI1), in which the amino acid serine (S) is replaced by asparagine (N). The presence of the GFI1-36N gene variant is associated with a reduced DNA repair capacity favoring myeloid leukemogenesis and leads to an inferior prognosis of acute myeloid leukemia (AML) patients. However, the underlying reasons for the reduced DNA repair capacity in GFI1-36N leukemic cells are largely unknown. Since we have demonstrated that GFI1 plays an active role in metabolism, in this study, we investigated whether increased levels of reactive oxygen species (ROS) could contribute to the accumulation of genetic damage in GFI1-36N leukemic cells. Methods: We pursued this question in a murine model of human AML by knocking in human GFI1-36S or GFI1-36N variant constructs into the murine Gfi1 gene locus and retrovirally expressing MLL-AF9 to induce AML. Results: Following the isolation of leukemic bone marrow cells, we were able to show that the GFI1-36N SNP in our model is associated with enhanced oxidative phosphorylation (OXPHOS), increased ROS levels, and results in elevated γ-H2AX levels as a marker of DNA double-strand breaks (DSBs). The use of free radical scavengers such as N-acetylcysteine (NAC) and α-tocopherol (αT) reduced ROS-induced DNA damage, particularly in GFI1-36N leukemic cells. Conclusions: We demonstrated that the GFI1-36N variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage.},
}
@article {pmid39857416,
year = {2025},
author = {Cusato, J and Mulasso, A and Ferrara, M and Manca, A and Accardo, G and Palermiti, A and Antonucci, M and Bianco, G and Chiara, F and Mula, J and Tettoni, MC and Cuomo, S and Trevisan, G and Bonora, S and Di Perri, G and Lupo, C and Rainoldi, A and D'Avolio, A},
title = {How Antiretroviral Drug Concentrations Could Be Affected by Oxidative Stress, Physical Capacities and Genetics: A Focus on Dolutegravir Treated Male PLWH.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {1},
pages = {},
pmid = {39857416},
issn = {2076-3921},
support = {CUSJ_RILO_21_01//Medical Sciences Department University of Turin/ ; },
abstract = {High levels of reactive oxygen species (ROS) are present in people living with HIV (PLWH), produced by intense physical activity; in response, our body produces antioxidant molecules. ROS influence the expression of gene-encoding enzymes and transporters involved in drug biotransformation. In addition, pharmacogenetics can influence transporter activity, and thus drug exposure. Currently, no studies concerning this topic are present in the literature. The aim of this study was to investigate whether some antioxidant molecules, physical exercise, and genetic variants could affect dolutegravir (DTG) concentrations in PLWH, switching from triple to dual therapy. Thirty PLWH were recruited and analyzed at baseline (triple therapy), and 6 months after (dual therapy). Physical capacities were investigated using validated tools. Drug concentrations and oxidative stress biomarkers levels were evaluated through liquid chromatography coupled with tandem mass spectrometry, while genetic variants through real-time PCR. No statistical differences were suggested for drug concentrations, with the exception of intracellular DTG (p = 0.047). Statistically significant correlations between DTG plasma concentrations and white blood cells (p = 0.011; S = 0.480) and cytoplasmic N-acetyl-cysteine (p = 0.033; S = -0.419) were observed. Finally, white blood cells and BMI remained in the final multivariate regression model as predictors of DTG concentrations. This is the first study showing possible factors related to oxidative stress impacting DTG exposure.},
}
@article {pmid39855039,
year = {2025},
author = {Wang, Y and Wang, Q and Ji, Q and An, P and Wang, X and Ju, Y and Li, R and Ruan, Y and Zhao, J and Cao, M and Chen, X},
title = {Supplementation with N-Acetyl-L-cysteine during in vitro maturation improves goat oocyte developmental competence by regulating oxidative stress.},
journal = {Theriogenology},
volume = {235},
number = {},
pages = {221-230},
doi = {10.1016/j.theriogenology.2025.01.016},
pmid = {39855039},
issn = {1879-3231},
mesh = {Animals ; *Oxidative Stress/drug effects ; *In Vitro Oocyte Maturation Techniques/veterinary ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Goats/embryology/physiology ; *Oocytes/drug effects/physiology ; Female ; Embryonic Development/drug effects ; Antioxidants/pharmacology ; Embryo Culture Techniques/veterinary ; },
abstract = {Oocyte quality can affect mammal fertilization rate, early embryonic development, pregnancy maintenance, and fetal development. Oxidative stress induced by reactive oxygen species (ROS) is one of the most important causes of poor oocyte maturation in vitro. To reduce the degree of cellular damage caused by ROS, supplementation with the antioxidant N-Acetyl-L-cysteine (NAC) serves as an effective pathway to alleviate glutathione (GSH) depletion during oxidative stress. This study investigated the effects of NAC supplementation during in vitro maturation of goat oocytes and explored the molecular mechanisms of maturation by transcriptome sequencing of MⅡ oocytes. The results showed that 1.5 mM NAC significantly increased the rates of oocyte maturation and cumulus cell expansion and improved the subsequent development of embryos. During the subsequent culture of parthenogenetically activated embryos, 1.5 mM NAC significantly increased the division rate of oocytes and blastocyst rate. It also reduced the accumulation of ROS, increased the level of GSH, alleviated oxidative stress, and enhanced the antioxidant capacity and cell metabolic activity. Transcriptome sequencing results revealed that NAC treatment significantly increased the expression of SIRT1, GGCT, and MITF genes related to the cellular antioxidant system, as well as the IDH3G gene related to energy metabolism, and decreased the expression of CASP8, FOS, and MMP1 genes related to apoptosis and cell invasion, as well as the CCL2. and CXCL8 genes related to the inflammatory response. In conclusion, the findings suggest that NAC supplementation significantly reduces oxidative stress, improves antioxidant capacity and metabolic activity, promotes oocyte maturation, and improves oocyte quality.},
}
@article {pmid39852136,
year = {2024},
author = {Cimmino, A and Gioia, M and Clementi, ME and Faraoni, I and Marini, S and Ciaccio, C},
title = {Polydatin-Induced Shift of Redox Balance and Its Anti-Cancer Impact on Human Osteosarcoma Cells.},
journal = {Current issues in molecular biology},
volume = {47},
number = {1},
pages = {},
pmid = {39852136},
issn = {1467-3045},
support = {MUR Prin 2022PFFPBL//Italian Ministry of University and Research/ ; },
abstract = {Cancer cells demonstrate remarkable resilience by adapting to oxidative stress and undergoing metabolic reprogramming, making oxidative stress a critical target for cancer therapy. This study explores, for the first time, the redox-dependent anticancer effects of Polydatin (PD), a glucoside derivative of resveratrol, on the human Osteosarcoma (OS) cells SAOS-2 and U2OS. Using cell-based biochemical assays, we found that cytotoxic doses of PD (100-200 µM) promote ROS production, deplete glutathione (GSH), and elevate levels of both total iron and intracellular malondialdehyde (MDA), which are key markers of ferroptosis. Notably, the ROS scavenger N-acetylcysteine (NAC) and the ferroptosis inhibitor ferrostatin-1 (Fer-1) partially reverse PD's cytotoxic effects. Interestingly, PD's ability to hinder cell adhesion and migration appears independent of its pro-oxidant effect. Analysis of the oxidative stress regulators SIRT1 and Nrf2 at the gene and protein levels using real-time PCR and Western blot indicates an early oxidative response to PD treatment. PD remains effective under tumor-like conditions of hypoxia and serum starvation, and sensitizes OS cells to ROS-inducing chemotherapeutics like doxorubicin (DOX) and cisplatin (CIS). Importantly, PD exhibits minimal toxicity to non-tumorigenic cells (hFOB), suggesting a favorable therapeutic profile. Overall, our findings underscore that PD-induced redox imbalance plays a crucial role in its anti-OS effects, warranting further exploration into the molecular mechanisms behind its pro-oxidant activity.},
}
@article {pmid39847829,
year = {2025},
author = {Moka, MK and George, M and Rathakrishnan, D and Jagadeeshwaran, V and D K, S},
title = {Trends in drug repurposing: Advancing cardiovascular disease management in geriatric populations.},
journal = {Current research in translational medicine},
volume = {73},
number = {2},
pages = {103496},
doi = {10.1016/j.retram.2025.103496},
pmid = {39847829},
issn = {2452-3186},
mesh = {Humans ; *Drug Repositioning/trends/methods ; *Cardiovascular Diseases/drug therapy/epidemiology ; Aged ; Middle Aged ; },
abstract = {Drug repurposing is a promising strategy for managing cardiovascular disease (CVD) in geriatric populations, offering efficient and cost-effective solutions. CVDs are prevalent across all age groups, with a significant increase in prevalence among geriatric populations. The middle-age period (40-65 years) is critical due to factors like obesity, sedentary lifestyle, and psychosocial stress. In individuals aged 65 and older, the incidence of CVDs is highest due to age-related physiological changes and prolonged exposure to risk factors. In this review we find that certain drugs, such as non-cardiovascular drugs like anakinra, probenecid, N-acetyl cysteine, quercetin, resveratrol, rapamycin, colchicine, bisphosphonates, hydroxychloroquine, SGLT-2i drugs, GLP-1Ras drugs and sildenafil are recommended for drug repurposing to achieve cardiovascular benefits in geriatric patients. However, agents such as canakinumab, methotrexate, ivermectin, erythromycin, capecitabine, carglumic acid, chloroquine, and furosemide are constrained in their therapeutic use and warrant meticulous consideration, rendering them less favorable for this specific application. This review emphasizes the importance of exploring alternative therapeutic strategies to improve outcomes in geriatric populations and suggests drug repurposing as a promising avenue to enhance treatment efficacy.},
}
@article {pmid39843512,
year = {2025},
author = {Candela, ME and Addison, M and Aird, R and Man, TY and Cartwright, JA and Ashmore-Harris, C and Kilpatrick, AM and Starkey Lewis, PJ and Drape, A and Barnett, M and Mitchell, D and McLean, C and McGowan, N and Turner, M and Dear, JW and Forbes, SJ},
title = {Cryopreserved human alternatively activated macrophages promote resolution of acetaminophen-induced liver injury in mouse.},
journal = {NPJ Regenerative medicine},
volume = {10},
number = {1},
pages = {5},
pmid = {39843512},
issn = {2057-3995},
support = {MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; },
abstract = {Acute liver failure is a rapidly progressing, life-threatening condition most commonly caused by an overdose of acetaminophen (paracetamol). The antidote, N-acetylcysteine (NAC), has limited efficacy when liver injury is established. If acute liver damage is severe, liver failure can rapidly develop with associated high mortality rates. We have previously demonstrated that alternatively, activated macrophages are a potential therapeutic option to reverse acute liver injury in pre-clinical models. In this paper, we present data using cryopreserved human alternatively activated macrophages (hAAMs)-which represent a potential, rapidly available treatment suitable for use in the acute setting. In a mouse model of APAP-induced injury, peripherally injected cryopreserved hAAMs reduced liver necrosis, modulated inflammatory responses, and enhanced liver regeneration. hAAMs were effective even when administered after the therapeutic window for NAC. This cell therapy approach represents a potential treatment for APAP overdose when NAC is ineffective because liver injury is established.},
}
@article {pmid39842600,
year = {2025},
author = {Gu, D and Zhou, L and Zhang, Y and Jin, H and Nie, W and Zhang, M and Dong, Y},
title = {N-acetylcysteine and chitosan conjugate modified dexamethasone nanostructured lipid carriers: Enhanced permeability, precorneal retention and lower inflammation for the treatment of dry eye syndrome.},
journal = {International journal of biological macromolecules},
volume = {299},
number = {},
pages = {140123},
doi = {10.1016/j.ijbiomac.2025.140123},
pmid = {39842600},
issn = {1879-0003},
mesh = {*Dexamethasone/chemistry/pharmacology/pharmacokinetics ; *Chitosan/chemistry ; *Dry Eye Syndromes/drug therapy/pathology/metabolism ; Animals ; *Drug Carriers/chemistry ; *Acetylcysteine/chemistry ; Rabbits ; *Nanostructures/chemistry ; Cornea/drug effects/metabolism/pathology ; Permeability ; *Lipids/chemistry ; Humans ; Inflammation/drug therapy ; Ophthalmic Solutions ; },
abstract = {Dexamethasone (Dex) is a primary medication for treating dry eye syndrome, and tobramycin-dexamethasone eye drops are commercially available. However, the eye's complex physiological environment reduces its bioavailability, and repeated use can lead to significant systemic toxicity and side effects. This study introduces a novel conjugate of chitosan (CS) and N-acetylcysteine (NAC), a bioadhesive material, which was grafted onto the surface of a Dex-supported nanostructured lipid carrier (NLC) to develop an innovative nanoparticle lipid ocular drug delivery system (CS-NAC@Dex-NLC). The enhancements afforded by CS-NAC, such as adhesion, osmotic, and targeting properties, address the limitations of traditional eye drops. NMR characterization confirmed the successful synthesis of the copolymer (CS-NAC). Particle size (PS), zeta potential, and transmission electron microscopy (TEM) verified the proper formation of the CS-NAC@Dex-NLC system. Cytotoxicity tests confirmed its excellent biocompatibility and safety. Cellular uptake studies showed that CS-NAC@Dex-NLC achieved the highest efficiency. Pharmacokinetic assessments revealed a significant increase in Dex's bioavailability in tears and aqueous humor. In vitro corneal penetration and in vivo imaging experiments demonstrated effective corneal penetration and retention, enhancing the drug's duration on the ocular surface and overcoming the barrier effect. Pharmacodynamic studies in rabbits with dry eye syndrome indicated that CS-NAC@Dex-NLC effectively alleviates symptoms, repairs corneal damage, and stabilizes the tear film. ELISA results showed a reduction in inflammation caused by dry eye. These findings suggest that CS-NAC@Dex-NLC is a promising vector for dry eye treatment, offering significant clinical relevance.},
}
@article {pmid39832189,
year = {2025},
author = {Mishra, S and Botlagunta, M and Rajasekaran, S},
title = {Arsenic-Induced Inflammatory Response via ROS-Dependent Activation of ERK/NF-kB Signaling Pathways: Protective Role of Natural Polyphenol Tannic Acid.},
journal = {Journal of applied toxicology : JAT},
volume = {45},
number = {5},
pages = {795-807},
doi = {10.1002/jat.4748},
pmid = {39832189},
issn = {1099-1263},
support = {ICMR-NIREH/BPL/IMP-PJ-40/2021-22/473//Indian Council of Medical Research (ICMR)-Intramural funding of the National Institute for Research in Environmental Health (NIREH)/ ; },
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Tannins/pharmacology ; *NF-kappa B/metabolism ; Animals ; Mice ; *Arsenic/toxicity ; *Polyphenols/pharmacology ; Signal Transduction/drug effects ; *Inflammation/chemically induced/metabolism/prevention &amp; control ; *MAP Kinase Signaling System/drug effects ; Cell Line ; *Anti-Inflammatory Agents/pharmacology ; Macrophages/drug effects ; },
abstract = {Arsenic (As), a highly toxic metalloid, is present throughout our environment as a result of both natural and human-related activities. Furthermore, As exposure could lead to a persistent inflammatory response, which may facilitate the pathogenesis of several diseases in various organs. This study was performed to investigate the As-induced inflammatory response and the underlying molecular mechanisms in vitro. Further, the anti-inflammatory effects of a natural dietary polyphenol tannic acid (TA) were also explored. In human normal bronchial (BEAS-2B), adenocarcinoma alveolar basal (A549), and murine macrophages (J774) cell lines, a trivalent form of As (as As[3+]) exposure markedly induced the expression of various pro-inflammatory mediators (cytokines and chemokines). Additionally, it was found that As[3+] exposure induced reactive oxygen species (ROS) generation and activation of the nuclear factor-kappa B (NF-kB) p65 and extracellular signal-regulated kinase (ERK)1/2 pathways in BEAS-2B cells. As expected, the blockade of either ERK1/2 (PD98059) or NF-kB p65 (IMD0354), or both pathways attenuated As[3+]-induced pro-inflammatory mediators release. Interestingly, pre-treatment with ROS inhibitor N-acetylcysteine (NAC) attenuated activation of ERK/NF-kB pathways, suggesting that ROS have a critical role in pathway's activation and subsequent inflammatory response. Further, TA pre-treatment effectively attenuated As[3+]-induced inflammatory response by suppressing ROS production and ERK/NF-kB signaling pathways activation. Therefore, this study provides scientific evidence for the anti-inflammatory activities of TA and the underlying molecular mechanisms.},
}
@article {pmid39830891,
year = {2025},
author = {Shri, P and Singh, KP and Rani, V and Nagar, DP and Acharya, J and Bhaskar, ASB},
title = {N-acetylcysteine prevents cholinergic and non-cholinergic toxic effects induced by nerve agent poisoning in rats.},
journal = {Toxicology research},
volume = {14},
number = {1},
pages = {tfae223},
pmid = {39830891},
issn = {2045-452X},
abstract = {OBJECTIVE: Organophosphorus Nerve Agent, VX [(O-Ethyl S-diisopropylaminomethyl) methylphosphonothioate] compound interferes with acetylcholine signaling by targeting the AChE enzyme. Studies suggest that in nerve agents poisoning, non-cholinergic effects are also responsible for damage in peripheral tissues including long term damage in brain. Present study reports cholinergic and non-cholinergic effects of VX poisoning and their prevention by use of N-acetylcysteine (NAC) in addition to conventional antidotes atropine sulphate and 2-PAM chloride as an antioxidant. NAC was chosen being an approved drug for medical conditions including oxidative damage and as mucolytic.<br><br>RESULTS: Results of the study showed that after 1x LD 50 exposure to VX and standard atropine and oxime therapy resulted in recovery of cholinesterase activity up to 51%, while additional NAC administration resulted in increased recovery up to 89% in brain cholinesterase activity. NAC also helped in maintaining intracellular and tissue GSH level, reduced ROS generation and lipid peroxidation. NAC treatment could able to reduce the lipid peroxidation (MDA) levels in liver of NAC administered groups as compared to standard treatment of atropine sulphate and PAM chloride at 10 LD 50 VX. Likewise, a 20% higher level of GSH was found in NAC treated group at 1x LD 50 dose in brain. Cell cycle analysis and histopathological results showed that NAC prevents VX induced damage.<br><br>CONCLUSION: it was found that use of antioxidant agent NAC along with standard atropine-oxime treatment is helpful in reducing the cholinergic and oxidative stress mediated toxicity induced by VX.},
}
@article {pmid39830885,
year = {2025},
author = {Abd El-Khalek, SH and Amin, SA and El-Ebiary, AA and Elfeky, A and Kandeel, F},
title = {The potential role of N-acetylcysteine as an adjuvant therapy in acute aluminum phosphide poisoning: a randomized clinical trial.},
journal = {Toxicology research},
volume = {14},
number = {1},
pages = {tfae210},
pmid = {39830885},
issn = {2045-452X},
abstract = {OBJECTIVE: Aluminum phosphide (AP) intoxication is a life-threatening emergency with no available effective antidote. This study evaluated the efficacy and safety of N-acetylcysteine (NAC) infusion in cases of acute AP poisoning.<br><br>METHODS: This randomized, single-blinded, parallel-group, controlled, clinical trial enrolled 96 patients with acute AP poisoning. The patients were allocated to two groups and received either conventional treatment (control group) or conventional treatment plus NAC infusion (NAC group). The patients were subjected to full clinical evaluation, routine laboratory investigations, silver nitrate test, and evaluation of the oxidative markers, malondialdehyde (MDA) and total antioxidant capacity (TAC), at admission and after 24&#xa0;h treatment. The primary outcome was mortality, and the secondary outcomes were the arterial blood pressure, the length of hospital stay, and the need for intubation or mechanical ventilation.<br><br>RESULTS: Compared to the control group, the NAC group showed significantly lower MDA (median [interquartile range (IQR)]: 4.6 [1.9-10.6] vs. 6.8 [3.5-17.4] nmol/mL, P&#xa0;=&#xa0;0.014) and higher TAC levels (median [IQR]: 0.7 [0.6-0.7] vs. 0.6 [0.6-06] mM/L, P&#xa0;<&#xa0;0.001). The mortality rate and the need for mechanical ventilation were comparable in both groups (P&#xa0;=&#xa0;0.601 and 0.505, respectively). However, the NAC group showed significant improvements of both systolic and diastolic blood pressure values (both P&#xa0;=&#xa0;0.030). The duration of hospitalization was significantly shorter in the NAC group (P&#xa0;=&#xa0;0.017). No adverse events were reported in patients who received NAC infusion.<br><br>CONCLUSION: In patients with acute AP poisoning, the use of NAC mitigates oxidative stress and partially enhances clinical manifestations without inducing noticeable adverse effects.},
}
@article {pmid39825811,
year = {2024},
author = {Linares-Ramírez, JD and Córdoba, AC and Calderón-Franco, CH and Aponte-Martín, DM and Dávila, F and Sabbagh, LC},
title = {Premedication in upper gastrointestinal endoscopy to improve mucosal visualization. A systematic review.},
journal = {Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru},
volume = {44},
number = {4},
pages = {346-353},
pmid = {39825811},
issn = {1609-722X},
mesh = {Humans ; *Endoscopy, Gastrointestinal/methods ; *Premedication/methods ; *Gastric Mucosa/diagnostic imaging ; Randomized Controlled Trials as Topic ; *Expectorants/administration &amp; dosage ; Simethicone/administration &amp; dosage ; *Antifoaming Agents/administration &amp; dosage ; },
abstract = {OBJECTIVE: This review aims to evaluate the efficacy and safety of premedication comprising mucolytics and/or defoaming agents to improve the quality of visualization during elective upper digestive endoscopy (elective upper GI endoscopy) procedure.<br><br>MATERIALS AND METHODS: A systematic review of the literature contained in electronic databases (Medline/Pubmed, Embase, and Lilacs) was performed to identify randomized controlled trials and systematic reviews that assessed patients undergoing upper gastrointestinal endoscopy (elective upper GI Endoscopy) under sedation, after being premedicated with mucolytics and/or defoaming agents for mucous clearance. A meta-analysis was conducted to determine the relative efficacy and safety profile of such premedication.<br><br>RESULTS: In patients undergoing an elective procedure, premedication with defoaming and/or mucolytic agents improved the visibility score of the gastric antrum during upper GI endoscopy. The use of combined agents such as simethicone vs. water and N-acetyl cysteine (NAC) vs. water showed significant differences in favor of the active substance; however, no significant differences were found between the use of simethicone alone vs. simethicone + NAC. The use of pronase and dimethylpolysiloxane, among others, produced no significant difference (additive effect) in the visualization score. This is associated with the limited number of studies that performed similar comparisons and the heterogeneity of the outcomes. No major adverse effects were reported in the studies that were included regarding safety outcomes (i.e., volume of fluids required for clearance, risk of bronchoaspiration, and disinfection of equipment).<br><br>CONCLUSIONS: The results of this review evidence that premedication with simethicone (a drug registered in Colombia for use against functional gastrointestinal disorders; ATC group A03A) is safe and effective for improving the quality of visualization during elective upper GI endoscopy procedures. However, no significant differences were observed in the visualization quality with the use or addition of other agents. The use simethicone should be set as off-label use and should be implemented at the prescriber's discretion. The use of simethicone as a premedication is recommended to improve the endoscopic visualization score in elective procedures.},
}
@article {pmid39825593,
year = {2025},
author = {Wang, J and Yang, Y and Ma, J and Li, P and Li, Y and Yang, C and Zhao, B and Zhao, Z and Ding, X and Chen, H and Huo, S and Yang, Y and Luo, W},
title = {Molecular Mechanism of N-Acetylcysteine Regulating Proliferation and Hormone Secretion of Granulosa Cells in Sheep.},
journal = {Reproduction in domestic animals = Zuchthygiene},
volume = {60},
number = {1},
pages = {e70006},
doi = {10.1111/rda.70006},
pmid = {39825593},
issn = {1439-0531},
support = {32460907//National Natural Science Foundation of China/ ; 20240036//Plateau Animal Disease Innovation Team/ ; 2022-2-44//Lanzhou Science and Technology Plan Project/ ; },
mesh = {Animals ; Female ; *Granulosa Cells/drug effects/metabolism ; *Acetylcysteine/pharmacology ; *Cell Proliferation/drug effects ; Apoptosis/drug effects ; Sheep ; Antioxidants ; Progesterone/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction/drug effects ; },
abstract = {Granulosa cells (GCs) are pivotal in the development of ovarian follicles, serving not only as supportive cells but also as the primary producers of steroid hormones. The proliferation of these cells and the synthesis of steroid hormones are crucial for follicular development and atresia. In our study, GCs were isolated using follicular fluid aspiration and subsequently identified through immunofluorescence. We investigated the impact of varying concentrations of N-acetylcysteine (NAC) at 50, 100, 500, and 1000 μmol/L on sheep GCs, focusing on antioxidant levels, proliferation, apoptosis, and steroid hormone secretion. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) inhibitor LY294002 was used to explore the molecular mechanism of NAC on GCs proliferation and steroid hormone secretion in sheep. Our findings indicate that all concentrations of NAC tested promoted GC proliferation and suppressed apoptosis in sheep GCs. Notably, 100 μmol/L NAC exhibited the most pronounced effect on GC proliferation after 48 h. The expression levels of CCND1, CDK4, and Bcl-2 were significantly elevated in all NAC concentration groups, whereas Bax expression was notably reduced. Furthermore, all NAC concentrations led to a significant reduction in reactive oxygen species (ROS) levels and an increase in the expression of CAT and SOD1. NAC also significantly enhanced the expression of CYP19A1 and 3β-HSD, as well as the secretion of estradiol (E2) and progesterone (P4) by GCs. In summary, NAC activates the PI3K/AKT signalling pathway, thereby promoting the proliferation of GCs and the secretion of E2 and P4 by sheep GCs in vitro.},
}
@article {pmid39821896,
year = {2025},
author = {Zarowin, DH and Buros Stein, A and Sheppard, SE and Treat, JR},
title = {A Retrospective Review of Oral N-Acetylcysteine for Habit-Driven Cutaneous Disorders.},
journal = {Pediatric dermatology},
volume = {42},
number = {3},
pages = {560-563},
pmid = {39821896},
issn = {1525-1470},
support = {ZIA HD009003/ImNIH/Intramural NIH HHS/United States ; ZIA-HD009003-01//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //Pediatric Dermatology Research Alliance/ ; },
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/therapeutic use/adverse effects ; Retrospective Studies ; Child ; Male ; Female ; Administration, Oral ; Child, Preschool ; Adolescent ; *Skin Diseases/drug therapy/etiology ; *Habits ; Treatment Outcome ; Infant ; },
abstract = {Oral N-acetylcysteine (NAC) has shown efficacy for debilitating habit-driven and neuropsychiatric disorders in small, mostly adult studies. We retrospectively evaluated the therapeutic use and safety of oral NAC in 93 children from the Children's Hospital of Philadelphia. This study supports the use of oral NAC for habit-driven skin, hair, and nail abnormalities in pediatric patients.},
}
@article {pmid39817046,
year = {2025},
author = {Shishodia, S and Rinnert, H and Balan, L and Jasniewski, J and Bruyère, S and Medjahdi, G and Gries, T and Schneider, R},
title = {Microwave-assisted synthesis of highly photoluminescent core/shell CuInZnSe/ZnS quantum dots as photovoltaic absorbers.},
journal = {Nanoscale advances},
volume = {7},
number = {5},
pages = {1326-1334},
pmid = {39817046},
issn = {2516-0230},
abstract = {Water-dispersible core/shell CuInZnSe/ZnS (CIZSe/ZnS) quantum dots (QDs) were efficiently synthesized under microwave irradiation using N-acetylcysteine (NAC) and sodium citrate as capping agents. The photoluminescence (PL) emission of CIZSe/ZnS QDs can be tuned from 593 to 733 nm with varying the Zn : Cu molar ratio in the CIZSe core. CIZSe/ZnS QDs prepared with a Zn : Cu ratio of 0.5 exhibit the highest PL quantum yield (54%) and the longest PL lifetime (515 ns) originating from the recombination of donor-acceptor pairs. The potential of CIZSe/ZnS QDs as photoabsorbers in QD-sensitized solar cells was also evaluated. An adequate type-II band alignment is observed between TiO2 and CIZSe/ZnS QDs, indicating that photogenerated electrons in CIZSe/ZnS QDs could efficiently be injected into TiO2.},
}
@article {pmid39815362,
year = {2025},
author = {Jing, Q and Wu, Y and Li, Y and Zhou, C and Zhang, J and Xia, J and Li, K and Shen, Y and Yao, H and Tong, X and Du, J and Yu, L and Wang, Y},
title = {Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma.},
journal = {Biology direct},
volume = {20},
number = {1},
pages = {7},
pmid = {39815362},
issn = {1745-6150},
support = {ZRY2020B001//Outstanding Youth Foundation of Zhejiang Provincial People's Hospital/ ; LBY23H080004, LBY23H080005//Zhejiang Province Public Welfare Technology Application Research Project/ ; 82102938//National Natural Science Foundation of China/ ; },
mesh = {*Thioredoxins/metabolism/antagonists &amp; inhibitors ; *Myelodysplastic Syndromes/drug therapy/metabolism ; *Telomerase/metabolism/antagonists &amp; inhibitors ; Humans ; Animals ; *Lymphoma/drug therapy ; Mice ; Cell Line, Tumor ; Cell Death/drug effects ; Apoptosis/drug effects ; Antineoplastic Agents/pharmacology ; },
abstract = {Thioredoxin1 (TRX1) and telomerase are both attractive oncology targets that are tightly implicated in tumor initiation and development. Here, we reported that the 6-dithio-2-deoxyguanosine analog thiotert exhibits an effective cytotoxic effect on myelodysplastic syndromes (MDS) cell SKM-1 and lymphoma cell U-937. Further studies confirmed that thiotert effectively disrupts cellular redox homeostasis, as evidenced by elevated intracellular reactive oxygen species (ROS) levels, increased MnSOD, accelerated DNA impairment, and activated apoptosis signal. Mechanistically, our present study revealed that thiotert treatment effectively inhibited the function of the TRX1/TRXR1 system and telomerase reverse transcriptase (TERT), rendering oxidative damage and impairment of telomeres. Meanwhile, pharmacological administration of glutathione (GSH), N-acetylcysteine (NAC), and mitoquinone (MitoQ), or genetic overexpression of TRX1 or TERT in MDS and cells could dampen the toxicity caused by thiotert. Remarkably, the in vivo mouse model of MDS demonstrated that thiotert administration exhibited greater efficacy in tumor reduction compared to the conventional chemotherapy drug cytarabine. Collectively, these results provide experimental insights into the mechanism of thiotert-induced MDS and lymphoma cell death and unveil that thiotert may be an effective and promising new drug for future MDS and lymphoma treatment.},
}
@article {pmid39813214,
year = {2025},
author = {Fatima, S},
title = {N-acetyl-L-cysteine and lauric acid; effective antioxidant and antimicrobial feed additives for juvenile Pacific white shrimp (Litopenaeus vannamei) cultured at high stocking density.},
journal = {PloS one},
volume = {20},
number = {1},
pages = {e0315819},
pmid = {39813214},
issn = {1932-6203},
mesh = {Animals ; *Penaeidae/growth &amp; development/drug effects/immunology/metabolism ; *Antioxidants/pharmacology ; *Lauric Acids/pharmacology ; *Animal Feed ; *Acetylcysteine/pharmacology ; Dietary Supplements ; Aquaculture ; *Anti-Infective Agents/pharmacology ; },
abstract = {Present study aimed at improving the immune and antioxidant response of Pacific white shrimp (Litopenaeus vannamei) cultured at high stocking density fed with 0.2% supplementation of lauric acid (LA) and N-acetyl-L-cysteine (NAC). Shrimp (initial average weight = 0.65 g; n = 270) were grown at low stocking density (LSD) (n = 10/0.80 ft3 per replicate) and high stocking density (HSD) (n = 20/0.80 ft3 per replicate). They were randomly distributed into five groups (T1: negative control at LSD, T2: positive control at HSD, T3: at HSD and fed with LA supplement diet, T4: at HSD and fed with NAC supplemented diet, T5: at HSD and fed with combination of LA and NAC). All these five treatments were studied in triplicates and study continued for eight weeks. Better growth and higher levels of glucose, total protein, total hemocyte count and phagocytic index were observed in shrimp fed with NAC and LA supplemented diets. Observed survival rate and feed conversion ratio in all treatments was 75-89% and < 0.82, respectively. All parameters indicating stress were observed to be higher in T1 as compared to T2. Improved expression of superoxide dismutase and glutathione peroxidase and lower levels of malondialdehyde genes in T3, T4 and T5 showed that supplementation with these nutraceuticals can improve antioxidant response at high stocking density. A parallel increase was observed in the profiles of prophenoloxidase and lysozyme, underscoring the immune-boosting effects of both NAC and LA. This finding was further supported by higher expression of innate immune signaling pathway-related gene, toll like receptor-2 in T3, T4 and T5. In conclusion, NAC and LA, can possibly improve the resistance of white pacific shrimp against oxidative stress and pathogens when cultured in intensive production system.},
}
@article {pmid39810570,
year = {2025},
author = {Baraldi, F and Bigoni, T and Foschino Barbaro, MP and Micheletto, C and Scioscia, G and Vatrella, A and Papi, A},
title = {Mucus production and chronic obstructive pulmonary disease, a possible treatment target: zooming in on N-acetylcysteine.},
journal = {Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace},
volume = {},
number = {},
pages = {},
doi = {10.4081/monaldi.2025.3159},
pmid = {39810570},
issn = {2532-5264},
abstract = {Mucus hypersecretion is a trait of chronic obstructive pulmonary disease (COPD) associated with poorer outcomes. As it may be present before airway obstruction, its early treatment may have a preventive role. This narrative review of the literature presents the role of mucus dysfunction in COPD, its pathophysiology, and the rationale for the use of N-acetylcysteine (NAC). NAC can modify mucus rheology, improving clearance and reducing damage induced MUC5AC expression. It exerts a direct and indirect (glutathione replenishment) antioxidant mechanism; it interferes with inflammatory molecular pathways, including inhibition of nuclear factor-kB activation in epithelial airway cells and reduction in the expression of cytokine tumor necrosis factor α, interleukin (IL)-6, and IL-10. Some clinical experiences suggest that the adjunctive use of NAC may reduce symptoms and improve outcomes for patients with COPD. In conclusion, NAC may be a candidate drug for the early treatment of subjects at risk of COPD development.},
}
@article {pmid39809659,
year = {2025},
author = {Finotti, M and Zanetto, A and Vitale, A and Rodriguez-Davalos, M and Burra, P and Cillo, U and D'Amico, F},
title = {N-Acetylcysteine and Liver Transplant. Advantages of its Administration in Multi-Organ Donors Especially During World-Economical-Crisis. Long-Term Sub-Group Analysis in a Randomized Study.},
journal = {Transplantation proceedings},
volume = {57},
number = {2},
pages = {264-271},
doi = {10.1016/j.transproceed.2024.11.038},
pmid = {39809659},
issn = {1873-2623},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/economics ; *Liver Transplantation/economics/mortality/adverse effects ; Retrospective Studies ; *Tissue Donors/supply &amp; distribution ; Graft Survival/drug effects ; Male ; Middle Aged ; Female ; Adult ; Time Factors ; Treatment Outcome ; },
abstract = {BACKGROUND: Liver transplantation (LT) is the main indication for the treatment of end-stage liver disease but have to face organ shortages. Using marginal donors is an option to increase the donor pool. Previous studies showed that the graft procured using N-acetylcysteine (NAC) provides a longer survival compared to perfusion with standard solutions, especially in marginal liver donors. We now evaluate the effect of NAC perfusion compared to control (no NAC protocol) at a 5-year follow-up, with a special focus on the overall survival (OS) and graft survival.<br><br>METHODS: Single-center, retrospective review of the OS and graft survival among NAC and control group, with a sub-stratification based on the LT indication.<br><br>RESULTS: 140 donors were enrolled: 69 in the NAC protocol and 71 in the control group. The 5-year OS was 84% in the NAC protocol compared to 63% in the control (P = .0045). In LT for HCC, the OS at 5 years was 80% and 55% in the study group and control group, respectively (P = .04), with no statistical difference in the RFS (P = .46). Furthermore, in cost analysis, the resources needed for the NAC protocol is negligible compared to the control group. Beneficial tendency of NAC protocol application has been seen in the other organs (lungs, hearts, pancreas, kidney and intestine) CONCLUSION: The application of NAC infusion in liver donors improves the overall survival of the recipient, especially in the HCC and HCV LT indications.},
}
@article {pmid39802290,
year = {2025},
author = {Tanadi, C and Pajala, FB and Supranoto, YTN and Tandarto, K and Stella, MM and Adiwinata, R and Simadibrata, P and Simadibrata, M},
title = {Simethicone with or without N-acetylcysteine as premedication in esophagogastroduodenoscopy: a systematic review and meta-analysis.},
journal = {Annals of gastroenterology},
volume = {38},
number = {1},
pages = {28-40},
pmid = {39802290},
issn = {1108-7471},
abstract = {BACKGROUND: The impairment of gastrointestinal mucosa visibility during esophagogastroduodenoscopy (EGD), due to the presence of foam and bubbles, may lead to reduced quality in the EGD results. The combination of simethicone, a defoaming agent, along with N-acetylcysteine (NAC), which has mucolytic properties, has been proposed to improve the visibility of the mucosa. This study aimed to evaluate the effectiveness of pre-procedural administration of simethicone and N-acetylcysteine in improving mucosal visibility, procedure time and mucosal cleansing volume needed during EGD.<br><br>METHODS: We conducted a comprehensive literature search from inception to November 23, 2023, in PubMed, CENTRAL, ProQuest, SAGE, and JSTOR. We included randomized clinical trials that investigated the effects of simethicone with or without NAC as premedication in EGD. For the quantitative analysis, standardized mean difference (SMD) was used to assess continuous outcomes and risk ratio for dichotomous outcomes. The Cochrane risk of bias 2 tool was used to evaluate the risk of bias.<br><br>RESULTS: This meta-analysis comprised a total of 20 studies and found that simethicone with or without NAC improved mucosal visibility compared with control (SMD -1.27, 95% confidence interval [CI] -1.74 to -0.81, P<0.001). The combination of simethicone and NAC was significantly better than simethicone alone (SMD -0.68, 95%CI -1.08 to -0.28, P=0.001). Simethicone with or without NAC also shortened the procedure time compared to control (MD -1.40, 95%CI -2.67 to -0.12, P=0.03). The risk of bias was low with a moderate grade of certainty.<br><br>CONCLUSION: The administration of simethicone with or without NAC may improve EGD quality.},
}
@article {pmid39801742,
year = {2025},
author = {Ford, JW and VanNatta, JM and Mondal, D and Lin, CM and Deng, Y and Bai, R and Hamel, E and Trawick, ML and Pinney, KG},
title = {Drug-Linker Constructs Bearing Unique Dual-Mechanism Tubulin Binding Payloads Tethered through Cleavable and Non-Cleavable Linkers.},
journal = {Tetrahedron},
volume = {171},
number = {},
pages = {},
pmid = {39801742},
issn = {0040-4020},
support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; R01 CA140674/CA/NCI NIH HHS/United States ; R01 CA238624/CA/NCI NIH HHS/United States ; },
abstract = {Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels. These payloads have been incorporated into a variety of drug-linker constructs utilizing the clinically relevant cathepsin B cleavable Val-Cit dipeptide linker, employed within several FDA approved ADCs, along with other non-cleavable constructs. Various synthetic strategies were evaluated to prepare these drug-linker constructs. Aniline-based payloads were incorporated utilizing the Val-Cit dipeptide linker similar to FDA approved ADCs such as Adcetris[®] (brentuximab vedotin). An additional self-immolative group, previously described in the literature for related model systems, was employed to tether the phenolic payloads. A variety of drug-linker constructs (with each bearing a unique dual mechanism payload) were synthesized and evaluated biologically for their enzyme-mediated release of payload and inhibition of tubulin polymerization. Following deactivation of the highly electrophilic maleimido terminus as its corresponding N-acetyl cysteine (NAC) derivative, the most promising construct (NAC-4) demonstrated approximately 90% release of an aniline-functionalized payload (1) upon treatment with cathepsins B or L over 90 minutes. Building on these promising results, future studies will examine the conjugation of drug-linker construct 4 to selected antibodies and engineered proteins and evaluate the biological activity of the resultant antibody-drug conjugates (ADCs).},
}
@article {pmid39800517,
year = {2025},
author = {Wang, YS and Dong, C and Zou, L and Zhao, L and Qin, JH and Mo, HL},
title = {Ligand engineering boosts catalase-like activity of gold nanoclusters for cascade reactions combined with glucose oxidase in ZIF-8 matrix.},
journal = {Analytica chimica acta},
volume = {1337},
number = {},
pages = {343565},
doi = {10.1016/j.aca.2024.343565},
pmid = {39800517},
issn = {1873-4324},
mesh = {*Glucose Oxidase/metabolism/chemistry ; *Gold/chemistry/metabolism ; *Metal Nanoparticles/chemistry ; *Catalase/metabolism/chemistry ; *Zeolites/chemistry ; Glucose/metabolism/analysis ; *Metal-Organic Frameworks/chemistry ; Ligands ; Hydrogen Peroxide/chemistry/metabolism ; Acetylcysteine/chemistry ; Imidazoles ; },
abstract = {BACKGROUND: Integrating natural enzymes and nanomaterials exhibiting tailored enzyme-like activities is an effective strategy for the application of cascade reactions. It is essential to develop a highly efficient and robust glucose oxidase-catalase (GOx-CAT) cascade system featuring controllable enzyme activity, a reliable supply of oxygen, and improved stability for glucose depletion in cancer starvation therapy. However, the ambiguous relationship between structure and performance, and the difficulty in controlling enzyme-mimic activity, significantly hinder their broader application. Herein, the CAT-like activity of atomically precise Au25(MPA)18 (MPA = 3-mercaptopropionic acid) nanoclusters (AuNCs) was modulated by incorporating N-acetyl-l-cysteine (NAC) in a series of ratio.<br><br>RESULTS: It is found that Au25(NAC)14-17(MPA)4-1 exhibited superior CAT-like activity and structural stability than Au25(MPA)18 owing to the intramolecular hydrogen bond in NAC. Moreover, the synergetic effects of glucose-depletion catalyzed by GOx, oxygen generation from the intermediate hydrogen peroxide (H2O2) facilitated by Au25(NAC)14-17(MPA)4-1, and protective function and nanoconfinement effect of zeolitic imidazolate framework-8 (ZIF-8) enabled the GOx-Au25(NAC)14-17(MPA)4-1@ZIF-8 composite to degrade more glucose. Compared to that treated with a single enzyme or free enzymes, the residual intermediate H2O2 level after treatment with GOx-Au25(NAC)14-17(MPA)4-1@ZIF-8 was about 93&#xa0;% lower than that after treatment with GOx alone. This composite showed higher catalytic activity, stability, and tolerance when applied to GOx-mediated glucose depletion.<br><br>SIGNIFICANCE: In brief, the study provides a feasible strategy for realizing robust and efficient cascade reaction by integrating the merits of natural enzymes and atomically precise metal NCs with adjustable enzyme-like activity. This research offers essential guidance for developing a biocompatible and tailored cascade system.},
}
@article {pmid39790357,
year = {2025},
author = {Mohammed, SS and Zaaqoq, A and Talaat, S and Abdelkader, SI},
title = {A randomized, clinical trial of intravenous N-acetylcysteine as an antioxidant therapy in acute organophosphorus pesticide poisoning.},
journal = {Toxicology research},
volume = {14},
number = {1},
pages = {tfae234},
pmid = {39790357},
issn = {2045-452X},
abstract = {The incidence of acute organophosphate (OP) poisoning has steadily increased in developing countries. Many studies showed that oxidative stress could have a significant role in its mechanism. The current study aimed to evaluate the role of N acetylcysteine (NAC) as an antioxidant in acute OP poisoned. A randomized, controlled, parallel-group trial was conducted in the period from the beginning of January 2022 to the end of June 2022. The study included 56 acute OP poisoned patients admitted to the intensive care unit (ICU) at the Poison Control Center of Ain Shams University Hospitals within 6 h after the exposure. The patients were randomly allocated in two equal groups; group (A): received the standard treatment plus NAC in a total dose of 300 mg/kg administered intravenously (IV) while group (B) received the standard treatment. Then both groups were compared as regards clinical parameters, laboratory investigations, ECG, and outcomes. Baseline parameters were comparable between the groups. However, NAC treatment significantly elevated concentrations of both serum catalase and glutathione peroxidase levels at 24 h, it did not significantly affect the total dose of atropine required, duration of atropine and oximes treatment or need for mechanical ventilation, and length of hospital stay. Mortality was lower in the NAC group (2 out of 28) than the standard treatment-only group (5 out of 28) but the difference was not statistically significant. This trial found that NAC improved antioxidant enzyme levels including serum CAT and GPX but did not affect clinically relevant outcomes.},
}
@article {pmid39780844,
year = {2024},
author = {Nemetova, U and Önem, AN and Er, A and Çelik, S and Özel, AE and Akyüz, S and Özyürek, M and Şahinler Ayla, S},
title = {A fast and responsive turn-on fluorescent probe based on a quinone conjugated alkoxy derivative for biothiols and a cellular imaging study.},
journal = {Turkish journal of chemistry},
volume = {48},
number = {6},
pages = {830-842},
pmid = {39780844},
issn = {1300-0527},
abstract = {The detection of intracellular biothiols (cysteine, N-acetyl cysteine, and glutathione) with high selectivity and sensitivity is important to reveal biological functions. In this study, a 2-(2-methoxy-4-methylphenoxy)-3-chloro-5,8-dihydroxynaphthalene-1,4-dione (DDN-O) compound (3) was newly synthesized and used as a fluorogenic probe (detector molecule) in the fluorometric method for the rapid, highly selective, and sensitive determination of biothiols. The intensity values (λex = 260 nm, λem = 620 nm) of the product were measured by adding biothiols to the reaction medium at varying concentrations and the glutathione equivalent thiol content values of each biothiol were calculated. Using compound 3, glutathione as the reference biothiol was detected in the linear concentration range of 10-70 μM and the LOD value was found to be 0.11 μM. Biothiol detection with structurally simple compound 3 was performed at the cellular level within 1 min and the probe was also successfully used in bioimaging with low cytotoxicity. It was concluded that this probe can serve as an alternative to existing fluorescence-based biothiol probes with applications in rapid biothiol detection at the cellular level for biological functions. To evaluate the molecular structure of 3, conformational analysis was performed using the PM3 semiempirical method. The most stable obtained molecular geometry was then optimized at the DFT/wb97xd/6-311++G(d,p) level of theory. Frontier molecular orbitals (HOMO and LUMO) and molecular electrostatic potential map analyses were performed for the optimized structure. Molecular docking studies demonstrated the interactions of 3 with HAS (1AO6) and FhGST (2FHE) target proteins.},
}
@article {pmid39779606,
year = {2025},
author = {Li, P and Tang, W and Wen, H and Zhou, S and Cao, H},
title = {Senkyunolide I prevent chondrocytes from oxidative stress through Nrf2/HO-1 signaling pathway.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {398},
number = {7},
pages = {8335-8344},
pmid = {39779606},
issn = {1432-1912},
support = {2042023kf0049//the Fundamental Research Funds for the Central Universities/ ; },
mesh = {*Chondrocytes/drug effects/metabolism ; *Oxidative Stress/drug effects ; *NF-E2-Related Factor 2/metabolism ; Signal Transduction/drug effects ; *Heme Oxygenase-1/metabolism ; Reactive Oxygen Species/metabolism ; Cells, Cultured ; Humans ; Osteoarthritis/drug therapy/metabolism/pathology ; *Benzofurans/pharmacology ; Interleukin-1beta/pharmacology ; Animals ; Cellular Senescence/drug effects ; *Senotherapeutics/pharmacology ; Antioxidants/pharmacology ; },
abstract = {Osteoarthritis (OA) is a degenerative musculoskeletal disease, featured by the destruction of articular cartilage. Oxidative stress, one of the drivers of the extracellular matrix degradation in cartilage, plays a vital role in OA pathogenesis. Senkyunolide I (SEI) is a natural compound with a prominent anti-oxidative stress property against multiple diseases. However, the protective effect of SEI on OA has not been explored. Here, we aimed to elucidate the effect of SEI on OA in vitro. Our results showed that SEI suppressed the expression of senescence-related markers such as P16 and P21 in IL-1β-induced chondrocytes. Besides, SEI alleviated IL-1β-induced the degradation of extracellular matrix (ECM) by suppressing the matrix proteinase like MMP13 and ATAMDS5 while promoting matrix synthesis regulated biomarkers like COL2A1 and ACAN in chondrocytes. Mechanically, the mitochondrial dysfunction and overproduction of intracellular reactive oxygen species (ROS) in chondrocytes induced by IL-1β were reversed by SEI. Additionally, the ROS inhibitor N-acetylcysteine (NAC) synergistically enhanced the biological effect of SEI in IL-1β-induced chondrocytes. Moreover, it was also found that the expression of Nrf2 and HO-1 was increased by the treatment of SEI in IL-1β-stimulated chondrocytes, while the Nrf2 inhibitor ML385 reversed the protective effect of SEI on OA chondrocytes. In conclusion, SEI could inhibit senescence, the degradation of ECM, and the production of ROS through activating Nrf2/ HO-1 signaling pathway, which provide a novel candidate for OA treatment.},
}
@article {pmid39775338,
year = {2025},
author = {Hamed, S and Emara, M and Tohidifar, P and Rao, CV},
title = {N-Acetyl cysteine exhibits antimicrobial and anti-virulence activity against Salmonella enterica.},
journal = {PloS one},
volume = {20},
number = {1},
pages = {e0313508},
pmid = {39775338},
issn = {1932-6203},
mesh = {*Salmonella enterica/drug effects/pathogenicity ; *Acetylcysteine/pharmacology ; *Microbial Sensitivity Tests ; Virulence/drug effects ; *Anti-Bacterial Agents/pharmacology ; Animals ; Mice ; Salmonella Infections/microbiology/drug therapy ; Humans ; Drug Resistance, Multiple, Bacterial/drug effects ; },
abstract = {Salmonella enterica is a common foodborne pathogen that causes intestinal illness varying from mild gastroenteritis to life-threatening systemic infections. The frequency of outbreaks due to multidrug-resistant Salmonella has been increased in the past few years with increasing numbers of annual deaths. Therefore, new strategies to control the spread of antimicrobial resistance are required. In this work, we found that N-acetyl cysteine (NAC) inhibits S. enterica at MIC of 3 mg ml-1 and synergistically activates the bactericidal activities of common antibiotics from three-fold for ampicillin and apramycin up to1000-fold for gentamycin. In addition, NAC inhibits the expression of virulence genes at sub-inhibitory concentrations in a dose-dependent manner. The whole-genome sequencing revealed that continuous exposure of S. enterica to NAC leads to the development of resistance; these resistant strains are attenuated for virulence. These results suggest that NAC may be a promising adjuvant to antibiotics for treating S. enterica in combination with other antibiotics.},
}
@article {pmid39773189,
year = {2025},
author = {Wang, K and Qu, H and Hu, R and Lassègue, B and Eaton, DC and Song, C and Mu, J and Griendling, KK and Hernandes, MS},
title = {Polymerase delta-interacting protein 2 mediates brain vascular permeability by regulating ROS-mediated ZO-1 phosphorylation and localization at the interendothelial border.},
journal = {Cell communication and signaling : CCS},
volume = {23},
number = {1},
pages = {9},
pmid = {39773189},
issn = {1478-811X},
support = {R01 HL169373/HL/NHLBI NIH HHS/United States ; R01 NS127964/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; Phosphorylation ; *Zonula Occludens-1 Protein/metabolism ; *Reactive Oxygen Species/metabolism ; *Capillary Permeability ; Mice ; Humans ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Mice, Knockout ; Nuclear Proteins/metabolism/genetics ; Brain Ischemia/metabolism ; Endothelial Cells/metabolism ; Tight Junctions/metabolism ; },
abstract = {BACKGROUND: Polymerase delta-interacting protein 2 (Poldip2) is a novel regulator of vascular permeability that has been shown to be involved in aggravating blood-brain barrier (BBB) disruption following stroke; however, the underlying mechanisms are unknown. While endothelial tight junctions (TJ) are critical mediators of BBB permeability, the effect of Poldip2 on TJ function has not been elucidated yet. Here, we aim to define the mechanism by which Poldip2 mediates BBB disruption, specifically focusing on phosphorylation and stabilization of the TJ integral protein ZO-1.<br><br>METHODS AND RESULTS: Cerebral ischemia was induced in endothelial-specific&#xa0;Poldip2 knockout mice and controls. Cerebral vascular permeability was assessed by Evans blue dye extravasation. Endothelial-specific Poldip2 deletion abolished Evans blue dye extravasation after ischemia induction. In vitro permeability assays demonstrated that Poldip2 knockdown suppressed TNF-&#x3b1;-induced endothelial cell (EC) permeability. Immunofluorescence staining showed that Poldip2 depletion prevented TNF-&#x3b1;-induced ZO-1 disruption at interendothelial junctions. Conversely, Poldip2 overexpression increased endothelial permeability, loss of ZO-1 localization at cell-cell junctions and enhanced reactive oxygen species (ROS) production. Treatment with the antioxidant N-acetyl cysteine (NAC) reduced Poldip2-induced ZO-1 disruption at inter interendothelial junctions. Immunoprecipitation studies demonstrated Poldip2 overexpression induced tyrosine phosphorylation of ZO-1, which was prevented by treatment with NAC or MitoTEMPO, a mitochondrial ROS scavenger.<br><br>CONCLUSIONS: These data reveal a novel mitochondrial ROS-driven mechanism by which Poldip2 induces ZO-1 tyrosine phosphorylation and promotes EC permeability following cerebral ischemia.},
}
@article {pmid39772929,
year = {2025},
author = {La Mensa, A and Buscetta, M and Woldhuis, RR and Cimino, M and Giuffrè, MR and Cristaldi, M and Dino, P and Fiore, L and Fucarino, A and Lo Iacono, G and Bertani, A and Brandsma, CA and Bucchieri, F and Cipollina, C},
title = {Caspase inhibition restores collagen Iα1 and fibronectin release in cigarette smoke extract-exposed human lung fibroblasts.},
journal = {American journal of physiology. Lung cellular and molecular physiology},
volume = {328},
number = {2},
pages = {L239-L252},
doi = {10.1152/ajplung.00214.2024},
pmid = {39772929},
issn = {1522-1504},
support = {G78I18000930007//Sicilian Region/ ; },
mesh = {Humans ; *Fibroblasts/metabolism/drug effects/pathology ; *Fibronectins/metabolism ; *Lung/metabolism/pathology/drug effects ; *Caspase Inhibitors/pharmacology ; *Collagen Type I/metabolism ; *Smoke/adverse effects ; Extracellular Matrix/metabolism/drug effects ; Oxidative Stress/drug effects ; Cell Line ; Pulmonary Disease, Chronic Obstructive/metabolism/pathology ; Caspases/metabolism ; },
abstract = {Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by obstructed airflow, airway remodeling, and inflammation, with cigarette smoke (CS) exposure being the main risk factor. Although CS extract (CSE) has been shown to activate caspases in various cell types, the role of caspases in human lung fibroblasts (hLFs) in COPD remains poorly understood. Recent studies have linked caspases to extracellular matrix (ECM) remodeling in skin and kidney fibrosis. Caspase activation can be triggered by oxidative stress, with active caspase-3 executing the pore-forming protein gasdermin E (GSDME) in the cleaved N-terminal form GSDME-NT. We investigated whether CSE activates caspases and GSDME in hLFs and their role in ECM remodeling. MRC-5 lung fibroblasts were treated with CSE with or without the antioxidant N-acetyl-cysteine (NAC) and the caspase-8 inhibitor z-IETD-fmk. We measured the effects on caspase-1-8-3/7 activation, GSDME cleavage, ECM remodeling (procollagen Iα1, COLIα1, and fibronectin, FN), and mitochondrial superoxide (mSOX) generation. Key findings were validated in patient-derived hLFs (phLFs). Our results showed that CSE induced caspase-1-8-3/7 activation, mSOX generation, and decreased COLIα1 and FN levels in MRC-5. CSE caused caspase-8-dependent activation of caspase-3, leading to GSDME cleavage. Treatment with NAC inhibited mSOX and caspase activation. Inhibition of caspase-8 and mSOX restored FN and COLIα1 levels. In phLFs, we confirmed caspase-1 and -8 activation, mSOX increase, COLIα1/FN decrease, and the effects of NAC. Our findings highlight the role of the axis caspase-8-3/7-GSDME and mSOX in regulating ECM protein, suggesting that these pathways may contribute to remodeling in COPD.NEW &amp; NOTEWORTHY This research investigates the connection between caspases, gasdermins, and extracellular matrix (ECM) remodeling in the context of cigarette smoke-associated lung diseases. The study found that cigarette smoke extract (CSE) activates caspases and gasdermin E in human lung fibroblasts, leading to decreased ECM protein expression and release. Findings herein reported suggest that targeting the caspase-8-3/7-gasdermin axis and mitochondrial reactive oxygen species may help restore ECM remodeling in chronic lung diseases associated with cigarette smoke exposure.},
}
@article {pmid39770941,
year = {2024},
author = {Kim, TW and Ko, SG},
title = {Anti-Inflammatory and Anticancer Effects of Kaurenoic Acid in Overcoming Radioresistance in Breast Cancer Radiotherapy.},
journal = {Nutrients},
volume = {16},
number = {24},
pages = {},
pmid = {39770941},
issn = {2072-6643},
support = {2018R1D1A1B07048556//NRF/ ; 2020R1A5A2019413//NRF/ ; },
mesh = {Animals ; *Breast Neoplasms/radiotherapy/drug therapy/pathology ; Humans ; Female ; Mice ; *Anti-Inflammatory Agents/pharmacology ; *Diterpenes/pharmacology ; *PPAR gamma/metabolism ; *Apoptosis/drug effects ; Radiation Tolerance/drug effects ; MCF-7 Cells ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Endoplasmic Reticulum Stress/drug effects/radiation effects ; Antineoplastic Agents/pharmacology ; Reactive Oxygen Species/metabolism ; Cytokines/metabolism ; Mice, Inbred BALB C ; },
abstract = {Background/Objectives: Peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in mediating anti-inflammatory and anticancer effects in the tumor microenvironment. Kaurenoic acid (KA), a diterpene compound isolated from Sphagneticola trilobata (L.) Pruski, has been demonstrated to exert anti-inflammatory, anticancer, and antihuman immunodeficiency virus effects. Methods: In this study, we identified KA as a novel activator of PPARγ with potent anti-inflammatory and antitumor effects both in vitro and in vivo. Given the potential of PPARγ regulators in overcoming radioresistance and chemoresistance in cancer therapies, we hypothesized that KA may enhance the efficacy of breast cancer radiotherapy. Results: In a lipopolysaccharide (LPS)-induced mouse inflammation model, KA treatment reduced the levels of pro-inflammatory cytokines, including COX-2, IL-6, IL-1β, and TNFα. In a xenograft mouse mode of breast cancer, KA treatment inhibited tumor growth. Specifically, KA treatment enhanced caspase-3 activity and cytotoxicity against MDA-MB-231 and MCF-7 breast cancer cells. When KA was co-treated with a caspase inhibitor, Z-VAD-FMK, caspase-dependent apoptosis was suppressed in these cells. KA was found to induce the generation of cytosolic calcium ions (Ca[2+]) and reactive oxygen species (ROS), triggering endoplasmic reticulum (ER) stress via the PERK-ATF4-CHOP axis. Hence, the ER stressor thapsigargin (TG) synergized with KA treatment to enhance apoptosis in these cells, while the loss of the PERK or CHOP function inhibited this phenomenon. KA treatment was shown to induce oxidative stress via the NADPH oxidase 4 (NOX4) and stimulate ROS production. Specifically, NOX4 knockdown (KD) and antioxidant treatment (N-acetyl cysteine or diphenyleneiodonium) suppressed such ER stress-mediated apoptosis by inhibiting KA-enhanced caspase-3 activity, cytotoxicity, and intracellular ROS production in the treated cells. In radioresistant MDA-MB-231R and MCF-7R cells, KA combined with 2 Gy radiation overcame radioresistance by upregulating PPARγ and modulating epithelial-mesenchymal transition (EMT) markers, such as E-cadherin, N-cadherin, and vimentin. In PPARγ KD MDA-MB-231R and MCF-7R cells, this phenomenon was inhibited due to reduced PPARγ and NOX4 expression. Conclusions: In conclusion, these findings demonstrated KA as a novel PPARγ regulator with promising potential to enhance the efficacy of breast cancer radiotherapy.},
}
@article {pmid39770034,
year = {2024},
author = {Karwowski, BT},
title = {A Comparison of the Electronic Properties of Selected Antioxidants Vitamin C, Uric Acid, NAC and Melatonin with Guanosine Derivatives: A Theoretical Study.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {24},
pages = {},
pmid = {39770034},
issn = {1420-3049},
support = {503/3-045-02/503-31-002//Medical University of Lodz/ ; },
mesh = {*Melatonin/chemistry/pharmacology ; *Antioxidants/chemistry/pharmacology ; *Ascorbic Acid/chemistry/pharmacology ; *Uric Acid/chemistry ; *Acetylcysteine/chemistry/pharmacology ; *Guanosine/chemistry ; Electrons ; Humans ; Oxidation-Reduction ; Models, Theoretical ; },
abstract = {Each cell in the human body is continually exposed to harmful external and internal factors. During evolution, cells have developed various defence systems, divided into enzymatic and non-enzymatic types, to which low-weight molecule antioxidants belong. In this article, the ionisation potential and electron affinity, as well as global reactivity descriptors of Vitamin C, Melatonin, Uric Acids, and N-acetyl-L-cysteine, were theoretically investigated at the MP-2/aug-cc-pVTZ level of theory in the condensed (aqueous) phase. The vertical ionisation potential and electron affinity are discussed in terms of non-equilibrated and equilibrated solvent-solute interactions. Additionally, at the same theoretical level, the electronic properties of canonical and oxidised derivatives of guanine were analysed. The presented results indicate that the selected antioxidants for this study (Vitamin C, Uric Acid, NAC, and Melatonin) exhibit the highest adiabatic electron affinity, while guanine derivatives (Gua, [OXO]Gua, Guo, dGuo, [OXO]Guo, [OXO]dGuo) are more prone to adiabatic radical cation formation. A red-ox balance (redox homeostasis) is crucial for intracellular signalling pathways that are reactive oxygen and nitrogen species (RO/NS)-dependent. Should this gentle balance be disrupted, either by an overload or deficit of species, physiological consequences may result, which in turn lead to pathological outcomes. On the other hand, maintaining the stability of the above balance of antioxidants/radicals may result in the improved effectiveness and safety of anticancer radiotherapy/chemotherapy or combined therapies with a subsequent increase in a patient's quality of life.},
}
@article {pmid39765760,
year = {2024},
author = {Martin, V and Trus, M and Atlas, D},
title = {Thiol-Based Redox Molecules: Potential Antidotes for Acrylamide Toxicity.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {12},
pages = {},
pmid = {39765760},
issn = {2076-3921},
support = {MYP G5852//North Atlantic Treaty Organization/ ; },
abstract = {Acrylamide (ACR) is a low-molecular weight, non-aromatic reagent, widely used in industry, such as in the manufacture of paper, textiles, plastics, cosmetics, and dyes. ACR is formed during the cooking of starchy food and its toxicity results mainly by conferring oxidative stress by elevating reactive oxygen species (ROS). To identify potential antidotes for ACR toxicity, we evaluated the efficacy of several thiol-based molecules known for ROS-scavenging, disulfide-reducing properties, and inhibition of oxidative stress-induced activation of the mitogen-activated protein kinases (MAPKs): the extracellular-signal-regulated-kinases (ERK1/2), p38-mitogen-activated-protein-kinases (p38[MAPK]), and c-Jun-N-terminal-kinases (JNKs). We established a reproducible assay testing N-acetylcysteine (NAC), AD4/NACA, and the N-and C-blocked tri- and tetra-thioredoxin-mimetic (TXM) peptides, in PC12 cells. Our results demonstrate that these compounds exhibited high efficacy in suppressing ACR-induced MAPK activation, either prior to or subsequent to ACR exposure. The inhibition by single cysteine (Cys) residue, NAC and AD4/NACA (NAC-amide), 2 Cys peptides TXM-CB30, AcDCys-Gly-DCysNH2, TXM-CB20, AcCys-Gly-CysNH2, SuperDopa (SD, Ac-CysL-Levodopa-CysNH2, TXM-CB13, AcCys-Met-Lys-CysNH2, and a 3-Cys peptide, TXM-CB16, AcCys-γGlu-Cys-CysNH2 was dose-dependent and potency displayed a direct correlation with the number of Cys residues. Cellular proteolysis of SD, which consists of levodopa flanked by two Cys, may suppress the manifestation of Parkinson's disease (PD)-like symptoms mediated by chronic ACR exposure not only through lowering oxidative stress but also by replenishing cellular levels of dopamine. Overall, these results could advance the clinical application of TXM peptides as potential treatments for acute and/or chronic exposure to ACR and show promise as antidotes for preventing ACR-triggered PD-like neurotoxic symptoms.},
}
@article {pmid39765110,
year = {2025},
author = {Farhadi, M and Sohbatzadeh, F and Moghaddam, AH and Firouzjaei, Y and Cheng, C},
title = {Enhancing the efficacy of low doses of N-acetyl-L-cysteine in mitigating CCl4-induced hepatotoxicity in animal model using physical cold plasma.},
journal = {Ecotoxicology and environmental safety},
volume = {289},
number = {},
pages = {117642},
doi = {10.1016/j.ecoenv.2024.117642},
pmid = {39765110},
issn = {1090-2414},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage/therapeutic use ; Carbon Tetrachloride/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention &amp; control ; Rats ; Male ; Oxidative Stress/drug effects ; *Antioxidants/pharmacology ; Liver/drug effects/pathology/metabolism ; *Plasma Gases ; Glutathione/metabolism ; Kidney/drug effects/pathology ; Rats, Wistar ; Disease Models, Animal ; },
abstract = {Liver diseases have become widespread especially due to various factors of modern life. Although the effect of N-acetyl-L-cysteine (NAC) is investigated in the recovery of liver damage, gas plasma therapy can be identified as a promising candidate. Our study aimed to enhance the effectiveness of ineffective doses of NAC in stopping CCl4-induced hepatotoxicity in rats by physical cold plasma. The plasma-treated NAC (PTN) structural changes were investigated through FTIR and LCMS/MS analysis. It was observed that the PTN consists of various chemical bioproducts with different molecular weights. We investigated an ineffective dose of NAC and its parallel effect through the administration of PTN on liver and kidney morphology and several biochemical factors including ALT, AST, and ALP. Additionally, we examined oxidative stress, antioxidant parameters, and glutathione (GSH) levels. Results showed that PTN exhibited greater antioxidant properties and increased GSH levels, contributing to its therapeutic effects. Also, the antioxidant enzymes and oxidative stress activities improved after receiving PTN. It also enhanced histological parameters, although various damages were detected in both liver and kidney tissues after CCl4 injection, PTN remarkably prevented the tissue changes caused by CCl4. PTN could protect against liver damage even at a very low dose of NAC, acting as a prophylactic drug with a high margin of safety for hepatotoxicity.},
}
@article {pmid39760429,
year = {2025},
author = {Li, X and Duan, Z and Zhao, Z and Zhang, X and Cheng, W and Guo, W and Wang, B},
title = {Mercury(II)-Triggered Targeted and NIR-II Fluorescence/Photoacoustic Imaging Probe for High-Sensitivity Early Diagnosis and Evaluating Drug against Acute Liver and Kidney Injury.},
journal = {Analytical chemistry},
volume = {97},
number = {2},
pages = {1446-1456},
doi = {10.1021/acs.analchem.4c06622},
pmid = {39760429},
issn = {1520-6882},
mesh = {*Mercury/analysis ; Animals ; Mice ; *Photoacoustic Techniques/methods ; *Acute Kidney Injury/drug therapy/chemically induced/diagnostic imaging ; *Optical Imaging ; Early Diagnosis ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Chemical and Drug Induced Liver Injury/drug therapy/diagnostic imaging ; Acetylcysteine/pharmacology/therapeutic use ; Male ; Mice, Inbred C57BL ; Infrared Rays ; },
abstract = {Mercury ions (Hg[2+]) have been found to disrupt the body's antioxidant defense mechanisms, leading to oxidative stress and physiological dysfunction. Early diagnosis and real-time monitoring of Hg[2+] fluctuations in organ damage are crucial but limited due to the lack of noninvasive and deep tissue imaging probes. Herein, a Hg[2+]-triggered targeted and NIR-II fluorescence/photoacoustic (PA) dual-mode molecular probe (NHG-2) was developed for real-time monitoring Hg[2+] fluctuations in Hg[2+]-induced acute liver and kidney injury mice. NHG-2 was designed through rational adjustment of the conjugated ring structure and further screening processes, enabling it to sensitively recognize Hg[2+] and subsequently open mitochondrial targeting, producing NIR-II fluorescence/PA signals. This probe allowed for noninvasive NIR-II fluorescence/PA imaging for real-time monitoring of Hg[2+]-induced acute liver and kidney injury, demonstrating excellent detection sensitivity. Furthermore, NHG-2 can be utilized to evaluate the efficacy of N-acetylcysteine (NAC) in Hg[2+]-induced liver and kidney injury through dual signal indication. Mechanism studies suggested that NAC activated the antioxidant Akt/Nrf2 signaling pathway, reversed the changes of related biomarkers, and restored mitochondrial membrane potential. Thus, this study not only presents the first specific NIR-II fluorescence/PA dual-mode probe for Hg[2+] but also provides a potential tool for early diagnosis and treatment evaluation and potential pathogenesis study.},
}
@article {pmid39756697,
year = {2025},
author = {Mapamba, DA and Sabi, I and Lalashowi, J and Sauli, E and Buza, J and Olomi, W and Mtafya, B and Kibona, M and Bakuli, A and Rachow, A and Velen, K and Hoelscher, M and Ntinginya, NE and Charalambous, S and Churchyard, G and Wallis, RS and , },
title = {N-acetylcysteine modulates markers of oxidation, inflammation and infection in tuberculosis.},
journal = {The Journal of infection},
volume = {90},
number = {2},
pages = {106379},
doi = {10.1016/j.jinf.2024.106379},
pmid = {39756697},
issn = {1532-2742},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; Adult ; Male ; Biomarkers/blood ; Female ; Middle Aged ; *Tuberculosis, Pulmonary/drug therapy ; Sputum/microbiology/chemistry ; Inflammation/drug therapy ; Mycobacterium tuberculosis/drug effects ; Glutathione/blood/analysis ; *Antitubercular Agents/therapeutic use ; Oxidation-Reduction ; Cytokines/blood ; Oxidative Stress/drug effects ; Young Adult ; },
abstract = {BACKGROUND: Half the global tuberculosis health burden is due to post-tuberculosis lung disease. Host-directed therapies have been proposed to reduce this burden. N-acetylcysteine (NAC) provides the conditionally essential amino acid cysteine required for synthesis of glutathione, an antioxidant thiol. We recently reported clinical outcomes of a trial of adjunctive NAC in patients with pulmonary tuberculosis, finding that NAC improved the secondary endpoint of recovery of lung function. Here we report the effects of NAC on biomarkers of oxidation, inflammation, and infection in that trial.<br><br>METHODS: 140 adults with moderate or far-advanced pulmonary tuberculosis were randomly assigned to standard tuberculosis treatment with or without NAC 1200&#xa0;mg twice daily for months 1-4. Sputum and blood samples were obtained at specified intervals to measure total glutathione, MTB-induced cytokines, hemoglobin, whole blood mycobactericidal activity (WBA), and sputum MTB burden.<br><br>RESULTS: NAC treatment rapidly increased total glutathione (P<.0001), but levels did not reach those of healthy volunteers (P<.001). NAC reduced MTB-induced TNF-&#x3b1; (P =.011) without affecting IL-10, and accelerated the recovery of hemoglobin in participants with low values on entry. NAC did not affect killing in ex vivo whole blood culture but did slow the clearance of MTB from sputum (P=0.003).<br><br>CONCLUSION: Adjunctive NAC showed antioxidant and anti-inflammatory effects consistent with the amelioration of immunopathology seen in preclinical models. Two biomarkers of antimicrobial activity showed discordant results; neither demonstrated the enhanced antimicrobial effects seen preclinically. The reduction of oxidative stress and inflammation by NAC may explain its effects on the recovery of lung function post-TB.},
}
@article {pmid39752784,
year = {2025},
author = {Lin, J and Zhang, T and Zhang, L},
title = {Arsenite-induced liver apoptosis via oxidative stress and the MAPK signaling pathway in marine medaka.},
journal = {Aquatic toxicology (Amsterdam, Netherlands)},
volume = {279},
number = {},
pages = {107226},
doi = {10.1016/j.aquatox.2024.107226},
pmid = {39752784},
issn = {1879-1514},
mesh = {Animals ; *Oryzias/physiology ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; *Liver/drug effects/metabolism/pathology ; *Water Pollutants, Chemical/toxicity ; *MAP Kinase Signaling System/drug effects ; *Arsenites/toxicity ; Reactive Oxygen Species/metabolism ; Cell Line ; Hepatocytes/drug effects ; },
abstract = {Arsenic (As) is widely recognized for its hazards to aquatic organisms; however, its toxicological impacts on apoptosis in marine fish remain inadequately explored. This study investigated the effects of in vivo dietary exposure to 50 or 500 mg/kg AsIII (as NaAsO2) over 28 days in marine medaka, alongside in vitro exposure to 50-750 μg/L AsIII for 48 h in a hepatic cell line derived from marine medaka, to elucidate the toxicity and underlying molecular mechanisms. In vivo, As significantly accumulated in liver tissue (1.79-fold compared to the control), causing hepatic lesions and increased apoptosis (4.85 ± 0.56 % and 9.29 ± 1.82 %, respectively). Gene expression analysis showed downregulation of bcl2l1 and upregulation of bax, caspase-3 and caspase-9, indicating mitochondrial pathway-mediated apoptosis. In vitro, As exposure induced hepatocyte morphological changes, reactive oxygen species (ROS) production, and apoptosis. Additionally, mapk1 and mapk3 (ERK pathway) were downregulated both in vivo and in vitro, while mapk14a (P38 pathway), mapk8b and mapk9 (JNK pathway) were upregulated exclusively in hepatocytes. Furthermore, n-acetyl cysteine (NAC) attenuated As-induced apoptosis and modulated the expression of MAPK signaling pathway genes, including mapk3 and mapk8b, suggesting that As-induced oxidative stress regulates apoptosis via the MAPK signaling pathway. In contrast, phenylbutyric acid (PBA) was ineffective in preventing apoptosis. Overall, these results demonstrate that As induces endogenous apoptosis through oxidative stress and the MAPK signaling pathway in marine medaka.},
}
@article {pmid39748984,
year = {2024},
author = {Shokoohi, M and Khaki, AA and Roshangar, L and Nasr Esfahani, MH and Soltani, GG and Alihemmati, A},
title = {The impact of N-acetylcysteine on hypoxia-induced testicular apoptosis in male rats: TUNEL and IHC findings.},
journal = {Heliyon},
volume = {10},
number = {22},
pages = {e40097},
pmid = {39748984},
issn = {2405-8440},
abstract = {The present study aimed to evaluate the impact of N-acetylcysteine (NAC) on testicular hypoxia caused by varicocele, focusing specifically on the regulation of genes related to apoptosis and oxidative stress in the testes of mature Wistar rats. Thirty-two rats were divided into four groups: Control (Sham), hypoxia, testicular hypoxia treated with NAC (Hypoxia + NAC), and healthy animals treated with NAC. After the 8-week treatment period, testicular histopathology and the levels of oxidative stress markers-superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA)-in serum were examined. The expression of Bax and Bcl-2 mRNA was analyzed using immunocytochemistry and RT-qPCR assays, while the apoptosis rate was determined using the TUNEL method. Histopathological evaluations showed that parameters such as Johnsen's score, epithelium width, and seminiferous tubule diameter indicated significant improvement in the Hypoxia + NAC group compared to the Hypoxia group. NAC administration resulted in elevated serum levels of GPx and SOD, accompanied by a reduction in MDA levels (p < 0.003). Furthermore, the study revealed that NAC decreased Bax expression and enhanced Bcl-2 gene and protein expression compared to the varicocele group (p < 0.05). Additionally, NAC administration significantly decreased the rate of apoptosis in germ cells (p < 0.05). These findings suggest that NAC administration can mitigate testicular damage induced by hypoxia from varicocele in rats, primarily due to its antioxidant properties.},
}
@article {pmid39747891,
year = {2025},
author = {Bahramibanan, F and Rad, MV and Ranjbar, A and Karbasi, A and Abbasifard, A},
title = {Comparison of oxidative stress status in the kidney tissue of male rats treated with paraquat and nanoparaquat.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {389},
pmid = {39747891},
issn = {2045-2322},
mesh = {Animals ; *Paraquat/toxicity ; *Oxidative Stress/drug effects ; Male ; *Kidney/metabolism/drug effects ; *Rats, Wistar ; Rats ; *Lipid Peroxidation/drug effects ; *Antioxidants/metabolism ; Malondialdehyde/metabolism ; Herbicides/toxicity ; Nanoparticles ; Acetylcysteine/pharmacology ; },
abstract = {The study aimed to compare the oxidative stress status in the kidney tissue of rats treated with paraquat and nanoparaquat. The levels of oxidative stress markers, including malondialdehyde (MDA), total antioxidant capacity (TAC), and thiol groups (TTG), were measured in the kidney tissue samples. A total of forty male Wistar rats were randomly assigned to eight groups, each consisting of five rats: a control group, a paraquat (PQ) group, an N-acetylcysteine (NAC) group, groups receiving nanoparaquat α and β (α and β), groups receiving PQ and NAC (PQ + NAC), and groups receiving nanoparaquat α and β with NAC (+ NACα and β). Paraquat, a widely used herbicide, induces severe oxidative damage in kidneys through radical formation and cellular stress. Newly developed nanoparaquat formulations may modify its toxicity profile and tissue distribution patterns. The results revealed that rats treated with paraquat showed a significant increase in Lipid Peroxidation Oxidation (LPO) levels compared to the control group and those treated with NAC. However, treatment with nanoparaquat α and β resulted in a decrease in LPO levels compared to the paraquat-treated group. Additionally, when nanoparaquat α and β were administered in combination with NAC, a further reduction in LPO levels was observed compared to the PQ treated group. Regarding TAC levels, the PQ group exhibited a significant decrease compared to the control group and the NAC-treated group. However, treatment with nanoparaquat β resulted in higher TAC levels compared to the PQ group. Moreover, when nanoparaquat α and β were administered in combination with NAC, there was an increase in TAC levels compared to the PQ group. In terms of TTG levels, the PQ group showed a significant decrease compared to the control group and the NAC group. However, treatment with nanoparaquat β led to an increase in TTG levels compared to the PQ group. Furthermore, when nanoparaquat α and β were administered in combination with NAC, there was an increase in TTG levels compared to the PQ group. Overall, the results suggest that treatment with nanoparaquat, especially nanoparaquat β, may have a protective effect against oxidative stress induced by PQ toxicity in the kidney tissue of rats. Further studies are warranted to elucidate the underlying mechanisms and potential therapeutic implications of nanoparaquat in oxidative stress-related kidney disorders.},
}
@article {pmid39742610,
year = {2025},
author = {Yang, X and Li, Y and Shen, R and Song, R and Duan, Y and Zhang, X and Shi, H and Kong, X and Hua, Y and Zhang, L},
title = {New insights into the tenderization pattern of yak meat by ROS-ERS: Promotion of ERS-associated apoptosis through feedback regulation of PERK/IRE1/ATF6 and caspase-12 activity.},
journal = {Food chemistry},
volume = {470},
number = {},
pages = {142705},
doi = {10.1016/j.foodchem.2024.142705},
pmid = {39742610},
issn = {1873-7072},
mesh = {Animals ; Cattle ; *Reactive Oxygen Species/metabolism ; *Apoptosis ; *Endoplasmic Reticulum Stress ; *Meat/analysis ; *Caspase 12/metabolism/genetics ; *Activating Transcription Factor 6/metabolism/genetics ; *eIF-2 Kinase/metabolism/genetics ; Muscle, Skeletal/metabolism ; },
abstract = {This study aimed to investigate the molecular mechanisms of reactive oxygen species (ROS)-induced endoplasmic reticulum stress (ERS) in apoptosis and meat tenderization during postmortem aging. Yak longissimus dorsi muscle was incubated with N-acetylcysteine (NAC), 4-phenylbutyric acid (4-PBA) and NAC + 4-PBA, respectively, and stored at 4 °C for 0 h, 12 h, 24 h, 72 h, 120 h and 168 h. The results showed that NAC and 4-PBA treatments significantly reduced ROS content and endoplasmic reticulum stress levels. Meanwhile, the specific inhibitory effect of 4-PBA affected Ca[2+] content, caspase-12 activity, endoplasmic reticulum apoptotic cascade reaction and meat tenderization by preventing myogenic fiber degradation. Additionally, the combined treatment of NAC + 4-PBA had a more significant effect than the other groups, confirming the necessity of targeted regulation of the ROS-ERS axis. Overall, our findings provide new insights into the critical role of ROS-mediated ERS in caspase-12-dependent apoptosis and yak meat tenderization during yak meat postmortem.},
}
@article {pmid39739120,
year = {2024},
author = {Essam, R and Nasr, M and Khater, MW and Fayez, B and Anis, N},
title = {Anti-microbial impact of non-antibiotic agents; salicylic acid, N-acetylcysteine, and isotretinoin against Cutibacterium acnes in patients with acne vulgaris.},
journal = {Archives of dermatological research},
volume = {317},
number = {1},
pages = {155},
pmid = {39739120},
issn = {1432-069X},
mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Young Adult ; *Acetylcysteine/pharmacology/therapeutic use ; *Acne Vulgaris/drug therapy/microbiology ; Anti-Bacterial Agents/pharmacology/therapeutic use ; *Biofilms/drug effects ; *Isotretinoin/therapeutic use/pharmacology ; Microbial Sensitivity Tests ; Propionibacterium acnes/drug effects/isolation &amp; purification ; *Salicylic Acid ; },
abstract = {There are two main strategies to eliminate Cutibacterium acnes and to reduce antibiotic resistance in acne treatment. The first is to target the pathogenic bacteria and the second is to change the environment for their growth. The present study aimed to evaluate the anti-microbial role of non-antibiotic agents against Cutibacterium acnes (C. acnes) in acne vulgaris patients. The three agents of interest in the study were isotretinoin, salicylic acid, and N-acetylcysteine (NAC). The study included forty-eight patients with acne vulgaris with ages ranging from 16 to 30 years, and they had different grades of the disease. Azithromycin and Doxycycline sensitivity and the ability of biofilm formation of C. acnes isolated from all patients were assessed before and after adding the 3 agents. Azithromycin and Doxycycline sensitivity was improved after adding the 3 agents and the ability of biofilm formation of C. acnes was also reduced. Isotretinoin, salicylic acid, and NAC can be promising adjuvants in treating acne vulgaris by their anti-microbial effect in reducing biofilm formation and improving antibiotic sensitivity. Clinical Trial NCT06179056.},
}
@article {pmid39738092,
year = {2024},
author = {Higazy, D and Ahmed, MN and Ciofu, O},
title = {The impact of antioxidant-ciprofloxacin combinations on the evolution of antibiotic resistance in Pseudomonas aeruginosa biofilms.},
journal = {NPJ biofilms and microbiomes},
volume = {10},
number = {1},
pages = {156},
pmid = {39738092},
issn = {2055-5008},
mesh = {*Biofilms/drug effects/growth &amp; development ; *Ciprofloxacin/pharmacology ; *Pseudomonas aeruginosa/drug effects/genetics/physiology ; *Antioxidants/pharmacology ; *Microbial Sensitivity Tests ; *Anti-Bacterial Agents/pharmacology ; *Mutation ; *Drug Resistance, Bacterial ; Whole Genome Sequencing ; Bacterial Proteins/genetics/metabolism ; Acetylcysteine/pharmacology ; Oxidative Stress/drug effects ; DNA-Binding Proteins ; Transcription Factors ; },
abstract = {The evolution of antimicrobial resistance (AMR) in biofilms, driven by mechanisms like oxidative stress, is a major challenge. This study investigates whether antioxidants (AOs) such as N-acetyl-cysteine (NAC) and Edaravone (ED) can reduce AMR in Pseudomonas aeruginosa biofilms exposed to sub-inhibitory concentrations of ciprofloxacin (CIP). In vitro experimental evolution studies were conducted using flow cells and glass beads biofilm models. Results showed that combining CIP with antioxidants (CIP-AOs) effectively reduced the development of CIP resistance. Isolates from biofilms treated with CIP-AO had significantly lower minimum inhibitory concentrations (MICs) of CIP compared to those treated with CIP alone. Whole-genome sequencing (WGS) revealed mutations in the negative regulators of efflux pumps, nfxB, and nalC, in CIP-only treated biofilm populations. The occurrence of nfxB mutations was significantly lower in flow cell biofilms treated with CIP-AO compared to CIP alone. These findings suggest that antioxidants could play a role in mitigating AMR development in biofilms.},
}
@article {pmid39737962,
year = {2024},
author = {Xing, T and Hu, LJ and Zhao, HY and Li, CY and Wang, ZK and Shen, MZ and Lyu, ZS and Wang, J and Wang, Y and Jiang, H and Jiang, Q and Chang, YJ and Zhang, XH and Kong, Y and Huang, XJ},
title = {Bone Marrow Endothelial Progenitor Cells remodelling facilitates normal hematopoiesis during Acute Myeloid Leukemia Complete Remission.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {10832},
pmid = {39737962},
issn = {2041-1723},
mesh = {*Leukemia, Myeloid, Acute/pathology/drug therapy ; Animals ; *Hematopoiesis ; Humans ; *Endothelial Progenitor Cells/metabolism ; Mice ; *Acetylcysteine/pharmacology ; *Remission Induction ; Male ; Female ; Bone Marrow/pathology ; Mice, Inbred C57BL ; Hematopoietic Stem Cells/metabolism ; Tumor Microenvironment ; Reactive Oxygen Species/metabolism ; Middle Aged ; Adult ; Disease Models, Animal ; },
abstract = {Although acute myeloid leukemia (AML) affects hematopoietic stem cell (HSC)-supportive microenvironment, it is largely unknown whether leukemia-modified bone marrow (BM) microenvironment can be remodeled to support normal hematopoiesis after complete remission (CR). As a key element of BM microenvironment, endothelial progenitor cells (EPCs) provide a feasible way to investigate BM microenvironment remodeling. Here, we find reduced and dysfunctional BM EPCs in AML patients, characterized by impaired angiogenesis and high ROS levels, could be partially remodeled after CR and improved by N-acetyl-L-cysteine (NAC). Importantly, HSC-supporting ability of BM EPCs is partially recovered, whereas leukemia-supporting ability is decreased in CR patients. Mechanistically, the transcriptome characteristics of leukemia-modified BM EPCs return to near-normal after CR. In a classic AML mouse and chemotherapy model, BM vasculature and normal hematopoiesis are reversed after CR. In summary, we provide further insights into how leukemia-modified BM microenvironment can be remodeled to support normal hematopoiesis after CR, which can be further improved by NAC.},
}
@article {pmid39737637,
year = {2025},
author = {Coşkun, &#xc7; and Aksu, T and Gülhan, B and Düzova, A and Ünal, &#x15e;},
title = {Plasma Exchange and N-Acetylcysteine Therapy in a Case of Congenital Thrombotic Thrombocytopenic Purpura Presenting With Acute Renal Failure.},
journal = {Journal of pediatric hematology/oncology},
volume = {47},
number = {1},
pages = {e65-e67},
doi = {10.1097/MPH.0000000000002963},
pmid = {39737637},
issn = {1536-3678},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Acute Kidney Injury/etiology/therapy ; ADAM Proteins/genetics ; *ADAMTS13 Protein/deficiency/genetics ; Mutation ; *Plasma Exchange ; *Purpura, Thrombotic Thrombocytopenic/therapy/drug therapy/genetics/complications ; Child ; },
abstract = {Congenital thrombotic thrombocytopenic purpura (cTTP), which is associated with mutations in the gene for a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13), is a chronic and lifelong disease. The clinical course is variable. Regularly using ADAMTS13-containing products such as fresh frozen plasma (FFP) for long-term prophylaxis is the most important treatment to prevent thrombotic microangiopathy (TMA) episodes. Here, we identified novel pathogenic mutations of ADAMTS13 in our patients who experienced severe acute renal failure. Infections can trigger acute hemolytic episodes, and if the initiation of FFP therapy is delayed, this leads to severe organ dysfunction, as in our case. We have shown that regular use of products containing ADAMTS13 can reverse TMA episodes and long-term morbidity and mortality. When severe acute renal failure occurs, daily plasma exchange and N-acetylcysteine (NAC) are useful.},
}
@article {pmid39736315,
year = {2025},
author = {Mao, K and Huang, Y and Liu, Z and Sui, W and Liu, C and Li, Y and Zeng, J and Qian, X and Ma, X and Lin, X and Lou, B},
title = {Oxidative stress mediates retinal damage after corneal alkali burn through the activation of the cGAS/STING pathway.},
journal = {Experimental eye research},
volume = {251},
number = {},
pages = {110228},
doi = {10.1016/j.exer.2024.110228},
pmid = {39736315},
issn = {1096-0007},
mesh = {Animals ; *Oxidative Stress/physiology ; Mice ; *Membrane Proteins/metabolism ; *Eye Burns/chemically induced/metabolism/pathology ; *Nucleotidyltransferases/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Signal Transduction ; Apoptosis ; *Burns, Chemical/metabolism/pathology ; *Corneal Injuries/chemically induced/metabolism ; *Retinal Diseases/metabolism/etiology/pathology ; Male ; Retina/pathology/metabolism ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; },
abstract = {Retinal damage accounts for irreversible vision loss following ocular alkali burn (OAB), but the underlying mechanisms remain largely unexplored. Herein, using an OAB mouse model, we examined the impact of oxidative stress (OS) in retinal damage and its molecular mechanism. Results revealed that OS in the retina was enhanced soon after alkali injury. Antioxidant therapy with N-acetylcysteine (NAC) preserved the retinal structure, suppressed cell apoptosis and decreased retinal inflammation, confirming the role of OS. Moreover, enhanced OS was linked to mitochondrial dysfunction, mtDNA leakage and initiation of the cytosolic DNA-sensing signaling. The activation of the major DNA sensors cyclic GMP-AMP Synthase (cGas) and cGAS-Stimulator of Interferon Genes (cGAS/STING) pathway was then identified. Notably, inhibiting cGAS/STING signaling with C-176 markedly reduced inflammation and cell apoptosis and ultimately protected the retina against OAB. Overall, our study reveals the vital function of OS in the occurrence of OAB-induced retinal damage and the involvement of cGAS/STING activation. Furthermore, our provides preclinical validation of the use of an antioxidant or a STING inhibitor as a potential therapeutic approach to protect the retina after OAB.},
}
@article {pmid39734022,
year = {2025},
author = {Li, Z and Nie, J and Zhou, R and Huang, H and Li, X and Wang, L and Lv, L and Ren, S and Zhao, M},
title = {Thiostrepton suppresses colorectal cancer progression through reactive oxygen species related endoplasmic reticulum stress.},
journal = {Toxicology and applied pharmacology},
volume = {495},
number = {},
pages = {117221},
doi = {10.1016/j.taap.2024.117221},
pmid = {39734022},
issn = {1096-0333},
mesh = {*Endoplasmic Reticulum Stress/drug effects/physiology ; *Reactive Oxygen Species/metabolism ; *Colorectal Neoplasms/drug therapy/pathology/metabolism ; Humans ; Animals ; Endoplasmic Reticulum Chaperone BiP ; *Thiostrepton/pharmacology/therapeutic use ; Apoptosis/drug effects ; Mice, Nude ; Cell Movement/drug effects ; Xenograft Model Antitumor Assays ; Mice ; Mice, Inbred BALB C ; Cell Line, Tumor ; HCT116 Cells ; *Antineoplastic Agents/pharmacology ; Disease Progression ; Cell Survival/drug effects ; },
abstract = {Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Due to the poor therapeutic efficacy of CRC treatments and poor prognosis of the disease, effective treatment strategies are urgently needed. As long-term proteotoxic stress is a major cause of cell death, agents that induce proteotoxic stress offer a promising strategy for cancer intervention. Thiostrepton is a natural antibiotic derived from the Streptomyces genus. In the present study, we found that thiostrepton triggered apoptosis, reduced the migration of CRC cells, and inhibited xenograft tumour growth in vivo. Mechanistically, thiostrepton reduced proteasome activity; induced the aggregation of ubiquitinated proteins; caused endoplasmic reticulum (ER) stress, which was characterized by increased protein levels of GRP78, ATF4, P-eIF2α, and CHOP and cytosolic calcium release; and ultimately resulted in cell death. Thiostrepton-related changes in cell survival and cell migration, as well as mechanistical processes, were almost completely reversed by treatment with the antioxidant N-acetylcysteine (NAC), suggesting that the mechanism is dependent on reactive oxygen species (ROS). These results demonstrated that thiostrepton induced apoptosis and inhibited migration through ROS-induced ER stress and proteotoxic stress in colorectal cancer.},
}
@article {pmid39731665,
year = {2024},
author = {Rasheed, H and Ijaz, M and Ahmed, A and Ali, MM},
title = {Antimicrobial resistance, virulence profiling, and drug repurposing analysis of Staphylococcus aureus from camel mastitis.},
journal = {Veterinary research communications},
volume = {49},
number = {1},
pages = {59},
pmid = {39731665},
issn = {1573-7446},
mesh = {Animals ; *Camelus ; Female ; *Staphylococcus aureus/drug effects/genetics/pathogenicity ; *Mastitis/veterinary/microbiology/drug therapy ; *Staphylococcal Infections/veterinary/microbiology/drug therapy ; *Anti-Bacterial Agents/pharmacology ; *Drug Resistance, Bacterial ; Virulence/genetics ; Drug Repositioning ; Virulence Factors/genetics ; Microbial Sensitivity Tests/veterinary ; Methicillin-Resistant Staphylococcus aureus/drug effects/genetics/pathogenicity ; Phylogeny ; },
abstract = {Camel mastitis especially caused by Staphylococcus aureus (S. aureus), is a major risk to animal health and milk production. The current investigation evaluated the antibiotic susceptibility and virulence factors of S. aureus isolates from subclinical mastitis in camels. A total of 384 milk samples were collected and submitted to isolate S. aureus. The S. aureus isolates exhibiting resistance to Penicillin and Cefoxitin disc on Kirby-Bauer disc diffusion method were considered as β-lactam resistant S. aureus (BRSA) and methicillin-resistant S. aureus (MRSA) which were further confirmed by PCR targeting blaZ and mecA genes, respectively. The results showed that S. aureus was found in 57.06% of subclinical (SCM) positive camel milk samples. A high molecular prevalence of BRSA and MRSA were found to be 48.51% and 46.53% respectively depicting that treating these infections is challenging due to their high resistance levels. The phylogenetic analysis revealed a significant resemblance of the study isolates with each other and with already reported sequences from different countries which shows the potential for the spread of pathogen. Virulence profiling of antibiotic resistance strains showed the presence of virulence markers (nuc and coag genes), intercellular adhesion genes (icaA, icaD), Panton-Valentine leukocidin (pvl) gene, and enterotoxin-producing genes including sea, seb, sec, and sed. In-vitro antibiotic susceptibility testing revealed that the most resistant antibiotic group was penicillin followed by aminoglycosides and cephalosporins. Drug repurposing analysis of different non-antibiotics for combination therapies with resistant antibiotics was done to combat the S. aureus isolates harboring the mecA and blaZ genes. The results revealed the synergistic effect of amoxicillin, sulfamethoxazole, gentamicin, and doxycycline with ketoprofen, amikacin with flunixin meglumine, and gentamicin with N-acetylcysteine (NAC) against study isolates. The current investigation provides the status of antibiotic-resistant strains and virulence factors of S. aureus in the udder of dromedary camels. The combinational therapy of resistant antibiotics with non-antibiotics provides a potential therapeutic option for the treatment of resistant strains.},
}
@article {pmid39730568,
year = {2024},
author = {Li, M and Liu, Z and Cao, X and Xiao, W and Wang, S and Zhao, C and Zhao, Y and Xie, Y},
title = {[Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {30924},
pmid = {39730568},
issn = {2045-2322},
support = {81670742//National Natural Science Foundation of China/ ; SKJY2021082//Suzhou Municipal Health Commission/ ; ML12301323//Conversion Base - Endocrinology and Metabolism/ ; },
mesh = {Humans ; *Sirtuins/metabolism ; *Cellular Senescence/drug effects ; *Glucose/metabolism ; *Reactive Oxygen Species/metabolism ; *Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; },
abstract = {High glucose (HG) induced endothelial senescence is related to endothelial dysfunction and cardiovascular complications in diabetic patients. Humanin, a member of mitochondrial derived peptides (MDPs), is thought to contribute to aging-related cardiovascular protection. The goal of the study is to explore the pathogenesis of HG-induced endothelial senescence and potential anti-senescent effects of Humanin. Human umbilical vein endothelial cells (HUVECs) were exposed to glucose to induce senescence, determined by β-galactosidase staining and the expressions of p21, p53, and p16. A clinically relevant dose of HG (15 mM, HG) induced endothelial senescence after 72 h incubation without elevated apoptosis. HG-induced senescence was attributed to the induction of reactive oxygen species (ROS) caused by SIRT6 downregulation, as ROS inhibitor N-acetyl cysteine blocked HG-induced senescence, while inactivation of SIRT6 increased ROS levels and promoted senescence. Strikingly. pretreatment with [Gly14]-Humanin (HNG) antagonized the downregulation of SIRT6 in response to HG and alleviated ROS production and cell senescence. HG-induced reduction of SIRT6 results in ROS overproduction and endothelial senescence. Humanin protects against HG-induced endothelial senescence via SIRT6. This study provides new directions for biological products related to Humanin to be a potential candidate for the prevention of vascular aging in diabetes.},
}
@article {pmid39729531,
year = {2025},
author = {Muhammad, W and Liang, M and Wang, B and Xie, J and Ahmed, W and Gao, C},
title = {NAC-Grafted ROS-Scavenging Polymer Nanoparticles for Modulation of Acute Lung Injury Microenvironment In Vivo.},
journal = {Biomacromolecules},
volume = {26},
number = {1},
pages = {528-540},
doi = {10.1021/acs.biomac.4c01290},
pmid = {39729531},
issn = {1526-4602},
mesh = {*Acute Lung Injury/drug therapy/pathology/chemically induced/metabolism ; Animals ; *Nanoparticles/chemistry ; *Acetylcysteine/chemistry/pharmacology/administration &amp; dosage ; *Polymers/chemistry ; Mice ; Reactive Oxygen Species/metabolism ; *Free Radical Scavengers/chemistry/pharmacology ; Lipopolysaccharides/toxicity ; Male ; Oxidative Stress/drug effects ; },
abstract = {N-Acetyl cysteine (NAC) is an essential molecule that boosts acute lung injury (ALI) defense via its direct antioxidant capability. Nevertheless, the therapeutic use of NAC is limited due to its poor bioavailability and short half-life. In this study, NAC was grafted to the polyurethane consisting of poly(propylene fumarate), poly(thioketal), and 1,6-hexamethylene diisocyanate (PFTU) to reduce excessive oxidative stress and inflammatory factors in ALI. The NAC-grafted polymer nanoparticles (NPT@NPs) were prepared as a drug delivery system, which could effectively scavenge free radicals and reduce inflammation in vitro. The administration of NPT@NPs exhibited notable efficacy in ameliorating pulmonary edema, attenuating the presence of inflammatory cells, suppressing myeloperoxidase expression, diminishing the levels of pro-inflammatory cytokines, and reversing cell apoptosis in an ALI model induced by lipopolysaccharide (LPS). The NPT@NPs demonstrated significantly better efficacy compared to the free NAC in mitigating the deleterious effects of LPS on pulmonary tissue, thereby providing more effective protection against pulmonary inflammation.},
}
@article {pmid39727662,
year = {2024},
author = {Alrashed, M and Alyousef, A and Badreldin, HA and Bin Saleh, K and Al Harbi, S and Albekairy, AM and Alghamdi, A and Al-Nahdi, A and Alonazi, D and Alnuhait, M and Alshammari, A and Alqahtani, T},
title = {Comparison of Three-Bag Method Acetylcysteine Versus Two-Bag Method Acetylcysteine for the Treatment of Acetaminophen Toxicity: An Updated Systematic Review and Meta-Analysis.},
journal = {Diseases (Basel, Switzerland)},
volume = {12},
number = {12},
pages = {},
pmid = {39727662},
issn = {2079-9721},
abstract = {BACKGROUND: Acetaminophen is generally considered safe when used according to the recommended guidelines. Consumption in excessive doses can lead to severe liver damage and, in critical cases, may even result in death. To reduce the effects of acetaminophen overdose, N-acetylcysteine (NAC) has been established as the preferred intervention to prevent liver damage.<br><br>OBJECTIVES: The purpose of this updated systematic review and meta-analysis is to evaluate the potential benefits of a two-bag N-acetylcysteine (NAC) dosing regimen compared to the traditional three-bag protocol in the treatment of acetaminophen-induced liver toxicity.<br><br>METHODS: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The research team utilized the PubMed and Cochrane databases to perform a thorough and comprehensive search of the relevant literature from the inception of these databases up until January 2024.<br><br>RESULTS: Nine studies were included. The overall use of two-bag NAC was associated with lower anaphylactic reactions and gastrointestinal symptoms compared to the three-bag method. The rate of liver toxicity resolution was the same between the two treatment groups.<br><br>CONCLUSIONS: The two-bag NAC regimen can be considered a safe and effective method for managing acetaminophen toxicity.},
}
@article {pmid39726479,
year = {2024},
author = {Ntchana, A and Muhumza, R},
title = {Use of N-Acetylcysteine in the Management of Isoniazid-Induced Liver Injury in a Tuberculosis Patient: A Case Report.},
journal = {Cureus},
volume = {16},
number = {11},
pages = {e74445},
pmid = {39726479},
issn = {2168-8184},
abstract = {Drug-induced liver injury (DILI) is a rare but significant cause of acute liver failure, often challenging to diagnose due to its clinical similarity to other liver conditions. Since most drugs are metabolized by liver enzymes, the liver is at risk for hepatotoxicity. Although DILI has a low incidence in clinical practice, it remains a critical consideration for patients on potentially hepatotoxic medications. Acetaminophen is the most commonly implicated drug in DILI cases and is prioritized in toxicology screenings. Effective management of DILI requires the prompt discontinuation of the offending drug and supportive care. This case report discusses a 65-year-old male patient who developed elevated liver enzymes three weeks after starting tuberculosis treatment, raising suspicion of DILI. This report explores the diagnostic process, management strategies, and therapeutic role of N-acetylcysteine (NAC), emphasizing its mechanism of action, current clinical applications, and potential future uses in treating DILI.},
}
@article {pmid39725121,
year = {2025},
author = {Khanal, S and Shin, EJ and Yoo, CJ and Kim, J and Choi, DY},
title = {Inosine exerts dopaminergic neuroprotective effects via mitigation of NLRP3 inflammasome activation.},
journal = {Neuropharmacology},
volume = {266},
number = {},
pages = {110278},
doi = {10.1016/j.neuropharm.2024.110278},
pmid = {39725121},
issn = {1873-7064},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists &amp; inhibitors ; Animals ; *Inosine/pharmacology ; *Neuroprotective Agents/pharmacology ; *Inflammasomes/metabolism/drug effects ; Mice ; Microglia/drug effects/metabolism ; Humans ; Lipopolysaccharides/pharmacology ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Male ; Cell Line ; Cell Line, Tumor ; Cell Survival/drug effects ; *Dopaminergic Neurons/drug effects/metabolism ; },
abstract = {Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Transformation of pro-interleukin (IL)-1β into a mature IL-1β via active inflammasome may be related to the progression of PD. Therefore, the modification of inflammasome activity may be a potential therapeutic strategy for PD. Inosine has been shown to exert anti-inflammatory effects in various disease models. In this study, we evaluated inosine's inhibitory effects on the microglial NLRP3 inflammasome, which may be related to the dopaminergic neuroprotective effects of inosine. Inosine suppresses lipopolysaccharides (LPS)-induced NLRP3 inflammasome activation in BV-2 microglial cells dose dependently. When SH-SY5Y cells were treated with conditioned medium from BV-2 cells treated with LPS and inosine, an NLRP3 inhibitor, or a caspase-1 inhibitor, the viability of SH-SY5Y cells was reduced indicating that LPS-induced microglial inflammasome activation could contribute to neuronal death. Inosine's modulatory effect on NLRP3 inflammasome activity appears to rely on the adenosine A2A and A3 receptors activation, as A2A or A3 receptor antagonists reversed the amelioration of NLRP3 activation by inosine. In addition, inosine treatment attenuated intracellular and mitochondrial ROS production mediated by LPS and this effect might be related to attenuation of NLRP3 inflammasome activity, as the antioxidant, N-acetyl cysteine ameliorated LPS-induced activation of the inflammasome. Finally, we assessed the inosine's neuroprotective effects via inflammasome activity modulation in mice receiving an intranigral injection of LPS. Immunohistochemical analysis revealed that LPS caused a significant loss of nigral dopaminergic neurons, which was mitigated by inosine treatment. LPS increased NLRP3 expression in IBA1-positive microglial cells, which was attenuated by inosine injection. These findings indicate that inosine can rescue neurons from LPS-induced injury by ameliorating NLRP3 inflammasome activity. Therefore, inosine could be applied as an intervention for neuroinflammatory diseases such as Parkinson's disease.},
}
@article {pmid39724484,
year = {2025},
author = {Kokurcan, A and Sandıkçı, F and Yılmaz, M&#x15e; and Öztürk, U and Doğan, K and Yılmazer, D and Aydın, FN and Yalçındağ, A and İmamoğlu, A},
title = {Protective effects of tadalafil and N-acetyl cysteine therapy on cisplatin-induced testicular toxicity.},
journal = {International urology and nephrology},
volume = {57},
number = {5},
pages = {1441-1449},
pmid = {39724484},
issn = {1573-2584},
mesh = {Male ; Animals ; *Cisplatin/toxicity/adverse effects ; *Tadalafil/therapeutic use/pharmacology ; Rats, Wistar ; *Acetylcysteine/therapeutic use/pharmacology ; *Testis/drug effects/pathology/metabolism ; Rats ; Testosterone/blood ; *Antineoplastic Agents/adverse effects/toxicity ; Malondialdehyde/metabolism ; Drug Therapy, Combination ; Organ Size/drug effects ; *Phosphodiesterase 5 Inhibitors/therapeutic use ; Apoptosis/drug effects ; },
abstract = {PURPOSE: To investigate whether tadalafil (TAD) and N-acetyl cysteine (NAC) can prevent cisplatin (CIS)-induced testicular toxicity.<br><br>METHODS: Forty Wistar-Albino rats were divided into five groups: Control group, CIS group, TAD group, NAC group and TAD&#x2009;+&#x2009;NAC group. All groups were compared regarding body and testicular weights, testicular volumes, blood testosterone levels, testicular tissue malondialdehyde (MDA) levels, histopathological features, and testicular Cosentino and Johnsen scores.<br><br>RESULTS: There was no significant difference between the groups regarding body weights and Johnsen scores. It was observed that TAD and NAC affected the apoptotic index, and Cosentino scores were lower in these groups than in the control group. This effect was most prominent in the TAD&#x2009;+&#x2009;NAC group. The CIS treatment led to a decrease in serum testosterone levels. While testosterone levels were higher in the TAD Group, no statistically significant difference was found between the groups. Combination therapy and NAC did not affect blood testosterone levels.<br><br>CONCLUSIONS: Cisplatin has adverse effects on the testicular tissue. The histopathological changes caused by this agent can be prevented by TAD&#x2009;+&#x2009;NAC combination therapy.},
}
@article {pmid39721495,
year = {2025},
author = {Zhu, Y and Dutta, S and Han, Y and Choi, D and Polverino, F and Owen, CA and Somanath, PR and Wang, X and Zhang, D},
title = {Oxidative stress promotes lipid-laden macrophage formation via CYP1B1.},
journal = {Redox biology},
volume = {79},
number = {},
pages = {103481},
pmid = {39721495},
issn = {2213-2317},
support = {U54 AG062334/AG/NIA NIH HHS/United States ; KL2 TR002381/TR/NCATS NIH HHS/United States ; F32 HL147437/HL/NHLBI NIH HHS/United States ; R00 HL141685/HL/NHLBI NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; R03 AI169063/AI/NIAID NIH HHS/United States ; R56 HL163607/HL/NHLBI NIH HHS/United States ; },
mesh = {*Oxidative Stress/drug effects ; *Cytochrome P-450 CYP1B1/metabolism/genetics ; Humans ; Reactive Oxygen Species/metabolism ; *Macrophages/metabolism/drug effects ; Pulmonary Disease, Chronic Obstructive/metabolism/pathology/etiology ; Animals ; Mice ; Lipid Metabolism ; *Macrophages, Alveolar/metabolism ; Male ; },
abstract = {Emerging evidence suggests that lipid-laden macrophages (LLM) participate in lung damage in various clinical conditions. However, the mechanisms involved in LLM formation are not fully understood. In this study, we aimed to investigate the link between reactive oxygen species (ROS) and LLM formation. We found that ROS triggered by cigarette smoke extract (CSE) or H2O2 significantly promoted LLM formation. Given the key role of ROS in LLM formation, we further demonstrated that LLM formation is induced by various ROS-producing stimuli, including bacteria, oxidized low-density lipoprotein (OxLDL), hyperoxia, and E-cigarette vapor extract (EVE). Meanwhile, cytochrome P450 family-1 subfamily B member 1 (CYP1B1) was highly upregulated in lung macrophages from chronic obstructive pulmonary disease (COPD) patients and CSE-treated macrophages. Functionally, CYP1B1 contributes to the CSE-induced lipid accumulation and LLM formation. CYP1B1 expression and LLM formation were effectively suppressed by antioxidant N-acetylcysteine (NAC) and carvedilol. The formation of LLM was also associated with classically activated M1 but not the M2 state. CSE-induced LLM showed time-dependent alterations in inflammatory response and phagocytic ability. In summary, our study highlights the role of oxidative stress in LLM formation. CYP1B1 contributes to ROS-induced LLM formation and may serve as a therapeutic target for reducing LLM-induced lung damage.},
}
@article {pmid39720578,
year = {2024},
author = {Qiu, X and Yao, Y and Chen, Y and Li, Y and Sun, X and Zhu, X},
title = {TRPC5 Promotes Intermittent Hypoxia-Induced Cardiomyocyte Injury Through Oxidative Stress.},
journal = {Nature and science of sleep},
volume = {16},
number = {},
pages = {2125-2141},
pmid = {39720578},
issn = {1179-1608},
abstract = {PURPOSE: Intermittent hypoxia (IH), a defining feature of obstructive sleep apnea (OSA), is associated with heart damage and linked to transient receptor potential canonical channel 5 (TRPC5). Nonetheless, the function of TRPC5 in OSA-induced cardiac injury remains uncertain. For this research, we aimed to explore the role and potential mechanism of TRPC5 in cardiomyocyte injury induced by intermittent hypoxia.<br><br>METHODS: 30 patients with newly diagnosed OSA and 30 patients with primary snoring(PS) were included in this study. Participants were subjected to polysomnography (PSG) for OSA diagnosis. Echocardiography was used to evaluate the structure and function of the heart, while peripheral blood samples were obtained. Additionally, RT-qPCR was utilized to quantify the relative expression level of TRPC5 mRNA in peripheral blood. H9c2 cells experienced IH or normoxia. TRPC5 levels in H9c2 cells were determined via RT-qPCR and Western blotting (WB) methods. H9c2 cells overexpressing TRPC5 were subjected to either normoxic or intermittent hypoxia conditions. Cell viability was determined by CCK8, the apoptosis rate, reactive oxygen species(ROS) levels, and Ca[2+] concentration were assessed by flow cytometry, and the protein levels of TRPC5, Bcl-2, Bax, and Caspase-3 were analyzed by WB. Mitochondrial membrane potential(MMP), mitochondrial membrane permeability transition pore(mPTP), and transmission electron microscopy(TEM) were employed to observe mitochondrial function and structure. After inhibiting ROS with N-acetylcysteine (NAC), apoptosis, mitochondrial function and structure, and the concentration of Ca[2+] were further detected.<br><br>RESULTS: TRPC5 and left atrial diameter (LAD) were higher in OSA individuals, while the E/A ratio was lower(all P<0.05). IH impaired cell viability, triggered cell apoptosis, and enhanced TRPC5 expression in H9c2 cells(all P<0.05). The effects of IH on apoptosis, cell viability, mitochondrial function and structure damage, and oxidative stress (OxS) in H9c2 cells were accelerated by the overexpression of TRPC5(all P<0.05). Furthermore, cell apoptosis and mitochondrial structural and functional damage caused by overexpression of TRPC5 were attenuated by ROS inhibition.<br><br>CONCLUSION: TRPC5 is associated with structural and functional cardiac damage in patients with OSA, and TRPC5 promotes IH-induced apoptosis and mitochondrial damage in cardiomyocytes through OxS. TRPC5 may be a novel target for the diagnosis and treatment of OSA-induced myocardial injury.},
}
@article {pmid39714274,
year = {2025},
author = {Huang, KT and Tsai, WH and Chen, CW and Hwang, YS and Cheng, HC and Yeh, CW and Lin, YH and Cheng, AJ and Chang, HC and Lin, SJ and Yen, MC and Chang, WT},
title = {Hyperoxia induces autophagy in pulmonary epithelial cells: insights from in vivo and in vitro experiments.},
journal = {Free radical research},
volume = {59},
number = {1},
pages = {9-22},
doi = {10.1080/10715762.2024.2446321},
pmid = {39714274},
issn = {1029-2470},
mesh = {*Autophagy/drug effects ; Humans ; Animals ; *Hyperoxia/pathology/metabolism ; Rats ; A549 Cells ; *Epithelial Cells/metabolism/pathology/drug effects ; Reactive Oxygen Species/metabolism ; Acetylcysteine/pharmacology ; *Lung/pathology/metabolism ; Oxidative Stress ; Rats, Sprague-Dawley ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {Patients with hypoxemia require high-concentration oxygen therapy. However, prolonged exposure to oxygen concentrations 21% higher than physiological concentrations (hyperoxia) may cause oxidative cellular damage. Pulmonary alveolar epithelial cells are major targets for hyperoxia-induced oxidative stress. In this study, we evaluated the therapeutic potential of the antioxidant N-acetyl-L-cysteine (NAC) for preventing hyperoxia-induced cell death. In vitro experiments were performed using the human lung cancer cell line A549. In brief, NAC-treated and untreated cells were exposed to various concentrations of oxygen (hyperoxia) for different durations. The results indicated that hyperoxia inhibited proliferation and caused cell cycle arrest in A549 cells. It also induced necrosis and autophagy. Furthermore, hyperoxia increased intracellular reactive oxygen species levels and altered mitochondrial membrane potential. Co-treatment with NAC improved the survival of cells exposed to 95% oxygen for 24 h. Experiments performed using a neonatal rat model of acute lung injury confirmed that hyperoxia induced an autophagic response. This study provides evidence for hyperoxia-induced autophagy both in vitro and in vivo. NAC can protect A549 cells from death induced by short-term hyperoxia. Our findings may inform protective strategies against hyperoxia-induced injury in developing lungs-for example, bronchopulmonary dysplasia in premature infants.},
}
@article {pmid39710209,
year = {2025},
author = {Xu, M and Yu, S and Li, P and Chen, Y and Chen, Y and Pan, J and Deng, X and Hu, H},
title = {Tailored multilayer nanoparticles against resistant P. aeruginosa by disrupting the thickened mucus, dense biofilm and hyperinflammation.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {378},
number = {},
pages = {588-604},
doi = {10.1016/j.jconrel.2024.12.040},
pmid = {39710209},
issn = {1873-4995},
mesh = {*Biofilms/drug effects ; *Pseudomonas aeruginosa/drug effects/physiology ; Animals ; Humans ; *Nanoparticles/chemistry/administration &amp; dosage ; Mucus/drug effects/microbiology ; *Anti-Bacterial Agents/administration &amp; dosage/pharmacology/chemistry/therapeutic use ; *Pseudomonas Infections/drug therapy/microbiology ; Inflammation/drug therapy ; Chitosan/chemistry/administration &amp; dosage ; Swine ; Drug Resistance, Multiple, Bacterial ; Mice ; Sputum/microbiology ; },
abstract = {Therapeutic challenges of chronic pulmonary infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRP. aeruginosa) biofilms due to significantly enhanced antibiotic resistance. This resistance is driven by reduced outer membrane permeability, biofilm barriers, and excessive secretion of virulence factors. Thickened mucus in the airways exacerbates the problem by impeding antibiotic penetration, providing a breeding ground for biofilms, consequently aggravating infection. Moreover, biofilms recruit numerous immune cells, resulting in chronic inflammation and lung tissue damage. In turn, damaged airway further facilitates bacterial colonization and elevated mucus production. To thoroughly disintegrate the stubborn triad of "thickened mucus &amp; dense biofilm &amp; excessive inflammation" and address drug resistance, tailored multilayer nanoparticles (NPVC/PBIP NPs) were developed. NPVC/PBIP NPs were engineered through self-assembly of vanillin-chitosan amphiphilic polymer loading polymyxin B-linoleic acid ion pairs in. Then polyaspartic acid and N-acetylcysteine-ε-poly-l-lysine were coated by layer-by-layer on the surface of vanillin-chitosan NPs via electrostatic interactions. As expected, the NAC units on NPVC/PBIP NPs effectively thinned human clinical sputum and porcine sputum, resulting in rapid sputum penetration followed by biofilm permeation. NPVC/PBIP NPs achieved over 99 % eradication of mature biofilms in vitro. Furthermore, they effectively inhibited virulence factors production and bacteria re-adhesion (biofilm reformation) while exhibiting superior anti-inflammatory and antioxidant activities. In a chronic pulmonary infection model, NPVC/PBIP NPs remarkably thinned airway mucus, reduced bacterial burden by 99.7 %, alleviated inflammatory cell infiltration, and minimized lung tissue damage. In summary, the NPVC/PBIP NPs represent a novel and promising strategy to manage MDRP. aeruginosa biofilms associated infections by disintegrating the stubborn triad of "thickened mucus &amp; dense biofilm &amp; excessive inflammation".},
}
@article {pmid39710118,
year = {2025},
author = {Luo, G and Yang, W and Geng, Z and Cheng, Y and Xu, Y and Xiao, Y and Liu, J},
title = {Molecular mechanism of GSH metabolism and autophagy in NAC-promoted recombinant human serum albumin and follicle stimulating hormone beta fusion protein secretion in Pichia pastoris.},
journal = {Journal of biotechnology},
volume = {398},
number = {},
pages = {146-157},
doi = {10.1016/j.jbiotec.2024.12.006},
pmid = {39710118},
issn = {1873-4863},
mesh = {*Autophagy/drug effects ; Humans ; *Glutathione/metabolism ; *Serum Albumin, Human/metabolism/genetics ; *Acetylcysteine/pharmacology ; *Recombinant Fusion Proteins/metabolism/genetics ; Animals ; Swine ; *Saccharomycetales/metabolism/genetics ; },
abstract = {The Pichia pastoris expression system is a favorable platform for production of pharmaceutical proteins. Treatment of strains with N-acetyl-L-cysteine (NAC) has been shown to enhance the yield of recombinant proteins, thereby contributing to a reduction in production costs. However, the specific mechanism of action of NAC remains unclear. Previous research has indicated that glutathione (GSH) and autophagy are involved in the increased production of human serum albumin and porcine follicle-stimulating hormone β (HSA-pFSHβ) by NAC. This study investigated the potential interaction between GSH and autophagy in the production of HSA-pFSHβ. The findings indicated that sulfhydryl-free antioxidants such as melatonin, vitamin C, or vitamin E did not exhibit similar effects to NAC in enhancing HSA-pFSHβ yield. Moreover, NAC was found to enhance HSA-pFSHβ production by modulating GSH metabolism to reduce GSH consumption, increase total GSH levels, as well as glutathione peroxidase (GSH-Px) and glutathione reductase (GR) activities. Additionally, inhibition of autophagy through disruption of autophagy scaffolding proteins Atg1 or Atg11 led to an increase in recombinant HSA-pFSHβ production. Furthermore, NAC significantly decreased the phosphorylation of Slt2, and the absence of the SLT2 gene influenced the effect of NAC on HSA-pFSHβ secretion by modulating mitophagy and GSH metabolism. In conclusion, these results suggest a complex interplay between GSH metabolism and autophagy in the regulation of NAC-induced HSA-pFSHβ secretion.},
}
@article {pmid39707625,
year = {2024},
author = {Jiang, ZB and Xu, C and Xu, P and Huang, DH and Kang, LP},
title = {Lycorine Suppresses Non-Small-Cell Lung Cancer Progression Through Activating STING Pathway and Stimulating an Antitumor Immune Response.},
journal = {Chemical biology &amp; drug design},
volume = {104},
number = {6},
pages = {e70036},
doi = {10.1111/cbdd.70036},
pmid = {39707625},
issn = {1747-0285},
support = {2022M713650//China Postdoctoral Science Foundation/ ; 2022A1515110790//Guangdong Basic and Applied Basic Research Foundation of China/ ; 2024A1515012478//Guangdong Basic and Applied Basic Research Foundation of China/ ; 20221361//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 20241290//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 20241285//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; No.20251345//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 2320004000290//Zhuhai Science and Technology Bureau/ ; 2420004000007//Zhuhai Science and Technology Bureau/ ; 2420004000022//Zhuhai Science and Technology Bureau/ ; },
mesh = {*Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism/pathology ; Humans ; Animals ; *Lung Neoplasms/drug therapy/pathology/metabolism ; *Membrane Proteins/metabolism ; Mice ; Cell Line, Tumor ; *Amaryllidaceae Alkaloids/pharmacology/chemistry/therapeutic use ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; *Phenanthridines/pharmacology/chemistry/therapeutic use ; Cell Proliferation/drug effects ; Signal Transduction/drug effects ; Antineoplastic Agents/pharmacology/chemistry ; STING Protein ; },
abstract = {Non-small-cell lung cancer (NSCLC) stands as a primary contributor to cancer-related deaths worldwide. It has been demonstrated that Lycorine (LYD), a naturally occurring active sesquiterpene present in Chinese medicinal plants, exhibits anti-cancer properties across various cancer cell lines. However, the underlying mechanisms of LYD-induced anti-tumor in NSCLC are not fully known. This study demonstrated that LYD significantly reduced the proliferation of NSCLC and induced apoptosis by increasing intracellular ROS levels. The inhibition of ROS using N-acetylcysteine (NAC) eliminated the apoptosis effects of LYD, resulting in increased cell viability. Additionally, LYD treatment significantly activated the STING pathway in NSCLC and induced the expression of CXCL10, CXCL9 and CCL5 in NSCLC cells. Mechanistically, LYD was found to significantly reduce the protein levels of P70S6K and S6K, which are key proteins involved in cell growth and survival. Notably, in vivo experiments demonstrated that LYD significantly inhibited the growth of H358 xenograft and LLC1 tumor, exhibiting anti-tumor activity by elevating CD8[+] T cells in the NSCLC mouse model. Our findings suggest that LYD possesses potent anti-cancer properties in NSCLC by inducing apoptosis through ROS generation and modulating the STING pathway and key chemokines. Furthermore, LYD also exerts its antitumor effects by inhibiting crucial proteins involved in cell growth. Overall, LYD shows promise as a potential therapeutic agent for NSCLC treatment.},
}
@article {pmid39707526,
year = {2024},
author = {Yang, C and Fu, J and Zheng, F and Fu, Y and Duan, X and Zuo, R and Zhu, J},
title = {Aconitine promotes ROS-activated P38/MAPK/Nrf2 pathway to inhibit autophagy and promote myocardial injury.},
journal = {Journal of cardiothoracic surgery},
volume = {19},
number = {1},
pages = {665},
pmid = {39707526},
issn = {1749-8090},
support = {202301AY070001-213//the Kunming medical joint special project-surface project/ ; },
mesh = {*Aconitine/pharmacology/analogs &amp; derivatives ; *Autophagy/drug effects ; *Reactive Oxygen Species/metabolism ; *Myocytes, Cardiac/drug effects/metabolism/pathology ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Rats ; *NF-E2-Related Factor 2/metabolism ; Animals ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; MAP Kinase Signaling System/drug effects/physiology ; Signal Transduction/drug effects ; },
abstract = {BACKGROUND: Aconitine has cardiotoxicity, but the mechanism of cardiotoxicity induced by aconitine is limited. The aim of this study was to investigate the mechanism of myocardial injury induced by aconitine.<br><br>METHODS: Using aconitine, ROS inhibitor N-acetylcysteine(NAC), the autophagy activitor Rapamycin (Rap) or the P38/MAPK pathway activitor Dehydrocorydaline treats H9C2 cells. CCK-8 assay was used to assay cell proliferation activity. Flow Cytometry was used to detect cell apoptosis. Dichloro-dihydrofluorescein diacetate was used to detect ROS levels. The expression of LC3 was detected by Immunofluorescence Staining. Western blotting detected the expression of related proteins. The mRNA levels of inflammatory factors were detected by RT-qPCR.<br><br>RESULTS: Aconitine inhibits cardiomyocyte proliferation, induces apoptosis and secretion of inflammatory factors. Aconitine activates the P38/MAPK/Nrf2 pathway, induces ROS increase, and promotes autophagy. NAC can inhibit proliferation inhibition, apoptosis, inflammation and P38/MAPK/Nrf2 pathway activation induced by aconitine. Rap and P38 activators can partially recover the effects of NAC on proliferation, apoptosis, inflammation and autophagy of cardiomyocytes.<br><br>CONCLUSION: Aconitine promotes ROS-activated P38/MAPK/Nrf2 pathway to inhibit autophagy and promote myocardial injury.},
}
@article {pmid39706252,
year = {2024},
author = {Lomeli, N and Pearre, DC and Lepe, J and Argueta, DA and Arellano, MA and Ricks-Oddie, JL and Gupta, K and Bota, DA},
title = {N-acetylcysteine prevents cisplatin-induced cognitive impairments in an ovarian cancer rat model.},
journal = {Cancer letters},
volume = {611},
number = {},
pages = {217405},
pmid = {39706252},
issn = {1872-7980},
support = {TL1 TR001415/TR/NCATS NIH HHS/United States ; T32 NS082174/NS/NINDS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; K08 NS072234/NS/NINDS NIH HHS/United States ; R01 CA263806/CA/NCI NIH HHS/United States ; K99 AT012494/AT/NCCIH NIH HHS/United States ; },
abstract = {Cancer-related cognitive impairment (CRCI) is prevalent among cancer patients. A critical disparity in the CRCI field is that most pre-clinical studies have been conducted on young cancer-free male rodents, although CRCI predominantly affects breast cancer and ovarian cancer women survivors. Since oxidative stress is widely implicated in the development of CRCI, we developed an ovarian cancer xenograft rat model of CRCI in Cr:NIH-RNU female rats to examine whether administration of the antioxidant N-acetylcysteine (NAC) prevents cisplatin-induced CRCI without altering its anti-cancer efficacy. In vitro, delayed treatment with NAC (10 h) following cisplatin treatment in the human ovarian cancer cell line SKOV3.ip1 did not decrease cisplatin's anti-cancer efficacy while mitigating hippocampal dendritic branching damage and neuronal apoptosis. Rats received subcutaneous and intraperitoneal implantation of SKOV3.ip1 cells. Rats received one cisplatin (5 mg/kg) injection every two weeks for a total of four cycles, with or without NAC (250 mg/kg/day), given for five consecutive days during cisplatin treatment. NAC was administered 10 h after cisplatin, based on our in vitro data. Cognitive testing was performed six to seven weeks after treatment cessation. In vivo, cognitive impairments were observed in tumor-bearing rats in the vehicle and cisplatin-treatment groups, while delayed NAC prevented cognitive impairments. Delayed NAC administration did not affect cisplatin-induced tumor volume reduction. Our study supports using NAC to mitigate cisplatin-induced CRCI through the novel development of an ovarian cancer rodent model. This study highlights the importance of developing clinically relevant tumor-bearing models to elucidate the underlying mechanisms associated with CRCI, which will aid in identifying potential therapeutic agents for preventing CRCI.},
}
@article {pmid39705849,
year = {2025},
author = {Jog, E and Jainarayanan, AK and La Ferlita, A and Chakraborty, A and Dalwai, A and Yahya, S and Shivashankar, A and Choudhary, BS and Chandramouli, A and Kazi, M and Jain, D and Khapare, N and B, A and Khan, BK and Gera, P and Patil, P and Thorat, R and Verma, N and Sehgal, L and Saklani, A and Kamat, SS and Dalal, SN and Chaudhary, N},
title = {Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer.},
journal = {Redox biology},
volume = {79},
number = {},
pages = {103458},
pmid = {39705849},
issn = {2213-2317},
mesh = {Humans ; *Colorectal Neoplasms/metabolism/drug therapy/pathology/genetics ; *Lipogenesis/drug effects ; Animals ; Mice ; *Drug Resistance, Neoplasm/drug effects ; Phosphatidate Phosphatase/genetics/metabolism ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Lipid Droplets/metabolism ; },
abstract = {A significant clinical challenge in patients with colorectal cancer (CRC), which adversely impacts patient survival, is the development of therapy resistance leading to a relapse. Therapy resistance and relapse in CRC is associated with the formation of lipid droplets (LD) by stimulating de novo lipogenesis (DNL). However, the molecular mechanisms underlying the increase in DNL and the susceptibility to DNL-targeted therapies remain unclear. Our study demonstrates that colorectal drug-tolerant persister cells (DTPs) over-express Lipin1 (LPIN1), which facilitates the sequestration of free fatty acids into LDs. The increased expression is mediated by the ETS1-PTPN1-c-Src-CEBPβ pathway. Blocking the conversion of free fatty acids into LDs by treatment with statins or inhibiting lipin1 expression disrupts lipid homeostasis, leading to lipotoxicity and ferroptotic cell death in both DTPs and patient-derived organoids (PDOs) in vitro. Ferroptosis inhibitors or N-acetylcysteine (NAC) can alleviate lipid ROS and cell death resulting from lipin1 inhibition. This strategy also significantly reduces tumor growth in CRC DTP mouse xenograft and patient-derived xenograft (PDX) models. Our findings highlight a new metabolic vulnerability in CRC DTPs, PDO, and PDX models and provide a framework for the rational repurposing of statins. Targeting the phosphatidic acid (PA) to diacylglycerol (DAG) conversion to prevent lipid droplet formation could be an effective therapeutic approach for therapy-resistant CRC.},
}
@article {pmid39704007,
year = {2025},
author = {Braunreuther, M and Arenhoevel, J and Bej, R and Moose, C and Mall, MA and Haag, R and Fuller, GG},
title = {Magnetic microwire rheometer reveals differences in hydrogel degradation via disulfide reducing agents.},
journal = {Soft matter},
volume = {21},
number = {3},
pages = {427-434},
doi = {10.1039/d4sm01118j},
pmid = {39704007},
issn = {1744-6848},
mesh = {*Rheology ; *Disulfides/chemistry ; *Hydrogels/chemistry ; Acetylcysteine/chemistry ; Dithiothreitol/chemistry ; Hyaluronic Acid/chemistry ; Polymers/chemistry ; Glycerol/chemistry ; },
abstract = {Mucus is composed of a complex network of mucin polymers connected by disulfide bonds. In muco-obstructive diseases, an increase in mucin disulfide crosslinks contributes to pathologic mucus formation, characterized by an increase in mucus viscosity and stiffness. Reducing agents that break down the disulfide bonds between mucins can be used to treat pathologic mucus and restore healthy mucus flow properties. Here, we compare three reducing agents via a rheological assay. A mucus-mimetic disulfide-crosslinked hyaluronic acid hydrogel was treated with thiolated dendritic polyglycerol sulfate (dPGS-SH), N-acetylcysteine (NAC), or dithiothreitol (DTT). A magnetic microwire rheometer was used to track the rheology of the hydrogel over time as the treatment degraded the sample. This nondestructive and minimally invasive technique reveals differences in the degradation mechanism between these reducing agents, with potential implications for drug delivery and the treatment of muco-obstructive diseases.},
}
@article {pmid39701936,
year = {2024},
author = {Chen, S and Cao, Y and Fan, Z and Xu, L and Pan, Z and Gao, Y and Wei, L and Wei, Q and Tian, Y and Zhang, X and Liu, M and Ren, F},
title = {Depressed TFAM promotes acetaminophen-induced hepatotoxicity regulated by DDX3X-PGC1α-NRF2 signaling pathway.},
journal = {Molecular medicine (Cambridge, Mass.)},
volume = {30},
number = {1},
pages = {246},
pmid = {39701936},
issn = {1528-3658},
support = {82002243, 82100653//National Natural Science Foundation of China/ ; 82002243, 82100653//National Natural Science Foundation of China/ ; KZ202010025035//Key Projects of the Beijing Municipal Education Commission's Science and Technology Plan/ ; QML20201702//Beijing Hospitals Authority Youth Programme/ ; DFL20221503//Talent Cultivation plan of "Climbing the peak" of Beijing Municipal Hospital Administration/ ; Subject leaders-02-13//High-level public health technical personnel construction Project/ ; BJMB0012022028021//2022 Chronic disease prevention and health education research project/ ; PX2021065//Beijing Municipal Administration of Hospitals Incubating Program/ ; YARCKB2022008//Beijing You'an Hospital Construction of Talent Pool Program/ ; CX24PY23//Chinese Institutes for Medical Research/ ; L234046//Beijing Natural Science Foundation-Changping Innovation Joint Fund/ ; CCMU2023ZKYXZ003//Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University/ ; },
mesh = {*Acetaminophen/adverse effects ; Animals ; *Signal Transduction/drug effects ; Humans ; *Chemical and Drug Induced Liver Injury/metabolism/etiology/genetics ; Mice ; Male ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Transcription Factors/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Mitochondrial Proteins/metabolism/genetics ; *NF-E2-Related Factor 2/metabolism/genetics ; *DEAD-box RNA Helicases/metabolism/genetics ; Disease Models, Animal ; Mice, Inbred C57BL ; Female ; Gene Expression Regulation/drug effects ; High Mobility Group Proteins ; },
abstract = {BACKGROUND: Acetaminophen (APAP)-induced acute liver injury (AILI) is the most prevalent cause of acute liver failure and mitochondrial dysfunction plays a dominant role in the pathogenesis of AILI. Mitochondrial transcription factor A (TFAM) is an important marker for maintaining mitochondrial functional homeostasis, but its functions in AILI are unclear. This study aimed to investigate the function of TFAM and its regulatory molecular mechanism in the progression of AILI.<br><br>METHODS: The roles of TFAM and DEAD (Asp-Glu-Ala-Asp) box polypeptide 3 X-linked (DDX3X) in AILI were determined with TFAM overexpression and DDX3X knockdown, respectively.<br><br>RESULTS: TFAM expression was suppressed in AILI patients. TFAM overexpression alleviated liver necrosis and mitochondrial dysfunction. Treatment of the AILI mice model with N-acetylcysteine (NAC), a drug used to treat APAP overdose, resulted in significant TFAM activation. In vivo experiments confirmed that TFAM expression was negatively regulated by DDX3X. Mechanistic studies showed that nuclear respiratory factor 2 (NRF-2), a key regulator of TFAM, was selectively activated after DDX3X knockdown via activated peroxisome proliferator-activated receptor &#x3b3; coactivator 1 (PGC-1&#x3b1;), in vivo and in vitro.<br><br>CONCLUSIONS: This study demonstrates that depressed hepatic TFAM plays a key role in the pathogenesis of AILI, which is regulated by the DDX3X-PGC1&#x3b1;-NRF2 signaling pathway.},
}
@article {pmid39700869,
year = {2025},
author = {Poudel, SB and Kim, MH and Bhattarai, G and So, HS and Kook, SH and Lee, JC},
title = {n-acetyl-l-cysteine stimulates bone healing by recovering the age-associated degenerative complications relative to osteoblastic Wntless ablation.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {182},
number = {},
pages = {117761},
doi = {10.1016/j.biopha.2024.117761},
pmid = {39700869},
issn = {1950-6007},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Osteoblasts/drug effects/metabolism ; Mice ; *Oxidative Stress/drug effects ; Osteogenesis/drug effects ; Bone Regeneration/drug effects ; Wnt Signaling Pathway/drug effects ; Aging ; Mice, Inbred C57BL ; Male ; Antioxidants/pharmacology ; Receptors, G-Protein-Coupled ; },
abstract = {Dysregulated Wnt signaling causes age-related characteristics such as oxidative stress, stem cell senescence, and abnormal bone homeostasis. Here we explored whether supplemental n-acetyl-l-cysteine (NAC) recovers the age-associated complications relative to osteoblastic Wntless (Wls) ablation and examined the possible mechanisms therein. For this work, we administered Col2.3-Cre;Wls[fl/fl] mutant and littermate control (Wls[fl/fl]) mice (14 weeks of age) with NAC (40 mM)-supplemented or NAC-free water for four weeks. A proportion of these mice received non-critical-sized femoral defects at 16 weeks of age. Blood, bone, and bone marrow (BM) samples were collected and adjusted for in vivo, ex vivo, and in vitro analyses. Osteoblastic Wls deletion delayed bone mass accrual and the healing of bone defects, stimulated osteoclastic activation and inflammatory factor expression, and decreased antioxidant enzyme activity in the BM. Osteoblastic Wls deletion also promoted oxidative stress, apoptosis, and senescence in BM stromal cells (BMSCs) and decreased BMSC' multipotencies. Supplementation of Wls[fl/fl] mice with NAC enhanced bone mass accrual and regenerative bone healing via a Wnt signal-associated osteogenic activation. However, supplemental NAC induced new bone formation in the mutant mice by inhibiting the age-related complications of BM/BMSCs, as well as by restoring endogenous antioxidant system without any alterations in Wnt ligand secretion, hematopoiesis, and expression of osteogenic and growth factors. This study indicates that supplemental NAC protects mice against Wnt deficiency-mediated and age-associated degenerative complications. Overall, this study highlights the therapeutic potency of NAC for restoring the antioxidant system, stem cell function, and regenerative bone homeostasis in osteoblastic Wls-dispensable manner.},
}
@article {pmid39687604,
year = {2025},
author = {Gupta, K and Chen, D and Wells, RG},
title = {Microcystin-RR is a biliary toxin selective for neonatal extrahepatic cholangiocytes.},
journal = {JHEP reports : innovation in hepatology},
volume = {7},
number = {1},
pages = {101218},
pmid = {39687604},
issn = {2589-5559},
support = {P30 DK050306/DK/NIDDK NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 DK119290/DK/NIDDK NIH HHS/United States ; },
abstract = {BACKGROUND &amp; AIMS: Biliary atresia is a fibrosing cholangiopathy affecting neonates that is thought to result from a prenatal environmental insult to the bile duct. Biliatresone, a plant toxin with an α-methylene ketone group, was previously implicated in biliary atresia in Australian livestock, but is found in a limited location and is unlikely to be a significant human toxin. We hypothesized that other unsaturated carbonyl compounds, some with the potential for significant human exposure, might also be biliary toxins.<br><br>METHODS: We focused on the family of microcystins, cyclic peptide toxins from blue-green algae that are found worldwide, particularly during harmful algal blooms. We used primary extrahepatic cholangiocyte spheroids and extrahepatic bile duct explants from both neonatal [a total of 86 postnatal day (P) 2 mouse pups and 18 P2 rat pups (n&#xa0;= 8-10 per condition for both species)] and adult rodents [a total of 31 P15-18 mice (n&#xa0;= 10 or 11 per condition)] to study the biliary toxicity of microcystins and potential mechanisms involved.<br><br>RESULTS: Results showed that 400&#xa0;nM microcystin (MC)-RR, but not six other microcystins or the related algal toxin nodularin, caused >80% lumen closure in cell spheroids made from extrahepatic cholangiocytes isolated from 2-3-day-old mice (p <0.0001). By contrast, 400&#xa0;nM MC-RR resulted in less than an average 5% lumen closure in spheroids derived from neonatal intrahepatic cholangiocytes or cells from adult mice (p&#xa0;= 0.4366). In addition, MC-RR caused occlusion of extrahepatic bile duct explants from 2-day-old mice (p <0.0001), but not 18-day-old mice. MC-RR also caused a 2.3-times increase in reactive oxygen species in neonatal cholangiocytes (p <0.0001), and treatment with N-acetyl cysteine partially prevented microcystin-RR-induced lumen closure (p&#xa0;= 0.0004), suggesting a role for redox homeostasis in its mechanism of action.<br><br>CONCLUSIONS: We identified MC-RR as a selective neonatal extrahepatic cholangiocyte toxin and suggest that it acts by increasing redox stress.<br><br>IMPACT AND IMPLICATIONS: The plant toxin biliatresone causes a biliary atresia-like disease in livestock and vertebrate animal model systems. We tested the widespread blue-green algal toxin, microcystin-RR, another highly electrophilic unsaturated carbonyl compound that is released during harmful algal blooms, and found that it was also a biliary toxin with specificity for neonatal extrahepatic cholangiocytes. This work should drive further animal studies and, ultimately, studies to determine whether human exposure to microcystin-RR causes biliary atresia.},
}
@article {pmid39687303,
year = {2024},
author = {Mahmoud, NM and Elshazly, SM and El-Shaarawy, F and Zaitone, SA and Aldahish, AA and Ahmed, GA and Fawzy, MS and Aloyouni, SY and Abed, SY and Saeedi, T and El-Sayed, SS},
title = {Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1491249},
pmid = {39687303},
issn = {1663-9812},
abstract = {OBJECTIVES: Hepatotoxicity is a severe outcome of methotrexate (MTX) therapy, limiting its clinical use and contributing to its related morbidity and mortality. This study investigated the hepatoprotective effects of nitazoxanide (NTZ), an antiprotozoal drug, against MTX-induced hepatotoxicity and whether endoplasmic reticulum (ER) stress-modulation underlies the expected beneficial effects of NTZ.<br><br>METHODS: Thirty-six rats were allocated to six groups, one control group and five MTX groups, where induction of hepatotoxicity was achieved via injecting MTX (20&#xa0;mg/kg). Groups were assigned as MTX-vehicle, NTZ-100, and NTZ-200 groups (at 100 and 200&#xa0;mg/kg/day, gavage, respectively), N-acetyl cysteine (NAC) group (500&#xa0;mg/kg), and 4-phenyl butyric acid (4-PBA) group (150&#xa0;mg/kg, i.p). Liver function enzymes in serum, hepatic oxidative stress, proinflammatory cytokines, apoptosis, and ER-stress biomarkers were assessed. A histopathological examination was performed.<br><br>RESULTS: Treatment with NTZ lessened the serum liver enzymes, reduced malondialdehyde (lipid peroxidation product), enhanced antioxidant capacity, attenuated proinflammatory cytokines, and suppressed apoptosis. The protective effect of NTZ was dose-dependent, and the findings observed with the high-dose NTZ were similar to those obtained with the ER-stress inhibitor (4-PBA).<br><br>CONCLUSION: NTZ exerted a hepatoprotective effect in MTX-challenged rats that is mediated via modulation of ER stress and inhibiting apoptosis.},
}
@article {pmid39683654,
year = {2024},
author = {Bognár, G and Kenari, F and Pintér, Z and Borges, ID and Camargo, AJ and Oliveira, HCB and Sanches-Neto, FO and Carvalho-Silva, VH and Napolitano, HB and Perjési, P},
title = {(E)-2-Benzylidenecyclanones: Part XX-Reaction of Cyclic Chalcone Analogs with Cellular Thiols: Unexpected Increased Reactivity of 4-Chromanone- Compared to 1-Tetralone Analogs in Thia-Michael Reactions.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {23},
pages = {},
pmid = {39683654},
issn = {1420-3049},
mesh = {Humans ; *Sulfhydryl Compounds/chemistry ; Chromones/chemistry/pharmacology ; Tetralones/chemistry/pharmacology ; Chalcones/chemistry/pharmacology ; Glutathione/metabolism/chemistry ; Molecular Structure ; Models, Molecular ; Cell Line, Tumor ; Acetylcysteine/chemistry/pharmacology ; Chromatography, High Pressure Liquid ; },
abstract = {In vitro relative cytotoxicity (IC50 (IIb)/IC50 (IIIb) of (E)-3-(4'-methylbenzylidene)-4-chromanone (IIIb) towards human Molt 4/C8 and CEM T-lymphocytes showed a >50-fold increase in comparison to those of the respective tetralone derivative (IIb). On the other hand, such an increase was not observed in the analogous 4-OCH3 (IIc and IIIc) derivatives. In order to study whether thiol reactivity-as a possible basis of the mechanism of action-correlates with the observed cytotoxicities, the kinetics of the non-enzyme catalyzed reactions with reduced glutathione (GSH) and N-acetylcysteine (NAC) of IIIb and IIIc were investigated. The reactivity of the compounds and the stereochemical outcome of the reactions were evaluated using high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Molecular modeling calculations were performed to rationalize the unexpectedly higher thiol reactivity of the chromanones (III) compared to the carbocyclic analog tetralones (II). The results indicate the possible role of spontaneous thiol reactivity of compounds III in their recorded biological effects.},
}
@article {pmid39682737,
year = {2024},
author = {Dorcas Aremu, T and Ramírez Ortega, D and Blanco Ayala, T and González Esquivel, DF and Pineda, B and Pérez de la Cruz, G and Salazar, A and Flores, I and Meza-Sosa, KF and Sánchez Chapul, L and Rangel-López, E and Gómez-Manzo, S and Márquez Navarro, A and Roldán Roldán, G and Pérez de la Cruz, V},
title = {Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats.},
journal = {Cells},
volume = {13},
number = {23},
pages = {},
pmid = {39682737},
issn = {2073-4409},
support = {IN207025//PAPIIT DGAPA-UNAM/ ; },
mesh = {Animals ; *Kynurenic Acid/metabolism ; Female ; *Acetylcysteine/pharmacology ; *Rats, Wistar ; *Cognitive Dysfunction/drug therapy/metabolism/prevention &amp; control ; Rats ; *Brain/drug effects/metabolism/pathology ; *Cisplatin/adverse effects/pharmacology ; *Muscle Weakness/metabolism/drug therapy/pathology ; },
abstract = {Cisplatin (CIS) is a potent chemotherapeutic agent primarily used to treat hematologic malignancies and solid tumors, including lymphomas, sarcomas, and some carcinomas. Patients receiving this treatment for tumors outside the nervous system develop cognitive impairment. Alterations in the kynurenine pathway (KP) following CIS treatment suggest that certain KP metabolites may cross the blood-brain barrier, leading to increased production of the neuromodulator kynurenic acid (KYNA), which is associated with cognitive impairment. This study aimed to evaluate the effects of modulating brain KYNA levels by the administration of N-acetylcysteine (NAC), an inhibitor of kynurenine aminotransferase II (KATII), an enzyme responsible for KYNA biosynthesis on the cognitive and neuromuscular deficits induced by CIS. Female Wistar rats were divided into four groups: control, NAC (300 mg/day/8 days), CIS (3 mg/kg i.p/5 days), and NAC + CIS (both treatments co-administered in parallel). Seven days after the last CIS administration, cognitive performance, muscle strength, brain KYNA levels, KATII activity, and brain tissue redox profile (lipid peroxidation and oxidized/reduced glutathione (GSH/GSSG) ratio) were assessed. CIS did not affect short-term memory but induced long-term memory deficits and reduced muscle strength, effects which were prevented by NAC co-administration. CIS decreased the GSH/GSSG ratio and the number of cells in the brain cortex while it increased lipid peroxidation, KYNA levels, and marginal KATII activity. All these effects were attenuated by the co-administration of NAC. These findings suggest that NAC mitigates the side effects of CIS, such as chemo-brain and muscle weakness, by improving the redox imbalance and modulating KYNA levels by limiting its non-enzymatic production by reactive oxygen species (ROS).},
}
@article {pmid39677988,
year = {2024},
author = {Roy, S and Saleem, H},
title = {Mushroom Poisoning and Acute Liver Injury: A Case-Based Review.},
journal = {Cureus},
volume = {16},
number = {12},
pages = {e75706},
pmid = {39677988},
issn = {2168-8184},
abstract = {Mushrooms have always found their way into our dining plates due to their exotic looks and edibility. It is also one of the food items that can lead to fatal hepatotoxicity if the wrong species is picked up. Mushroom poisoning is frequently seen in forest adventure seekers and presents with variable time frames, mainly with acute gastrointestinal symptoms. Here we discuss a case of mushroom poisoning in a lady in her early sixties who presented with acute liver injury after 6 hours of wild toxic mushroom intake, having severely raised INR (International Normalized Ratio). She was managed with N-acetylcysteine (NAC), vitamin K, and regular benzylpenicillin in the liver-intensive therapy unit (ITU). The data regarding the treatment of mushroom poisoning is not tested in conventional rigorous randomized control trials. However, the role of good supportive care in liver-ITU, the addition of NAC, and benzylpenicillin in some cases, is reassuring. And if that fails, then liver transplant is a viable option. Her case underscores the critical importance of early diagnosis and immediate initiation of supportive care, including the addition of NAC and regular benzylpenicillin in selected cases. For those not responding to these conventional therapies, the possibility of a liver transplant, as a last resort, must be considered.},
}
@article {pmid39674107,
year = {2025},
author = {Wang, X and Luo, J and Cao, M and Ju, Y and Long, Q and Yang, R and Ji, Q and Zhou, G and Zhang, J and Li, R and Chen, X},
title = {Effects of different concentrations of N-acetylcysteine on the sperm quality, antioxidant enzyme activity, and antioxidant gene expression of cryopreserved goat semen.},
journal = {Theriogenology},
volume = {234},
number = {},
pages = {101-109},
doi = {10.1016/j.theriogenology.2024.12.009},
pmid = {39674107},
issn = {1879-3231},
mesh = {Male ; Animals ; *Goats ; *Acetylcysteine/pharmacology ; *Spermatozoa/drug effects ; *Oxidoreductases/metabolism ; Enzyme Activation/drug effects ; *Gene Expression Regulation, Enzymologic/drug effects ; *Cryopreservation/veterinary ; Cryoprotective Agents/pharmacology ; Sperm Motility/drug effects ; },
abstract = {During cryopreservation, spermatozoa produce excess reactive oxygen species (ROS), which attack the plasma membrane, disrupt the physiological structure of the sperm, and ultimately decrease semen quality. This study investigated the effects of different N-acetylcysteine (NAC) concentrations on the cryopreservation of semen from Qianbei Ma goats. Semen samples were collected from five bucks with motility rates above 80 %. The treatment groups were diluted 20-fold in extenders containing 3 or 9 mM NAC and cryopreserved in liquid nitrogen, whereas the control group did not include NAC. After thawing, the sperm motility, antioxidant gene expression, enzyme activity, and cell structure were analysed. The NAC-treated groups showed improved post-thaw sperm motility. The 9 mM NAC group presented the highest catalase (CAT) and glutathione peroxidase activities, lowest ROS levels, and fewest apoptotic sperms. Moreover, the 3 mM NAC group presented the highest superoxide dismutase activity and L-cysteine levels and the lowest malondialdehyde levels. Additionally, sperm membrane integrity and mitochondrial membrane potential were significantly higher in the NAC-treated group than that in the control. Further analysis of antioxidant and apoptotic gene expression in the treated sperm revealed that the 9 mM NAC group presented significantly greater CAT and GPX4 expression than the control and 3 mM NAC groups, whereas the apoptotic genes BAX and Caspase3 were elevated in the control group compared to both the NAC groups. In summary, adding NAC to semen extenders enhanced antioxidant gene expression, increased enzyme activity, and improved post-thaw semen quality, with the 9 mM NAC treatment showing the optimal effects.},
}
@article {pmid39674082,
year = {2025},
author = {Tsuji, Y and Ninomiya-Tsuji, J and Shen, MYF and DiFrancesco, BR},
title = {Modulation of iron metabolism by new chemicals interacting with the iron regulatory system.},
journal = {Redox biology},
volume = {79},
number = {},
pages = {103444},
pmid = {39674082},
issn = {2213-2317},
support = {R35 GM139601/GM/NIGMS NIH HHS/United States ; P30 ES025128/ES/NIEHS NIH HHS/United States ; },
mesh = {Humans ; *Iron/metabolism ; Receptors, Transferrin/genetics/metabolism ; *Iron Regulatory Protein 2/metabolism/antagonists &amp; inhibitors/genetics ; Reactive Oxygen Species/metabolism ; Ferritins/genetics/metabolism ; Small Molecule Libraries/pharmacology ; Mitochondria/metabolism/drug effects ; Antigens, CD ; },
abstract = {Despite the vital role of iron and vulnerability of iron metabolism in disease states, it remains largely unknown whether chemicals interacting with cellular proteins are responsible for perturbation of iron metabolism. We previously demonstrated that cisplatin was an inhibitor of the iron regulatory system by blocking IRP2 (iron regulatory protein 2) binding to an iron-responsive element (IRE) located in the 3'- or 5'-UTR (untranslated region) of key iron metabolism genes such as transferrin receptor 1 (TfR1) and ferritin mRNAs. To guide the development of new chemical probes to modulate the IRP-IRE regulatory system, we used an artificial intelligence (AI)-based ligand design and screened a chemical library composed of cysteine-reactive warheads. Using wild type and mutant IRE-luciferase reporter cells, we identified new IRP-IRE inhibitors such as V004-0872 harboring chloroacetamide, while its analog V011-6261 with chloropropanamide completely lost the inhibitory activity. V004-0872 inhibited the human IRP2 via Cys512 and caused decreased iron levels through reciprocal TfR1 downregulation and ferritin upregulation. V004-0872 increased production of mitochondrial reactive oxygen species (ROS) and exhibited cytotoxicity that was inhibited by N-acetyl cysteine but not the ferroptosis inhibitor ferrostatin-1. Furthermore, we found that widely used haloketone protease inhibitors and acetamide herbicides inhibit the IRP-IRE system. Since IRP2 overexpression is responsible for iron excess conditions to promote growth of several cancers and exacerbation of iron-overload diseases, these results and new compounds lay the groundwork for new reagents and strategies to limit the availability of iron and oxidative stress in iron-overloaded disease conditions.},
}
@article {pmid39672615,
year = {2024},
author = {Ju, Z and Bi, Y and Gao, M and Yin, Y and Xu, T and Xu, S},
title = {Emamectin benzoate and nanoplastics induce PANoptosis of common carp (Cyprinus carpio) gill through MAPK pathway.},
journal = {Pesticide biochemistry and physiology},
volume = {206},
number = {},
pages = {106202},
doi = {10.1016/j.pestbp.2024.106202},
pmid = {39672615},
issn = {1095-9939},
mesh = {Animals ; *Carps/metabolism ; *Gills/drug effects/metabolism ; *Ivermectin/analogs &amp; derivatives/toxicity ; *MAP Kinase Signaling System/drug effects ; Microplastics/toxicity ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Water Pollutants, Chemical/toxicity ; Nanoparticles/toxicity ; },
abstract = {Emamectin benzoate (EMB) is a pesticide that is frequently used. Nanoplastics (NPs) are a recently identified class of pollutants that are ubiquitous in the environment. In the aquatic environment, NPs can appear together with EMB, which may exacerbates the damage to water and aquatic organisms. However, the damage and mechanism of EMB and NPs to the gill tissue of common carp (Cyprinus carpio) remain unclear. Therefore, an EMB or/NPs exposure model was constructed to explore the mechanism of EMB or/NPs exposure on carp gill damage. This study was done by immunofluorescence, RT-qPCR, Western blot and other methods. Both in vitro and in vivo data indicated that EMB or NPs exposure could lead to gill tissue destruction, oxidative stress with the increased of ROS fluorescence intensity, MDA and H2O2 content, and the decreased CAT and GSH-PX activity, and the activation of MAPK pathway. Subsequently, PANoptosomes were activated with the up-regulated mRNA and protein expression of RIPK-1, Caspase-1,NLRP3, ACS, RIPK-3, Caspase-8, resulting in PANoptosis including the increased GSDMD, Caspase-3, MLKL expression. Notably, the results following combined exposure were more pronounced than those observed following exposure alone. The addition of N-acetylcysteine (NAC) and 3-methylindole (3-MI) further evidenced that EMB or/and NPs exposure can induce gill damage via the ROS/MAPK/PANoptosis pathway. Therefore, the present study reveals that EMB or/NPs exposure induces PANoptosis in carp gill by activating ROS/p38/MAPK signaling.},
}
@article {pmid39669379,
year = {2024},
author = {Letras-Luna, DE and Rosas-Murrieta, NH and Pazos-Salazar, NG and Flores-Hernández, J and Castelán, F and Venegas, B and Díaz, A and Treviño, S and Juárez-Serrano, D and García-Suastegui, WA and Handal-Silva, A and Morán-Perales, JL},
title = {Efficacy of Local N-Acetylcysteine Administration in Mitigating OHSS Parameters: A Comparative Analysis With Dopaminergic Agonist in the OHSS Model.},
journal = {International journal of endocrinology},
volume = {2024},
number = {},
pages = {1634072},
pmid = {39669379},
issn = {1687-8337},
abstract = {In this study, we evaluated the effects of intrabursal administration of cabergoline and N-acetylcysteine on ovarian hyperstimulation syndrome (OHSS) in an immature rat model. The study assessed body, ovarian, and uterine weights, as well as the concentrations of vascular endothelial growth factor A (VEGF-A). Moreover, levels of MDA, 4-HDA, and nitrites were assessed in ovarian homogenates, and vascular permeability was quantified in the peritoneal cavity. Ovarian morphology was characterized using histology and hematoxylin-eosin staining, determining the count of ovarian follicles and corpus luteum. Our results demonstrated a significant increase in lipoperoxidation, nitrite levels, and VEGF-A concentrations in the OHSS group compared to the control group. These biochemical alterations corroborate the successful induction of OHSS in the experimental model. Direct injection into the ovarian bursa resulted in reduced vascular permeability and VEGF-A levels, suggesting that the effects of cabergoline are predominantly ovarian. Particularly, cabergoline did not significantly alter other parameters such as ovarian weight, lipoperoxidation, nitrite levels, or morphology. Conversely, low concentrations of N-acetylcysteine (25-50 µg/kg) significantly reduced ovarian and uterine weights, VEGF-A levels, and vascular permeability. Interestingly, this dose-response relationship was not observed at higher NAC concentrations (100-200 μg/kg), suggesting a potential threshold beyond which NAC loses efficacy in these specific parameters. Our results suggest that the localized administration of N-acetylcysteine shows promise as a therapeutic strategy for OHSS by modulating key parameters associated with the syndrome. These promising results warrant further investigation into its mechanisms and efficacy, potentially expanding therapeutic options for OHSS management.},
}
@article {pmid39662870,
year = {2025},
author = {Eker, A and Eraslan, G},
title = {Single and combined effect of chrysin and N-acetylcysteine against deltamethrin exposure in rats.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {196},
number = {},
pages = {115191},
doi = {10.1016/j.fct.2024.115191},
pmid = {39662870},
issn = {1873-6351},
mesh = {Animals ; *Pyrethrins/toxicity ; *Nitriles/toxicity/pharmacology ; Male ; *Acetylcysteine/pharmacology ; *Rats, Wistar ; *Flavonoids/pharmacology ; *Oxidative Stress/drug effects ; Rats ; *Liver/drug effects/metabolism ; Insecticides/toxicity ; },
abstract = {Effects of chrysin and N-acetylcysteine on deltamethrin exposure in rats were investigated. Eighty male Wistar Albino rats, weighing between 150 and 200 g and aged 2-3 months, were used and evenly allocated into eight groups. The control group of rats received a corn oil vehicle. Chrysin (50 mg/kg.bw), N-acetylcysteine (50 mg/kg.bw), a combination of chrysin and N-acetylcysteine, deltamethrin (10 mg/kg.bw), deltamethrin combined with chrysin, deltamethrin combined with N-acetylcysteine, and a combination of deltamethrin, chrysin, and N-acetylcysteine were administered via oral gavage for a duration of 21 days. Tissue (liver, kidney, brain, testis, heart, lung) and blood of oxidative stress markers (MDA, NO, GSH, SOD, CAT, GSH-Px, GR, GST, G6PD), hepatic caspase 3, 9 and p53 protein levels, biochemical parameters (glucose, triglyceride, cholesterol, BUN, creatinine, uric acid, total protein, albumin, LDH, AST, ALT, ALP, PChE activities/levels), as well as rat body/organ weights and plasma/liver deltamethrin concentrations. The administration of chrysin and N-acetylcysteine independently did not alter the assessed parameters. Significant differences were observed in most parameters assessed in the deltamethrin-alone group compared to the control group, whereas the parameter values in the groups treated with chrysin, NAC, or their combination with deltamethrin were similar to those of the control.},
}
@article {pmid39643123,
year = {2025},
author = {Zhang, D and Chen, Y and Sun, Y and Xu, H and Wei, R and Zhou, Y and Li, F and Li, J and Wang, J and Chen, P and Xi, L},
title = {Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells.},
journal = {Biochemical pharmacology},
volume = {232},
number = {},
pages = {116695},
doi = {10.1016/j.bcp.2024.116695},
pmid = {39643123},
issn = {1873-2968},
mesh = {Female ; *Xanthones/pharmacology/therapeutic use ; *Reactive Oxygen Species/metabolism ; Humans ; *Ovarian Neoplasms/metabolism/drug therapy/pathology ; Animals ; *Pyroptosis/drug effects/physiology ; *Mitochondria/metabolism/drug effects ; Signal Transduction/drug effects/physiology ; *Caspase 3/metabolism/genetics ; Cell Line, Tumor ; *Tumor Suppressor Protein p53/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Xenograft Model Antitumor Assays/methods ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Gasdermins ; },
abstract = {Gambogic acid (GA) is a naturally active compound extracted from the Garcinia hanburyi with various anticancer activities. However, whether GA induces pyroptosis (a newly discovered inflammation-mediated programmed cell death mechanism) in ovarian cancer (OC) has not yet been reported. This study revealed that GA treatment reduced cell viability by inducing pyroptosis in OC cell lines. Typical pyroptosis morphological manifestations such as cell swelling with large bubbles and loss of cell membrane integrity, were observed. Cleaved caspase-3 and GSDME-N levels increased after GA treatment, and knocking out GSDME or using a caspase-3 inhibitor could switch GA-induced cell death from pyroptosis to apoptosis, indicating GA induced caspase-3/GSDME-dependent pyroptosis. Furthermore, this research indicated that GA significantly increased reactive oxygen species (ROS) and p53 phosphorylation. OC cells pretreated with ROS inhibitor N-Acetylcysteine (NAC) and the specific p53 inhibitor pifithrin-μ could completely reverse the pyroptosis post-treatment. Elevated p53 and phosphorylated p53 reduced mitochondrial membrane potential (MMP) and Bcl-2, increase the expression of Bax, and damage mitochondria by releasing cytochrome c to activate the downstream pyroptosis pathway. Different doses of GA inhibited tumor growth in ID8 tumor-bearing mice, and high-dose GA increased in tumor-infiltrating lymphocytes CD3, CD4, and CD8 were detected in tumor tissues. Notably, the expressions of GSDME-N, cleaved caspase-3 and other proteins were increased in tumor tissues with high-dose GA groups. These findings demonstrate that GA-treated OC cells could induce GSDME-mediated pyroptosis through the ROS/p53/mitochondria signaling pathway and caspase-3/-9 activation. Thus, GA is a promising therapeutic agent for OC treatment.},
}
@article {pmid39641827,
year = {2024},
author = {Yang, Y and Ren, D and Peng, B and Huang, J and Yang, B},
title = {The role of FOXM1 in acetylcysteine improving diabetic periodontitis.},
journal = {Journal of molecular histology},
volume = {56},
number = {1},
pages = {34},
pmid = {39641827},
issn = {1567-2387},
support = {2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; 2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; 2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; 2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; 2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; },
mesh = {Animals ; Mice ; *Forkhead Box Protein M1/metabolism/genetics ; *Acetylcysteine/pharmacology ; *Periodontitis/metabolism/pathology/genetics/complications ; *Diabetes Mellitus, Experimental/metabolism/complications ; Reactive Oxygen Species/metabolism ; Male ; Osteoclasts/metabolism ; Macrophages/metabolism ; Disease Models, Animal ; Oxidative Stress ; Diabetes Complications/metabolism ; Cell Differentiation ; RAW 264.7 Cells ; },
abstract = {Diabetic periodontitis (DP) stems from hyperglycemia-driven oxidative stress amplification and chronic inflammation, leading to periodontal tissue breakdown. Misregulated forkhead box protein M1 (FOXM1) play key roles in this process, exacerbating both inflammation and oxidative stress. In light of N-Acetylcysteine (NAC)'s potent anti-oxidative capacity and anti-inflammatory potential, understanding how it modulates these central pathways to alleviate DP holds high scientific and clinical importance. An animal model of diabetic mice periodontitis was established, and the model mice were injected with FOXM 1 adenovirus to enrich FOXM 1, and the periodontal pathological histology of each group was evaluated by HE staining. Western blotting and RT-PCR evaluated the expression levels of factors involved in bone destruction. ELISA evaluated the amount of inflammatory factors in mice serum. FOXM 1 over-expression and NAC were treated in murine macrophages, and the intracellular reactive oxygen species(ROS) levels in macrophages were measured using a DCFH-DA probe. Receptor activator of NF-κB ligand (RANKL) and lipopolysaccharide (LPS) were used to establish the macrophage osteoclast differentiation model and test the expression level of osteoclast differentiation factors after giving NAC. Hydrogen peroxide was used to establish a peroxidation environment, the plasmid silenced C-JUN, and the DNA binding activity of activating protein-1(AP1) was detected by EMSA. The effect of peroxidation on the osteoclast differentiation level was determined by WB. Mice with DP model had epithelial damage and inflammatory infiltration in periodontal tissues, and in the FOXM1 enriched group, the periodontal epithelial damage was repaired and inflammation was alleviated. FOXM1 enrichment resulted in DP model lower expression of RANKL (P < 0.01), macrophage colony-stimulating factor (M-CSF) (P < 0.01) and elevated expression of osteoprotegerin (OPG) (P < 0.001). Serum levels of pro-inflammatory factors interleukin (IL)-1β, tumor necrosis factor (TNF-α), and inducible nitric oxide synthase (iNOS) were elevated in DP mice (P < 0.001), and anti-inflammatory factor IL-10 was reduced(P < 0.001),, and FOXM1 enrichment significantly reversed inflammatory factor levels (P < 0.01). Overexpression of FOXM1 reduced ROS content in macrophages (P < 0.001), and NAC was performed to further reduce ROS content (P < 0.01). Silencing of FOXM1 elevated the expression of osteoclast-specific genes NFATc1, TRAP and OSCAR (P < 0.01), and the addition of NAC on top of silencing of FOXM1 markedly suppressed the expression level of osteoclast-specific genes (P < 0.01). ROS increased the transcriptional activity of AP1 (P < 0.001), which promoted osteoclast-specific gene expression (P < 0.001), and osteoclast-specific gene expression was decreased after silencing C-JUN (P < 0.01). FOXM1 relieve diabetic periodontitis inflammation and promote bone formation, regulates ROS production and ROS increases the transcriptional activity of AP1 and affects the osteoclastic differentiation of macrophages, which plays a positive role in bone protection in diabetic periodontitis.},
}
@article {pmid39632267,
year = {2024},
author = {Sadowski, M and Zawieja, E and Chmurzynska, A},
title = {The impact of N-acetylcysteine on lactate, biomarkers of oxidative stress, immune response, and muscle damage: A systematic review and meta-analysis.},
journal = {Journal of cellular and molecular medicine},
volume = {28},
number = {23},
pages = {e70198},
pmid = {39632267},
issn = {1582-4934},
support = {//Ministerstwo Edukacji i Nauki/ ; },
mesh = {*Acetylcysteine/pharmacology ; *Biomarkers ; Humans ; *Oxidative Stress/drug effects ; *Lactic Acid/metabolism ; Glutathione/metabolism ; Muscle, Skeletal/drug effects/metabolism ; Dietary Supplements ; Myalgia/drug therapy ; Tumor Necrosis Factor-alpha/metabolism/blood ; Exercise ; Immunity/drug effects ; Interleukin-6/metabolism/blood ; },
abstract = {N-acetylcysteine (NAC) is a compound whose mechanism of action is intricately linked to the provision of cysteine for glutathione synthesis. It has been used in medicine and has also made significant inroads into sports, as it can modify the levels of several biomarkers, including those of oxidative processes, inflammation and muscle damage after exercise. Because the effectiveness of NAC supplementation is unclear, the primary objective of the present study was to perform a meta-analysis elucidating how NAC supplementation alters the concentrations of GSH (glutathione), GSSG (glutathione disulfide), TBARS (thiobarbituric acid reactive substances), IL-6 (interleukin 6), TNF-α (tumour necrosis factor alpha), CK (creatine kinase), lactate, and muscle soreness after physical exertion. Suitable studies were searched for from February to September 2023, and the results of those included (n = 20) indicate that NAC supplementation significantly diminishes both muscle soreness (p = 0.03; the mean difference (MD) of NAC's effect was -0.43 with a 95% confidence interval (CI), -0.81, -0.04) and lactate concentrations after exercise (p = 0.03; the MD -0.56 mmol/L; 95% CI, -1.07, -0.06). A substantial decrease was observed in concentrations of IL-6 (p = 0.03; the standardized MD (SMD) was -1.71; 95% CI, -3.26, -0.16) and TBARS (p = 0.02; SMD was -1.03, 95% CI, -1.90, -0.15). Furthermore, an elevation in GSH concentration was observed following supplementation. However, we saw no significant effect of NAC on TNF-α, CK or GSSG concentrations. NAC supplementation holds promise for attenuating muscle soreness, lactate, TBARS and IL-6 concentrations and increasing GSH level following physical exertion.},
}
@article {pmid39631278,
year = {2025},
author = {Li, G and Wu, M and Chen, K and Xu, Y and Zhang, X and Chen, Y and Zhang, H and Zhang, R and Huang, X},
title = {ROS-mediated M1 polarization-necroptosis crosstalk involved in Di-(2-ethylhexyl) phthalate-induced chicken liver injury.},
journal = {Poultry science},
volume = {104},
number = {1},
pages = {104558},
pmid = {39631278},
issn = {1525-3171},
mesh = {Animals ; *Chickens ; *Diethylhexyl Phthalate/toxicity/adverse effects ; *Reactive Oxygen Species/metabolism ; *Poultry Diseases/chemically induced ; *Plasticizers/toxicity/adverse effects ; *Chemical and Drug Induced Liver Injury/veterinary/etiology ; *Macrophages/drug effects ; Oxidative Stress/drug effects ; *Necroptosis/drug effects ; *Liver/drug effects ; Cell Line ; },
abstract = {The widespread use of plasticizers poses a serious threat to the environment and poultry health. Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer that can cause liver damage with prolonged exposure. Oxidative stress is closely associated with DEHP toxicity. Macrophage polarization plays an important role in many physiological and pathological processes and regulates disease development. This study aims to elucidate the mechanism of chronic DEHP exposure leading to chicken liver injury through oxidative stress-induced M1 polarization-necroptosis. In this study, the DEHP exposure model of chicken liver and the single and co-culture model of LMH and HD11 cells were established. With increasing dose and time, DEHP decreased body weight, increased liver coefficient, raised activities of liver function indicators and caused pathological liver damage in chickens. Further studies revealed the increase of reactive oxygen species (ROS) level and malonaldehyde (MDA) content, and the decrease of total antioxidant capacity (T-AOC) level, total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activities, which led to excessive oxidative stress in the liver. In addition, there was increased infiltration of liver macrophages (CD68), upregulation of M1 polarization indicators (CD86, iNOS, IL-1β, TNF-α) and downregulation of M2 polarization indicators (CD163, Arg-1, IL-10, TGF-β) and appearance of necroptosis (RIPK1, RIPK3, MLKL). The vitro experiments confirmed the addition of N-acetylcysteine (NAC) inhibited M1 polarization and necroptosis. Besides, M1 polarization of HD11 cells promoted necroptosis of LMH cells in the HD11-LMH co-culture system. In brief, ROS-mediated M1 polarization-necroptosis is involved in DEHP-induced liver injury. This study provides a reference for environmental toxicant exposure in livestock and poultry farming.},
}
@article {pmid39628758,
year = {2024},
author = {Ejubović, M and Kapic, D and Custovic, S and Lazović Salčin, E and Lepara, O and Kurtović, A and Jahić, R and Kulo Cesic, A and Paralija, B and Ziga Smajic, N and Jagodić Ejubović, A and Hasanbegovic, S and Katica, M and Besic, A and Djesevic, E and Fajkić, A},
title = {Therapeutic Potential of N-acetylcysteine and Glycine in Reducing Pulmonary Injury in Diabetic Rats.},
journal = {Cureus},
volume = {16},
number = {11},
pages = {e72902},
pmid = {39628758},
issn = {2168-8184},
abstract = {INTRODUCTION: Diabetes mellitus is associated with systemic complications, including the development of pulmonary injury, characterized mainly by excessive accumulation of extracellular matrix components and inflammatory cell infiltration in lung tissue. This process is driven by oxidative stress and chronic inflammation, both caused and exacerbated by hyperglycemia. N-acetylcysteine (NAC) and glycine, known for their antioxidant and anti-inflammatory effects, offer potential therapeutic benefits in mitigating diabetes-induced lung injury.<br><br>OBJECTIVE: The study aimed to investigate the effects of supplementation by either NAC or glycine or their combination on reducing lung injury in rats with type 1 diabetes Materials and methods: The study used 30 adult Wistar albino rats (10 weeks old, weighing between 180 g and 380 g). Six of them were used as controls, while 24 adult rats (10 weeks old, 180-380 g) with type 1 diabetes, induced through a single intraperitoneal injection of streptozotocin (STZ) at a dose of 55 mg/kg, were randomly assigned to four experimental groups: control (CTL), diabetic (Db), NAC treatment (diabetic+NAC), glycine treatment (diabetic+glycine), and combined NAC and glycine treatment (diabetic+NAC+glycine). NAC (100 mg/kg) and glycine (250 mg/kg) were administered orally for 12 weeks. At the end of the study, lung tissues were collected for histopathological examination. Qualitative, semi-quantitative, and stereological histological analysis was used to analyze structural changes in the lung tissue. Semi-quantitative scoring was carried out to evaluate the extent of inflammation, while stereological analysis was performed to determine the volume density of alveolar spaces and septal connective tissue. The semi-quantitative scoring included scores ranging from 0 (absent), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe).<br><br>RESULTS: Qualitative histological analysis revealed pronounced inflammation and fibrosis in the lungs of untreated diabetic rats, characterized by thickened alveolar septa and immune cell infiltration. Both treatments with NAC and glycine individually reduced inflammation and fibrosis compared to untreated diabetic rats. The greatest improvement was observed in the NAC+glycine group, where the alveolar structure appeared almost normal, with minimal inflammation. Semiquantitative analysis showed statistically significant differences in peribronchial and peribrochiolar infiltrates between the diabetic group (2.16&#xb1;0.47) and the control group (0.33&#xb1;0.21, p=0.026). The combination of NAC and glycine significantly reduced peribronchial and peribronchiolar infiltrates (0.33&#xb1;0.33, p=0.026) compared to the diabetic group. Similarly, septal inflammatory infiltrates were significantly lower in the NAC+glycine group (1&#xb1;0.36) compared to diabetic rats (3.33&#xb1;0.33, p=0.004). Total airway inflammatory infiltration was also significantly reduced in the NAC+glycine group (1.33&#xb1;0.33, p=0.002) compared to the diabetic group (5.5&#xb1;0.5).<br><br>CONCLUSION: As the combination of NAC and glycine demonstrated protective effects against lung inflammation and fibrosis in diabetic rats, a synergistic effect of NAC and glycine in mitigating pulmonary complications associated with type 1 diabetes may be suggested. These findings warrant further exploration of the combination for managing diabetic lung disease and potentially other fibrotic conditions.},
}
@article {pmid39626181,
year = {2025},
author = {Sivasinprasasn, S and Chattipakorn, K and Pratchayasakul, W and Chattipakorn, SC and Chattipakorn, N},
title = {N-Acetylcysteine enhances low-dose estrogen efficacy against ischemia-reperfusion injury in estrogen-deprived obese insulin-resistant rats.},
journal = {Menopause (New York, N.Y.)},
volume = {32},
number = {1},
pages = {81-90},
pmid = {39626181},
issn = {1530-0374},
mesh = {Animals ; Female ; *Insulin Resistance ; *Rats, Wistar ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Rats ; *Obesity/drug therapy/complications ; *Estrogens/administration &amp; dosage/pharmacology ; *Ovariectomy ; *Myocardial Reperfusion Injury/drug therapy/prevention &amp; control ; *Estradiol/blood/pharmacology/administration &amp; dosage ; Diet, High-Fat/adverse effects ; Ventricular Function, Left/drug effects ; Reperfusion Injury/drug therapy/prevention &amp; control ; Disease Models, Animal ; },
abstract = {OBJECTIVES: Postmenopausal women are at higher risk of metabolic syndrome and cardiovascular disease, which are aggravated by obesity. Although estrogen provides cardiometabolic protection, chronic high-dose treatment could be harmful. This study investigated the efficacy of combined N-acetylcysteine (NAC) and low-dose estrogen treatment against cardiometabolic dysfunction in female estrogen-deprived obese rats with cardiac ischemia-reperfusion (I/R) injury.<br><br>METHODS: Bilateral ovariectomized (O) female Wistar rats were fed a high-fat diet (H) for 12 weeks. Then, rats were treated for 4 weeks with one of the following: vehicle (OH; sesame oil), regular-dose estrogen (E; 50 &#x3bc;g/kg/d), low-dose estrogen (e; 25 &#x3bc;g/kg/d), NAC (N; 100 mg/kg/d), or combined low-dose estradiol with NAC (eN). All rats then underwent cardiac I/R injury, and the left ventricle (LV) function and mitochondrial function were investigated (n = 6/group). Statistical analysis was performed by one-way ANOVA followed by Fisher's least significant difference post hoc test.<br><br>RESULTS: Body weight, visceral fat, plasma glucose, and plasma cholesterol were significantly increased with impaired LV function and heart rate variability in OH rats. OH-E rats had decreased plasma insulin and Homeostatic Model Assessment for Insulin Resistance index. Both OH-E and OH-eN rats had similarly improved heart rate variability and LV function. During cardiac I/R, OH-E and OH-eN rats had preserved left ventricular ejection fraction, stroke volume, and attenuated arrhythmias. Impaired cardiac mitochondrial function and infarct size were similarly reduced in OH-E and OH-eN rats.<br><br>CONCLUSIONS: Combined NAC and low-dose estrogen treatment shares similar efficacy as regular-dose estrogen in attenuating cardiac dysfunction, cardiac mitochondrial dysfunction, and protecting the heart against I/R injury in estrogen-deprived obese insulin-resistant rats.},
}
@article {pmid39624277,
year = {2024},
author = {Maurer, S and Fuchs, M and Brenner, RE and Riegger, J},
title = {Glutathione has cell protective and anti-catabolic effects in articular cartilage without impairing the chondroanabolic phenotype.},
journal = {Heliyon},
volume = {10},
number = {22},
pages = {e40368},
pmid = {39624277},
issn = {2405-8440},
abstract = {Joint injuries and consequent oxidative stress is a high-risk factor for developing post-traumatic osteoarthritis (OA). While antioxidative therapy using N-acetylcysteine (NAC) has cell- and chondroprotective effects following cartilage injury, it strongly impairs matrix synthesis. Consequently, direct application of Glutathione (GSH) was tested as an alternative therapeutic approach using an ex vivo cartilage trauma model and isolated chondrocytes, with comparison to NAC. Porcine cartilage explants were traumatized using a drop tower with an impact energy of 0.47 J and afterwards treated with 0.5-2 mM GSH or 2 mM NAC for 4 days according to a standardized protocol. The effects of antioxidative treatment on the chondrogenic phenotype were tested in a 3D pellet culture for 28 days. Our results demonstrated that both antioxidants had cell protective effects after cartilage trauma. GSH was most effective at a concentration of 0.5 mM, as confirmed in experiments with isolated human chondrocytes exposed to H2O2. At this concentration, GSH did not impair cell proliferation or hyaline cartilage matrix synthesis, while NAC suppressed the chondrogenic phenotype in pellet culture. Both, NAC and GSH elevated the intracellular GSH concentration, indicating an efficient uptake of the antioxidants. Furthermore, both therapeutics inhibited the activity of the matrix degrading enzyme MMP-2. Our results demonstrated cell- and chondroprotective effects by NAC and GSH therapy after cartilage trauma, with GSH demonstrating advantages in preserving the chondrogenic phenotype.},
}
@article {pmid39624161,
year = {2024},
author = {Zhang, D and Qin, C and Meng, F and Han, X and Guo, X},
title = {N-Acetylcysteine Treats Spinal Cord Injury by Inhibiting Astrocyte Proliferation.},
journal = {Analytical cellular pathology (Amsterdam)},
volume = {2024},
number = {},
pages = {6624283},
pmid = {39624161},
issn = {2210-7185},
mesh = {Animals ; *Spinal Cord Injuries/pathology/metabolism/drug therapy ; *Astrocytes/drug effects/metabolism/pathology ; *Cell Proliferation/drug effects ; *Acetylcysteine/pharmacology ; *Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Rats ; Janus Kinases/metabolism ; STAT Transcription Factors/metabolism ; Connexin 43/metabolism ; Male ; Glial Fibrillary Acidic Protein/metabolism ; Disease Models, Animal ; },
abstract = {Astrocyte proliferation commonly occurs after spinal cord injury (SCI). N-Acetylcysteine (NAC) has a regulatory effect on many diseases. In this study, we investigated the effect and underlying mechanism of NAC on astrocytes in SCI. We isolated rat primary astrocytes and stimulated with lipopolysaccharide to induce cell proliferation and degeneration. A rat model of SCI was also established, and the Basso-Beattie-Bresnahan score was determined. The localization of glial fibrillary acidic protein in the cells and tissues was determined using TUNEL staining and immunofluorescence, while that of connexin 43 was assessed via immunofluorescence. Pathological changes associated with SCI were detected using hematoxylin and eosin staining, and inflammatory factors were detected using enzyme-linked immunosorbent assay. Additionally, JAK/STAT expression was evaluated using western blotting and quantitative reverse transcription polymerase chain reaction. NAC downregulated the glial fibrillary acidic protein abundance and connexin 43 in reactive astrocytes and SCI rat models while inhibiting the abundance of secreted proteins DSPG, HSPG, KSPG, tenascin C, vimentin, CSPG, ephrin-B2, and nestin. NAC also regulated the JAK/STAT signaling pathway by downregulating the expression of JAK2, STAT5, STAT3, STAT1, PIM1, NFATc1, COL1, COL3, TGF-β, SMAD1, CTGF, CyCD1, and CDK4, thus alleviating SCI. Finally, NAC exhibited durable effects, with no SCI recurrence within 60 days. Therefore, NAC relieves SCI by inhibiting the proliferation of reactive astrocytes and suppressing the expression of secretory and JAK/STAT pathway proteins.},
}
@article {pmid39618229,
year = {2024},
author = {He, T and Ren, K and Xiang, L and Yao, H and Huang, Y and Gao, Y},
title = {Efficacy of N-Acetylcysteine as an Adjuvant Therapy for Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.},
journal = {British journal of hospital medicine (London, England : 2005)},
volume = {85},
number = {11},
pages = {1-16},
doi = {10.12968/hmed.2024.0560},
pmid = {39618229},
issn = {1750-8460},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Arthritis, Rheumatoid/drug therapy ; *Randomized Controlled Trials as Topic ; Antioxidants/therapeutic use ; Blood Sedimentation ; Treatment Outcome ; },
abstract = {Aims/Background Rheumatoid arthritis (RA) is an inflammatory autoimmune disease and N-acetylcysteine (NAC) is considered a potential therapeutic agent for RA due to strong antioxidant and anti-inflammatory properties. Therefore, this systematic review and meta-analysis aimed to evaluate the efficacy of NAC as an adjuvant therapy for RA. Methods A systematic search was conducted across five databases from inception to 1 August 2024, including CINAHL, Cochrane Library, EMBASE, PubMed, and Web of Science. The Cochrane risk-of-bias tool for randomized trials was used to assess the quality of the included studies. Sensitivity analysis was performed when significant heterogeneity was identified. Results Four studies involving 204 patients were included in our meta-analysis. The results indicated that NAC alleviated disease activity in RA patients (Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR): mean difference (MD) = 0.54). Additionally, NAC reduced inflammatory markers (erythrocyte sedimentation rate (ESR): MD = 3.00). However, the beneficial effects of NAC on oxidative stress in RA patients were not observed. Conclusion This meta-analysis demonstrated the efficacy of NAC in reducing inflammatory markers, improving joint tenderness, and swelling in patients with RA.},
}
@article {pmid39617257,
year = {2025},
author = {Wang, L and Chen, JH and Zhang, YJ and Zhang, MB and Zeng, T},
title = {PPARβ/δ agonist GW0742 mitigates acute liver damage induced by acetaminophen overdose in mice.},
journal = {Toxicology and applied pharmacology},
volume = {494},
number = {},
pages = {117180},
doi = {10.1016/j.taap.2024.117180},
pmid = {39617257},
issn = {1096-0333},
mesh = {Animals ; *Acetaminophen/toxicity ; *PPAR-beta/agonists ; Male ; *PPAR delta/agonists ; *Chemical and Drug Induced Liver Injury/pathology/prevention &amp; control/drug therapy/etiology ; Mice ; *Mice, Inbred C57BL ; *Thiazoles/pharmacology ; Oxidative Stress/drug effects ; Drug Overdose/drug therapy ; Liver/drug effects/pathology/metabolism ; Kupffer Cells/drug effects/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/agonists ; Inflammasomes/metabolism ; Phenols ; Sulfhydryl Compounds ; },
abstract = {Liver damage caused by acetaminophen (APAP) overdose remains a worldwide medical problem. New therapeutic medicines for APAP poisoning are needed as the efficacy of the only antidote, N-acetyl-cysteine (NAC), significantly decreases if administered after 8 h of APAP intake and massive APAP overdose remains to induce hepatotoxicity despite the timely administration of NAC. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) possesses versatile roles including regulation of lipid homeostasis and anti-inflammation in the liver. This study aimed to investigate the effects of GW0742, one specific PPARβ/δ agonist, on APAP-caused liver damage in mice. We found that GW0742 (40 mg/kg, i.p.) pretreatment completely blocked the increase of serum aminotransferase activities, hepatocyte necrosis, oxidative stress, and liver inflammation in mice exposed to 300 mg/kg APAP (i.p.). Mechanistically, GW0742 pretreatment significantly suppressed the M1 polarization of liver Kupffer cells and activation of NLRP3 inflammasome. Interestingly, GW0742 remained effective when administered 6 h after APAP exposure, although its efficacy was less pronounced than that administered 6 h before the APAP challenge. Notably, GW0742 exhibited a more profound effect than NAC evidenced by the lower serum alanine transaminase (ALT) level and the improved histopathological manifestation. Furthermore, exposure to APAP for 6 h had resulted in dramatic liver inflammation, while pretreatment with GW0742 prior to APAP exposure did not influence the increase in serum aminotransferase activity and oxidative stress at 2 h after APAP exposure. These results highlight that PPARβ/δ may be a promising therapeutic target for treating APAP-caused acute liver damage probably acting on liver macrophages.},
}
@article {pmid39616487,
year = {2024},
author = {Su, R and Qiao, M and Gao, T and Gao, J and Nie, L and Li, S and Wang, Y and Pang, Y and Li, Q},
title = {Effect of N-acetylcysteine on apoptosis and autophagy of macrophages infected with Mycobacterium tuberculosis.},
journal = {Journal of infection in developing countries},
volume = {18},
number = {10},
pages = {1566-1575},
doi = {10.3855/jidc.19372},
pmid = {39616487},
issn = {1972-2680},
mesh = {*Autophagy/drug effects ; *Acetylcysteine/pharmacology ; *Macrophages/drug effects/microbiology ; *Apoptosis/drug effects ; *Mycobacterium tuberculosis/drug effects ; Humans ; *Reactive Oxygen Species/metabolism ; *Oxidative Stress/drug effects ; Bacterial Load/drug effects ; },
abstract = {INTRODUCTION: The purpose of this study was to observe the effect of N-acetylcysteine (NAC) on oxidative stress (OS), intracellular Mycobacterium tuberculosis (MTB) load, apoptosis, and autophagy of macrophages infected with H37Rv MTB. In addition, we explored the possible mechanism of action, to provide a rationale for the use of NAC in the treatment of tuberculosis.<br><br>METHODOLOGY: We divided THP-1 macrophages into four groups: control, control + NAC, H37Rv, and H37Rv + NAC. OS, apoptosis, autophagy and intracellular MTB colony-forming unit (CFU) indexes were measured at 0, 4, 24, and 48 hours, respectively. Then, various indicator changes were systematically compared.<br><br>RESULTS: The levels of reactive oxygen species (ROS), malondialdehyde (MDA), apoptosis rate, and LC3II/ &#x3b2;-actin ratio in the H37Rv group increased at 4 hours and reached their peak at 48 hours. The ROS and MDA in the H37Rv + NAC group were lower than those in the H37Rv group. CFU in the H37Rv + NAC group increased at 24 hours and decreased at 48 hours after treatment with NAC, relative to the H37Rv group. In addition, the H37Rv + NAC group showed a decrease in LC3II/&#x3b2;-actin ratio 48 hours after NAC treatment, compared to the H37Rv group.<br><br>CONCLUSIONS: MTB infection can lead to an increase in macrophage OS, apoptosis, and autophagy levels. However, after treatment with NAC, the growth of MTB in macrophages is inhibited, and OS and autophagy levels are reduced. The antioxidant effect and inhibitory effect of NAC on MTB are related to MTB-mediated macrophage OS and autophagy.},
}
@article {pmid39616350,
year = {2024},
author = {Zhang, H and Pertiwi, H and Michiels, J and Gaublomme, D and Majdeddin, M and Hou, Y and Boone, M and Elewaut, D and Josipovic, I and Degroote, J},
title = {Improvement of antioxidant capability by dietary N-acetyl cysteine supplementation alleviates bone loss induced by chronic heat stress in finisher broilers.},
journal = {Journal of animal science and biotechnology},
volume = {15},
number = {1},
pages = {158},
pmid = {39616350},
issn = {1674-9782},
abstract = {BACKGROUND: Heat stress (HS) incidence is associated with the accumulation of reactive substances, which might be associated with bone loss. N-Acetylcysteine (NAC) exhibits strong antioxidants due to its sulfhydryl group and being as the precursor for endogenous glutathione synthesis. Therefore, interplay between oxidative stress and bone turnover of broilers and the effects of dietary NAC inclusion on antioxidant capability and "gut-bone" axis were evaluated during chronic HS.<br><br>RESULTS: Implementing cyclic chronic HS (34&#xa0;&#xb0;C for 7&#xa0;h/d) evoked reactive oxygen species excessive production and oxidant stress, which was accompanied by compromised tibia mass. The RNA-seq of proximal tibia also revealed the enrichment of oxidation-reduction process and inflammatory outbursts during HS. Although no notable alterations in the growth performance and cecal microbiota were found, the diet contained 2&#xa0;g/kg NAC enhanced the antioxidant capability of heat-stressed broiler chickens by upregulating the expression of Nrf2 in the ileum, tibia, and bone marrow. Simultaneously, NAC tended to hinder NF-&#x3ba;B pathway activation and decreased the mRNA levels of the proinflammatory cytokines in both the ileum and bone marrow. As a result, NAC suppressed osteoclastogenesis and osteoclast activity, thereby increasing osteocyte-related gene expression. Furthermore, the inclusion of NAC tended to increase the ash content and density of the whole tibia, as well as improve cortical thickness and bone volume of the diaphysis.<br><br>CONCLUSIONS: These findings HS-mediated outburst of oxidant stress accelerates bone resorption and negatively regulates the bone quality of tibia, which is inhibited by NAC in broilers.},
}
@article {pmid39615429,
year = {2025},
author = {Antwi-Baah, R and Acquah, MEE and Dapaah, MF and Chen, X and Walker, J and Liu, H},
title = {Juxtaposing the antibacterial activities of different ZIFs in photodynamic therapy and their oxidative stress approach.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {247},
number = {},
pages = {114397},
doi = {10.1016/j.colsurfb.2024.114397},
pmid = {39615429},
issn = {1873-4367},
mesh = {*Anti-Bacterial Agents/pharmacology/chemistry ; *Photochemotherapy ; *Oxidative Stress/drug effects ; Microbial Sensitivity Tests ; *Zeolites/chemistry/pharmacology ; Chlorophyllides ; Reactive Oxygen Species/metabolism ; Particle Size ; Porphyrins/pharmacology/chemistry ; Singlet Oxygen/metabolism ; Escherichia coli/drug effects ; *Imidazoles/chemistry/pharmacology ; Staphylococcus aureus/drug effects ; *Metal-Organic Frameworks/pharmacology/chemistry ; Humans ; Photosensitizing Agents/pharmacology/chemistry ; Glutathione/metabolism ; },
abstract = {Instigating oxidative stress is a crucial aspect of antibacterial therapy. Yet, its behavior is poorly understood in the context of zeolitic imidazolate frameworks (ZIFs) - a group of highly promising antibacterial agents. To address this gap, a series of ZIF@Ce6 particles were synthesized to investigate the impact of particle shape, size, and metal ion type on oxidative stress and bactericidal activity. For the first time, the interplay between the physicochemical properties and antibacterial activities of different ZIF@Ce6 particles is demonstrated, while unearthing their oxidative stress strategy in photodynamic therapy. Notably, the incorporation of chlorin e6 (Ce6), combined with light irradiation, amplified the bactericidal effect of the ZIFs and achieved a rare minimum inhibition concentration (MIC) of 12.5 µgmL[-1] for ZIF-8. We discovered that singlet oxygen ([1]O2) production varies with particle shape and size, while photodynamic activity reshuffles the antibacterial performance sequence from pristine to modified ZIF-8. Interestingly, reactive oxygen species (ROS) accumulation and glutathione depletion tests revealed that oxidative stress in pristine ZIF-8 is predominantly induced by ROS, whereas both ROS and glutathione contribute to the oxidative stress in ZIF@Ce6 and pristine ZIF-67. When bacteria are preincubated with the antioxidant N-acetyl cysteine, the bactericidal activity of ZIF@Ce6 increases while the activity of pristine ZIF-8 is reduced and that of ZIF-67 remains unchanged. This study deepens our understanding of the antibacterial properties of ZIFs and their oxidative stress paths, paving way for the fabrication of ZIF-based materials with enriched and targeted antibacterial properties.},
}
@article {pmid39607014,
year = {2024},
author = {Esezobor, CI and Bhatt, GC and Effa, EE and Hodson, EM},
title = {Fenoldopam for preventing and treating acute kidney injury.},
journal = {The Cochrane database of systematic reviews},
volume = {11},
number = {11},
pages = {CD012905},
pmid = {39607014},
issn = {1469-493X},
mesh = {*Fenoldopam/therapeutic use ; Humans ; *Acute Kidney Injury/prevention &amp; control ; *Randomized Controlled Trials as Topic ; Child ; Adult ; *Bias ; *Dopamine Agonists/therapeutic use ; Postoperative Complications/prevention &amp; control ; Cardiac Surgical Procedures/adverse effects ; Sepsis/prevention &amp; control/complications ; },
abstract = {BACKGROUND: Fenoldopam is a short-acting benzazepine selective dopaminergic A1 (DA1) receptor agonist with increased activity at the D1 receptor compared with dopamine. Activation of the DA1 receptors increases kidney blood flow because of dilatation of the afferent and efferent arterioles. Previous reviews have been published on the efficacy and safety of fenoldopam for acute kidney injury (AKI); however, they either combined data on its effect on both prevention and treatment of AKI, focused on only those undergoing cardiac surgery and/or excluded children.<br><br>OBJECTIVES: This review aimed to assess the benefits and harms of fenoldopam for the prevention or treatment of AKI in children and adults.<br><br>SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 November 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.<br><br>SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating fenoldopam for the prevention or treatment of AKI in children and adults following surgery, radiocontrast exposure or sepsis.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility, assessed the studies for risk of bias and extracted data from the studies. Dichotomous outcomes were presented as relative risk (RR) with 95% confidence intervals (CI). For continuous outcomes, the mean difference (MD) with 95% CI was used. Statistical analysis was performed using the random-effects model. We assessed the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.<br><br>MAIN RESULTS: We identified 25 RCTs, including 3339 randomised participants. Twenty-three studies used fenoldopam for preventing AKI and two for the treatment of AKI. Nine studies included participants undergoing cardiac surgery, and one included children. The risks of bias for sequence generation and concealment were low in 11 and 13 studies, respectively. Only 13 and 18 studies were at low risk of performance bias and detection bias, respectively. The risk of attrition bias and selective reporting were judged to be at low risk of bias in 17 and 10 studies, respectively. We included data in the meta-analyses from eight of the 14 studies comparing fenoldopam with placebo or saline, all six studies comparing fenoldopam with dopamine, all five studies comparing fenoldopam with N-acetylcysteine (NAC) for the prevention of AKI and from the two studies comparing fenoldopam with placebo or saline for the treatment of AKI. Compared with placebo or saline fenoldopam probably results in fewer participants developing AKI (RR 0.72, 95% CI 0.53 to 0.98; 8 studies, 1147 participants; I[2] = 48%; moderate certainty) but may make little or no difference to the number requiring kidney replacement therapy (KRT) (RR 0.81, 95% CI 0.31 to 2.15; 7 studies, 835 participants; I[2] = 17%), risk of death (RR 0.76, 95% CI: 0.58 to 1.00; 7 studies, 944 participants; I[2] = 0%) or change in urine output (SMD 0.20, 95% CI -0.44 to 0.84; 2 studies, 58 participants; I[2] = 34%; all low certainty). Fenoldopam may result in a shorter stay in the ICU (MD -1.81 days; 95% CI -2.41 to -1.21; 4 studies, 403 participants; I[2] = 0%). It is uncertain whether adverse events (hypotension, myocardial infarction, drug intolerance, cardiac arrhythmias) differed between the treatment groups as the certainty of the evidence was very low. In patients undergoing cardiac surgery, fenoldopam, compared to placebo or saline, may make little or no difference to the prevention of AKI, the need for KRT or death. Compared with dopamine, fenoldopam may make little or no difference to the prevention of AKI (RR 0.62, 95% CI 0.23 to 1.68; 4 studies, 398 participants; I[2] = 78%), the number requiring KRT (RR 0.74, 95% CI 0.29 to 1.87; 4 studies, 434 participants; I[2] = 0%) or the risk of death (RR 1.27, 95% CI 0.36 to 4.50; 2 studies, 174 participants; I[2] = 0%) (all low certainty). It is uncertain whether participants receiving fenoldopam were more likely to develop hypotension compared with those receiving dopamine (RR 3.00, 95% CI 1.06 to 8.52; 1 study, 80 participants; very low certainty). Change in urine output was not reported. It is uncertain whether fenoldopam compared with NAC prevents AKI (RR 1.68, 95% CI 0.79 to 3.56; 3 studies, 359 participants; I[2] = 38%), reduces the need for KRT (RR 0.96, 95% CI 0.15 to 6.26; 2 studies, 137 participants; I[2] = 0%), or the risk of death (RR 1.05, 95% CI 0.07 to 15.66; 1 study, 39 participants) (all very low certainty). It is uncertain whether hypotension was more frequent with fenoldopam (RR 5.10, 95% CI 0.25, 104.94; 1 study, 192 participants; very low certainty). Change in urine output was not reported. In participants with established AKI, it is uncertain whether fenoldopam compared to placebo or half saline reduces the numbers needing KRT (RR: 0.91, 95% CI 0.54 to 1.54; 2 studies, 822 participants; I[2] = 58%; very low certainty) or the risk of death (RR 0.81, 95% CI 0.44 to 1.48; 2 studies, 822 participants; I[2] = 66%; very low certainty), or if it increases the risk of hypotension (RR 1.65, 95% CI 1.22 to 2.22; 2 studies, 822 participants; I[2] = 0%; very low certainty).<br><br>AUTHORS' CONCLUSIONS: Fenoldopam administration in patients at risk of AKI is probably associated with a lower risk of developing AKI and shorter ICU stay when compared with placebo or saline, but has little or no effect on the need for KRT or the risk of death. In those undergoing cardiac surgery, fenoldopam may not confer any benefits compared with placebo or saline. Furthermore, it remains unclear whether fenoldopam is more or less effective than either dopamine or NAC in reducing the risk for AKI or the need for KRT. Further well-designed and adequately powered studies are required to evaluate the efficacy and safety of fenoldopam in preventing or treating AKI.},
}
@article {pmid39600278,
year = {2024},
author = {Zhang, J and Chen, A and Song, Y},
title = {Propofol Triggers Cell Death in Lung Cancer Cells by Increasing PANX1 Expression, Activating the Mitochondrial Cell Death Pathway, and Enhancing ROS Levels.},
journal = {Discovery medicine},
volume = {36},
number = {190},
pages = {2231-2243},
doi = {10.24976/Discov.Med.202436190.205},
pmid = {39600278},
issn = {1944-7930},
mesh = {Humans ; *Propofol/pharmacology ; *Reactive Oxygen Species/metabolism ; *Connexins/metabolism/genetics ; *Lung Neoplasms/pathology/metabolism/drug therapy/genetics ; *Mitochondria/drug effects/metabolism ; A549 Cells ; *Nerve Tissue Proteins/metabolism/genetics ; Apoptosis/drug effects ; Cell Death/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Cell Line, Tumor ; Oxidative Stress/drug effects ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {BACKGROUND: Lung cancer treatment remains a global challenge due to tumor cell resistance. Propofol, traditionally used as an anesthetic, has demonstrated potential anti-tumor properties. This study seeks to elucidate how propofol induces cell death in lung cancer cells by upregulating Pannexin 1 (PANX1) expression, activating the mitochondrial cell death pathway, and augmenting reactive oxygen species (ROS) production.<br><br>METHODS: In this study, the A549 lung cancer cell line was employed as the experimental model. Cells underwent exposure to varying propofol concentrations and were pre-treated with H2O2 and N-acetylcysteine (NAC) to simulate oxidative stress and antioxidant conditions. Various techniques, including 5-Ethynyl-2'-deoxyuridine (EdU), colony formation, Transwell, 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA), Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL), and JC-1 (5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide) probes, were employed to evaluate propofol's effects on lung cancer cell viability, growth, invasion, ROS levels, apoptosis, and mitochondrial membrane potential. Western blot analysis was used to measure PANX1, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, and Cytochrome C (Cyt C) protein levels. Additionally, PANX1's influence on propofol-induced apoptosis was investigated through siRNA interference.<br><br>RESULTS: The experiment unveiled propofol's dose-dependent inhibition of A549 lung cancer cell growth, coupled with decreased cell proliferation and invasion attributable to heightened ROS production. Notably, propofol treatment significantly elevated mitochondrial membrane potential, signifying activation of the mitochondrial cell death pathway (p < 0.01). Furthermore, propofol upregulated PANX1 expression (p < 0.01), thereby intensifying apoptosis signaling, whereas PANX1 inhibition ameliorated propofol-induced apoptosis (p < 0.01). These findings underscore the pivotal role of PANX1 upregulation and ROS augmentation in propofol-induced apoptosis in lung cancer cells.<br><br>CONCLUSION: This study provides evidence that propofol induces cell death in lung cancer cells by upregulating PANX1, activating the mitochondrial apoptosis pathway, and increasing ROS production. These findings suggest that targeting PANX1 and ROS could enhance the anti-cancer efficacy of propofol in lung cancer.},
}
@article {pmid39599590,
year = {2024},
author = {Poulios, A and Papanikolaou, K and Draganidis, D and Tsimeas, P and Chatzinikolaou, A and Tsiokanos, A and Jamurtas, AZ and Fatouros, IG},
title = {The Effects of Antioxidant Supplementation on Soccer Performance and Recovery: A Critical Review of the Available Evidence.},
journal = {Nutrients},
volume = {16},
number = {22},
pages = {},
pmid = {39599590},
issn = {2072-6643},
mesh = {*Antioxidants/pharmacology ; Humans ; *Dietary Supplements ; *Soccer ; *Athletic Performance/physiology ; Oxidative Stress/drug effects ; Muscle, Skeletal/drug effects/metabolism ; Sports Nutritional Physiological Phenomena ; },
abstract = {Background Soccer is linked to an acute inflammatory response and the release of reactive oxygen species (ROS). Antioxidant supplements have shown promising effects in reducing muscle damage and oxidative stress and enhancing the recovery process after eccentric exercise. This critical review highlights the influence of antioxidant supplements on performance and recovery following soccer-related activity, training, or competition. Methods: English-language publications from the main databases that examine how antioxidant-based nutrition and supplements affect the recovery process before, during, and after soccer practice or competition were used. Results:Coenzyme Q10 (CoQ10), astaxanthin (Asx), red orange juice (ROJS), L-carnitine (LC), N-acetyl cysteine (NAC), beetroot (BET), turmeric root, and tangeretin reduce muscle damage (creatine kinase, myoglobin, cortisol, lactate dehudrogenase, muscle soreness). Tangeretin, docosahexaenoic acid (DHA), turmeric root, and aronia melanocarpa restrict inflammation (leukocytes, prostalagdin E2, C-reactive protein, IL-6 and 10). Q10, DHA, Asx, tangeretin, lippia citriodora, quercetin, allopurinol, turmeric root, ROJS, aronia melanocarpa, vitamins C-E, green tea (GTE), and sour tea (STE) reduce oxidative stress (malondialdehude, glutathione, total antioxidant capacity, superoxide dismutases, protein carbonyls, ascorbate, glutathione peroxidase, and paraoxonase 1). BET and NAC reinforce performance (endurance, jump, speed, strength). Conclusions: Further research is needed to determine the main mechanism and the acute and long-term impacts of antioxidant supplements in soccer.},
}
@article {pmid39598577,
year = {2024},
author = {Scialabba, C and Craparo, EF and Bonsignore, S and Cabibbo, M and Cavallaro, G},
title = {Lipid-Polymer Hybrid Nanoparticles in Microparticle-Based Powder: Evaluating the Potential of Methylprednisolone Delivery for Future Lung Disease Treatment via Inhalation.},
journal = {Pharmaceutics},
volume = {16},
number = {11},
pages = {},
pmid = {39598577},
issn = {1999-4923},
support = {B73C22001250006//Italian Ministry of University and Research under PNRR/ ; G71I22000950001//POC SICILIA 14-20/ ; },
abstract = {BACKGROUND: Lipid-polymer hybrid nanoparticles (LPHNPs) offer a promising method for delivering methylprednisolone (MePD) to treat lung inflammation, addressing aggregation issues seen with polymer-only formulations.<br><br>OBJECTIVES: This study aimed to develop LPHNPs for MePD delivery, assessing their physicochemical properties, drug loading, cytocompatibility, and release profiles, ultimately enabling inhalable microparticle-based powder.<br><br>METHODS: The nanoparticles were formulated using &#x3b1;,&#x3b2;-poly(N-2-hydroxyethyl)-DL-aspartamide-g-Rhodamine B-g-poly(lactic acid) (PHEA-g-RhB-g-PLA) and phospholipids DPPC, DOTAP, and DSPE-PEG2000 in a 45:30:25 weight ratio. Their size, redispersion after freeze-drying, drug loading (DL%), and controlled release were evaluated. Cytocompatibility was assessed on 16-HBE cell lines, measuring anti-inflammatory effects via IL-6 and IL-8 levels. Spray drying was optimized to produce microparticles using mannitol (MAN), leucine (LEU), and N-acetylcysteine (NAC).<br><br>RESULTS: The nanoparticles had a size of 186 nm and a DL% of 2.9% for MePD. They showed good cytocompatibility, significantly reducing IL-6 and IL-8 levels. Spray drying yielded microparticles with a fine particle fraction (FPF) of 62.3% and a mass median aerodynamic diameter (MMAD) of 3.9 &#xb5;m. Inclusion of LPHNPs@MePD (0.25% w/v) resulted in FPF and MMAD values of 56.7% and 4.4 &#xb5;m. In conclusion, this study described the production of novel inhalable powders as carriers for MePD-loaded nanostructures with favorable physicochemical properties, cytocompatibility, and promising aerosol performance, indicating their potential as an effective inhalable therapy for lung inflammation with corticosteroids, especially for treating chronic diseases.},
}
@article {pmid39598160,
year = {2024},
author = {Singh, M and Kim, A and Young, A and Nguyen, D and Monroe, CL and Ding, T and Gray, D and Venketaraman, V},
title = {The Mechanism and Inflammatory Markers Involved in the Potential Use of N-acetylcysteine in Chronic Pain Management.},
journal = {Life (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
pmid = {39598160},
issn = {2075-1729},
support = {R15 HL143545/HL/NHLBI NIH HHS/United States ; },
abstract = {N-acetylcysteine (NAC) has established use as an antidote for acetaminophen overdose and treatment for pulmonary conditions and nephropathy. It plays a role in regulating oxidative stress and interacting with various cytokines including IL-1β, TNFα, IL-8, IL-6, IL-10, and NF-κB p65. The overexpression of reactive oxygen species (ROS) is believed to contribute to chronic pain states by inducing inflammation and accelerating disease progression, favoring pain persistence in neuropathic and musculoskeletal pain conditions. Through a comprehensive review, we aim to explore the mechanisms and inflammatory pathways through which NAC may manage neuropathic and musculoskeletal pain. Evidence suggests NAC can attenuate neuropathic and musculoskeletal pain through mechanisms such as inhibiting matrix metalloproteinases (MMPs), reducing reactive oxygen species (ROS), and enhancing glutamate transport. Additionally, NAC may synergize with opioids and other pain medications, potentially reducing opioid consumption and enhancing overall pain management. Further research is needed to fully elucidate its therapeutic potential and optimize its use in pain management. As an adjuvant therapy, NAC shows potential for chronic pain management, offering significant benefits for public health.},
}
@article {pmid39596166,
year = {2024},
author = {Lee, MM and Chou, YX and Huang, SH and Cheng, HT and Liu, CH and Huang, GJ},
title = {Renoprotective Effects of Brown-Strain Flammulina velutipes Singer in Chronic Kidney Disease-Induced Mice Through Modulation of Oxidative Stress and Inflammation and Regulation of Renal Transporters.},
journal = {International journal of molecular sciences},
volume = {25},
number = {22},
pages = {},
pmid = {39596166},
issn = {1422-0067},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Flammulina/chemistry ; Mice ; *Renal Insufficiency, Chronic/drug therapy/metabolism/chemically induced/pathology ; *Cisplatin/adverse effects ; *Kidney/drug effects/metabolism/pathology ; *Mice, Inbred C57BL ; Male ; Inflammation/drug therapy/metabolism/pathology ; Antioxidants/pharmacology ; Disease Models, Animal ; Apoptosis/drug effects ; Plant Extracts/pharmacology/chemistry ; },
abstract = {Cisplatin, widely used in chemotherapy, acts through mechanisms such as oxidative stress to damage the DNA and cause the apoptosis of cancer cells. Although effective, cisplatin treatment is associated with considerable side effects including chronic kidney disease (CKD). Studies on brown-strain Flammulina velutipes Singer (FVB) have shown its significant antioxidant and immunomodulatory effects. High-performance liquid chromatography (HPLC) confirmed that the FVB extract contained gallic acid and quercetin. This study investigated whether FVB extract can improve and protect against cisplatin-induced CKD in mice. C57BL/6 mice were used as an animal model, and CKD was induced through intraperitoneal cisplatin injection. FVB was orally administered to the mice for 14 consecutive days. N-acetylcysteine (NAC) was administered in the positive control group. Organ pathology and serum biochemical analyses were conducted after the mice were sacrificed. Significant dose-dependent differences were discovered in body mass, kidney mass, histopathology, renal function, inflammatory factors, and antioxidant functions among the different groups. FVB extract reduced the severity of cisplatin-induced CKD in pathways related to inflammation, autophagy, apoptosis, fibrosis, oxidative stress, and organic ion transport proteins; FVB extract, thus, displays protective physiological activity in kidney cells. Additionally, orally administered high doses of the FVB extract resulted in significantly superior renal function, inflammatory factors, antioxidative activity, and fibrotic pathways. This study establishes a strategy for future clinical adjunctive therapy using edible-mushroom-derived FVB extract to protect kidney function.},
}
@article {pmid39594532,
year = {2024},
author = {Pangrazzi, L and Cerilli, E and Balasco, L and Dall'O', GM and Chelini, G and Pastore, A and Weinberger, B and Bozzi, Y},
title = {N-Acetylcysteine Counteracts Immune Dysfunction and Autism-Related Behaviors in the Shank3b Mouse Model of Autism Spectrum Disorder.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
pmid = {39594532},
issn = {2076-3921},
support = {2020//university of Trento/ ; 2021//Autism Research Institute/ ; },
abstract = {Autism spectrum disorder (ASD) includes a range of neurodevelopmental disabilities characterized by social interaction deficits, communication impairments, and repetitive behaviors. Previous studies have shown that pro-inflammatory conditions play a key role in ASD. Despite this, how oxidative stress and inflammation may contribute to ASD-related behaviors is still poorly understood. Here, we reported that increased levels of molecules related to inflammation are present in the cerebellum and peripheral blood (PB) of mice lacking Shank3b, an established model of syndromic ASD. In parallel, immune dysfunction was documented in the bone marrow (BM) and spleens of mutant mice. N-acetylcysteine (NAC) treatment rescued inflammation in the cerebellum and PB and impaired the production of pro-inflammatory molecules in the BM and spleen. In addition, social impairment was counteracted in NAC-treated Shank3b[-/-] animals. Taken together, our results provide clear evidence of the key role of cerebellar oxidative stress and inflammation in the establishment of ASD-related behaviors. Furthermore, our findings underscore the importance of considering ASD as a systemic disorder.},
}
@article {pmid39594521,
year = {2024},
author = {Aitken, RJ and Wilkins, A and Harrison, N and Kobarfard, K and Lambourne, S},
title = {Towards the Development of Novel, Point-of-Care Assays for Monitoring Different Forms of Antioxidant Activity: The RoXsta[TM] System.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
pmid = {39594521},
issn = {2076-3921},
support = {G2201336//Memphasys Ltd/ ; },
abstract = {(1) Background: This study set out to develop a series of simple, novel, rapid methods for assessing different forms of antioxidant activity. (2) Methods: An ABTS platform was used to engineer: (i) an electrochemical post-activation assay to assess free radical scavenging activity; (ii) an electrochemical pre-activation strategy to assesses the suppression of free radical formation; (iii) a horseradish peroxidase-mediated oxidation system to monitor hydrogen peroxide scavenging activity and (iv) a cumene peroxide-hematin system to determine the ability of samples to scavenge the mixture of organic peroxides and peroxyl and alkoxyl radicals generated in the presence of these reagents. Each assay was assessed against a panel of candidate antioxidant compounds to determine their relative activities and specificities. In addition, human semen samples were analyzed to determine how the results of these antioxidant assays correlated with semen quality. (3) Results: All 4 assays revealed dose-dependent antioxidant activity on the part of vitamin C, N-acetyl cysteine, hypotaurine, BSA, melatonin, glutathione, resveratrol and epigallocatechin gallate. The other compounds tested either completely lacked antioxidant activity or were only active in one of the assays. Using unfractionated human semen as an exemplar of biological fluids rich in antioxidants, the outputs from the individual assays were found to reflect different aspects of semen quality. When the data from all 4 assays were combined, accurate predictions were generated reflecting the importance of oxidative stress in defining semen quality as reflected by sperm count, seminal lipid aldehyde content, sperm DNA damage and free radical generation by the sperm mitochondria. (4) Conclusions: The methodologies described in this paper constitute the basis for rapid, point-of-care assessments of oxidative stress.},
}
@article {pmid39594437,
year = {2024},
author = {Wang, Y and Lv, J and Liu, G and Yao, Q and Wang, Z and Liu, N and He, Y and Il, D and Tusupovich, JI and Jiang, Z},
title = {ZnO NPs Impair the Viability and Function of Porcine Granulosa Cells Through Autophagy Regulated by ROS Production.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
pmid = {39594437},
issn = {2076-3921},
abstract = {The zinc oxide nanoparticles (ZnO NPs) is one of the most extensively utilized metal oxide nanoparticles in biomedicine, human food, cosmetics and livestock farming. However, growing evidence suggests that there is a potential risk for humans and animals because of the accumulation of ZnO NPs in cells, which leads to cell death through several different pathways. Nevertheless, the effects of ZnO NPs on porcine granulosa cells (PGCs) and how ZnO NPs regulate the follicular cells are unknown. In this study, we aimed to elucidate the role of ZnO NPs in the porcine ovary by using PGCs. Firstly, we identified the characterization of ZnO NPs used in this study and the results showed that the size of ZnO NPs was 29.0 nm. The results also demonstrated that ZnO NPs impaired cell viability and decreased steroid hormone secretion in PGCs. In addition, ZnO NPs induced reactive oxygen species (ROS) production, leading to oxidative stress of PGCs. Meanwhile, ZnO NPs also triggered autophagy in PGCs by increasing the ratio of LC3-II/LC3-I, along with the expression of SQSTM1 and ATG7. Finally, the results from N-acetylcysteine (NAC) addition suggested that ZnO NPs promoted autophagy through the enhancement of ROS production. In summary, this study demonstrates that ZnO NPs impair the viability and function of PGCs through autophagy, which is regulated by ROS production.},
}
@article {pmid39591907,
year = {2024},
author = {Bajpai, A and Bharathi, V and Kumawat, R and Tomar, RS and Patel, BK},
title = {Activation of the yeast MAP kinase, Slt2, protects against TDP-43 and TDP-25 toxicity in the Saccharomyces cerevisiae proteinopathy model.},
journal = {Biochemical and biophysical research communications},
volume = {741},
number = {},
pages = {151062},
doi = {10.1016/j.bbrc.2024.151062},
pmid = {39591907},
issn = {1090-2104},
mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Unfolded Protein Response/drug effects ; *Mitogen-Activated Protein Kinases/metabolism/genetics ; TDP-43 Proteinopathies/metabolism/genetics/pathology ; Humans ; Enzyme Activation ; Oxidative Stress/drug effects ; },
abstract = {TDP-43 proteinopathy is observed in human neurodegenerative diseases like ALS. Heterologous TDP-43 expression in the yeast model also mimics several proteinopathy features such as cytotoxicity, cytoplasmic mis-localization and oxidative stress. Among the pathways implicated in modulating the TDP-43 toxicity in yeast, the unfolded protein response (UPR) activation was also identified. Here, we examine the role of stress-regulated yeast MAP kinase, Slt2, which also links cellular stress with UPR activation, in modulating the toxicities of the full-length TDP-43 and its 25 kDa C-terminal fragment, TDP-25. We find enhancement in the cytotoxicity of TDP-43, as well as TDP-25, in the yeast cells deleted for the MAP kinase, Slt2, but not in those lacking other yeast MAP kinases, Kss1 and Fus3. Unlike in the wild-type yeast, upon treatment with an antioxidant N-acetyl cysteine, the TDP-43 toxicity could not be mitigated in the slt2Δ yeast but the TDP-25 toxicity was significantly rescued suggesting oxidative stress as an important contributor to the TDP-25 toxicity. Notably, TDP-43 as well as TDP-25 expressions could cause significant phosphorylation of Slt2 suggesting activation of this MAP Kinase due to their toxicities. Interestingly, in the slt2Δ cells, lacking the MAP Kinase activity, a treatment with low concentrations of an UPR activator molecule, DTT, caused significant reduction in the toxicities of both TDP-43 as well as TDP-25. Taken together, these findings suggest that TDP-43 and TDP-25 toxicity-induced stress-mediated activation of the MAP kinase Slt2 helps in mitigating their toxicities in the yeast model possibly through UPR activation.},
}
@article {pmid39590959,
year = {2024},
author = {Li, T and Bian, B and Ji, R and Zhu, X and Wo, X and Song, Q and Li, Z and Wang, F and Jia, Y},
title = {Polyethylene Terephthalate Microplastic Exposure Induced Reproductive Toxicity Through Oxidative Stress and p38 Signaling Pathway Activation in Male Mice.},
journal = {Toxics},
volume = {12},
number = {11},
pages = {},
pmid = {39590959},
issn = {2305-6304},
support = {42377430//National Natural Science Foundation of China/ ; 2021MS08046//Natural Science Foundation of Inner Mongolia/ ; BYJJ-DXK2022018//Scientific research Fund of Baotou Medical College/ ; HLJH202418//Bud plan of Baotou Medical College/ ; },
abstract = {Polyethylene terephthalate (PET) is a type of polymer plastic that is often used to make plastic bags, bottles, and clothes. However, the waste of such plastic products is decomposed into microplastics (MPs), which are plastic fragments smaller than 5 mm, by various external forces such as wind, UV radiation, mechanical wear, and biodegradation. PET MPs have been widely detected in the environment and human tissue samples; however, the toxicity and mechanism of PET MPs in mammals are still unclear. In this study, we investigated the male reproductive toxicity of PET MPs and their underlying mechanism. A total of 80 male mice were orally exposed to 0.01, 0.1, and 1 mg/d of PET MPs (with a diameter of 1 μm) for 42 days. The results showed that 1 μm PET MPs induced different degrees of pathological damage to testicular tissues, decreased sperm quality, and increased the apoptosis of spermatogenic cells via oxidative stress and p38 signaling pathway activation. To further illustrate and verify the mechanistic pathway, oxidative stress was antagonized using N-acetylcysteine (NAC), and the activation of the p38 signaling pathway was blocked using SB203580. The results revealed that the male reproductive injury effects after exposure to PET MPs were significantly ameliorated. Specifically, the testicular tissue lesions were relieved, the sperm quality improved, and the apoptosis of spermatogenic cells decreased. These results demonstrated that PET MP exposure induced male reproductive toxicity through oxidative stress and the p38 signaling pathway. This study provides new insights into the reproductive toxicity of MPs in males, as well as valuable references for public health protection strategies.},
}
@article {pmid39582278,
year = {2025},
author = {Zheng, Y and Tian, Q and Yang, H and Cai, Y and Zhang, J and Wu, Y and Zhu, S and Qiu, Z and Lin, Y and Hong, J and Zhang, Y and Dockrell, D and Ma, S},
title = {Identification of Nicotinic Acetylcholine Receptor for N-Acetylcysteine to Rescue Nicotine-induced Injury Using Beating Cilia in Primary Tissue Derived Airway Organoids.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {12},
number = {1},
pages = {e2407054},
pmid = {39582278},
issn = {2198-3844},
support = {2023B0909020003//Department of Science and Technology of Guangdong Province/ ; 32371470//National Natural Science Foundation of China/ ; 82341019//National Natural Science Foundation of China/ ; 82111530212//National Natural Science Foundation of China/ ; 2021B1515020092//Natural Science Foundation of Guangdong Province/ ; RCYX20200714114736146//Shenzhen Science and Technology Innovation Commission/ ; 2022QNA095//Health Committee of Fujian Province/ ; JC2022007//Cross-disciplinary Research and Innovation Fund of Tsinghua SIGS/ ; },
mesh = {*Acetylcysteine/pharmacology ; *Organoids/metabolism/drug effects ; *Nicotine/pharmacology/adverse effects ; *Receptors, Nicotinic/metabolism ; Humans ; *Cilia/drug effects/metabolism ; },
abstract = {Smoking is one of the major contributors to airway injuries. N-acetylcysteine (NAC) has been proposed as a treatment or preventive measure for such injuries. However, the exact nature of the smoking-induced injury and the protective mechanism of NAC are not yet fully understood. Here, patient tissue-derived airway organoids for modeling smoking-induced injury, therapeutic investigation, and mechanism studies are developed. Airway organoids consist mainly of ciliated cells, together with basal cells, goblet cells, and myofibroblast-like cells. The organoids display apical-out and basal-in polarity and are enriched in beating cilia, which are sensitive to smoking challenge and NAC treatment. An algorithm is developed to measure ciliary beating activity by analyzing the altered beating pattern of cilia in response to nicotine challenge and NAC treatment. Nicotinic acetylcholine receptors (nAChRs) expressed by airway organoids are involved in the mechanisms of nicotine-induced injury through the nicotine-nAChR pathway. In contrast to the common understanding that NAC has an antioxidative effect that mitigates airway damage, it is elucidated that NAC binding to nicotine can abolish the binding capacity of nicotine to nAChRs and thus prevent nicotine-induced injury. This study focuses on the advances and potential of humanized organoids in understanding biological processes, mechanisms, and identifying therapeutic targets.},
}
@article {pmid39580917,
year = {2024},
author = {Najjar, RS and Grace, WW and Siqueira, APS and Setka, AM and Lu, W and Wang, S and Feresin, RG},
title = {Polyphenols have unique cellular effects that are distinct from antioxidant function in Toll-like receptor 4-mediated inflammation in RAW264.7 macrophage-like cells.},
journal = {Nutrition research (New York, N.Y.)},
volume = {132},
number = {},
pages = {136-151},
doi = {10.1016/j.nutres.2024.10.007},
pmid = {39580917},
issn = {1879-0739},
mesh = {Animals ; *Polyphenols/pharmacology ; Mice ; *Antioxidants/pharmacology ; *Toll-Like Receptor 4/metabolism ; *Macrophages/drug effects/metabolism ; RAW 264.7 Cells ; *Lipopolysaccharides ; *Inflammation/metabolism/drug therapy ; Signal Transduction/drug effects ; Plant Extracts/pharmacology ; Spin Labels ; Cyclic N-Oxides/pharmacology ; Oxidation-Reduction ; Acetylcysteine/pharmacology ; },
abstract = {Plant polyphenols are bioactive compounds touted for their antioxidant effects, and this is often the primary attribute used to explain their health benefits. However, we hypothesize that polyphenols have molecular properties independent of antioxidant function. The objective of this study was to investigate whether polyphenols had distinct molecular effects compared to pure antioxidants. RAW 264.7 macrophages were pretreated with either TEMPOL, a superoxide scavenger, N-acetyl cysteine, a hydroxyl radical and hydrogen peroxide scavenger, or polyphenol extracts from blackberry, blueberry, raspberry, strawberry, kale, and baru nut. After 1 hour of pretreatment, cells were treated with lipopolysaccharides (100 ng/mL) for an additional 6 hour. Antioxidants and polyphenol extracts elicited antioxidant effects in vitro; however, polyphenols regulated redox proteins in a distinct, protective manner, whereas antioxidants, TEMPOL, and N-acetyl cysteine, did not. Additionally, distinct effects were observed in downstream Toll-like receptor 4 signaling and transcriptional activity of inflammatory proteins. We conclude that polyphenols have unique molecular effects that are independent of just their free radical scavenging capacity. This work advances our molecular understanding of how polyphenols act to target inflammation.},
}
@article {pmid39579577,
year = {2024},
author = {Li, WL and Li, K and Chang, WG and Shi, H and Zhang, WX and Wang, Z and Li, W},
title = {20(R)-ginsenoside Rg3 alleviates diabetic retinal injury in T2DM mice by attenuating ROS-mediated ER stress through the activation of the Nrf2/HO-1 axis.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {135},
number = {},
pages = {156202},
doi = {10.1016/j.phymed.2024.156202},
pmid = {39579577},
issn = {1618-095X},
mesh = {Animals ; *Ginsenosides/pharmacology ; *NF-E2-Related Factor 2/metabolism ; *Endoplasmic Reticulum Stress/drug effects ; *Diabetic Retinopathy/drug therapy/metabolism ; Male ; *Diabetes Mellitus, Experimental/drug therapy/complications ; *Heme Oxygenase-1/metabolism ; *Reactive Oxygen Species/metabolism ; Mice ; Humans ; *Mice, Inbred C57BL ; Endothelial Cells/drug effects/metabolism ; Retina/drug effects/metabolism ; Panax/chemistry ; Diabetes Mellitus, Type 2/drug therapy/metabolism ; Diet, High-Fat/adverse effects ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; Membrane Proteins ; },
abstract = {BACKGROUND: Although our previous work confirmed 20(R)-ginsenoside Rg3 (R-Rg3), which is an active ingredient in the Panax Ginseng C.A. Meyer, to have good anti-diabetic activity, its beneficial effect on diabetic retinal injury was found to be limited.<br><br>PURPOSE: This study aims to investigate the protective effects of R-Rg3 on diabetes-induced retinal injury and the associated molecular mechanisms of action.<br><br>METHODS: Diabetic retinal injury was induced in mice using a combination of a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). R-Rg3 (10 and 20 mg/kg) was subsequently administered for 6 weeks. The human retinal endothelial cells (HRECs) were subjected to high glucose (HG)-induced injury for the in vitro analysis and treated with R-Rg3 (4, 8, 16 &#x3bc;M), antioxidant N-Acetylcysteine (NAC, 1 mM) and Nrf2 inhibitor ML385 (5 &#x3bc;M). The mice retinas then underwent functional and histopathological analysis. Expression levels of proteins related to the Nrf2/HO-1 axis, tight junction proteins, endoplasmic reticulum (ER) stress and the apoptosis in retinal tissue and HRECs were determined by western blot. Expressions of ZO-1 and Nrf2 in the retina and HRECs were assessed by immunofluorescence. Additional evaluations included measuring body weights, fasting blood glucose (FBG), lipid levels and oxidative markers.<br><br>RESULTS: The results showed 6 weeks of R-Rg3 treatment significantly restored the functional changes and redox system imbalance that was induced by HFD/STZ in mice. R-Rg3 was also found to significantly reduce retinal barrier damage and thickness changes resulting from hyperglycaemia exposure. At the same time, R-Rg3 also protected HRECs from HG-induced damage. R-Rg3 could also activate Nrf2/HO-1 axis and inhibit endoplasmic reticulum stress as a means of alleviating retinal endothelial cells apoptosis. The molecular docking results also demonstrated that R-Rg3 had a good binding ability with Nrf2.<br><br>CONCLUSION: Our study suggested Nrf2/HO-1 axis might be crucial for the ability of R-Rg3 to prevent diabetic retinal injury.},
}
@article {pmid39574249,
year = {2025},
author = {Fong, KM and Ng, GWY and Leung, AKH and Lai, KY},
title = {High-dose Intravenous N-Acetylcysteine in Mechanically Ventilated Patients with COVID-19 Pneumonia: A Propensity-Score Matched Cohort Study.},
journal = {Journal of intensive care medicine},
volume = {40},
number = {5},
pages = {476-485},
doi = {10.1177/08850666241299391},
pmid = {39574249},
issn = {1525-1489},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/therapeutic use ; Male ; Female ; *Respiration, Artificial ; Retrospective Studies ; Middle Aged ; Propensity Score ; Aged ; *COVID-19/mortality/therapy/complications ; *COVID-19 Drug Treatment ; Intensive Care Units ; SARS-CoV-2 ; Treatment Outcome ; Administration, Intravenous ; },
abstract = {Background: Current therapies for severe COVID-19, such as steroids and immunomodulators are associated with various side effects. N-acetylcysteine (NAC) has emerged as a potential adjunctive therapy with minimal side effects for patients with cytokine storm due to COVID-19. However, evidence supporting high-dose intravenous NAC in severe COVID-19 pneumonia requiring mechanical ventilation is limited. Methods: We conducted a retrospective analysis of consecutive patients aged ≥ 18 who were admitted for acute respiratory failure (PaO2/FiO2 ratio <300) with SARS-CoV-2 infection to the Intensive Care Unit (ICU) of Queen Elizabeth Hospital from fifth July 2020 to 31[st] October 2022. Inclusion was limited to patients who required mechanical ventilation. High-dose NAC refers to a dosage of 10 g per day. The primary outcome was all-cause mortality within 28 days. Propensity-score matched analysis using logistic regression was performed. Results: Among the 136 patients analyzed, 42 (40.3%) patients received NAC. The unmatched NAC patients displayed a higher day-28 mortality (12 (28.6%) versus 4 (6.5%), p = 0.005) and fewer ventilator-free days (18.5 (0-23.0) versus 22.0 (18.3-24.0), p = 0.015). No significant differences were observed in ICU and hospital length of stays among survivors. In patients who were not treated with tocilizumab, those receiving NAC exhibited a trend toward a quicker reduction in C-reactive protein compared to those who did not receive NAC.After propensity score matching which included 64 patients with 33 (51.6%) receiving NAC, no significant differences were found in 28-day mortality, ventilator-free days, or ICU and hospital length of stay. After adjusting for potential confounders, logistic regression of the propensity score-matched population did not demonstrate that the use of NAC independently affected 28-day mortality. Conclusions: In patients with COVID-19 pneumonia requiring mechanical ventilation and receiving standard COVID-19 treatment, the addition of high-dose NAC did not lead to improved clinical outcomes.},
}
@article {pmid39570044,
year = {2024},
author = {Saha, M and Qiu, L and Han-Hallett, Y and Welch, CJ and Cooks, RG},
title = {Simultaneous Quantitation of Multiple Biological Thiols Using Reactive Ionization and Derivatization with Charged Mass Tags.},
journal = {Analytical chemistry},
volume = {96},
number = {49},
pages = {19414-19421},
doi = {10.1021/acs.analchem.4c03807},
pmid = {39570044},
issn = {1520-6882},
mesh = {*Sulfhydryl Compounds/chemistry/analysis/blood ; Humans ; Chromatography, High Pressure Liquid ; Mass Spectrometry/methods ; Oxidation-Reduction ; Animals ; Cysteine/blood/analysis/chemistry ; Homocysteine/analysis/blood ; },
abstract = {The biologically important thiols (cysteine, homocysteine, N-acetyl cysteine, and glutathione) are key species in redox homeostasis, and there is a clinical need to measure them rapidly, accurately, and simultaneously at low levels in complex biofluids. The solution to the challenge presented here is based on a new derivatizing reagent that combines a thiol-selective unit to optimize the chemical transformation and a precharged pyridinium unit chosen to maximize sensitivity in mass spectrometry. Derivatization is performed simultaneously with ionization ("reactive ionization"), and mass spectrometry is used to record and characterize the thiol reaction products. The method is applicable over the concentration range from 1 μM to 10 mM and is demonstrated for 25 blood serum, 1 plasma, and 3 types of tissue samples. The experiment is characterized by limited sample preparation (<4 min) and short analysis time (<1 min). High precision and accuracy (both better than 8%) are validated using independent HPLC-MS analysis. Cystine-cysteine redox homeostasis can be monitored by introducing an additional reduction step, and the accuracy and precision of these results are also validated by HPLC-MS.},
}
@article {pmid39565530,
year = {2025},
author = {Jiang, J and Li, D and Li, F and Li, H and Zhang, X and Feng, L},
title = {Catechin promotes endoplasmic reticulum stress-mediated gastric cancer cell apoptosis via NOX4-induced reactive oxygen species.},
journal = {Molecular and cellular biochemistry},
volume = {480},
number = {5},
pages = {3201-3215},
pmid = {39565530},
issn = {1573-4919},
mesh = {Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Catechin/pharmacology ; *NADPH Oxidase 4/metabolism/genetics ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; Endoplasmic Reticulum Chaperone BiP ; *Stomach Neoplasms/pathology/metabolism/drug therapy/genetics ; Cell Line, Tumor ; *Neoplasm Proteins/metabolism/genetics ; },
abstract = {Catechin, a polyphenolic compound in various foods and beverages, shows strong anti-cancer effects against gastric cancer (GC) cells. This study explored the effect of catechin on GC cell apoptosis and endoplasmic reticulum (ER) stress. GC cells were treated with different catechin concentrations to assess effects on cell viability, LDH release, invasion, migration, apoptosis, intracellular calcium (Ca[2][+]), ER stress markers, and reactive oxygen species (ROS). siRNA knockdown targeted GRP78, PERK, CHOP, and NOX4 to examine their roles in catechin-induced ER stress and apoptosis. Catechin treatment significantly reduced GC cell viability, increased LDH release, and induced apoptosis dose-dependently. Catechins elevated intracellular Ca[2][+] and ER stress markers. Co-treatment with thapsigargin (TG) intensified these effects, implicating ER stress in apoptosis. Knocking down GRP78, PERK, and CHOP mitigated catechin-induced apoptosis and restored viability. Additionally, catechins raised ROS levels, while co-treatment with Diphenyleneiodonium (DPI) or N-acetylcysteine (NAC) lowered ROS, cell damage, and ER stress markers. NOX4 knockdown countered catechin-induced viability loss and upregulated CHOP and cleaved caspase-3. Catechin induces apoptosis in GC cells through ER stress and ROS generation. Key mediators include GRP78, PERK, CHOP, and NOX4, suggesting potential therapeutic targets for enhancing catechin efficacy in GC treatment.},
}
@article {pmid39564655,
year = {2024},
author = {AbhijnaKrishna, R and Lu, YH and Wu, SP and Velmathi, S},
title = {Sensitive Detection of Sulfur Mustard Poisoning via N-Salicylaldehyde Naphthyl Thiourea Probe and Investigation into Detoxification Scavengers.},
journal = {ACS applied bio materials},
volume = {7},
number = {12},
pages = {8341-8350},
doi = {10.1021/acsabm.4c01143},
pmid = {39564655},
issn = {2576-6422},
mesh = {*Mustard Gas/poisoning/analogs &amp; derivatives ; Animals ; *Zebrafish ; *Thiourea/chemistry ; Aldehydes/chemistry ; Molecular Structure ; Biocompatible Materials/chemistry ; Materials Testing ; Particle Size ; Chemical Warfare Agents/poisoning ; Humans ; },
abstract = {Sulfur mustard (SM), a blister agent and toxic chemical warfare compound, leads to injuries in the skin, eyes, and lungs, with early diagnosis being difficult because of its incubation period. Developing scavengers for sulfur mustard (SM) and its simulant, 2-chloroethylsulfide (CEES), is essential due to the severe and long-lasting toxic effects these compounds have on the human body. Existing scavengers like cysteine, sodium hydrosulfide (NaHS), and sodium thiosulfate cannot cross the blood-brain barrier (BBB), rendering them ineffective for detoxifying SM in the brain and highlighting the need for lipophilic scavengers. In this study, an N-salicylaldehyde naphthyl thiourea probe (NCrHT) was developed for detecting SM simulant CEES and its in vivo and in vitro imaging capabilities were evaluated. Additionally, the detoxification potential of scavengers was tested under similar conditions, and we introduced N-acetyl cysteine, which is lipophilic in nature, as an effective scavenger for detoxifying CEES in the zebrafish brain.},
}
@article {pmid39556483,
year = {2024},
author = {Winterlind, EL and Malone, SG and Setzer, MR and Murphy, MA and Saunders, D and Gray, JC},
title = {N-acetylcysteine as a treatment for substance use cravings: A meta-analysis.},
journal = {Addiction biology},
volume = {29},
number = {11},
pages = {e70001},
pmid = {39556483},
issn = {1369-1600},
support = {R01 AA030041/AA/NIAAA NIH HHS/United States ; HU0001-22-2-0066//Department of Defense/ ; R01AA030041/AA/NIAAA NIH HHS/United States ; },
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Craving/drug effects ; Randomized Controlled Trials as Topic ; *Substance-Related Disorders/drug therapy ; },
abstract = {N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with SUD and (2) explore subgroup differences, risk of bias and publication bias across trials. Database searches of PubMed, Cochrane Library and ClinicalTrials.gov were conducted in June and July of 2023 to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analysed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses and leave-one-out analyses were conducted to examine the treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests and funnel plot tests were conducted to examine the risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015-0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. Overall, our findings are contrary to those of prior meta-analyses, suggesting a limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.},
}
@article {pmid39549915,
year = {2025},
author = {Higashi, Y and Nishida, C and Izumi, H and Sato, K and Kawai, N and Tomonaga, T and Morimoto, T and Yamasaki, K and Wang, KY and Higashi, H and Moriyama, A and Takeshita, JI and Kojima, T and Sakurai, K and Yatera, K and Morimoto, Y},
title = {Inhalation exposure to cross-linked polyacrylic acid induces pulmonary disorders.},
journal = {Toxicology},
volume = {510},
number = {},
pages = {154001},
doi = {10.1016/j.tox.2024.154001},
pmid = {39549915},
issn = {1879-3185},
mesh = {Animals ; Male ; *Acrylic Resins/toxicity/administration &amp; dosage ; *Rats, Inbred F344 ; *Inhalation Exposure/adverse effects ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Bronchoalveolar Lavage Fluid/cytology/chemistry ; Lung/drug effects/pathology/metabolism ; Rats ; Lung Diseases/chemically induced/pathology ; Oxidative Stress/drug effects ; Dose-Response Relationship, Drug ; Heme Oxygenase-1/metabolism ; Chemokine CXCL1/metabolism ; },
abstract = {Organic polymers, widely used in food, daily necessities, and medicines, include cross-linked polyacrylic acid (CL-PAA), which has been reported to induce severe lung disease. While previous studies mainly used intratracheal instillation, our research focused on inhalation exposure to corroborate these findings. We conducted 5-day (short-term) and 13-week (subchronic) inhalation exposure studies with CL-PAA. In the short-term study, male F344 rats inhaled CL-PAA at 0.2, 2.0, or 20 mg/m[3] for 6 hours/day over 5 days. Rats were dissected 3 days and 1 month post-exposure. In the subchronic study, rats inhaled CL-PAA at 0.2 or 2.0 mg/m[3] for 6 hours/day, 5 days/week for 13 weeks, with dissections from 3 days to 6 months post-exposure. To investigate the mechanism of pulmonary disorders, an additional short-term study with 20 mg/m[3] CL-PAA included intraperitoneal injections of the antioxidant N-acetylcysteine (NAC) (200 mg/kg) with dissection the day after exposure. Short-term exposure led to concentration-dependent increases in neutrophil influx, cytokine-induced neutrophil chemoattractant (CINC), total protein, lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in lung tissue. Histopathology showed concentration-dependent neutrophil infiltration. Subchronic exposure caused persistent increases in BALF total protein and lung HO-1, with ongoing neutrophil infiltration and fibrosis. NAC administration reduced neutrophils, total protein, LDH, and CINC in BALF, and HO-1 in lung tissue, improving histopathological findings. Inhalation of CL-PAA caused concentration-dependent lung inflammation and persistent fibrosis. The no observed adverse effect level (NOAEL) for chronic pulmonary disorders was 0.2 mg/m[3]. Oxidative stress linked to CL-PAA-induced inflammation was mitigated by NAC administration.},
}
@article {pmid39549861,
year = {2025},
author = {Li, Y and Yu, M and Wei, Y and Zhou, Z and Guo, Y and Yuan, M and Jin, J and Li, J and Shen, H and Wu, D},
title = {Risk assessment of developmental and neurotoxicity by the flavoring agent perillaldehyde: NAC (N-acetylcysteine) mitigation of oxidative stress-mediated inhibition of the Nrf2 pathway.},
journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP},
volume = {288},
number = {},
pages = {110071},
doi = {10.1016/j.cbpc.2024.110071},
pmid = {39549861},
issn = {1532-0456},
mesh = {Animals ; *Zebrafish ; *Oxidative Stress/drug effects ; *NF-E2-Related Factor 2/metabolism/genetics ; *Acetylcysteine/pharmacology ; Flavoring Agents/toxicity ; Acrolein/toxicity/analogs &amp; derivatives ; Risk Assessment ; Zebrafish Proteins/metabolism/genetics ; Neurotoxicity Syndromes/prevention &amp; control ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Embryo, Nonmammalian/drug effects ; Animals, Genetically Modified ; Antioxidants/pharmacology ; Monoterpenes ; },
abstract = {Perillaldehyde (PAE), a prevalent flavoring agent, has raised safety concerns due to conflicting evidence regarding its toxicity. This study provides a comprehensive assessment of the developmental and neurotoxic effects of PAE in zebrafish, elucidating the underlying mechanisms of its toxicity. Results showed that PAE affected the viability and hatching rate of zebrafish at 96 h postfertilization with the 50 % lethal concentration (LC50) of 7.975 mg/L. Furthermore, exposed‌ to a non-lethal concentration of 4 mg/L PAE induced a spectrum of morphological abnormalities, such as pericardial edema, delayed yolk sac absorption, reduced body length, and microphthalmia. Behavioral observations revealed that PAE reduced motor ability, and was accompanied by an increase in spontaneous turning angle and angular velocity. Using the TG(elav13:EGFP) transgenic model, we observed the number of newborn neurons was reduced, indicating that PAE induced obvious neurotoxic effects. Additionally, this concentration facilitated the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), concomitantly decreasing the activity of antioxidant enzymes. QRT-PCR analysis revealed that PAE down-regulated Nestin and Neurogenin1 gene expression, up-regulated Glipr1a and Nox1 gene expression, and inhibited the Nrf2/HO-1 pathway. Notably, co-administration of N-acetylcysteine (NAC), an inhibitor of oxidative stress, mitigated oxidative stress levels and partially ameliorated the neurotoxicity. These findings suggest that oxidative stress is the primary mediator of PAE-induced neurotoxicity. This study provides crucial insights for the safe application of PAE.},
}
@article {pmid39549856,
year = {2024},
author = {Scioscia, G and Baraldi, F and Bigoni, T and Papi, A and Vatrella, A and Micheletto, C and Foschino Barbaro, MP},
title = {The precision medicine strategy to treat COPD pulmonary traits in clinical practice: The role of N-acetylcysteine.},
journal = {Respiratory medicine},
volume = {235},
number = {},
pages = {107865},
doi = {10.1016/j.rmed.2024.107865},
pmid = {39549856},
issn = {1532-3064},
mesh = {Humans ; *Pulmonary Disease, Chronic Obstructive/drug therapy/physiopathology ; *Acetylcysteine/therapeutic use ; *Precision Medicine/methods ; Expectorants/therapeutic use ; Cough/drug therapy ; Disease Progression ; Bronchitis, Chronic/drug therapy/physiopathology ; },
abstract = {Chronic obstructive pulmonary disease (COPD) is a progressive lung condition and a leading cause of physical decline and death. COPD prevalence is expected to increase steadily in the coming years, and as a result, the healthcare and social burden of this condition will intensify. In this scenario, a patient-centric approach, the treatable trait (TT) strategy, based on the identification of traits that are clinically relevant, identifiable, monitorable and treatable, has emerged. The TT strategy, which considers behavioral/risk factors, as well as pulmonary and extrapulmonary traits, has shown to be a promising strategy in COPD management. This work reviews the TT strategy in COPD, giving special attention to the most relevant pulmonary traits, such as frequent productive cough, chronic bronchitis, type 2 inflammation, neutrophilic inflammation, lung hyperinflation, bronchiectasis, exacerbations and non-reversible airflow limitation. N-acetylcysteine (NAC), a widely used mucolytic agent, might be a major player in this strategy. Indeed, through a thorough review of the literature, it has been possible to highlight that, besides being essential in the treatment of frequent productive cough, NAC could bring benefits in case of airflow limitations, airways inflammation, exacerbations and bronchiectasis. A clinical case in which the TT strategy was able to reduce symptoms and improve lung function and quality of life, minimizing unnecessary medication and side effects, is also presented. The identification of TTs and their proper treatment through personalized medicine remarkably ameliorates COPD management. Of note, the mucolytic, antioxidant, and anti-inflammatory activities of NAC might have beneficial effects on several TTs.},
}
@article {pmid39549062,
year = {2025},
author = {Rajabian, F and Razavi, BM and Mehri, S and Amouian, S and Ghasemzadeh Rahbardar, M and Khajavi Rad, A and Hosseinzadeh, H},
title = {Evaluation of pathways involved in the protective effect of trans sodium crocetinate against contrast-induced nephropathy in rats.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {398},
number = {5},
pages = {5373-5387},
pmid = {39549062},
issn = {1432-1912},
support = {995678//National Institutes for Medical Research Development (NIMAD), Tehran, Iran/ ; 981809//Vice Chancellor of Research, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran/ ; },
mesh = {Animals ; Male ; Rats, Wistar ; *Contrast Media/adverse effects ; *Kidney Diseases/chemically induced/prevention &amp; control/pathology/metabolism ; Kidney/drug effects/pathology/metabolism ; Oxidative Stress/drug effects ; Rats ; *Vitamin A/analogs &amp; derivatives/pharmacology/therapeutic use ; Apoptosis/drug effects ; *Protective Agents/pharmacology/therapeutic use ; *Carotenoids/pharmacology/therapeutic use ; Autophagy/drug effects ; Antioxidants/pharmacology ; },
abstract = {Contrast-induced nephropathy (CIN) is the most important side effect following contrast media application. The purpose of this study was to investigate the nephroprotective effects of trans sodium crocetinate (TSC) against sodium amidotrizoate/meglumine amidotrizoate (SAMA). Wistar rats were classified into eight groups (n = 6, male, 220-250 g) including (1) sham, injection of solvents (intraperitoneally; i.p.), (2) premedication-control, N(ω)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.) + indomethacin (IND, 10 mg/kg, i.p.), (3) model (L-NAME + IND + SAMA (12.5 ml/kg, i.p.)), (4-6) TSC 10, 20, and 40 mg/kg/day, 7 days, i.p., and L-NAME + IND + SAMA, (7) N-acetylcysteine (NAC, 125 mg/kg/day, 7 days, i.p.) and L-NAME + IND + SAMA, (8) TSC alone (40 mg/kg/day, 7 days, i.p.). Rats were injected with L-NAME, IND, and SAMA 40 h after water deprivation. SAMA caused the enhancement of histopathological damage in kidney tissue, biochemical factors (serum blood urea nitrogen and creatinine), and oxidative stress. Moreover, SAMA increased inflammation (TNF-α), apoptosis proteins (Caspase 3-cleaved and Bax/Bcl-2 ratio), and autophagy markers (Beclin-1 and LC3 II/I ratio). TSC declined biochemical factors and oxidative stress. Also, TSC 40 mg/kg decreased histopathological damage, inflammation, apoptosis, and autophagy markers. This study demonstrated that TSC has nephroprotective effects through anti-oxidant, anti-inflammatory, and anti-apoptotic properties, as well as regulating autophagy.},
}
@article {pmid39548866,
year = {2025},
author = {Vaneev, AN and Gorelkin, PV and Barykin, EP and Kolmogorov, VS and Timoshenko, RV and Mitkevich, VA and Petrushanko, IY and Varshavskaya, KB and Salikhov, SV and Klyachko, NL and Makarov, AA and Erofeev, AS},
title = {Impact of Antioxidants on Mechanical Properties and ROS Levels of Neuronal Cells Exposed to β-Amyloid Peptide.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {26},
number = {1},
pages = {e202400786},
doi = {10.1002/cbic.202400786},
pmid = {39548866},
issn = {1439-7633},
support = {075-15-2022-264//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {*Amyloid beta-Peptides/pharmacology/metabolism ; Humans ; *Reactive Oxygen Species/metabolism ; *Antioxidants/pharmacology/chemistry ; *Neurons/metabolism/drug effects/cytology ; Superoxide Dismutase-1/metabolism ; *Peptide Fragments/pharmacology/metabolism ; Oxidative Stress/drug effects ; Acetylcysteine/pharmacology ; Cell Line, Tumor ; Elastic Modulus/drug effects ; },
abstract = {This study aims to investigate the potential role of antioxidants in oxidative stress and its consequent impact on the mechanical properties of neuronal cells, particularly the stress induced by amyloid-beta (1-42) (Aβ42) aggregates. A key aspect of our research involved using scanning ion-conductance microscopy (SICM) to assess the mechanical properties (Young's modulus) of neuronal cells under oxidative stress. Reactive oxygen species (ROS) level was measured in single-cell using the electrochemical method by low-invasive Pt nanoelectrode. We investigated the effects of the low molecular weight antioxidant N-acetylcysteine (NAC) and the antioxidant enzyme superoxide dismutase 1 (SOD1) on the physiological and mechanical properties of neuronal cells using SICM. Using electrochemical method and SICM, NAC effectively reduces oxidative stress and restores Young's Modulus in SH-SY5Y cells exposed to hydrogen peroxide and Aβ42 oligomers. Our study first examined the influence of SOD1 on intracellular ROS levels in the presence of Aβ oligomers. The investigation into the effects of SOD1 and its nanoparticle form SOD1 on SH-SY5Y cells reveals impacts on mechanical properties and oxidative stress. The combined use of SICM and electrochemical measurements provided a comprehensive understanding of how oxidative stress, including that triggered by the Aβ oligomers affects the mechanical properties of cells.},
}
@article {pmid39547318,
year = {2024},
author = {Koo, J and Sim, WJ and Lim, W and Lim, TG},
title = {Activation of mixed lineage kinase 3 by fine particulate matter induces skin inflammation in human keratinocytes.},
journal = {Toxicology letters},
volume = {402},
number = {},
pages = {38-43},
doi = {10.1016/j.toxlet.2024.11.002},
pmid = {39547318},
issn = {1879-3169},
mesh = {Humans ; *Particulate Matter/toxicity ; *Keratinocytes/drug effects/metabolism ; Phosphorylation ; *Reactive Oxygen Species/metabolism ; *Dinoprostone/metabolism ; *MAP Kinase Kinase Kinases/metabolism ; *Cyclooxygenase 2/metabolism ; *Mitogen-Activated Protein Kinase Kinase Kinase 11 ; HaCaT Cells ; Signal Transduction/drug effects ; Air Pollutants/toxicity ; Enzyme Activation ; Dermatitis/pathology ; Cell Line ; MAP Kinase Signaling System/drug effects ; Particle Size ; Proto-Oncogene Proteins ; },
abstract = {Fine particulate matter (PM2.5) induces a range of diseases, including skin disorders, through inflammatory responses. In this study, we investigated the novel mechanisms by which PM2.5 causes skin inflammation in human keratinocytes HaCaT. We observed increased protein expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) in PM2.5-treated HaCaT cells. To identify the pathways promoting the expression of these inflammatory proteins, we conducted a phospho-kinase antibody array and confirmed that the phosphorylation levels of JNK and p38 were increased by PM2.5-treated HaCaT cells. Further investigation of the phosphorylation levels of mitogen-activated protein kinases (MAPKs) and upstream signals revealed that PM2.5 activated the MKK4/7-JNK-c-Jun and MKK3/6-p38-p70[S6K] signaling pathways, while the phosphorylation level of ERK1/2 remained unchanged. HaCaT cells treated with PM2.5 phosphorylated Mixed-lineage kinase 3 (MLK3), an upstream regulator of p38 and JNK. Furthermore, inhibition of ROS production by N-Acetylcysteine (NAC) treatment inhibited MLK3 phosphorylation. Taken together, ROS production induced by PM2.5 activated the MLK3 signaling pathway and induced skin inflammation.},
}
@article {pmid39547016,
year = {2024},
author = {Guo, S and Tong, J and Liu, Y and Qin, D and Yan, J and Peng, H and Sun, L and Jing, X and Wu, X and Li, B},
title = {Synthesis of Eucommia ulmoides-derived carbon dots for anti-inflammatory and accelerated wound healing.},
journal = {International immunopharmacology},
volume = {143},
number = {Pt 3},
pages = {113606},
doi = {10.1016/j.intimp.2024.113606},
pmid = {39547016},
issn = {1878-1705},
mesh = {Animals ; *Wound Healing/drug effects ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Eucommiaceae/chemistry ; Rats ; *Carbon/chemistry ; Male ; Humans ; Rats, Sprague-Dawley ; Acetylcysteine/pharmacology/therapeutic use ; Cytokines/metabolism ; Skin/drug effects/pathology ; Mice ; Quantum Dots/chemistry ; Inflammation/drug therapy ; },
abstract = {Inflammation affects the pathology of wound healing and is strongly associated with many chronic wounds that do not heal. Natural herbs with anti-inflammatory effects have received much attention in clinical treatment because they are inexpensive, readily available, safe, and effective. In this study, EUO-NAC-CDs were prepared using a hydrothermal method in which Eucommia ulmoides (EUO) and n-acetylcysteine (NAC) were used as carbon sources. EUO-NAC-CDs have a small particle size distribution with an average particle size of 2.84 nm, emit stable blue-green fluorescence, and are biocompatible. EUO-NAC-CDs have been used for in vitro bioimaging, where high anti-inflammatory activity and accelerated wound healing have been demonstrated in vivo and in vitro. Additionally, EUO-NAC-CDs significantly decreased the expression of TNF-α, IL-6, and IL-1β and increased the expression of IL-10, suggesting that EUO-NAC-CDs had good anti-inflammatory effects. In a rat model of skin defects, EUO-NAC-CDs promoted wound healing, stimulated the formation of blood vessels and tissue regeneration near the wound, increased the expression of CD31, VEGF, and CD206, and decreased the expression of INOS, further demonstrating the therapeutic function of CDs. Therefore, fluorescent EUO-NAC-CDs can be effective in clinical wound treatment as imaging tools and functional wound dressings.},
}
@article {pmid39546096,
year = {2024},
author = {Xu, B and Wang, G and Xu, L and Ding, L and Li, S and Han, Y},
title = {Vitamin C ameliorates D-galactose-induced senescence in HEI-OC1 cells by inhibiting the ROS/NF-κB pathway.},
journal = {Molecular biology reports},
volume = {51},
number = {1},
pages = {1157},
pmid = {39546096},
issn = {1573-4978},
mesh = {*Galactose/pharmacology/metabolism ; *Reactive Oxygen Species/metabolism ; *Cellular Senescence/drug effects ; *Ascorbic Acid/pharmacology/metabolism ; *NF-kappa B/metabolism ; Animals ; *Signal Transduction/drug effects ; Cell Line ; *Hair Cells, Auditory/drug effects/metabolism ; Mice ; Cell Survival/drug effects ; Acetylcysteine/pharmacology ; },
abstract = {BACKGROUND: Cochlear hair cell senescence is one of the major causes of age-related hearing loss (ARHL) and is significantly related to reactive oxygen species (ROS) accumulation. Research shows that vitamin C (VC) can inhibit ROS accumulation; however, its association with cochlear hair cell senescence remains elusive.<br><br>METHODS AND RESULTS: Firstly, a cellular senescence model was established using D-galactose (D-gal) induced HEI-OC1 cells for 24 h. Senescent HEI-OC1 cells were then continued to be treated with the addition of VC or ROS inhibitor (N-acetylcysteine; NAC) for another 24 h, and explored the impact of VC on senescent cochlear hair cell and the potential regulatory mechanisms. The results indicated that D-gal-induced senescent HEI-OC1 cells, manifested as decreased cell viability, increased &#x3b2;-galactosidase activity and p21 protein level, and ROS and pro-inflammatory factors were upregulated, and NF-&#x3ba;B p65 phosphorylation was enhanced. However, the use of VC or NAC can significantly ameliorate these effects and improve HEI-OC1 cell senescence.<br><br>CONCLUSIONS: This research indicates that VC can ameliorate D-gal-induced senescence of HEI-OC1 cochlear hair cells, and its protective effect may be related to the inhibition of the ROS/NF-&#x3ba;B pathway, which provides a new research direction for the prevention and treatment of ARHL.},
}
@article {pmid39541698,
year = {2024},
author = {Jin, L and Yang, Q and Li, J and Li, X and Xia, Y and Chen, Z and Wen, Y and Wang, L and Wang, X and Tong, J and Shen, Y and Chen, K},
title = {The ROS/AKT/S6K axis induces corneal epithelial dysfunctions under LED blue light exposure.},
journal = {Ecotoxicology and environmental safety},
volume = {287},
number = {},
pages = {117345},
doi = {10.1016/j.ecoenv.2024.117345},
pmid = {39541698},
issn = {1090-2414},
mesh = {*Reactive Oxygen Species/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Epithelium, Corneal/drug effects/radiation effects ; Humans ; Animals ; *Light/adverse effects ; *Apoptosis/drug effects/radiation effects ; Mice ; Cell Movement/drug effects/radiation effects ; Cell Survival/drug effects/radiation effects ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction/drug effects ; Epithelial Cells/drug effects/radiation effects ; Acetylcysteine/pharmacology ; Blue Light ; Acetates ; Benzopyrans ; },
abstract = {In recent years, concerns have escalated regarding eye health problems arising from Light-emitting diode (LED), which emits high-energy blue light (BL), potentially causing corneal epithelial dysfunctions (CEpD). Nevertheless, the mechanisms underlying this damage remain poorly comprehended. This study endeavors to explore the specific mechanisms through which BL exposure induces CEpD. The study carried out diverse assays and treatments to investigate the toxicological effects of BL exposure. 48 hours (h) of 440 nm of BL exposure decreased the migration of human corneal epithelial cells (hCEpCs) while augmenting reactive oxygen species (ROS) production and apoptosis. RNA-Sequencing and bioinformatic analysis indicated that cellular oxidation and reduction equilibrium, wound healing, the positive regulation of the apoptotic process, and the Phosphoinositide 3-kinase (PI3K)/AKT pathway were significantly influenced by BL exposure. Treatment with N-acetylcysteine (NAC), a ROS scavenger, restored cell viability and AKT/S6 kinase (S6K) activation, suggesting the involvement of ROS in BL-induced damage. NAC also reversed BL-induced apoptosis and migration. Blocking AKT/S6K replicated detrimental effects, while pre-treatment with SC79 (SC), an AKT activator, alleviated the changes caused by BL exposure in hCEpCs. Furthermore, in mice, the combination of AKT inhibition and BL exposure led to CEpD. However, treatment with SC and NAC restored CEpD caused by BL exposure. These results imply that the regulation of the ROS/PI3K/AKT/S6K axis is implicated in BL-induced CEpD. Collectively, this study offers insights into the molecular mechanisms of BL-induced CEpD and proposes targeting the ROS/PI3K/AKT/S6K cascade as a potential therapeutic approach. The findings contribute to ocular health knowledge and establish the basis for developing interventions to safeguard the cornea from the detrimental effects of excessive BL exposure.},
}
@article {pmid39540528,
year = {2024},
author = {Yamauchi, K and Tsutsumi, Y and Kobayashi, T and Komura, JI},
title = {The effects of antioxidant administration in the early stages of radiation-induced tumorigenesis.},
journal = {Radiation protection dosimetry},
volume = {200},
number = {16-18},
pages = {1594-1597},
doi = {10.1093/rpd/ncae145},
pmid = {39540528},
issn = {1742-3406},
support = {//Aomori Prefecture, Japan/ ; },
mesh = {Animals ; Mice ; *Antioxidants/pharmacology ; *Neoplasms, Radiation-Induced/etiology ; Female ; *Gamma Rays/adverse effects ; *Acetylcysteine/pharmacology ; Male ; Carcinogenesis/radiation effects/drug effects ; Whole-Body Irradiation ; Mice, Inbred C57BL ; Intestinal Neoplasms/etiology ; Dose-Response Relationship, Radiation ; Adenomatous Polyposis Coli ; },
abstract = {ApcMin/+ mouse was a model mouse for human familial adenomatous polyposis, and irradiation at an early age increases tumors in the small and large intestine. To study the effects of antioxidant administration on tumor incidence after continuous whole-body exposure to gamma rays, ApcMin/+ mice were exposed to a medium-dose-rate, 200 mGy/d, from postnatal Day 0 to 21 of age or a high-dose-rate of 0.65 Gy/min (total dose 4.2 Gy) on postnatal Day 7. The dams and pups were supplied with the N-acetylcysteine (NAC) in drinking water (7 g/L), from gestation Day 15 until weaning (21 days-old). A significant increase in the number of intestinal tumors were observed in ApcMin/+ mice irradiated with high dose-rate gamma rays as compared with the non-irradiated controls, but there was no significant difference in tumor counts between the non-irradiated controls and the medium-dose rate irradiation groups. NAC administration did not have any significant effect at least at this dose. These results suggest that the supplementation of anti-oxidant at the early stage of tumorigenesis does not suppress the formation of irradiation-induced small intestinal tumors.},
}
@article {pmid39539442,
year = {2024},
author = {Xiang, C and Lu, Y and Hao, R and Wei, Y and Hu, Y and Yu, G},
title = {Catalpol alleviates amyloid- generation and neuronal oxidative stress injury via activating the Keap1-Nrf2/ARE signaling pathway in the immortalized lymphocytes from patients with late-onset Alzheimer's disease and SKNMC cells co-culture model.},
journal = {Iranian journal of basic medical sciences},
volume = {27},
number = {12},
pages = {1547-1557},
pmid = {39539442},
issn = {2008-3866},
abstract = {OBJECTIVES: To assess the effect of catalpol, the major bioactive constituents of Rehmannia glutinosa, on our Alzheimer's disease (AD) in vitro model.<br><br>MATERIALS AND METHODS: We employed the immortalized lymphocytes (lymphoblastoid cell line, LCL) from late-onset AD patients and co-cultured "them" to mimic the pathological process of late-onset AD and investigated the effect of catalpol on our AD in vitro model.<br><br>RESULTS: In the co-culture model, AD-derived LCL triggered excessive A&#x3b2;1-42 in SKNMC cells due to its high levels of oxidative stress and resulted in neuronal oxidative stress injury through inhibiting Keap1-Nrf2/ARE signaling pathway. Treatment with catalpol and N-acetylcysteine (NAC), an antioxidant, prevented the AD LCL-induced A&#x3b2;1-42 overproduction and reduced the level of &#x3b2;-site amyloid precursor protein cleaving enzyme-1 (BACE1) and amyloid precursor protein (APP)-C99. Catalpol and NAC also enhanced the antioxidant capacity and reduced apoptosis in SKNMC cells co-cultured with AD LCL. The anti-oxidative effect of catalpol was antagonized by ML385, the Nrf2 inhibitor. Therefore, we speculate that the antioxidant and anti-apoptotic effects of catalpol are mediated by activating the Keap1-Nrf2/ARE signaling pathway.<br><br>CONCLUSION: Catalpol affects the anti-A&#x3b2; generation and the antioxidative and antiapoptotic properties in the AD co-cultured model. So, it might be a novel natural drug and offer a potential therapeutic approach for AD.},
}
@article {pmid39537820,
year = {2024},
author = {Morales Fénero, C and Sacksteder, RE and Diamos, AG and Kimmey, JM},
title = {Heat-inactivated Streptococcus pneumoniae augments circadian clock gene expression in zebrafish cells.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {27805},
pmid = {39537820},
issn = {2045-2322},
support = {R35 GM147509/GM/NIGMS NIH HHS/United States ; R35GM147509/GM/NIGMS NIH HHS/United States ; Pew Biomedical Scholars//Pew Charitable Trusts/ ; },
mesh = {Animals ; *Zebrafish/microbiology ; *Circadian Clocks/genetics ; *Streptococcus pneumoniae/genetics ; *Zebrafish Proteins/genetics/metabolism ; Gene Expression Regulation/radiation effects ; Period Circadian Proteins/genetics/metabolism ; Hot Temperature ; Light ; Cell Line ; Cryptochromes/genetics/metabolism ; },
abstract = {The circadian clock is a cell-autonomous process that regulates daily internal rhythms by interacting with environmental signals. Reports across species show that infection can alter the expression of circadian genes; however, in teleosts, these effects are influenced by light exposure. Currently, no reports analyze the direct effects of bacterial exposure on the zebrafish clock. Using zebrafish Z3 cells, we demonstrate that exposure to heat-killed Streptococcus pneumoniae (HK-Spn) augments the expression of core repressive factors in a light- and time-dependent manner. In constant darkness, HK-Spn highly upregulated cry1a, per3, and per1b expression. In the presence of light, HK-Spn exposure rapidly and strongly upregulated per2 and cry1a, and this was proportionally increased with light intensity. The combinatorial effect of light and HK-Spn on per2 and cry1a was not duplicated with H2O2, a known byproduct of light exposure. However, the ROS inhibitor N-acetyl cysteine was sufficient to block HK-Spn augmentation of per2, cry1a, and per3. These findings demonstrate that exposure to an inactive bacteria influences the expression of zebrafish clock genes under different light conditions.},
}
@article {pmid39531327,
year = {2025},
author = {Monti, DA and Faezeh, V and Zabrecky, G and Alizadeh, M and Wintering, N and Bazzan, AJ and Mohamed, FB and Newberg, AB},
title = {Changes in Resting-State Functional Connectivity and Cognitive-Affective Symptoms in Patients With Post-Concussion Syndrome Treated With N-Acetyl Cysteine.},
journal = {The Journal of head trauma rehabilitation},
volume = {40},
number = {3},
pages = {E196-E207},
pmid = {39531327},
issn = {1550-509X},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Post-Concussion Syndrome/drug therapy/diagnostic imaging/physiopathology/psychology ; Male ; Female ; Adult ; Magnetic Resonance Imaging ; Young Adult ; Treatment Outcome ; Middle Aged ; *Antioxidants/therapeutic use/administration &amp; dosage ; },
abstract = {OBJECTIVE: Concussion accounts for more than 80% of people experiencing traumatic brain injury. Acute concussion is associated with characteristic cognitive and functional deficits that may persist for weeks to months. A subgroup of these patients (from 10% to 50%) have persistent symptoms referred to as chronic post-concussion syndrome (PCS). There are limited treatment options for these patients and the pathophysiology is poorly understood, though oxidative stress is thought to be a contributing factor. The purpose of this study was to evaluate whether an antioxidant, N -acetylcysteine (NAC), might be beneficial in patients with PCS.<br><br>SETTING: Outpatient medicine center.<br><br>PARTICIPANTS: Fifty patients with chronic PCS for at least 3 months post injury.<br><br>DESIGN: The patients with PCS were enrolled in this randomized unblinded clinical trial to receive the antioxidant NAC as a combination of daily oral and weekly intravenous infusions, or assigned to a waitlist control group where they would continue to receive standard of care.<br><br>MAIN MEASURES: Resting-state functional connectivity (FC) magnetic resonance imaging (rsFC-MRI) was performed pre and post either NAC or the waitlist period along with cognitive, emotional, and sensory symptom assessments.<br><br>RESULTS: The results demonstrated significant (P <&#xa0;.05) improvements in symptoms as determined by the Rivermead Post-Concussion Symptoms Questionnaire, Spielberger State-Trait Anxiety Inventory, and Profile of Mood Scale in the PCS group receiving NAC as compared to patients receiving ongoing standard care. Importantly, there were significant (P <&#xa0;.01) changes in FC in the NAC group, particularly in networks such as the default mode network, salience network, and executive control network. These changes in FC also correlated with improvements in symptoms.<br><br>CONCLUSIONS: In patients with chronic PCS, NAC treatment was associated with significant changes in resting state FC and improvement in a variety of symptoms, particularly cognitive and affective symptoms.},
}
@article {pmid39530276,
year = {2025},
author = {Gaffney, PJ and Shetty, KR and Yuksel, S and Kaul, VF},
title = {Antioxidant Therapies in the Treatment of Aminoglycoside-Induced Ototoxicity: A Meta-Analysis.},
journal = {The Laryngoscope},
volume = {135},
number = {4},
pages = {1278-1286},
doi = {10.1002/lary.31902},
pmid = {39530276},
issn = {1531-4995},
mesh = {*Aminoglycosides/adverse effects ; Humans ; *Antioxidants/therapeutic use ; *Ototoxicity/drug therapy/etiology ; Acetylcysteine/therapeutic use ; Oxidative Stress/drug effects ; *Anti-Bacterial Agents/adverse effects ; Randomized Controlled Trials as Topic ; },
abstract = {OBJECTIVE: A feared complication of aminoglycoside treatment is ototoxicity, which is theorized to be attributed to the production of aminoglycoside-induced reactive oxygen species. Previous studies using animal models have suggested that numerous therapies targeting reducing oxidative stress may prevent ototoxicity from aminoglycosides. However, few clinical studies have been conducted on these antioxidants. This systematic review and meta-analysis examines the effectiveness of antioxidant therapies in the treatment of aminoglycoside-induced ototoxicity.<br><br>DATA SOURCES: PubMed, Embase, Web of Science, and ClinicalTrials.gov.<br><br>REVIEW METHOD: A literature search was conducted in August 2024. This review sought randomized controlled trials to be conducted on humans to examining otologic outcomes in aminoglycoside-induced ototoxicity following administration of medications intended to reduce oxidative stress.<br><br>RESULTS: A systematic review yielded 2037 results, of which seven studies met inclusion criteria. N-acetylcysteine (NAC) was investigated in four studies, aspirin in two studies, and vitamin E in one study. Six studies examined the benefit of antioxidant treatments for up to 8&#x2009;weeks after administration while one study tested subjects' hearing after 1&#x2009;year. In pooled analysis, two studies assessing NAC showed the greatest reduction in ototoxicity (RR 0.112, 95% CI, 0.032-0.395; p&#x2009;=&#x2009;0.0007; I[2]&#x2009;=&#x2009;18%), followed by two studies examining aspirin (RR 0.229, 95% CI, 0.080-0.650; p&#x2009;=&#x2009;0.0057; I[2]&#x2009;=&#x2009;0%). One study performed with vitamin E did not find a reduction in ototoxicity compared to the placebo (RR 0.841, 95% CI, 0.153-4.617; p&#x2009;=&#x2009;0.8416).<br><br>CONCLUSIONS: Multiple studies have shown that NAC and aspirin are effective in reducing ototoxicity from treatment with aminoglycosides. However, there is a lack of high-quality evidence. Additional studies should examine whether aspirin and N-acetylcysteine provide long-term benefit, and which of the other promising antioxidants translate from animal models.<br><br>LEVEL OF EVIDENCE: NA Laryngoscope, 135:1278-1286, 2025.},
}
@article {pmid39526680,
year = {2025},
author = {Baune, BT and Fromme, SE},
title = {The role of immunomodulators in severe mental disorders: future perspectives.},
journal = {Current opinion in psychiatry},
volume = {38},
number = {1},
pages = {41-47},
doi = {10.1097/YCO.0000000000000976},
pmid = {39526680},
issn = {1473-6578},
mesh = {Humans ; *Immunologic Factors/therapeutic use ; Schizophrenia/drug therapy/immunology ; Immunomodulating Agents/therapeutic use ; Mental Disorders/drug therapy/immunology ; Bipolar Disorder/drug therapy/immunology ; },
abstract = {PURPOSE OF REVIEW: The immune system is of pivotal importance with regard to the development and maintenance of mental illness. Aberrant cytokine levels are significant immune markers, and research is increasingly focusing on the complement system and the gut-brain axis. The efficacy and safety of immunomodulatory interventions are currently the subject of clinical studies. Hence, this review is timeline and relevant to evaluate the latest evidence on the clinical value of immunomodulatory treatments from studies over the past 18 months in schizophrenia, bipolar disorder and unipolar depression.<br><br>RECENT FINDINGS: While conventional psychotropic drugs (antidepressants, antipsychotics, lithium) appear to have immunomodulatory adverse effects, antibiotics (minocycline), nonsteroid anti-inflammatory drugs (celecoxib) and anti-inflammatory therapeutics in particular are the subject of ongoing clinical trials. Integrative medical interventions such as nutritional supplements (e.g., N -acetyl- l -cysteine, polyunsaturated fatty acids) and exercise interventions (e.g., running, yoga) are being evaluated for their immunomodulatory effects and clinical value.<br><br>SUMMARY: No evidence-based recommendation can be made for the immunomodulatory treatment of depression, although celecoxib appears to be more effective than minocycline and omega-3 fatty acid. N -acetylcysteine (NAC) may be beneficial for the treatment of bipolar and schizophrenia disorders. However, further translational research is required to confirm these findings.},
}
@article {pmid39510433,
year = {2025},
author = {Jiang, W and Ma, X and Li, B and Jiang, T and Jiang, H and Chen, W and Gao, J and Mao, Y and Sun, X and Ye, Z and Zhao, S and Huang, S and Chen, Y},
title = {Role of the PGAM5-CypD mitochondrial pathway in methylglyoxal-induced bone loss in diabetic osteoporosis.},
journal = {Bone},
volume = {190},
number = {},
pages = {117322},
doi = {10.1016/j.bone.2024.117322},
pmid = {39510433},
issn = {1873-2763},
mesh = {Animals ; *Pyruvaldehyde/metabolism ; Mice ; *Mitochondria/metabolism/drug effects ; *Osteoporosis/metabolism/pathology ; *Osteoblasts/metabolism/drug effects ; *Peptidyl-Prolyl Isomerase F/metabolism ; *Apoptosis/drug effects ; Phosphoprotein Phosphatases/metabolism ; Cell Differentiation/drug effects ; Cyclophilins/metabolism ; Osteogenesis/drug effects ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Male ; Membrane Potential, Mitochondrial/drug effects ; Cell Line ; Signal Transduction/drug effects ; Bone Resorption/pathology/metabolism ; Diabetes Complications/pathology/metabolism ; },
abstract = {Diabetic osteoporosis (DOP) is a skeletal complication with a high rate of disability. It results in a great burden to the patient's family and society. Methylglyoxal (MG) is a toxic by-product of the glycolytic process that occurs during diabetic conditions. It causes osteoblastic injury and con-tributes to the initiation and development of DOP. Disruption of mitochondrial homeostasis has been implicated as a cause of dysregulated osteo-blastogenesis, an essential step in bone formation. It is unclear whether mitochondrial dysfunction is involved in MG-induced osteoblast dysfunction. In this study, we showed that mitochondrial dysfunction contributes to MG-induced MC3T3-E1 cell apoptosis and impaired differentiation. A significant reduction of mitochondrial membrane potential (MMP) and ATP production occurred in MG-induced osteoblasts as well as increasing mitochondrial reactive oxygen species (mtROS) and intracellular Ca[2+]. Classical antioxidant N-Acetylcysteine (NAC) significantly attenuated mitochondrial dysfunction as well as osteoblast apoptosis and osteogenic differentiation damage induced by MG. More importantly, we found that activating phosphoglycerate mutase family member 5 (PGAM5) and cyclophilin D (CypD), which contributes to mitochondrial homeostasis, is involved in MG-induced osteoblast injury. Both PGAM5 and CypD knockdown effectively reversed osteoblast viability and function, whereas PGAM5 or CypD overexpression aggravated osteoblast injury caused by MG. Moreover, the result of co-transfection revealed that PGAM5 is an upstream signaling molecule of CypD. By constructing type I diabetes mouse models, we further found that the expression of PGAM5 and CypD were both increased in the femur along with a reduction of ATP and increased TUNEL-positive cells. These results, for the first time, suggest that MG-induced mitochondrial dysfunction induces osteoblast injury through the PGAM5-CypD pathway. This study provides insight into the prevention and treatment of DOP. LAY SUMMARY: This study highlights the role of mitochondria in regulating osteoblast viability and function under conditions of diabetic osteoporosis (DOP). We found that the PGAM5-CypD mitochondrial pathway is activated following glycolytic by-product methylglyoxal (MG) treatment, which contributes to mitochondrial dysfunction and osteogenic dysfunction. This mechanism implicates mitochondria as a potential therapeutic target for osteoporosis.},
}
@article {pmid39506899,
year = {2024},
author = {Zhao, K and Zhu, GZ and Li, HZ and Gao, JW and Tu, C and Wu, DZ and Huang, YS and Han, D and Chen, XY and Wu, LY and Zhong, ZM},
title = {Accumulation of Advanced Oxidation Protein Products Promotes Age-Related Decline of Type H Vessels in Bone.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {80},
number = {1},
pages = {},
doi = {10.1093/gerona/glae271},
pmid = {39506899},
issn = {1758-535X},
support = {81871819//National Natural Science Foundation of China/ ; 2023A1515011943//Guangdong Provincial Basic and Applied Basic Research Fund Natural Science Foundation Project/ ; 2022-YB1273//Technology Project of Ganzhou/ ; 202310843//Technology Project of Health Commission of Jiangxi Province/ ; GJJ2201444//Youth Project of Foundation of Jiangxi/ ; //President Foundation of Nanfang Hospital/ ; 2022B026//Southern Medical University/ ; },
mesh = {Animals ; Mice ; *Advanced Oxidation Protein Products/metabolism ; *Aging/physiology/metabolism ; Bone and Bones/metabolism/blood supply ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism ; Male ; Neovascularization, Physiologic/drug effects/physiology ; NADPH Oxidases/metabolism ; Cell Proliferation/drug effects ; Osteogenesis/drug effects/physiology ; },
abstract = {Type H vessels have been proven to couple angiogenesis and osteogenesis. The decline of type H vessels contributes to bone loss in the aging process. Aging is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, whether AOPP accumulation is involved in age-related decline of type H vessels is unclear. Here, we show that the increase of AOPP levels in plasma and bone was correlated with the decline of type H vessels and loss of bone mass in old mice. Exposure of microvascular endothelial cells to AOPPs significantly inhibited cell proliferation, migration, and tube formation; increased NADPH oxidase activity and excessive reactive oxygen species generation; upregulated the expression of vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1; and eventually impaired angiogenesis, which was alleviated by redox modulator N-acetylcysteine and NADPH oxidase inhibitor apocynin. Furthermore, reduced AOPP accumulation by NAC treatment was able to alleviate significantly the decline of type H vessels, bone mass loss, and deterioration of bone microstructure in old mice. Collectively, these findings suggest that AOPPs accumulation contributes to the decline of type H vessels in the aging process, and illuminate a novel potential mechanism underlying age-related bone loss.},
}
@article {pmid39506442,
year = {2025},
author = {Barlattani, T and Celenza, G and Cavatassi, A and Minutillo, F and Socci, V and Pinci, C and Santini, R and Pacitti, F},
title = {Neuropsychiatric Manifestations of COVID-19 Disease and Post COVID Syndrome: The Role of N-acetylcysteine and Acetyl-L-carnitine.},
journal = {Current neuropharmacology},
volume = {23},
number = {6},
pages = {686-704},
pmid = {39506442},
issn = {1875-6190},
mesh = {Humans ; *COVID-19/complications/psychology ; *Acetylcysteine/therapeutic use/pharmacology ; *Acetylcarnitine/therapeutic use/pharmacology ; *Mental Disorders/drug therapy/etiology ; *COVID-19 Drug Treatment ; Animals ; SARS-CoV-2 ; },
abstract = {COVID-19 is associated with neuropsychiatric symptoms, such as anosmia, anxiety, depression, stress-related reactions, and psychoses. The illness can cause persistent cognitive impairment and "brain fog", suggesting chronic brain involvement. Clinical entities of ongoing symptomatic COVID-19 and Post COVID Syndrome (PCS) mainly present neuropsychiatric symptoms such as dysgeusia, headache, fatigue, anxiety, depression, sleep disturbances, and post-traumatic stress disorder. The pathophysiology of COVID-19-related brain damage is unclear, but it is linked to various mechanisms such as inflammation, oxidative stress, immune dysregulation, impaired glutamate homeostasis, glial and glymphatic damage, and hippocampal degeneration. Noteworthy is that the metabotropic receptor mGluR2 was discovered as a mechanism of internalisation of SARS-CoV-2 in Central Nervous System (CNS) cells. N-acetylcysteine (NAC) and acetyl-L-carnitine (ALC) are two supplements that have already been found effective in treating psychiatric conditions. Furthermore, NAC showed evidence in relieving cognitive symptomatology in PCS, and ALC was found effective in treating depressive symptomatology of PCS. The overlapping effects on the glutamatergic system of ALC and NAC could help treat COVID-19 psychiatric symptoms and PCS, acting through different mechanisms on the xc-mGluR2 network, with potentially synergistic effects on chronic pain and neuro-astrocyte protection. This paper aims to summarise the current evidence on the potential therapeutic role of NAC and ALC, providing an overview of the underlying molecular mechanisms and pathophysiology. It proposes a pathophysiological model explaining the effectiveness of NAC and ALC in treating COVID-19-related neuropsychiatric symptoms.},
}
@article {pmid39504621,
year = {2024},
author = {Peng, TR and Lin, HH and Tseng, TL and Huang, YH and Tsai, PY and Lin, CY and Lee, MC and Chen, SM},
title = {Efficacy of N-acetylcysteine for patients with depression: An updated systematic review and meta-analysis.},
journal = {General hospital psychiatry},
volume = {91},
number = {},
pages = {151-159},
doi = {10.1016/j.genhosppsych.2024.10.018},
pmid = {39504621},
issn = {1873-7714},
mesh = {*Acetylcysteine/administration &amp; dosage/therapeutic use ; Humans ; Outcome Assessment, Health Care ; Major Depressive Disorder/drug therapy ; Depressive Disorder/drug therapy ; },
abstract = {BACKGROUND: Results on whether N-acetylcysteine (NAC) ameliorates depression in patients with psychiatric problems, such as bipolar disorder and major depressive disorder, remain inconsistent, and several new studies have recently been published. Thus, we conducted an uptodated meta-analysis to evaluate the efficacy of NAC against depression.<br><br>METHODS: This systematic review and meta-analysis included randomized controlled trials where NAC was used to treat depression. The present study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase (Ovid), and Cochrane were searched for relevant articles. A random-effects model was used to evaluate the primary outcome-efficacy of NAC in ameliorating depression.<br><br>RESULTS: This review included 12 studies (904 patients with depression). The daily dose of NAC in the included studies ranged from 1000 to 3000&#xa0;mg. The duration of NAC treatment ranged from 8 to 24&#xa0;weeks. A significant difference was noted between NAC and placebo in terms of the change in mean depression score from baseline to treatment conclusion (standardized mean difference&#xa0;=&#xa0;-0.24; 95&#xa0;% confidence interval (CI)&#xa0;=&#xa0;-0.44 to -0.05; I[2]&#xa0;=&#xa0;45&#xa0;%; P&#xa0;=&#xa0;.02).<br><br>CONCLUSION: Our findings indicate that adjunctive NAC can ameliorate depressive symptoms in patients with psychiatric problems, particularly bipolar disorder. However, large-scale clinical trials were needed to substantiate our results due to the wide CI value.},
}
@article {pmid39500660,
year = {2024},
author = {Xie, R and Yang, Y and Jiang, X and Gao, L and Sun, J and Yang, J},
title = {The effect of modulating platelet reactive oxygen species by the addition of antioxidants to prevent clearance of cold-stored platelets.},
journal = {Hematology, transfusion and cell therapy},
volume = {46 Suppl 6},
number = {Suppl 6},
pages = {S272-S283},
pmid = {39500660},
issn = {2531-1387},
abstract = {BACKGROUND: It is known that the rapid clearance of cold-stored platelets is attributed to various storage lesions, including an abnormal increase in reactive oxygen species when platelets are exposed to cold temperatures. As an antioxidant, N-acetylcysteine exhibits some significant effects on scavenging various reactive oxygen species and inhibiting cell damage and apoptosis.<br><br>AIMS: This study aimed to investigate the effects of N-acetylcysteine on reducing reactive oxygen species production and protecting cold-stored platelets from phagocytosis and clearance, and to determine the optimal concentration of N-acetylcysteine.<br><br>METHODS: Platelet concentrates were divided into three groups: room-temperature-stored platelets, cold-stored platelets, and cold-stored platelets with the addition of different concentrations of N-acetylcysteine. After five days of storage, reactive oxygen species production, lipid peroxidation levels, activation marker expressions, GPIb/&#x251; desialylation with exposure of glycan residues and other quality parameters of platelets were measured and compared between the groups. Phagocytosis of platelets was detected by phorbol 12-myristate 13-acetate-activated THP-1 or Hep G2 cells. Moreover, the recovery of infused platelets was measured in severe combined immunodeficient mice at different timepoints.<br><br>RESULTS: After 5 days of storage, cytoplasmic reactive oxygen species significantly increased in chilled compared to non-chilled platelets; they were notably reduced with the addition of N-acetylcysteine, particularly at a concentration of 5 mM. Compared with chilled platelets, the P-selectin and phosphatidylserine expressions, as well as exposure of GPIb/&#x251; glycan residues, were significantly reduced with 5 mM of N-acetylcysteine. Phagocytosis of platelets by THP-1 or Hep G2 cells was significantly lower in 5 mM of N-acetylcysteine compared to cold-stored platelets without N-acetylcysteine.<br><br>CONCLUSIONS: This study demonstrated correlations between reactive oxygen species production and their pro-oxidant effects on platelet clearance after cold storage. The addition of N-acetylcysteine at an appropriate concentration do not only protects chilled platelets from storage lesions caused by reactive oxygen species overproduction but also prevents platelet phagocytosis in vitro and clearance in vivo, thereby extending circulating time.},
}
@article {pmid39497872,
year = {2024},
author = {Jain, E and Alex, R and Coutinho, T and Narula, N},
title = {Utility of N-acetylcysteine in Non-Acetaminophen-Induced Liver Injury Secondary to Influenza A Infection.},
journal = {Cureus},
volume = {16},
number = {10},
pages = {e70900},
pmid = {39497872},
issn = {2168-8184},
abstract = {Influenza A, which belongs to the Orthomyxoviridae viral family, is a known causative agent of respiratory illness and systemic inflammation. Annual influenza immunizations are crucial in reducing the incidence and severity of the flu. Intravenous (IV) N-acetylcysteine (NAC) is a pharmaceutical agent indicated for hepatic injury, particularly to address oxidative stress and inflammation secondary to acetaminophen toxicity. The authors present a case of a young female with acute liver injury and impending liver failure in the setting of viral influenza A infection, successfully treated with IV-NAC.},
}
@article {pmid39497389,
year = {2024},
author = {, },
title = {[Guidelines for diagnosis and management of drug-induced liver injury caused by anti-tuberculosis drugs (2024 version)].},
journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases},
volume = {47},
number = {11},
pages = {1069-1090},
doi = {10.3760/cma.j.cn112147-20240614-00338},
pmid = {39497389},
issn = {1001-0939},
support = {2023ZX10003001//National Key Research and Development Program/ ; 2023-2025//Shanghai Three-Year/ ; GWVI-11.1-05//Action Plan to Strengthen the Public Health System/ ; },
mesh = {*Chemical and Drug Induced Liver Injury/diagnosis/etiology/prevention &amp; control/therapy ; Humans ; *Antitubercular Agents/adverse effects ; China ; Tuberculosis/drug therapy/diagnosis ; },
abstract = {Drug-induced liver injury (DILI) is one of the most common adverse reactions of anti-tuberculosis treatment. To improve the diagnosis and management of anti-tuberculosis drug-induced liver injury (ATB-DILI) for clinicians and tuberculosis control workers, the Chinese Medical Association Tuberculosis Branch has developed guidelines for the diagnosis and treatment of ATB-DILI. These guidelines summarized recent research progress in relevant fields and provide detailed explanations, recommendations, and quality assessments related to ATB-DILI, covering aspects such as definition, risk factors, mechanisms, pathological manifestations, clinical classification, diagnosis, and management. The key recommendations are as follows.Recommendation 1: Risk factors: NAT2 slow acetylation genotype, GSTM1 gene variation, advanced age, hepatitis virus infection or concurrent acute/chronic liver disease, HIV infection, malnutrition, and alcohol (ethanol) intake are risk factors for ATB-DILI (2, B).Recommendation 2: R-value calculation: Calculate the R-value for suspected ATB-DILI patients at different time points during the course of the disease. ALT and ALP values should be obtained on the same day, with a maximum interval of no more than 48 hours. This helps to accurately determine the clinical type and prognosis of DILI (2, C).Recommendation 3: Comprehensive medical history collection: Collect information on past medication history, clinical features, dynamic changes in liver biochemical markers, drug rechallenge reactions, comorbidities, and underlying liver diseases (4, B).Recommendation 4: Liver biochemical tests: Include at least ALT, AST, ALP, GGT, TBil, DBil, and albumin. If necessary, measure prothrombin time or international normalized ratio (INR) (3, B).Recommendation 5: Abdominal imaging: Routine abdominal imaging should be performed for suspected ATB-DILI patients (3, B).Recommendation 6: Liver histopathological examination: Histology of liver biopsies aids in the diagnosis and differential diagnosis of DILI (4, B).Recommendation 7: Biochemical diagnostic criteria for acute ATB-DILI: Liver biochemical tests should meet one of the following criteria: ALT≥3×ULN and/or TBil≥2×ULN; simultaneous elevation of AST, ALP, and TBil, with at least one parameter≥2×ULN (4, C).Recommendation 8: Diagnostic criteria for ATB-DILI: Diagnosis requires:(1) A history of exposure to anti-tuberculosis drugs that can cause liver injury;(2)Rapid normalization of abnormal liver biochemical markers after drug discontinuation: For patients with hepatocellular injury, a decrease in the peak serum ALT level of at least 50% within 8 days is highly suggestive, while a decrease of at least 50% within 30 days is considered important. For patients with cholestatic injury, a serum ALP or TBil peak level that decreases by at least 50% within 180 days is also considered important;(3) Exclusion of other causes of liver injury;(4) Positive rechallenge reaction. Meeting three of the above criteria confirms ATB-DILI, whereas meeting (1) and (2) criteria indicates a suspected case. In practice, the vast majority of ATB-DILI are suspected cases (3, B).Recommendation 9: Avoid re-exposure: Minimize re-exposure to the same suspected drug, especially if the initial exposure caused severe liver injury (4, B).Recommendation 10: Causality assessment: Use the RUCAM scale as the primary method for assessing causality. In cases involving multiple hepatotoxic drugs, concurrent liver disease, or new drug clinical trials, combine expert opinions for reliable assessment (3, B).Recommendation 11: Baseline testing: All patients are recommended to undergo baseline liver biochemistry, HBsAg (if HBsAg is positive, further HBV DNA testing), anti-HCV testing, and abdominal imaging before starting anti-TB treatment (3, B).Recommendation 12: Monitoring frequency: Patients without high-risk factors should have monthly liver biochemical monitoring (4, C);high-risk patients or those using hepatotoxic drugs should be monitored every 2 weeks during the first 2 months of anti-tuberculosis treatment, then monthly (2, B).Recommendation 13: Avoid concurrent hepatotoxic drugs: Evaluate the benefit-risk ratio of using other hepatotoxic drugs or traditional Chinese medicine (4, C).Recommendation 14: Antiviral treatment: In ATB-DILI patients with viral hepatitis, consider prompt antiviral therapy if indicated (3, B).Recommendation 15: NAT2 genotyping: Guide isoniazid dosing based on NAT2 gene polymorphism (4, C).Recommendation 16: Application of preventive hepatoprotective drugs: People with high risk factors for liver damage may consider it (4, C); however, routine use in the general population is not recommended (2, B).Recommendation 17: Immediate discontinuation: In the case of ATB-DILI, suspected drugs should be discontinued immediately (4, A).Recommendation 18: N-acetylcysteine (NAC): Early intravenous administration of NAC is beneficial for acute liver failure and subacute liver failure induced by drugs in adults (4, D).Recommendation 19: Glucocorticoids: Use with caution;not recommended as routine treatment for ATB-DILI(4, C);may be considered for immune-mediated DILI with hypersensitivity and autoimmune features (3, B).Recommendation 20: For acute hepatocellular injury or mixed DILI with significantly elevated ALT/AST, bicyclol and/or magnesium isoglycyrrhizinate are recommended (2, B).Recommendation 21: For mild to moderate hepatocellular injury type DILI with elevated ALT/AST, reasonable choices include ammonium glycyrrhizinate, compound glycyrrhizin, and other glycyrrhizic acid derivatives, glutathione, silymarin, polyenylphosphatidylcholine, and other drugs (4, C); For cholestatic DILI with elevated ALP/GGT/TBil, ursodeoxycholic acid or S-adenosylmethionine may be selected (4, C); the combined use of two or more drugs that mainly reduce ALT is not recommended (4, B).Recommendation 22: Treatment of severe patients: For severe patients such as those with drug-induced liver failure, liver transplantation is recommended (2, B); artificial liver (high-volume plasma exchange, dual plasma molecular adsorption system, etc.) may be a beneficial option (4, C); ornithine aspartate may help reduce blood ammonia levels in patients with severe disease or liver failure (4, C).Recommendation 23: Rational drug use during the recovery period: During or after liver function recovery, clinicians should comprehensively assess the patient's liver injury severity, presence of liver injury-related risk factors, and tuberculosis severity. Based on this assessment, anti-tuberculosis drugs should be selected rationally (4, C). These recommendations provide clinical evidence and decision-making guidance for the standardized diagnosis and treatment of ATB-DILI.},
}
@article {pmid39494844,
year = {2025},
author = {Hassanzadeh, E and Sedighi Pashaki, A and Akbari Hamed, E and Mehrpooya, M and Mohammadian, K and Bayani, R and Sheikhi, K and Ranjbar, H and Abbasi, M},
title = {Evaluating N-acetylcysteine as a Protective Agent Against Chemotherapy-induced Neuropathy in Breast Cancer: A Triple-blind, Randomized Clinical Trial.},
journal = {American journal of clinical oncology},
volume = {48},
number = {3},
pages = {122-126},
doi = {10.1097/COC.0000000000001153},
pmid = {39494844},
issn = {1537-453X},
mesh = {Humans ; Female ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Peripheral Nervous System Diseases/chemically induced/prevention &amp; control ; *Breast Neoplasms/drug therapy/pathology ; Middle Aged ; Adult ; *Taxoids/adverse effects ; Double-Blind Method ; Aged ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Administration, Oral ; *Antineoplastic Agents/adverse effects ; Docetaxel ; Bridged-Ring Compounds/adverse effects ; },
abstract = {OBJECTIVES: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant clinical issue that affects patients' quality of life and can limit the dosing of chemotherapeutic agents. N-acetylcysteine (NAC) has been proposed as a potential chemoprotective agent against CIPN due to its antioxidant properties. This study aimed to investigate the efficacy of oral NAC in preventing and controlling taxane-induced neuropathy in patients with breast cancer.<br><br>METHODS: This randomized, triple-blind, placebo-controlled trial included 80 breast cancer patients undergoing taxane-based chemotherapy. Participants were divided into 2 groups: an intervention group receiving 1200&#xa0;mg of oral NAC in divided doses per day and a placebo group. Patients were evaluated for neuropathy grade and functional status at 1 and 12 weeks postintervention.<br><br>RESULTS: Our analysis revealed no significant difference in the incidence and severity of neuropathy between the intervention and placebo groups at 1 (P =0.328) and 12 weeks (P =0.569) postchemotherapy. Baseline characteristics such as age, number of treatment cycles, and disease stage were similar between groups, indicating a homogeneous population.<br><br>CONCLUSIONS: Oral NAC at a dose of 1200&#xa0;mg per day did not significantly reduce the incidence or severity of taxane-induced neuropathy. These findings suggest that the oral bioavailability of NAC may be insufficient to exert a protective effect and that future studies should consider alternative dosing strategies or routes of administration. The need for further research to optimize NAC's chemoprotective role in CIPN remains evident.},
}
@article {pmid39494328,
year = {2024},
author = {Kim, HB and Kim, YJ and Lee, YJ and Yoo, JY and Choi, Y and Kim, EM and Suh, SW and Woo, RS},
title = {N-Acetylcysteine Alleviates Depressive-Like Behaviors in Adolescent EAAC1[-/-] Mice and Early Life Stress Model Rats.},
journal = {International journal of biological sciences},
volume = {20},
number = {14},
pages = {5450-5473},
pmid = {39494328},
issn = {1449-2288},
mesh = {Animals ; *Acetylcysteine/therapeutic use/pharmacology ; Male ; Female ; Mice ; *Depression/drug therapy/metabolism ; Rats ; *Excitatory Amino Acid Transporter 3/metabolism ; *Stress, Psychological/drug therapy ; Hippocampus/metabolism/drug effects ; Oxidative Stress/drug effects ; Mice, Knockout ; Disease Models, Animal ; Rats, Sprague-Dawley ; Behavior, Animal/drug effects ; Maternal Deprivation ; },
abstract = {Exposure to adverse experiences during early life is associated with an increased risk of psychopathology during adolescence. In a previous study, we demonstrated that neonatal maternal separation (NMS) combined with social isolation led to impulsive and depressive-like behaviors in male adolescents. Additionally, it significantly reduced the expression of excitatory amino acid carrier 1 (EAAC1) in the hippocampus. Building upon this work, we investigated the effects of N-acetylcysteine (NAC), a precursor to glutathione, in early-life stress (ELS) model rats and in EAAC1[-/-] mice. EAAC1 plays a dual role in transporting both glutamate and cysteine into neurons. Our findings revealed that female adolescents subjected to in the ELS model also exhibited behavioral defects similar to those of males. NAC injection rescued depressive-like behaviors in both male and female NMS models, but it improved impulsive behavior only in males. Furthermore, we observed increased reactive oxidative stress (ROS) and neuroinflammation in the ventral hippocampus (vHPC) and prefrontal cortex of NMS model rats, which were mitigated by NAC treatment. Notably, NAC reversed the reduced expression of EAAC1 in the vHPC of NMS model rats. In EAAC1[-/-] mice, severe impulsive and depressive-like behaviors were evident, and the NAC intervention improved only depressive-like behaviors. Collectively, our results suggest that ELS contributes to depression and impulsive behaviors during adolescence. Moreover, the cysteine uptake function of EAAC1 in neurons may be specifically related to depression rather than impulsive behavior.},
}
@article {pmid39493971,
year = {2024},
author = {Xu, C and Chen, Y and Zhou, Z and Yan, Y and Fu, W and Zou, P and Ni, D},
title = {ML385, an Nrf2 Inhibitor, Synergically Enhanced Celastrol Triggered Endoplasmic Reticulum Stress in Lung Cancer Cells.},
journal = {ACS omega},
volume = {9},
number = {43},
pages = {43697-43705},
pmid = {39493971},
issn = {2470-1343},
abstract = {Lung cancer is one of the leading causes of death. Celastrol is a natural product that has shown anticancer activity but has not yet been applied in clinical settings due to its narrow therapeutic window. In this study, we discovered that celastrol stimulates an abnormal rise in the reactive oxygen species (ROS) level in lung cancer cells and that the ROS scavenger N-acetylcysteine (NAC) could counteract the cell death caused by celastrol. At the same time, celastrol upregulated the expression of cytoprotective transcription factor Nrf2 and its downstream proteins, which are effective in preventing the oxidative damage caused by ROS accumulation. Notably, we found that the overexpression of Nrf2 enhances the tolerance of lung cancer cells to celastrol and that lung cancer cells H460 with a Keap1 mutation are insensitive to celastrol. This indicates that the increase in Nrf2 contributes to the survival of lung cancer cells. Thus, we brought in an Nrf2 inhibitor ML385 to suppress the activation of Nrf2. We found that when ML385 and celastrol were added together the survival rates of lung cancer cells decreased more and the detected ROS level became much higher compared to treatment with celastrol alone. We also discovered that ML385 suppressed the expression of HO-1 and GCLC, which amplified celastrol-induced ATF4/CHOP-dependent endoplasmic reticulum stress (ER stress). Above all, our study found that ML385 enhanced celastrol-induced increases in ROS and ER stress, leading to lung cancer cell death. This research provides a potential strategy for the preclinical investigation of celastrol.},
}
@article {pmid39493366,
year = {2024},
author = {Rogliani, P and Manzetti, GM and Gholamalishahi, S and Cazzola, M and Calzetta, L},
title = {Impact of N-Acetylcysteine on Mucus Hypersecretion in the Airways: A Systematic Review.},
journal = {International journal of chronic obstructive pulmonary disease},
volume = {19},
number = {},
pages = {2347-2360},
pmid = {39493366},
issn = {1178-2005},
mesh = {Animals ; Humans ; *Acetylcysteine/pharmacology/therapeutic use ; *Expectorants/pharmacology/therapeutic use ; *Goblet Cells/drug effects/metabolism ; Hyperplasia ; *Lung/drug effects/metabolism ; Mucin 5AC/metabolism/genetics ; Mucin-5B/metabolism/genetics ; Mucociliary Clearance/drug effects ; *Mucus/metabolism ; *Pulmonary Disease, Chronic Obstructive/drug therapy/metabolism/physiopathology ; },
abstract = {Mucus clearance is crucial for airway protection, and its dysfunction leads to chronic obstructive pulmonary disease (COPD) characterized by mucus hypersecretion (MHS) and impaired clearance. MUC5AC and MUC5B mucin proteins are key components of airway mucus, with MUC5AC being particularly responsive to environmental stimuli, making it a potential COPD biomarker. N-acetylcysteine (NAC) is a mucolytic agent with known effects on mucus viscosity and clearance, but its precise mechanisms in COPD remain unclear. This systematic review evaluated the impact of NAC on MHS in the airways, reporting significant inhibitory effects on MUC5AC and MUC5B gene and protein expression, as well as a reduction in the number of goblet cells. NAC has demonstrated efficacy in vitro and in animal models of MHS, including COPD models, but data on human bronchial tissue are lacking. This systematic review suggests that NAC acts as a mucolytic and a mucoregulator, directly inhibiting mucus secretion and goblet cell hyperplasia. Given the critical role of MHS in COPD progression, exacerbations, and mortality, these findings highlight the potential of NAC as a targeted therapy for hypersecretion COPD phenotypes. However, further studies are needed to confirm the results of this systematic review, even in human bronchial tissue, to provide translatable evidence in clinical settings. Understanding the intimate mechanism of NAC versus MHS regulation may pave the way for more effective treatments targeting airway mucus dysfunction in COPD, ultimately improving patient outcomes and reducing morbidity and mortality associated with chronic mucus hypersecretion.},
}
@article {pmid39493346,
year = {2024},
author = {Pastore, A and Badolati, N and Manfrevola, F and Sagliocchi, S and Laurenzi, V and Musto, G and Porreca, V and Murolo, M and Chioccarelli, T and Ciampaglia, R and Vellecco, V and Bucci, M and Dentice, M and Cobellis, G and Stornaiuolo, M},
title = {N-acetyl-L-cysteine reduces testis ROS in obese fathers but fails in protecting offspring from acquisition of epigenetic traits at cyp19a1 and IGF11/H19 ICR loci.},
journal = {Frontiers in cell and developmental biology},
volume = {12},
number = {},
pages = {1450580},
pmid = {39493346},
issn = {2296-634X},
abstract = {INTRODUCTION: Paternal nutrition before conception has a marked impact on offspring's risk of developing metabolic disorders during adulthood. Research on human cohorts and animal models has shown that paternal obesity alters sperm epigenetics (DNA methylation, protamine-to-histone replacement, and non-coding RNA content), leading to adverse health outcomes in the offspring. So far, the mechanistic events that translate paternal nutrition into sperm epigenetic changes remain unclear. High-fat diet (HFD)-driven paternal obesity increases gonadic Reactive Oxygen Species (ROS), which modulate enzymes involved in epigenetic modifications of DNA during spermatogenesis. Thus, the gonadic pool of ROS might be responsible for transducing paternal health status to the zygote through germ cells.<br><br>METHODS: The involvement of ROS in paternal intergenerational transmission was assessed by modulating the gonadic ROS content in male mice. Testicular oxidative stress induced by HFD was counterbalanced by N-acetylcysteine (NAC), an antioxidant precursor of GSH. The sires were divided into four feeding groups: i) control diet; ii) HFD; iii) control diet in the presence of NAC; and iv) HFD in the presence of NAC. After 8&#xa0;weeks, males were mated with females that were fed a control diet. Antioxidant treatment was then evaluated in terms of preventing the HFD-induced transmission of dysmetabolic traits from obese fathers to their offspring. The offspring were weaned onto a regular control diet until week 16 and then underwent metabolic evaluation. The methylation status of the genomic region IGFII/H19 and cyp19a1 in the offspring gDNA was also assessed using Sanger sequencing and methylation-dependent qPCR.<br><br>RESULTS: Supplementation with NAC protected sires from HFD-induced weight gain, hyperinsulinemia, and glucose intolerance. NAC reduced oxidative stress in the gonads of obese fathers and improved sperm viability. However, NAC did not prevent the transmission of epigenetic modifications from father to offspring. Male offspring of HFD-fed fathers, regardless of NAC treatment, exhibited hyperinsulinemia, glucose intolerance, and hypoandrogenism. Additionally, they showed altered methylation at the epigenetically controlled loci IGFII/H19 and cy19a1.<br><br>CONCLUSION: Although NAC supplementation improved the health status and sperm quality of HFD-fed male mice, it did not prevent the epigenetic transmission of metabolic disorders to their offspring. Different NAC dosages and antioxidants other than NAC might represent alternatives to stop the intergenerational transmission of paternal dysmetabolic traits.},
}
@article {pmid39492659,
year = {2025},
author = {Angelini, A and Garcia Marquez, G and Malovannaya, A and Fiorotto, ML and Saltzman, A and Jain, A and Trial, J and Taffet, GE and Cieslik, KA},
title = {Sex Differences in Response to Diet Enriched With Glutathione Precursors in the Aging Heart.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {80},
number = {2},
pages = {},
pmid = {39492659},
issn = {1758-535X},
support = {3R01AG059599-03S1//Office of Dietary Supplements/ ; S10 OD026804/OD/NIH HHS/United States ; R01 AG059599/AG/NIA NIH HHS/United States ; //BCM Mass Spectrometry Proteomics Core/ ; P30 CA125123/CA/NCI NIH HHS/United States ; //Hankamer Foundation/ ; R01 AG080925/AG/NIA NIH HHS/United States ; RP210227//CPRIT Core Facility/ ; 1R01AG080925/AG/NIA NIH HHS/United States ; S10 OD026804/CD/ODCDC CDC HHS/United States ; },
mesh = {Animals ; Male ; Female ; *Aging/physiology ; Mice ; *Glutathione/metabolism ; *Glycine/pharmacology/administration &amp; dosage ; Mice, Inbred C57BL ; *Heart/physiology/drug effects ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Sex Factors ; Myocardium/metabolism ; Oxidative Stress/drug effects ; Dietary Supplements ; Diet ; Sex Characteristics ; Antioxidants ; },
abstract = {Common features of the aging heart are dysregulated metabolism, inflammation, and fibrosis. Elevated oxidative stress is another hallmark of cardiac aging that can exacerbate each of these conditions. We hypothesize that by increasing natural antioxidant levels (glutathione), we will improve cardiac function. Twenty-one-month-old mice were fed glycine and N-acetyl cysteine (GlyNAC; glutathione precursors)-supplemented or control diets for 12 weeks. Heart function was monitored longitudinally, and the exercise performance was determined at the end of the study. We found that the GlyNAC diet was beneficial for old male but not old female mice, leading to an increase of Ndufb8 expression (a subunit of the mitochondrial respiratory chain complex), and higher enzymatic activity for CPT1b and CrAT, 2 carnitine acyltransferases that are critical to cardiomyocyte metabolism. Although no quantifiable change of collagen turnover was detected, hearts from GlyNAC-fed old males exhibited a slight but significant enrichment in Fmod, a protein that can inhibit collagen fibril formation, possibly reducing extracellular matrix stiffness and thus improving diastolic function. Cardiac diastolic function was modestly improved in males but not females, and surprisingly GlyNAC-fed female mice showed a decline in exercise performance. In summary, our work supports the concept that aged male and female hearts are phenotypically different. These basic differences may affect the response to pharmacological and diet interventions, including antioxidants.},
}
@article {pmid39490995,
year = {2024},
author = {Zhao, E and Liang, R and Li, P and Lu, D and Chen, S and Tan, W and Qin, Y and Zhang, Y and Zhang, Y and Zhang, Q and Liu, Q},
title = {Mesenchymal stromal cells alleviate APAP-induced liver injury via extracellular vesicle-mediated regulation of the miR-186-5p/CXCL1 axis.},
journal = {Stem cell research &amp; therapy},
volume = {15},
number = {1},
pages = {392},
pmid = {39490995},
issn = {1757-6512},
support = {81971526 and 82370629//the National Natural Science Foundation of China/ ; 2022A1515012223//the Natural Science Foundation of Guangdong Province/ ; 202201020398, 202201020430//the Science and Technology Program of Guangzhou/ ; },
mesh = {*Mesenchymal Stem Cells/metabolism/cytology ; *MicroRNAs/metabolism/genetics ; *Chemokine CXCL1/metabolism/genetics ; *Extracellular Vesicles/metabolism ; Animals ; *Chemical and Drug Induced Liver Injury/metabolism/therapy ; Mice ; *Acetaminophen/adverse effects ; Humans ; Male ; Mice, Inbred C57BL ; Mesenchymal Stem Cell Transplantation/methods ; },
abstract = {BACKGROUND: Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury (DILI). N-acetylcysteine (NAC) is the first-line agent used in the clinic. However, it rarely benefits patients with advanced APAP toxicity. Mesenchymal stromal cells (MSCs) have demonstrated potential in treating DILI. However, the specific mechanism by which MSCs protect against APAP-induced liver injury remains unclear.<br><br>METHODS: APAP was injected intraperitoneally to induce a liver injury model. We then detected histopathology, biochemical indices, and inflammatory cytokine levels to assess the efficacy of MSCs and MSC extracellular vesicles (MSC-EVs). Flow cytometry was performed to reveal the immunoregulatory effects of MSCs and MSC-EVs on the neutrophils. RNA sequencing (RNA-Seq) of liver tissues was used to identify critical target genes for MSC treatment.<br><br>RESULTS: MSC and MSC-EV treatment effectively alleviated APAP-induced liver injury and inhibited neutrophil infiltration. RNA-Seq analysis and ELISA data indicated that C-X-C motif chemokine 1 (CXCL1), a chemoattractant for neutrophils, was a key molecule in the MSC-mediated amelioration of APAP-induced liver damage. In addition, neutralization of CXCL1 reduced APAP-induced liver damage, which was accompanied by decreased neutrophil infiltration. Importantly, we verified that MSC-EV-derived miR-186-5p directly binds to the 3'-UTR of Cxcl1 to inhibit its expression in hepatocytes. The agomir miR-186-5p showed excellent potential for the treatment of DILI.<br><br>CONCLUSIONS: Our findings suggest that MSCs and MSC-EVs are an effective approach to mitigate DILI. Targeting the miR-186-5p/CXCL1 axis is a promising approach to improve the efficacy of MSCs and MSC-EVs in the treatment of DILI.},
}
@article {pmid39489865,
year = {2024},
author = {Har-Zahav, A and Tobar, A and Fried, S and Sivan, R and Wilkins, BJ and Russo, P and Shamir, R and Wells, RG and Gurevich, M and Waisbourd-Zinman, O},
title = {Oral N-acetylcysteine ameliorates liver fibrosis and enhances regenerative responses in Mdr2 knockout mice.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {26513},
pmid = {39489865},
issn = {2045-2322},
support = {72-12//PSC Partners Seeking a Cure/ ; 1879/21//The Israeli Science Foundation/ ; },
mesh = {Animals ; Male ; Mice ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Administration, Oral ; *ATP Binding Cassette Transporter, Subfamily B/genetics/metabolism ; *ATP-Binding Cassette Sub-Family B Member 4 ; Disease Models, Animal ; Liver/drug effects/metabolism/pathology ; *Liver Cirrhosis/drug therapy/pathology/metabolism ; Liver Regeneration/drug effects ; Mice, Knockout ; },
abstract = {Cholangiopathies are poorly understood disorders with no effective therapy. The extrahepatic biliary tree phenotype is less studied compared to the intrahepatic biliary injury in both human disease and Mdr2[-/-] mice, the established cholestatic mouse model. This study aimed to characterize the extra hepatic biliary tree of Mdr2[-/-] mice at various ages and to determine if injury can be repaired with the antioxidant and glutathione precursor N-acetyl-L-Cysteine treatment (NAC). We characterized extra hepatic bile ducts (EHBD)s at various ages from 2 to 40 weeks old FVB/N and Mdr2[-/-] mice. We examined the therapeutic potential of local NAC ex vivo using EHBD explants at early and late stages of injury; and systematic therapy by in vivo oral administration for 3 weeks. EHBD and liver sections were assessed by histology and immunofluorescent stains. Serum liver enzyme activities were analyzed, and liver spatial protein expression analysis was performed. Mdr2[-/-] mice developed progressive EHBD injury, similar to extrahepatic PSC. NAC treatment of ex vivo EHBD explants led to improved duct morphology. In vivo, oral administration of NAC improved liver fibrosis, and decreased liver enzyme activities. Spatial protein analysis revealed cell-type specific differential response to NAC, collectively indicating a transition from pro-apoptotic into proliferative state. NAC treatment should be further investigated as a potential therapeutic option for human cholangiopathies.},
}
@article {pmid39489186,
year = {2024},
author = {Chen, C and Wang, T and Gao, TY and Chen, YL and Lu, YB and Zhang, WP},
title = {Ablation of NAMPT in dopaminergic neurons leads to neurodegeneration and induces Parkinson's disease in mouse.},
journal = {Brain research bulletin},
volume = {218},
number = {},
pages = {111114},
doi = {10.1016/j.brainresbull.2024.111114},
pmid = {39489186},
issn = {1873-2747},
mesh = {Animals ; *Nicotinamide Phosphoribosyltransferase/metabolism ; *Dopaminergic Neurons/metabolism/pathology/drug effects ; Mice ; *Rotenone/toxicity/pharmacology ; Parkinson Disease/metabolism/pathology ; Cytokines/metabolism ; Substantia Nigra/metabolism/pathology/drug effects ; NAD/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Knockout ; Mice, Inbred C57BL ; Humans ; Mitochondria/metabolism/drug effects ; Disease Models, Animal ; Male ; Cell Line, Tumor ; },
abstract = {Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the salvaging synthesize pathway of nicotinamide adenine dinucleotide (NAD). The neuroprotective roles of NAMPT on neurodegeneration have been explored in aging brain and Alzheimer's Disease. However, its roles in Parkinson's Disease (PD) remain to be elucidated. We found that the dopaminergic neurons in substantia nigra expressed higher levels of NAMPT than the other types of neurons. Using conditional knockout of the Nampt gene in dopaminergic neurons and utilizing a NAMPT inhibitor in the substantia nigra of mice, we found that the NAMPT deficiency triggered the time-dependent loss of dopaminergic neurons, the impairment of the dopamine nigrostriatal pathway, and the development of PD-like motor dysfunction. In the rotenone-induced PD mouse model, nicotinamide ribose (NR), a precursor of NAD, rescued the loss of dopaminergic neurons, the impairment of dopamine nigrostriatal pathway, and mitigated PD-like motor dysfunction. In SH-SY5Y cells, NAD suppression induced the accumulation of reactive oxygen species (ROS), mitochondrial impairment, and cell death, which was reversed by N-acetyl cysteine, an antioxidant and ROS scavenger. Rotenone decreased NAD level, induced the accumulation of ROS and the impairment of mitochondria, which was reversed by NR. In summary, our findings show that the ablation of NAMPT in dopaminergic neurons leads to neurodegeneration and contributes to the development of PD. The NAD precursors have the potential to protect the degeneration of dopaminergic neurons, and offering a therapeutic approach for the treatment of PD.},
}
@article {pmid39488036,
year = {2024},
author = {Joseph, JP and Kumar, T and Ramteke, NS and Chatterjee, K and Nandi, D},
title = {High intracellular calcium amounts inhibit activation-induced proliferation of mouse T cells: Tert-butyl hydroquinone as an additive enhancer of intracellular calcium.},
journal = {International immunopharmacology},
volume = {143},
number = {Pt 3},
pages = {113501},
doi = {10.1016/j.intimp.2024.113501},
pmid = {39488036},
issn = {1878-1705},
mesh = {Animals ; *Hydroquinones/pharmacology ; *Calcium/metabolism ; *Cell Proliferation/drug effects ; *T-Lymphocytes/drug effects/immunology/metabolism ; Mice ; *Lymphocyte Activation/drug effects ; *Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Colitis/drug therapy/chemically induced/immunology ; Cells, Cultured ; Ionomycin/pharmacology ; Dextran Sulfate ; NF-E2-Related Factor 2/metabolism/genetics ; Tetradecanoylphorbol Acetate/pharmacology ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism/genetics ; Female ; },
abstract = {Optimal T cell activation is critical to orchestrate adaptive immune responses. Calcium is critical for T cell activation and integrates signaling pathways necessary to activate key transcription factors. In fact, patients with calcium channelopathies are immunodeficient. Here, we investigated the effects of different concentrations of intracellular calcium on activation of mouse T cells. High intracellular calcium amounts inhibited in vitro T cell proliferation as evidenced by a decreased cell cycling-to-hypodiploidy ratio in two models of activation: the combination of phorbol 12-myristate 13-acetate (PMA) and Ionomycin (an ionophore)/Thapsigargin (a SERCA inhibitor) or plate bound anti-CD3 and anti-CD28. High intracellular calcium amounts increased the production of reactive oxygen species (ROS) in T cells activated with PMA and Ionomycin and scavenging excess ROS using N-acetyl cysteine (NAC) rescued the decrease in cycling-to-hypodiploidy ratio. To test the universality of our observations, we studied the effects of tert-Butylhydroquinone (tBHQ), a SERCA inhibitor and Nrf2 activator. tBHQ alone did not increase intracellular calcium amounts but the intracellular calcium amounts increased when tBHQ was used in combination with PMA. Also, tBHQ inhibited T cell activation in a dose-dependent manner in both in vitro models of T cell activation. Importantly, intraperitoneal injection of tBHQ ameliorated Dextran Sodium Sulfate (DSS)-induced colitis in mice as evidenced by rescue of colon length shortening and lower disease activity index. Overall, this study identifies high calcium amounts as a potential target to lower T cell activation. The implications of these observations are discussed in the context of calcium modulating drugs that are used to treat various diseases.},
}
@article {pmid39479839,
year = {2024},
author = {Yang, B and Zhao, LL and DU, JH and Yan, Y and Dai, KS},
title = {[Regulation of Reactive Oxygen Species on Platelet Activation and Apoptosis].},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {32},
number = {5},
pages = {1503-1508},
doi = {10.19746/j.cnki.issn.1009-2137.2024.05.031},
pmid = {39479839},
issn = {1009-2137},
mesh = {*Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; Humans ; *Blood Platelets/metabolism ; *Membrane Potential, Mitochondrial ; *Platelet Activation ; *P-Selectin/metabolism ; *Thrombin/pharmacology ; *Platelet Aggregation ; Signal Transduction ; Acetylcysteine/pharmacology ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; },
abstract = {OBJECTIVE: To investigate how reactive oxygen species (ROS) regulates the signal transduction of platelet activation and apoptosis, and to explore the relationship between platelet activation and apoptosis.<br><br>METHODS: Platelets were directly stimulated with thrombin or pretreated with ROS inhibitor N-acetylcysteine (NAC) before being stimulated with thrombin, and then flow cytometry was used to detect the effects of thrombin and NAC on P-selectin expression, &#x3b1;&#x2161;b&#x3b2;3 activation, mitochondrial membrane potential depolarization, phosphatidylserine (PS) externalization, ROS expression and platelet aggregation.<br><br>RESULTS: Thrombin could induce the production of ROS in platelets in a concentration- and time-dependent manner. 0.01 U thrombin induced ROS-dependent high degree of integrin &#x3b1;&#x2161;b&#x3b2;3 activation, P-selectin expression, and platelet aggregation. The platelets induced by different concentration gradients of thrombin exhibited ROS-dependent mitochondrial membrane potential depolarization and PS externalization in platelets. After induction with thrombin for 30 min, the activation of integrin &#x3b1;&#x2161;b&#x3b2;3 in platelets reached its maximum level, and after 60 minutes, the depolarization of mitochondrial membrane potential in platelets reached its maximum level. However, the expression of P-selectin, depolarization of mitochondrial membrane potential, and platelet aggregation function were all inhibited to a certain extent when the platelets were pretreated with ROS inhibitor NAC and then induced with thrombin.<br><br>CONCLUSION: When platelets are induced by thrombin, ROS first regulates the activation of platelets, and then regulates the apoptosis of platelets. Both platelet activation and apoptosis depend on the production of ROS in platelets, and the signals of activation and apoptosis occur orderly. Inhibiting the ROS signal in platelets can effectively inhibit the activation and apoptosis of platelets.},
}
@article {pmid39478327,
year = {2025},
author = {Ma, Y and Chen, M and Huang, K and Chang, W},
title = {The impact of cysteine on lifespan in three model organisms: A systematic review and meta-analysis.},
journal = {Aging cell},
volume = {24},
number = {2},
pages = {e14392},
pmid = {39478327},
issn = {1474-9726},
support = {MYRG2022-00251-FHS//Universidade de Macau/ ; 0061/2022/A//Fundo para o Desenvolvimento das Ci&#xea;ncias e da Tecnologia/ ; 0077/2020/A2//Fundo para o Desenvolvimento das Ci&#xea;ncias e da Tecnologia/ ; 0099/2022/AFJ//Fundo para o Desenvolvimento das Ci&#xea;ncias e da Tecnologia/ ; },
mesh = {Animals ; *Cysteine/pharmacology ; *Longevity/drug effects ; *Caenorhabditis elegans/drug effects/physiology ; Mice ; Drosophila ; Models, Animal ; Humans ; Dietary Supplements ; },
abstract = {Cysteine is an amino acid present in thiol proteins and often dictates their secondary structures. Although considered nonessential, cysteine may be essential for patients with certain metabolic diseases and can reduce the requirement for dietary methionine. Cysteine and some of its derivatives, such as N-acetylcysteine, are considered antioxidants and widely used in animal aging studies. To provide insights into the potential anti-aging effects of cysteine, we systematically reviewed and performed a meta-analysis to investigate the impact of cysteine supplementation on lifespan using three model organisms: mice, nematodes, and fruit flies. A total of 13 mouse studies, 13 C. elegans studies, and 5 Drosophila studies were included in the analysis. The findings revealed that cysteine supplementation significantly reduced the risk of mortality in mice and C. elegans. Subgroup analysis showed consistent results across different starting times and administration methods and revealed adverse effects of high doses on worms and a lack of effect in nondisease mouse models. Similar to mice, the effects of cysteine supplementation on Drosophila were not statistically significant, except in transgenic flies. The study identified certain limitations, including the quality of the included studies and the potential for publication bias. We also discussed uncertainties in the underlying molecular mechanisms and the clinical application of dietary cysteine.},
}
@article {pmid39474327,
year = {2024},
author = {Guo, Y and Yang, Y and Zhou, Z and Zhao, C and Li, Y and Zhou, H and Ren, S and Gu, Y and Gao, Z},
title = {Propylparaben Induces Reproductive Toxicity in Human Extravillous Trophoblast Cells via Apoptosis and Cell Cycle Pathways.},
journal = {Environment &amp; health (Washington, D.C.)},
volume = {2},
number = {5},
pages = {301-310},
pmid = {39474327},
issn = {2833-8278},
abstract = {Parabens (PBs), especially propylparaben, commonly used in consumer products, pose environmental and health concerns. This study explored propylparaben's cytotoxicity on HTR-8/SVneo human trophoblast cells, revealing significant dose-dependent cytotoxic effects, particularly post 48-h exposure. Elevated propylparaben levels triggered apoptosis, evidenced by increased Bax and activated Caspase-3, and induced the G0/G1 cell cycle arrest. Concurrently, an increase in reactive oxygen species and reduced mitochondrial membrane potential indicated oxidative stress and mitochondrial dysfunction. Although N-acetylcysteine (NAC) treatment reduced oxidative stress, cell invasiveness persisted, suggesting propylparaben might affect cell migration through nonoxidative mechanisms. Integrated transcriptome analysis through RNA sequencing revealed 3488 differentially expressed genes affected by propylparaben, highlighting changes in pathways like apoptosis and cell cycle regulation and identifying seven hub genes as potential biomarkers for pregnancy-related complications. This study comprehensively demonstrates the cytotoxic effects of propylparaben on human trophoblast cells, notably through apoptosis induction and cell cycle disruption, thereby providing crucial insights into its potential risks for reproductive health.},
}
@article {pmid39473642,
year = {2024},
author = {Mendes Abreu, J and Quitério, A and Cerqueira, &#xc9; and Ribeiro, R and Nunes, T and Figueiredo, JP and Corte Real, A},
title = {Evaluating the Impact of Different Treatments on the Quality of Life in Patients With Burning Mouth Syndrome: A Scoping Review.},
journal = {Cureus},
volume = {16},
number = {9},
pages = {e70419},
pmid = {39473642},
issn = {2168-8184},
abstract = {The profound impact of burning mouth syndrome (BMS) on patients' quality of life (QoL) highlights the critical need to identify effective treatments for this condition. This study aims to evaluate and compare the health-related quality of life (HRQoL) and oral health-related quality of life (OHRQoL) among individuals diagnosed with BMS, focusing on different treatment modalities. For that purpose, a scoping review was designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for scoping review reporting guidelines and the registration with the International Prospective Register of Systematic Reviews (PROSPERO). An electronic search was then conducted in March 2024, encompassing the following databases: PubMed, Embase, Cochrane, Web of Science, and Trip Database. Publications were deemed eligible if they assessed the impact of different treatments for BMS on health-related and oral health-related QoL. Out of the initial 5400, only 13 studies were considered suitable to be included in this review. The instrument used to evaluate HRQoL was the 36-Item Short Form Survey (SF-36). For OHRQoL, the preferred tools were the Oral Health Impact Profile (OHIP) and the Geriatric Oral Health Assessment Index (GOHAI). Literature reported improvements in patients' HRQoL across the majority of analyzed treatment modalities. However, low-level laser therapy (LLLT) and n-acetylcysteine (NAC) plus clonazepam were the most effective in improving OHRQoL. This review highlights several promising treatment options for improving both HRQoL and OHRQoL in individuals with BMS. Nevertheless, the variability among the studies analyzed underscores the need for further research to identify and establish consistently effective treatments for this condition, reflecting the need for consistent trial designs to accurately assess the true impact of treatments on the disease.},
}
@article {pmid39472133,
year = {2024},
author = {Li, WK and Zhang, Y and Qu, XY and Lin, YQ and Zhao, YZ and Liu, N},
title = {[N-acetylcysteine regulates NF-κB signaling pathway alleviates the pulmonary toxicity induced by indium-tin oxide nanoparticles in rats].},
journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases},
volume = {42},
number = {10},
pages = {721-729},
doi = {10.3760/cma.j.cn121094-20230919-00061},
pmid = {39472133},
issn = {1001-9391},
support = {H2024209031//Natural Science Foundation of Hebei Province/ ; 24130225C//Tangshan Science and Technology Project/ ; },
mesh = {Animals ; Rats ; Male ; *NF-kappa B/metabolism ; *Rats, Sprague-Dawley ; *Signal Transduction/drug effects ; *Acetylcysteine/pharmacology ; *Tin Compounds/toxicity ; *Oxidative Stress/drug effects ; *Lung/metabolism/drug effects/pathology ; Nanoparticles/toxicity ; Pulmonary Alveolar Proteinosis/metabolism ; },
abstract = {Objective: The current study aimed to evaluate the possible protective effects of N-acetylcysteine (NAC) against Indum-tin oxide (ITO) nanoparticle (Nano-ITO) -induced pulmonary alveolar proteinosis (PAP) in rats, especially via modulation of nuclear factor kappa B (NF-κB) signaling. Methods: In October 2019, 50 adult male Sprague-Dawley rats were randomly allocated into five groups (10 rats each) as follows: blank control group, saline control group, NAC control group (200 mg/kg), Nano-ITO group (receiving a repeated intratracheal dose of 6 mg/kg Nano-ITO) and NAC intervention group (pre-treated intraperitoneally with 200 mg/kg NAC 1.5 h before the administration of an intratracheal dose of 6 mg/kg Nano-ITO). The rats were exposed twice a week for 12 weeks. Rats were then euthanized under anesthesia, and their lungs were removed for histopathological and immunohistochemical analysis. The comparison of indicators reflecting oxidative stress and pulmonary inflammation among groups was conducted using one-way analysis of variance (ANOVA) and Bonferroni's test. The effect of NAC on Nano-ITO induced NF-κB signaling pathway in rats was analyzed. Results: Histopathological examination of Nano-ITO exposed rats revealed diffuse alveolar damage, including PAP, cholesterol crystals, alveolar fibrosis, pulmonary fibrosis, and alveolar emphysema. Immunohistochemical results of Nano-ITO exposed rats showed strong positive for nuclear factor κB p65 (NF-κB p65) and nuclear factor Kappa B inhibitory factor kinase (IKK-β) and weak positive for nuclear factor κB inhibitory protein α (IκB-α) in the nuclei of bronchiolar and alveolar epithelial cells. Compared with blank control group, saline control group and NAC control group, the level of total protein (TP) in bronchoalveolar lavage fluid of rats in Nano-ITO group was significantly increased (P<0.05), and the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) were significantly increased (P<0.05), the levels of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were significantly increased (P<0.05), and the levels of NF-κB p65, IKK-β, inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) in lung tissue were significantly increased (P<0.05). Compared with Nano-ITO group, the levels of TP, T-AOC, MDA and TNF-α in bronchoalveolar lavage fluid of rats in NAC intervention group were significantly decreased (P<0.05), and the levels of NF-κB p65 and ROS in lung tissue were significantly decreased (P<0.05). Western blot results showed that compared with the control groups, the protein expressions of NF-κB p65 and IKK-β in the lung tissue of Nano-ITO group were increased, while the protein expression of IκB-α was decreased (P<0.05). Compared with Nano-ITO group, the protein expressions of NF-κB p65 and IKK-β in lung tissue of rats in NAC intervention group were decreased, while the protein expression of IκB-α was increased (P<0.05) . Conclusion: The study demonstrated that Nano-ITO might induce pulmonary toxicity through the activation of NF-κB signaling pathway, and NAC could antagonize the pulmonary toxicity of Nano-ITO by inhibiting the NF-κB signaling pathway.},
}
@article {pmid39471200,
year = {2024},
author = {Quintanilla, ME and Morales, P and Santapau, D and Gallardo, J and Rebolledo, R and Riveras, G and Acuña, T and Herrera-Marschitz, M and Israel, Y and Ezquer, F},
title = {Morphine self-administration is inhibited by the antioxidant N-acetylcysteine and the anti-inflammatory ibudilast; an effect enhanced by their co-administration.},
journal = {PloS one},
volume = {19},
number = {10},
pages = {e0312828},
pmid = {39471200},
issn = {1932-6203},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Antioxidants/pharmacology/administration &amp; dosage ; *Rats, Wistar ; Rats ; *Morphine/pharmacology/administration &amp; dosage ; Male ; *Oxidative Stress/drug effects ; *Pyridines/pharmacology/administration &amp; dosage ; *Self Administration ; *Anti-Inflammatory Agents/pharmacology/administration &amp; dosage ; Morphine Dependence/drug therapy/metabolism ; Excitatory Amino Acid Transporter 2/metabolism ; Hippocampus/metabolism/drug effects ; Nucleus Accumbens/metabolism/drug effects ; Indolizines ; Pyrazoles ; },
abstract = {BACKGROUND: The treatment of opioid addiction mainly involves the medical administration of methadone or other opioids, aimed at gradually reducing dependence and, consequently, the need for illicit opioid procurement. Thus, initiating opioid maintenance therapy with a lower level of dependence would be advantageous. There is compelling evidence indicating that opioids induce brain oxidative stress and associated glial activation, resulting in the dysregulation of glutamatergic homeostasis, which perpetuates drug intake. The present study aimed to determine whether inhibiting oxidative stress and/or neuroinflammation reduces morphine self-administration in an animal model of opioid dependence.<br><br>METHODS: Morphine dependence, assessed as voluntary morphine self-administration, was evaluated in Wistar-derived UChB rats. Following an extended period of morphine self-administration, animals were administered either the antioxidant N-acetylcysteine (NAC; 40 mg/kg/day), the anti-inflammatory ibudilast (7.5 mg/kg/day) or the combination of both agents. Oxidative stress and neuroinflammation were evaluated in the hippocampus, a region involved in drug recall that feeds into the nucleus accumbens, where the levels of the glutamate transporters GLT-1 and xCT were further assessed.<br><br>RESULTS: Daily administration of either NAC or ibudilast led to a mild reduction in voluntary morphine intake, while the co-administration of both therapeutic agents resulted in a marked inhibition (-57%) of morphine self-administration. The administration of NAC or ibudilast markedly reduced both the oxidative stress induced by chronic morphine intake and the activation of microglia and astrocytes in the hippocampus. However, only the combined administration of NAC + ibudilast was able to restore the normal levels of the glutamate transporter GLT-1 in the nucleus accumbens.<br><br>CONCLUSION: Separate or joint administration of an antioxidant and anti-inflammatory agent reduced voluntary opioid intake, which could have translational value for the treatment of opioid use disorders, particularly in settings where the continued maintenance of oral opioids is a therapeutic option.},
}
@article {pmid39469595,
year = {2024},
author = {Khoury, RD and Abu Hasna, A and Gagliardi, CF and Marinho, RMM and Carvalho, CAT and Bresciani, E and Valera, MC},
title = {Antimicrobial and anti-endotoxin activity of N-acetylcysteine, calcium hydroxide and their combination against Enterococcus faecalis, Escherichia coli and lipopolysaccharides.},
journal = {PeerJ},
volume = {12},
number = {},
pages = {e18331},
pmid = {39469595},
issn = {2167-8359},
mesh = {*Enterococcus faecalis/drug effects ; *Calcium Hydroxide/pharmacology ; *Acetylcysteine/pharmacology ; *Escherichia coli/drug effects ; Humans ; *Lipopolysaccharides/pharmacology ; Dental Pulp Cavity/microbiology/drug effects ; Anti-Infective Agents/pharmacology ; Biofilms/drug effects ; Anti-Bacterial Agents/pharmacology ; Root Canal Irrigants/pharmacology ; },
abstract = {BACKGROUND: The management of endodontic infections is a complex challenge, mainly due to the involvement of diverse microorganisms and their by-products. This study aimed to evaluate the efficacy of N-acetylcysteine (NAC), calcium hydroxide (Ca(OH)2), and their combined application as intracanal medications in combating Enterococcus faecalis, Escherichia coli, and lipopolysaccharides (LPS) from E. coli.<br><br>METHODS: A total of 60 single-rooted human teeth were carefully selected and divided into six groups. These tooth canals were deliberately exposed to E. faecalis (ATCC 29212) and E. coli (ATCC 25922) to induce biofilm formation. Subsequently, the specimens were treated with NAC, Ca(OH)2, or a combination of both substances. Three samples of the root canals were collected at three moments: the first sample (S1) was to confirm the initial contamination, the second sample (S2) was immediately post-instrumentation, and the third sample (S3) was collected after the use of the intracanal medication. The antimicrobial efficacy of these intracanal medications was assessed by enumerating colony-forming units per milliliter (CFU/mL). In addition to this, the kinetic chromogenic Limulus Amebocyte Lysate (LAL) assay by Lonza was used to quantify LPS from E. coli. Data tested for normality; then, Kruskal-Wallis and Friedman tests were used, and Dunn's for multiple comparisons.<br><br>RESULTS: The findings of this study showed significant reductions in the microbial load of E. faecalis and E. coli by S3. Notably, there were no statistically significant differences among the treatment groups concerning these microorganisms. However, it was observed that only the combination of NAC and Ca(OH)2 led to a noteworthy decrease in the quantity of E. coli's LPS after 7-days, demonstrating a statistically significant difference from the other treatment groups. NAC + Ca(OH)2 combination, applied for a duration of 7-days, proved to be more suitable in reducing the presence of E. faecalis, E. coli, and LPS from E. coli within the context of endodontic infections.},
}
@article {pmid39467998,
year = {2024},
author = {Zhang, M and Dai, GC and Zhang, YW and Lu, PP and Wang, H and Li, YJ and Rui, YF},
title = {Enhancing osteogenic differentiation of diabetic tendon stem/progenitor cells through hyperoxia: Unveiling ROS/HIF-1α signalling axis.},
journal = {Journal of cellular and molecular medicine},
volume = {28},
number = {20},
pages = {e70127},
pmid = {39467998},
issn = {1582-4934},
support = {BK20221462//Natural Science Foundation of Jiangsu Province/ ; No.81871812//National Natural Science Foundation of China/ ; YL20220525//Winfast Charity Foundation Project/ ; CZXM-GSP-RC46//Research Personnel Cultivation Programme of Zhongda Hospital Southeast University/ ; },
mesh = {*Osteogenesis ; Animals ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; *Stem Cells/metabolism/cytology ; *Signal Transduction ; *Cell Differentiation ; Rats ; *Tendons/metabolism/pathology ; Male ; *Diabetes Mellitus, Experimental/metabolism/pathology ; Rats, Sprague-Dawley ; Hyperoxia/metabolism ; Acetylcysteine/pharmacology ; },
abstract = {Diabetic calcific tendinopathy is the leading cause of chronic pain, mobility restriction, and tendon rupture in patients with diabetes. Tendon stem/progenitor cells (TSPCs) have been implicated in the development of diabetic calcified tendinopathy, but the molecular mechanisms remain unclear. This study found that diabetic tendons have a hyperoxic environment, characterized by increased oxygen delivery channels and carriers. In hyperoxic environment, TSPCs showed enhanced osteogenic differentiation and increased levels of reactive oxygen species (ROS). Additionally, hypoxia-inducible factor-1a (HIF-1a), a protein involved in regulating cellular responses to hyperoxia, was decreased in TSPCs by the ubiquitin-proteasome system. By intervening with antioxidant N-acetyl-L-cysteine (NAC) and overexpressing HIF-1a, we discovered that blocking the ROS/HIF-1a signalling axis significantly inhibited the osteogenic differentiation ability of TSPCs. Animal experiments further confirmed that hyperoxic environment could cause calcification in the Achilles tendon tissue of rats, while NAC intervention prevented calcification. These findings demonstrate that hyperoxia in diabetic tendons promotes osteogenic differentiation of TSPCs through the ROS/HIF-1a signalling axis. This study provides a new theoretical basis and research target for preventing and treating diabetic calcified tendinopathy.},
}
@article {pmid39461063,
year = {2025},
author = {Jin, Y and Zhang, J and Chen, X and Li, F and Xue, T and Yi, K and Xu, Y and Wang, H and Lao, YH and Chan, HF and Shao, D and Li, M and Tao, Y},
title = {3D printing incorporating gold nanozymes with mesenchymal stem cell-derived hepatic spheroids for acute liver failure treatment.},
journal = {Biomaterials},
volume = {315},
number = {},
pages = {122895},
doi = {10.1016/j.biomaterials.2024.122895},
pmid = {39461063},
issn = {1878-5905},
mesh = {*Gold/chemistry ; *Liver Failure, Acute/therapy ; *Printing, Three-Dimensional ; *Mesenchymal Stem Cells/cytology ; *Spheroids, Cellular/drug effects ; Animals ; *Hydrogels/chemistry ; Hepatocytes/cytology/drug effects ; Metal Nanoparticles/chemistry ; Humans ; Reactive Oxygen Species/metabolism ; Male ; Tissue Scaffolds/chemistry ; Mice ; Alginates/chemistry ; },
abstract = {Acute liver failure (ALF) is a highly fatal disease, necessitating the advancement and optimization of alternative therapeutic strategies to benefit patients awaiting liver transplantation. In this study, we innovatively established the antioxidant nanozyme-hepatocyte-like cells (HLCs) microtissue sheets (HS/N-Au@composite) for ALF therapy. We first prepared a 3D-printed hyaluronic acid/gelatin/sodium alginate scaffold with N-acetylcysteine (NAC)-capped gold nanoclusters (NAC-Au NCs), forming the N-Au@hydrogel. For the encapsulation of HLC spheroids, we used a biocompatible hybrid hydrogel composed of decellularized extracellular matrix (dECM), thrombin, and fibrinogen, resulting in the HS@dECM hydrogel. Utilizing 3D printing technology, we integrated the N-Au@hydrogel with the HS@dECM hydrogel to create the HS/N-Au@composite for in situ transplantation to treat ALF. Our results demonstrated that NAC-Au NCs effectively mitigated reactive oxygen species (ROS)-induced liver necrosis in ALF. Additionally, the N-Au@hydrogel provided mechanical support, ensuring the proper landing and effective functioning of the transplanted HLC spheroids. The HS/N-Au@composite synergistically decreased serum transaminase levels, reduced the accumulation of pro-inflammatory cytokines, accelerated liver function recovery, and promoted liver regeneration in ALF treatment. This combination of HLC spheroids and NAC-Au NCs nanozymes via 3D-printed composite scaffolds represents a promising strategy for enhancing hepatocyte transplantation and advancing stem cell regenerative medicine in ALF therapy.},
}
@article {pmid39456416,
year = {2024},
author = {Yun, HM and Kim, SH and Kwon, YJ and Park, KR},
title = {Effect of Spicatoside a on Anti-Osteosarcoma MG63 Cells through Reactive Oxygen Species Generation and the Inhibition of the PI3K-AKT-mTOR Pathway.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
pmid = {39456416},
issn = {2076-3921},
support = {K412000//Korea Basic Science Institute/ ; 2022R1C1C1003491//National Research Foundation of Korea/ ; },
abstract = {Osteosarcoma is a primary malignant tumor found in the bones of children and adolescents. Unfortunately, many patients do not respond well to treatment and succumb to the illness. Therefore, it is necessary to discover novel bioactive compounds to overcome therapeutic limitations. Liriope platyphylla Wang et Tang is a well-known herb used in oriental medicine. Studies have shown that metabolic diseases can be clinically treated using the roots of L. platyphylla. Recent studies have demonstrated the anticarcinoma potential of root extracts; however, the exact mechanism remains unclear. The aim of this study was to examine the anti-osteosarcoma activity of a single compound extracted from the dried roots of L. platyphylla. We purified Spicatoside A (SpiA) from the dried roots of L. platyphylla. SpiA significantly inhibited the proliferation of human osteosarcoma MG63 cells in a dose- and time-dependent manner. SpiA also regulated the expression of various downstream proteins that mediate apoptosis (PARP, Bcl-2, and Bax), cell growth (cyclin D1, Cdk4, and Cdk6), angiogenesis (VEGF), and metastasis (MMP13). The Proteome Profiler Human Phospho-Kinase Array Kit showed that the AKT signaling protein was a target of SpiA in osteosarcoma cells. We also found that SpiA suppressed the constitutive activation of the PI3K-AKT-mTOR-p70S6K1 signaling pathway. We further validated the effects of SpiA on the AKT signaling pathway. SpiA induced autophagosome formation and suppressed necroptosis (a form of programmed cell death). SpiA increased the generation of reactive oxygen species (ROS) and led to the loss of mitochondrial membrane potential. N-acetylcysteine (NAC)-induced inhibition of ROS generation reduced SpiA-induced AKT inhibition, apoptotic cell death, and anti-metastatic effects by suppressing cell migration and invasion. Overall, these results highlight the anti-osteosarcoma effect of SpiA by inhibiting the AKT signaling pathway through ROS generation, suggesting that SpiA may be a promising compound for the treatment of human osteosarcoma.},
}
@article {pmid39452251,
year = {2024},
author = {Recinella, L and Pinti, M and Libero, ML and Di Lodovico, S and Veschi, S and Piro, A and Generali, D and Acquaviva, A and Nilofar, N and Orlando, G and Chiavaroli, A and Ferrante, C and Menghini, L and Di Simone, SC and Brunetti, L and Di Giulio, M and Leone, S},
title = {Beneficial Effects Induced by a Proprietary Blend of a New Bromelain-Based Polyenzymatic Complex Plus N-Acetylcysteine in Urinary Tract Infections: Results from In Vitro and Ex Vivo Studies.},
journal = {Antibiotics (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
pmid = {39452251},
issn = {2079-6382},
abstract = {Background/Objectives: Urinary tract infections (UTIs) are infections that involve the urethra, bladder, and, in much more severe cases, even kidneys. These infections represent one of the most common diseases worldwide. Various pathogens are responsible for this condition, the most common being Escherichia coli (E. coli). Bromelain is a proteolytic complex obtained from the stem and stalk of Ananas comosus (L.) Merr. showing several beneficial activities. In addition to bromelain, N-acetylcysteine (NAC) has also been used. Methods: The purpose of this experiment was to evaluate the antibacterial, anti-motility, and anti-biofilm effects of a new polyenzymatic complex (DIF17BRO[®]) in combination with NAC (the Formulation) on various strains of E. coli isolated from patients with UTIs. Subsequently, the anti-inflammatory and antioxidant effects of the Formulation were studied in an ex vivo model of cystitis, using bladder samples from mice exposed to E. coli lipopolysaccharide (LPS). Results: Our results showed that the Formulation significantly affects the capability of bacteria to form biofilm and reduces the bacteria amount in the mature biofilm. Moreover, it combines the interesting properties of NAC and a polyenzyme plant complex based on bromelain in a right dose to affect the E. coli adhesion capability. Finally, the Formulation exhibited protective effects, as confirmed by the inhibitory activities on multiple inflammatory and oxidative stress-related pathways on bladder specimens exposed to LPS. Conclusions: This blend of active compounds could represent a promising and versatile approach to use to overcome the limitations associated with conventional therapies.},
}
@article {pmid39450216,
year = {2024},
author = {Yahia, Z and Yahia, A and Abdelaziz, T},
title = {N-acetylcysteine Clinical Applications.},
journal = {Cureus},
volume = {16},
number = {10},
pages = {e72252},
pmid = {39450216},
issn = {2168-8184},
abstract = {This study aims to evaluate the therapeutic application of N-acetylcysteine (NAC) as a treatment or adjunct therapy for various medical conditions. While its efficacy in treating acetaminophen overdose, cystic fibrosis, and chronic obstructive pulmonary disease is well-established, emerging evidence suggests that NAC may also benefit a broader spectrum of illnesses due to its safety, simplicity, and affordability. A comprehensive review was conducted by searching PubMed, relevant books, and conference proceedings for publications discussing NAC about the specified health conditions. The clinically relevant data were analysed using the American Family Physician Evidence-Based Medicine Toolkit, following a standard integrated review methodology. NAC shows potential as an adjunctive treatment for a wide range of medical conditions, particularly chronic diseases. It may be beneficial for polycystic ovary syndrome, endometriosis, male infertility, cataracts, glaucoma, dry eye syndrome, parkinsonism, multiple sclerosis, Alzheimer's disease, stroke outcomes, non-acetaminophen-induced acute liver failure, Crohn's disease, ulcerative colitis, schizophrenia, bipolar disorder, and obsessive-compulsive disorder. Although evidence for some conditions is less robust, NAC's therapeutic potential warrants further investigation. Given the aging population and the decline in glutathione levels, the use of NAC should be considered across a variety of medical conditions. This paper suggests that NAC supplementation could play a significant role in reducing morbidity and mortality associated with numerous chronic diseases.},
}
@article {pmid39447843,
year = {2024},
author = {Zheng, M and Song, W and Huang, P and Huang, Y and Lin, H and Zhang, M and He, H and Wu, J},
title = {Drug conjugates crosslinked bioresponsive hydrogel for combination therapy of diabetic wound.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {376},
number = {},
pages = {701-716},
doi = {10.1016/j.jconrel.2024.10.046},
pmid = {39447843},
issn = {1873-4995},
mesh = {Animals ; *Wound Healing/drug effects ; *Fibroblast Growth Factor 2/administration &amp; dosage/chemistry ; *Hydrogels/chemistry/administration &amp; dosage ; *Acetylcysteine/administration &amp; dosage ; Antioxidants/administration &amp; dosage/chemistry/pharmacology ; Male ; Diabetes Mellitus, Experimental/drug therapy ; Oxidative Stress/drug effects ; Drug Liberation ; Rats, Sprague-Dawley ; Mice ; Cross-Linking Reagents/chemistry ; },
abstract = {Basic fibroblast growth factor (bFGF) has proved to be effective for wound healing, yet its effectiveness is extremely retarded in diabetic wounds due to the severe oxidative stress in wound beds. To solve this issue, herein a novel combination therapy of bFGF and N-acetylcysteine (NAC, antioxidant) was devised for improved diabetic wound repair. To avoid rapid loss of both drugs in the wound beds, a bioresponsive hydrogel (bFGF-HSPP-NAC) was engineered by incorporating bFGF and NAC into polymer-drug conjugates (HSPP) via thiol-disulfide exchange reactions. In response to oxidative stress (e.g., reactive oxygen species), the disulfide bonds (SS) within the hydrogel are broken into thiol groups (-S-H), thereby promoting hydrogel degradation and enabling controlled drug release. Initially, NAC is released to scavenge free radicals and ameliorate oxidative damage. Subsequently, bFGF is released to expedite tissue regeneration. This combinatorial strategy is tailored to the specific characteristics of the wound microenvironment at various stages of diabetic wound healing, thereby achieving therapeutic efficacy. The results indicate that the bFGF-HSPP-NAC hydrogel markedly enhances re-epithelialization, collagen deposition, hair follicle regeneration, and neovascularization. In conclusion, the bioresponsive bFGF-HSPP-NAC hydrogel demonstrates significant potential for application in combinatorial therapeutic approaches for diabetic wound healing.},
}
@article {pmid39436429,
year = {2025},
author = {Galicia-Moreno, M and Monroy-Ramirez, HC and Caloca-Camarena, F and Arceo-Orozco, S and Muriel, P and Sandoval-Rodriguez, A and García-Bañuelos, J and García-González, A and Navarro-Partida, J and Armendariz-Borunda, J},
title = {A new opportunity for N-acetylcysteine. An outline of its classic antioxidant effects and its pharmacological potential as an epigenetic modulator in liver diseases treatment.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {398},
number = {3},
pages = {2365-2386},
pmid = {39436429},
issn = {1432-1912},
mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Humans ; *Antioxidants/pharmacology/therapeutic use/adverse effects ; *Epigenesis, Genetic/drug effects ; *Liver Diseases/drug therapy/genetics/metabolism ; Animals ; Oxidative Stress/drug effects ; },
abstract = {Liver diseases represent a worldwide health problem accountable for two million deaths per year. Oxidative stress is critical for the development of these diseases. N-acetyl cysteine (NAC) is effective in preventing liver damage, both in experimental and clinical studies, and evidence has shown that the pharmacodynamic mechanisms of NAC are related to its antioxidant nature and ability to modulate key signaling pathways. Here, we provide a comprehensive description of the beneficial effects of NAC in the treatment of liver diseases, addressing the first evidence of its role as a scavenger and precursor of reduced glutathione, along with studies showing its immunomodulatory action, as well as the ability of NAC to modulate epigenetic hallmarks. We searched the PubMed database using the following keywords: oxidative stress, liver disease, epigenetics, antioxidants, NAC, and antioxidant therapies. There was no time limit to gather all available information on the subject. NAC has shown efficacy in treating liver damage, exerting mechanisms of action different from those of free radical scavengers. Like different antioxidant therapies, its effectiveness and safety are related to the administered dose; therefore, designing new pharmacological formulations for this drug is imperative to achieve an adequate response. Finally, there is still much to explore regarding its effect on epigenetic marker characteristics of liver damage, turning it into a drug with broad therapeutic potential. According to the literature reviewed, NAC could be an appropriate option in clinical studies related to hepatic injury and, in the future, a repurposing alternative for treating liver diseases.},
}
@article {pmid39430194,
year = {2024},
author = {Hernández-Cruz, EY and Aparicio-Trejo, OE and Hammami, FA and Bar-Shalom, D and Tepel, M and Pedraza-Chaverri, J and Scholze, A},
title = {N-acetylcysteine in Kidney Disease: Molecular Mechanisms, Pharmacokinetics, and Clinical Effectiveness.},
journal = {Kidney international reports},
volume = {9},
number = {10},
pages = {2883-2903},
pmid = {39430194},
issn = {2468-0249},
abstract = {N-acetylcysteine (NAC) has shown beneficial effects in both acute kidney disease and chronic kidney disease (CKD) in preclinical and clinical studies. Different dosage and administration forms of NAC have specific pharmacokinetic properties that determine the temporal pattern of plasma concentrations of NAC and its active metabolites. Especially in acute situations with short-term NAC administration, appropriate NAC and glutathione (GSH) plasma concentrations should be timely ensured. For oral dosage forms, bioavailability needs to be established for the respective NAC formulation. Kidney function influences NAC pharmacokinetics, including a reduction of NAC clearance in advanced CKD. In addition, mechanisms of action underlying beneficial NAC effects depend on kidney function as well as comorbidities, both involving GSH deficiency, alterations in nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent signaling, oxidative stress, mitochondrial dysfunction, and disturbed mitochondrial bioenergetics. This also applies to nonrenal NAC mechanisms. The timing of preventive NAC administration in relation to potential injury is important. NAC administration seems most effective either preceding, or preceding and paralleling conditions that induce tissue damage. Furthermore, studies suggest that very high concentrations of NAC should be avoided because they could exert reductive stress. Delayed administration of NAC might interfere with endogenous repair mechanisms. In conclusion, studies on NAC treatment regimens need to account for both NAC pharmacokinetics and NAC molecular effects. Kidney function of the patient population and pathomechanisms of the kidney disease should guide rational NAC trial design. A targeted trial approach and biomarker-guided protocols could pave the way for the use of NAC in precision medicine.},
}
@article {pmid39423623,
year = {2024},
author = {Liu, M and Gao, M and Shi, X and Yin, Y and Liu, H and Xie, R and Huang, C and Zhang, W and Xu, S},
title = {Quercetin attenuates SiO2-induced ZBP-1-mediated PANoptosis in mouse neuronal cells via the ROS/TLR4/NF-κb pathway.},
journal = {Journal of environmental management},
volume = {370},
number = {},
pages = {122948},
doi = {10.1016/j.jenvman.2024.122948},
pmid = {39423623},
issn = {1095-8630},
mesh = {Animals ; Mice ; *Silicon Dioxide/toxicity ; *Toll-Like Receptor 4/metabolism ; *NF-kappa B/metabolism ; *Quercetin/pharmacology ; *Reactive Oxygen Species/metabolism ; *Neurons/drug effects ; Oxidative Stress/drug effects ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; },
abstract = {With the increasing development of the society, silicon dioxide (SiO2) has been used in various fields, such as agriculture, food industry, etc., and its residues can pose a potential health threat to organisms. Quercetin (Que) is a potent free radical scavenger commonly found in plants. C57BL/6 mice were chosen to established a mouse model of SiO2 exposure and Que antagonism to investigate the mechanism of action of Que in rescuing the toxic damage of SiO2 on mouse cerebellum tissue. The results showed that cytoplasmic vacuolization, and inflammatory cell infiltration caused by SiO2 were alleviated by the addition of Que, and reduced oxidative stress in mouse cerebellum, alleviated the activation of TLR4 pathway induced by SiO2, and substantially reduced the occurrence of ZBP-1-mediated PANoptosis induced by SiO2 exposure in mouse cerebellum. In NS20Y cells, the oxidative stress activator (Elesclomol) and inhibitor N-acetyl cysteine (NAC), and the NF-κB activator 2 (NA2) were added. Elesclomol and NAC confirm the involvement of ROS in regulating the TLR4/NF-κB pathway, the TLR4/NF-κB pathway regulated ZBP-1-mediated PANoptosis in cerebellum and NS20Y cells induced by SiO2 exposure. In conclusion, the present experimental data suggest that Que mitigates the onset of ZBP-1-mediated PANoptosis in neuronal cells induced by SiO2 through the ROS/TLR4/NF-κB pathway. The present experimental findings help to understand the detoxification effect of Que in more tissues and provide an important reference for the rescue of organisms in long-term SiO2 environment.},
}
@article {pmid39420342,
year = {2024},
author = {Zhou, W and Qu, M and Yue, Y and Zhong, Z and Nan, K and Sun, X and Wu, Q and Zhang, J and Chen, W and Miao, C},
title = {Acetylcysteine synergizes PD-1 blockers against colorectal cancer progression by promoting TCF1[+]PD1[+]CD8[+] T cell differentiation.},
journal = {Cell communication and signaling : CCS},
volume = {22},
number = {1},
pages = {503},
pmid = {39420342},
issn = {1478-811X},
mesh = {Animals ; *Colorectal Neoplasms/pathology/drug therapy/immunology/metabolism ; *CD8-Positive T-Lymphocytes/immunology/drug effects ; *Cell Differentiation/drug effects ; *Programmed Cell Death 1 Receptor/metabolism/antagonists &amp; inhibitors/immunology ; Mice ; *Acetylcysteine/pharmacology ; *Hepatocyte Nuclear Factor 1-alpha/metabolism/genetics ; *Disease Progression ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; Humans ; Cell Line, Tumor ; Mice, Inbred C57BL ; Drug Synergism ; },
abstract = {BACKGROUND: Programmed cell death protein 1 (PD-1) blockade is essential in treating progressive colorectal cancer (CRC). However, some patients with CRC do not respond well to immunotherapy, possibly due to the exhaustion of CD8[+] T cells in the tumor microenvironment. N-Acetylcysteine (NAC) can reduce CD8[+] T cell exhaustion in vitro and induce their differentiation into long-lasting phenotypes, thus enhancing the anti-tumor effect of adoptive T cell transfer. However, whether NAC can be combined with PD-1 blockade in CRC treatment and how NAC regulates CD8[+] T cell differentiation remain unclear. Hence, in this study, we aimed to investigate whether NAC has a synergistic effect with PD-1 blockers against CRC progression.<br><br>METHODS: We constructed a mouse CRC model to study the effect of NAC on tumors. The effect of NAC on CD8&#x2009;+&#x2009;T cell differentiation and its potential mechanism were explored using cell flow assay and other studies in vitro and ex vivo.<br><br>RESULTS: We demonstrated that NAC synergized PD-1 antibodies to inhibit CRC progression in a mouse CRC model mediated by CD8[+] T cells. We further found that NAC can induce TCF1[+]PD1[+]CD8[+] T cell differentiation and reduce the formation of exhausted T cells in vitro and in vivo. Moreover, NAC enhanced the expression of Glut4 in CD8[+] T cells, promoting the differentiation of TCF1[+]PD1[+]CD8[+] T cells.<br><br>CONCLUSIONS: Our study provides a novel idea for immunotherapy for clinically progressive CRC and suggests that Glut4 may be a new immunometabolic molecular target for regulating CD8[+] T cell differentiation.},
}
@article {pmid39415242,
year = {2024},
author = {Fang, YQ and Ding, H and Li, T and Zhao, XJ and Luo, D and Liu, Y and Li, Y},
title = {N-acetylcysteine supplementation improves endocrine-metabolism profiles and ovulation induction efficacy in polycystic ovary syndrome.},
journal = {Journal of ovarian research},
volume = {17},
number = {1},
pages = {205},
pmid = {39415242},
issn = {1757-2215},
mesh = {*Polycystic Ovary Syndrome/drug therapy/metabolism ; Female ; *Acetylcysteine/pharmacology/therapeutic use ; Animals ; Mice ; Humans ; *Ovulation Induction/methods ; Adult ; Oxidative Stress/drug effects ; Mice, Inbred C57BL ; Pregnancy ; Dietary Supplements ; Antioxidants/pharmacology/therapeutic use ; Ovary/drug effects/metabolism ; Metformin/pharmacology/therapeutic use ; Insulin Resistance ; Letrozole/pharmacology ; },
abstract = {BACKGROUND: Polycystic ovary syndrome (PCOS) affects 6-20% of women worldwide, with insulin resistance and hyperinsulinemia occurring in 50-70% of patients. Hyperinsulinemia exacerbates oxidative stress, contributing to PCOS pathogenesis. N-acetylcysteine (NAC) is an antioxidant and insulin sensitizer that shows promise as a therapeutic for PCOS. Our current study aimed to investigate the effects of NAC supplementation on endocrine-metabolic parameters in PCOS mice and its effect on ovulation induction (OI) efficacy in women with PCOS.<br><br>METHODS: Female C57BL/6 mice were orally administered letrozole (LE) to induce PCOS and then randomly divided into groups receiving daily oral administration of 160&#xa0;mg/kg NAC (PCOS&#x2009;+&#x2009;NAC group), 200&#xa0;mg/kg metformin (PCOS&#x2009;+&#x2009;Met group), or 0.5% carboxymethyl cellulose (drug solvent) (pure PCOS group) for 12 days. Healthy female mice served as pure controls. Estrous cycles were monitored during the intervention. Metabolic and hormone levels, ovarian phenotypes, antioxidant activity in ovarian tissues, and oxidative stress levels in oocytes were assessed post-intervention. Furthermore, a pragmatic, randomized, controlled clinical study was conducted with 230 PCOS women, randomly assigned to the NAC group (1.8&#xa0;g/day oral NAC, n&#x2009;=&#x2009;115) or the control group (n&#x2009;=&#x2009;115). Patients in both groups underwent&#x2009;&#x2264;&#x2009;3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups.<br><br>RESULTS: Similar to metformin, NAC supplementation significantly improved the estrous cycles and ovarian phenotypes of PCOS mice; reduced the LH concentration, LH/FSH ratio, and T level; and increased glucose clearance and insulin sensitivity. Notably, NAC significantly reduced oocyte ROS levels and increased the mitochondrial membrane potential in PCOS mice. Additionally, NAC significantly enhanced enzymatic and nonenzymatic antioxidant activities in PCOS mouse ovaries, whereas metformin had no such effect. In the clinical trial, compared to women in the control group, women receiving NAC had significantly lower average uFSH dosage and duration (p&#x2009;<&#x2009;0.005) and significantly greater clinical pregnancy rates per OI cycle and cumulative clinical pregnancy rates per patient (p&#x2009;<&#x2009;0.005).<br><br>CONCLUSION: NAC supplementation improved endocrine-metabolic parameters in PCOS mice and significantly enhanced OI efficacy with sequential LE and uFSH in women with PCOS. Therefore, NAC could be a valuable adjuvant in OI for women with PCOS.},
}
@article {pmid39409801,
year = {2024},
author = {Ninković, M and Žutić, J and Tasić, A and Arsić, S and Bojkovski, J and Zdravković, N},
title = {An Innovative Approach: The Usage of N-Acetylcysteine in the Therapy of Pneumonia in Neonatal Calves.},
journal = {Animals : an open access journal from MDPI},
volume = {14},
number = {19},
pages = {},
pmid = {39409801},
issn = {2076-2615},
support = {451-03-66/2024-03/200030//This research was funded by the Serbian Ministry of Science, Technological Development and In-novation, grant numbers 451-03-66/2024-03/200030 and Collaborative Grant Scheme Program Call (ID: 50404) of the Innovation Found of The Republic of Serbia./ ; },
abstract = {NAC has mucolytic, antioxidant, and antimicrobial effects in living organisms. However, the therapeutic effects of NAC on clinical recovery among neonatal calves with respiratory diseases have not yet been studied. Our study represents the first investigation of the effects of NAC in neonatal calves with pneumonia. The objective of this work was to observe the effects of NAC in the treatment of neonatal pneumonia, including its ability to reduce the clinical score, shorten the duration of the treatment, and improve the overall health condition of neonatal calves. For this study, calves were divided into two groups: a treatment group that received NAC and amoxicillin with clavulanic acid, and a control group that received amoxicillin with clavulanic acid (antimicrobial only). The findings of this study indicate that NAC treatment significantly shortened the time to resolution (p < 0.001), compared to the results in the group without NAC treatment. Generally, NAC-supplemented therapy reduced the recovery time by more than 27 h (or slightly more than one day), compared to that in the antimicrobial-only group. Our study presents the first reported usage of NAC in therapy for respiratory disorders.},
}
@article {pmid39409186,
year = {2024},
author = {Lien, TS and Sun, DS and Wu, WS and Chang, HH},
title = {Dengue Envelope Protein as a Cytotoxic Factor Inducing Hemorrhage and Endothelial Cell Death in Mice.},
journal = {International journal of molecular sciences},
volume = {25},
number = {19},
pages = {},
pmid = {39409186},
issn = {1422-0067},
support = {104-2320-B-320 -009 -MY3, 107-2311-B-320-002-MY3, 111-2320-B320-006-MY3, 112-2320-B-320-007//National Science and Technology Council, Taiwan/ ; TCMMP104-06, TCMMP108-04, TCMMP 111-01, TCAS111-02, TCAS-112-02, TCAS113-04, TCRD112-033, TCRD113-041//Tzu-Chi Medical Foundation/ ; },
mesh = {Animals ; Mice ; *Dengue Virus ; Humans ; *Endothelial Cells/drug effects/metabolism ; *Viral Envelope Proteins/metabolism ; *Apoptosis/drug effects ; *Severe Dengue/pathology/drug therapy ; *Hemorrhage/drug therapy ; Caspase 3/metabolism ; Disease Models, Animal ; Dengue/drug therapy/pathology ; Cell Line ; Cell Death/drug effects ; },
abstract = {Dengue virus (DENV) infection, prevalent in tropical and subtropical regions, can progress to dengue hemorrhagic fever (DHF), which increases mortality during secondary infections. DHF is characterized by endothelial damage and vascular leakage. Despite its severity, no specific antiviral treatments exist, and the viral factors responsible for endothelial damage remain unclear. This study examines the role of the DENV envelope protein domain III (EIII) in inducing endothelial apoptosis using a mouse model. Additionally, we aim to explore whether cell death-inducing pathways could serve as drug targets to ameliorate EIII-induced endothelial injury and hemorrhage. In vitro experiments using human endothelial HMEC-1 cells demonstrated that both recombinant EIII (rEIII) and DENV markedly induced caspase-3-mediated endothelial cell death, an effect that was attenuated by co-treatment with chondroitin sulfate B (CSB), N-acetyl cysteine (NAC), and the caspase-3 inhibitor z-DEVD-FMK. In vivo, sequential injections of rEIII and anti-platelet immunoglobulin in mice, designed to mimic the clinical phase of DHF with peak viremia followed by an increase in DENV-induced Ig, including autoantibodies, revealed that these dual treatments markedly triggered caspase-3-dependent apoptosis in vascular endothelial cells at hemorrhage sites. Treatments with z-DEVD-FMK effectively reduced DHF-like symptoms such as thrombocytopenia, hemorrhage, inflammation, hypercoagulation, and endothelial damage. Additionally, CSB and NAC alleviated hemorrhagic symptoms in the mice. These results suggest that targeting EIII, reactive oxygen species, and caspase-3-mediated apoptosis could offer potential therapeutic strategies for addressing EIII-induced hemorrhagic pathogenesis.},
}
@article {pmid39396855,
year = {2024},
author = {Gago, S and Diaz-Muñoz, J and Mogas, T},
title = {Impact of N-acetyl-L-cysteine on spindle morphology and reactive oxygen species in vitrified/warmed in vitro matured bovine oocytes.},
journal = {Reproduction in domestic animals = Zuchthygiene},
volume = {59 Suppl 3},
number = {},
pages = {e14619},
doi = {10.1111/rda.14619},
pmid = {39396855},
issn = {1439-0531},
support = {PID2020-116531RB-I00//Ministerio de Ciencia e Innovaci&#xf3;n/ ; 2021 SGR 00900//Generalitat de Catalunya/ ; },
mesh = {Animals ; Cattle ; *Acetylcysteine/pharmacology ; *Oocytes/drug effects ; *Reactive Oxygen Species/metabolism ; *In Vitro Oocyte Maturation Techniques/veterinary/methods ; *Vitrification ; Female ; *Spindle Apparatus/drug effects ; Antioxidants/pharmacology ; Cryopreservation/veterinary ; },
abstract = {Low developmental potential of vitrified in vitro matured (IVM) bovine oocytes is frequently attributed to high levels of reactive oxygen species (ROS) and abnormal spindle assembly. This study aimed to evaluate the efficacy of N-acetyl-L-cysteine (NAC), a cell-permeating antioxidant, added to IVM medium in reducing ROS and preserving spindle configuration of vitrified/warmed IVM bovine oocytes. Oocytes collected from abattoir ovaries were either cultured in IVM medium or in IVM medium supplemented with 1 mM NAC for the initial 8 h of IVM. Half of the oocytes of each group were vitrified/warmed, and spindle morphology and ROS production were assessed at 24 h of IVM. Results indicated that fresh oocytes IVM with NAC improved spindle configuration, with significantly lower ROS levels compared to the control group. Vitrification resulted in lower percentages of bovine oocytes reaching the metaphase II stage but similar ROS levels to non-vitrified oocytes, regardless of NAC supplementation. However, the supplementation of NAC during maturation had no effect on spindle or chromosome configuration of vitrified oocytes. These findings emphasize NAC's potential in enhancing the quality of IVM bovine oocytes but its addition at 1 mM for 8 h to IVM medium did not decrease levels of ROS nor improve spindle assembly after vitrification.},
}
@article {pmid39395220,
year = {2024},
author = {Xiang, RH and Wang, JQ and Li, ZG},
title = {Crosstalk of methylglyoxal and calcium signaling in maize (Zea mays L.) thermotolerance through methylglyoxal-scavenging system.},
journal = {Journal of plant physiology},
volume = {303},
number = {},
pages = {154362},
doi = {10.1016/j.jplph.2024.154362},
pmid = {39395220},
issn = {1618-1328},
mesh = {*Zea mays/physiology/drug effects/metabolism/genetics ; *Pyruvaldehyde/metabolism ; *Calcium Signaling ; *Thermotolerance/physiology ; Seedlings/physiology/drug effects ; Calcium/metabolism ; Heat-Shock Response/physiology ; Plant Proteins/metabolism/genetics ; Gene Expression Regulation, Plant/drug effects ; },
abstract = {Methylglyoxal (MG) and calcium ion (Ca[2+]) can increase multiple-stress tolerance including plant thermotolerance. However, whether crosstalk of MG and Ca[2+] exists in the formation of maize thermotolerance and underlying mechanism still remain elusive. In this paper, maize seedlings were irrigated with MG and calcium chloride alone or in combination, and then exposed to heat stress (HS). The results manifested that, compared with the survival percentage (SP, 45.3%) of the control seedlings, the SP of MG and Ca[2+] alone or in combination was increased to 72.4%, 74.2%, and 83.4% under HS conditions, indicating that Ca[2+] and MG alone or in combination could upraise seedling thermotolerance. Also, the MG-upraised SP was separately weakened to 42.2%, 40.3%, 52.1%, and 39.4% by Ca[2+] chelator (ethylene glycol tetraacetic acid, EGTA), plasma membrane Ca[2+] channel blocker (lanthanum chloride, LaCl3), intracellular Ca[2+] channel blocker (neomycin, NEC), and calmodulin (CaM) antagonist (trifluoperazine, TFP). However, significant effect of MG scavengers N-acetylcysteine (NAC) and aminoguanidine (AG) on Ca[2+]-induced thermotolerance was not observed. Similarly, an endogenous Ca[2+] level in seedlings was increased by exogenous MG under non-HS and HS conditions, while exogenous Ca[2+] had no significant effect on endogenous MG. These data implied that Ca[2+] signaling, at least partly, mediated MG-upraised thermotolerance in maize seedlings. Moreover, the activity and gene expression of glyoxalase system (glyoxalase I, glyoxalase II, and glyoxalase III) and non-glyoxalase system (MG reductase, aldehyde reductase, aldo-keto reductase, and lactate dehydrogenase) were up-regulated to a certain extent by Ca[2+] and MG alone in seedlings under non-HS and HS conditions. The up-regulated MG-scavenging system by MG was enhanced by Ca[2+], while impaired by EGTA, LaCl3, NEC, or TFP. These data suggest that the crosstalk of MG and Ca[2+] signaling in maize thermotolerance through MG-scavenging system. These findings provided a theoretical basis for breeding climate-resilient maize crop and developing smart agriculture.},
}
@article {pmid39394703,
year = {2024},
author = {Meng, T and Guo, HJ and Yao, Y and Mi, ZH and Tian, Y and Yu, JZ},
title = {[Study on the molecular mechanism of autophagy and apoptosis induced by ultrafine carbon black in human bronchial epithelial cells and the intervention effect of N-acetylcysteine].},
journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases},
volume = {42},
number = {9},
pages = {656-667},
doi = {10.3760/cma.j.cn121094-20231010-00080},
pmid = {39394703},
issn = {1001-9391},
support = {81502845//National Natural Science Foundation for Young Scholars of China/ ; 2021XM17//Four "Batches" Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province/ ; 202103021224311//Fundamental Research Program of Shanxi Province/ ; 20220808, XDC2021135//Innovation and Entrepreneurship Training Program for College Students/ ; },
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Apoptosis/drug effects ; *Autophagy/drug effects ; *Epithelial Cells/drug effects/metabolism ; *Bronchi/cytology ; *Soot/toxicity ; *Oxidative Stress/drug effects ; Cell Line ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Malondialdehyde/metabolism ; Catalase/metabolism ; bcl-2-Associated X Protein/metabolism/genetics ; Glutathione Peroxidase/metabolism ; Cell Survival/drug effects ; },
abstract = {Objective: To investigate the molecular mechanism of autophagy and apoptosis induced by ultrafine carbon black in human bronchial epithelial cells (BEAS-2B cells), and to study the intervention effect and mechanism of N-acetylcysteine (NAC) on ultrafine carbon black-induced oxidative damage in BEAS-2B cells. Methods: In March 2023, BEAS-2B cells were used as research object, an in vitro airway model exposed to ultrafine carbon black was constructed. A control group and three carbon black exposure groups (50, 100, 200 μg/ml) were set up, and the cells were treated with corresponding concentrations of ultrafine carbon black for 24 hours. In addition, the experiment was divided into control group, NAC+ control group, 100 μg/ml carbon black exposure group and NAC+ exposure group. The corresponding groups were treated with 2 mmol/L NAC for 1 h and 100 μg/ml ultrafine carbon black for 24 h, respectively. Cell viability was measured by CCK-8 assay. Intracellular reactive oxygen species (ROS) level was detected by chemical fluorescence method. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), as well as the content of malondialdehyde (MDA) were detected by colorimetry. The mRNA and protein expressions of autophagy-related genes[Atg5, Atg7, Beclin1, microtubule-associated protein light chain 3B (LC3B), p62 and lysosome-associated membrane protein 2 (LAMP2) ] and apoptosis-related genes [B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase3, Caspase9 and poly (ADP-ribose) polymerase 1 (PARP1) ] were determined by fluorescence quantitative PCR and Western blot. Cell apoptosis was determined by flow cytometry. Results: Compared with the control group, the relative survival rates of BEAS-2B cells in 50, 100, 200 μg/ml carbon black exposure groups were significantly decreased, the levels of ROS and MDA were significantly increased, and the activities of SOD, GSH-Px and CAT were significantly decreased (P<0.05). The relative survival rate, ROS and MDA levels, SOD, GSH-Px and CAT activities were significantly correlated with the exposure dose of ultrafine carbon black (r(s)=-0.755, 0.826, 0.934, -0.810, -0.880, -0.840, P<0.05). Compared with the control group, the relative expression levels of Atg5, Atg7, Beclin1, LC3B, p62, LAMP2, Bax, Caspase3, Caspase9, PARP1 mRNA and Atg5, Atg7, Beclin1, LC3BⅡ, p62, LAMP2, Bax, cleaved Caspase3 (C-Caspase3), cleaved Caspase9 (C-Caspase9), cleaved PARP1 (C-PARP1) protein and the ratio of LC3BⅡ/LC3BⅠ in 50, 100 and 200 μg/ml carbon black exposure groups were significantly increased, while the relative expression levels of Bcl-2 mRNA and protein were significantly decreased (P<0.05). The changes of the above indexes were significantly correlated with the exposure dose of carbon black (r(s)=0.892, 0.879, 0.944, 0.892, 0.828, 0.880, 0.814, 0.794, 0.931, 0.918, 0.813, 0.866, 0.774, 0.695, 0.918, 0.761, 0.794, 0.944, 0.833, 0.866, 0.905, -0.886, -0.748, P<0.05). Compared with 100 μg/ml carbon black exposure group, the relative survival rate, the activities of SOD, GSH-Px and CAT in NAC+exposure group were significantly increased, while the levels of ROS and MDA were significantly decreased, and the relative expression levels of LC3B, p62 and Caspase3 mRNA and protein as well as the ratio of LC3BⅡ/LC3BⅠ were significantly decreased, and the differences were statistically significant (P<0.05). Compared with the control group, the apoptosis rates of BEAS-2B cells in 50, 100, 200 μg/ml carbon black exposure groups were significantly increased (P<0.05), and there was a significant positive correlation between ultrafine carbon black exposure dose and cell apoptosis rate (r(s)=0.944, P<0.05). While compared with 100 μg/ml carbon black exposure group, the apoptosis rate of NAC+exposure group was significantly decreased, and the difference was statistically significant (P<0.05) . Conclusion: Cell autophagy and apoptosis may be important pathophysiological mechanisms of ultrafine carbon black-induced oxidative damage in BEAS-2B cells. NAC can alleviate the occurrence of BEAS-2B cell damage caused by ultrafine carbon black by regulating oxidative stress and the cascading autophagy and apoptosis pathways.},
}
@article {pmid39393575,
year = {2024},
author = {Feng, J and Liu, H and Jiang, K and Gong, X and Huang, R and Zhou, C and Mao, J and Chen, Y and Xu, H and Zhang, X and Yang, X and Zhao, D},
title = {Enhanced oxidative stress aggravates BLM-induced pulmonary fibrosis by promoting cellular senescence through enhancing NLRP3 activation.},
journal = {Life sciences},
volume = {358},
number = {},
pages = {123128},
doi = {10.1016/j.lfs.2024.123128},
pmid = {39393575},
issn = {1879-0631},
mesh = {Animals ; *Bleomycin/toxicity ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Cellular Senescence/drug effects ; Mice ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Mice, Inbred C57BL ; Humans ; *Pulmonary Fibrosis/metabolism/chemically induced/pathology ; A549 Cells ; Male ; Inflammasomes/metabolism ; Disease Models, Animal ; Idiopathic Pulmonary Fibrosis/metabolism/pathology/chemically induced ; Transforming Growth Factor beta/metabolism ; },
abstract = {AIMS: Idiopathic pulmonary fibrosis (IPF) is a disease associated with aging, where increased oxidative stress accelerates the progression of pulmonary fibrosis (PF). The specific mechanisms through which oxidative stress intensifies PF are still not fully understood.<br><br>MATERIALS AND METHODS: In this study, we used bleomycin (BLM)-induced PF mouse model and TGF-&#x3b2;-induced collagen deposition cells for in vivo and in vitro experiments, respectively. Additionally, we employed BSO, a glutathione synthesis inhibitor, to induce excess reactive oxygen species (ROS).<br><br>KEY FINDINGS: Our findings revealed that heightened ROS production significantly exacerbated PF development in mice and increased collagen deposition in A549 cells. We also showed that cellular senescence was further intensified by the combined treatment of BSO with BLM or TGF-&#x3b2;, as indicated by the increased levels of p53 and p21, along with an increase in &#x3b2;-galactosidase-positive cells. Moreover, inflammatory responses, including inflammatory cells, inflammatory cytokines, and ROS levels were dramatically increased with the BSO and BLM or TGF-&#x3b2; combination. Mechanistically, we found that NLRP3 inflammasome was activated more significantly by the combined treatments of BSO with BLM or TGF-&#x3b2;. Inhibition of NLRP3 ameliorated the aging-related phenotype and reduced p53 and p21 expression. Furthermore, we showed that N-acetylcysteine (NAC) treatment significantly attenuated BLM or BLM plus BSO-enhanced PF in vivo.<br><br>SIGNIFICANCE: Our study demonstrates that elevated ROS levels contribute to the development of PF via NLRP3-mediated cellular senescence. We also provide that targeting oxidative stress might be an effective strategy for treating PF.},
}
@article {pmid39389326,
year = {2025},
author = {Qiao, J and Du, D and Wang, Y and Xi, L and Zhu, W and Morigen, },
title = {Uncovering the effects of non-lethal oxidative stress on replication initiation in Escherichia coli.},
journal = {Gene},
volume = {933},
number = {},
pages = {148992},
doi = {10.1016/j.gene.2024.148992},
pmid = {39389326},
issn = {1879-0038},
mesh = {*Oxidative Stress/drug effects ; *Escherichia coli/genetics/metabolism/drug effects ; *Escherichia coli Proteins/genetics/metabolism ; *DNA Replication/drug effects ; *Hydrogen Peroxide/pharmacology ; Superoxide Dismutase/metabolism/genetics ; Protease La/metabolism/genetics ; Bacterial Proteins/genetics/metabolism ; DNA Glycosylases/genetics/metabolism ; Endopeptidase Clp/genetics/metabolism ; Acetylcysteine/pharmacology ; Catalase ; },
abstract = {Cell cycle adaptability assists bacteria in response to adverse stress. The effect of oxidative stress on replication initiation in Escherichia coli remains unclear. This work examined the impact of exogenous oxidant and genetic mutation-mediated oxidative stress on replication initiation. We found that 0-0.5 mM H2O2 suppresses E. coli replication initiation in a concentration-dependent manner but does not lead to cell death. Deletion of antioxidant enzymes SodA-SodB, KatE, or AhpC results in delayed replication initiation. The antioxidant N-acetylcysteine (NAC) promotes replication initiation in ΔkatE and ΔsodAΔsodB mutants. We then explored the factors that mediate the inhibition of replication initiation by oxidative stress. MutY, a base excision repair DNA glycosylase, resists inhibition of replication initiation by H2O2. Lon protease deficiency eliminates inhibition of replication initiation mediated by exogenous H2O2 exposure but not by katE or sodA-sodB deletion. The absence of clpP and hslV further delays replication initiation in the ΔktaE mutant, whereas hflK deletion promotes replication initiation in the ΔkatE and ΔsodAΔsodB mutants. In conclusion, non-lethal oxidative stress inhibits replication initiation, and AAA+ proteases are involved and show flexible regulation in E. coli.},
}
@article {pmid39384146,
year = {2024},
author = {Zeng, Q and Lv, C and Qi, L and Wang, Y and Hao, S and Li, G and Sun, H and Du, L and Li, J and Wang, C and Zhang, Y and Wang, X and Ma, R and Wang, T and Li, Q},
title = {Sodium selenite inhibits cervical cancer progression via ROS-mediated suppression of glucose metabolic reprogramming.},
journal = {Life sciences},
volume = {357},
number = {},
pages = {123109},
doi = {10.1016/j.lfs.2024.123109},
pmid = {39384146},
issn = {1879-0631},
mesh = {Humans ; Animals ; *Reactive Oxygen Species/metabolism ; *Uterine Cervical Neoplasms/drug therapy/pathology/metabolism ; Female ; Mice ; *Mice, Nude ; *Glucose/metabolism ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; *Sodium Selenite/pharmacology ; *Xenograft Model Antitumor Assays ; HeLa Cells ; Glycolysis/drug effects ; Mice, Inbred BALB C ; Membrane Potential, Mitochondrial/drug effects ; Cell Line, Tumor ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Disease Progression ; Metabolic Reprogramming ; },
abstract = {AIMS: This study aims to explore the inhibitory effect of selenium on cervical cancer through suppression of glucose metabolic reprogramming and its underlying mechanisms.<br><br>METHODS: Sodium selenite (SS) treated HeLa and SiHa cells were assessed for proliferation using the CCK-8 assay and immunofluorescence. DNA synthesis was measured with the EdU assay. A nude mouse xenograft model evaluated SS's anti-cervical cancer effects. Reactive oxygen species (ROS) and mitochondrial membrane potential were measured using flow cytometry, DCFH-DA, and JC-1 probes, respectively. Apoptosis was detected via Annexin V/PI staining and Western blot. Glucose uptake, lactate production, and ATP generation were determined using 2-NBDG probes and assay kits. The mRNA and protein levels of glycolysis-related genes HK2, GLUT1, and PDK1 were measured using RT-qPCR and Western blot.<br><br>KEY FINDINGS: SS inhibited HeLa and SiHa cells viability in a dose- and time-dependent manner. Intraperitoneal injection of SS in nude mice significantly inhibited HeLa cell xenograft growth without evident hepatotoxicity or nephrotoxicity. SS inhibited glucose metabolic reprogramming in cancer cells primarily via ROS-mediated AKT/mTOR/HIF-1&#x3b1; pathway inhibition. Pretreatment with N-acetylcysteine (NAC) or MHY1485 (an mTOR activator) partially reversed the inhibitory effects of SS on glucose metabolic reprogramming, cell proliferation, and migration, as well as its pro-apoptotic effects.<br><br>SIGNIFICANCE: SS exhibited anti-cervical cancer effects, likely through the induction of ROS generation and inhibition of glucose metabolic reprogramming in cervical cancer cells, thereby inhibiting cell proliferation and promoting apoptosis. These findings provide new insights into understanding the molecular mechanisms underlying SS for potential new drug development for cervical cancer.},
}
@article {pmid39381531,
year = {2024},
author = {Ghazaiean, M and Aliasgharian, A and Karami, H and Ghasemi, MM and Darvishi-Khezri, H},
title = {Antioxidative effects of N-acetylcysteine in patients with β-thalassemia: A quick review on clinical trials.},
journal = {Health science reports},
volume = {7},
number = {10},
pages = {e70096},
pmid = {39381531},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Several studies have highlighted the potent antioxidant properties of N-acetyl cysteine (NAC). This review aimed to assess the impact of NAC on oxidative stress biomarkers in patients with β-thalassemia.<br><br>METHODS: The review included articles published before 2024 that investigated the effects of NAC on oxidative stress in individuals with &#x3b2;-thalassemia. A comprehensive search was conducted across various databases, including Scopus, PubMed, Web of Science, Trip, and CENTRAL. Only English-language clinical trials were considered for inclusion in this review. Besides, the number needed to treat (NNT) was calculated based on the included studies.<br><br>RESULTS: Ninety-nine articles were retrieved from electronic databases, and after a thorough review, eight articles were selected for comprehensive text analysis. The highest dose of NAC administered was 10&#x2009;mg/kg/day (equivalent to 600&#x2009;mg/day) over a period of 3-6 months. All the studies assessing the impact of NAC on oxidative stress indicators in &#x3b2;-thalassemia patients demonstrated positive effects during the 3-month follow-up period. Most estimated NNTs fell into 1-5, suggesting significant clinical therapeutic value in this context.<br><br>CONCLUSION: The current potency of NAC alone appears to be effective in ameliorating oxidative stress in patients with &#x3b2;-thalassemia major. While a 3-month duration seems adequate to demonstrate the antioxidant properties of NAC in this population, larger and well-designed clinical trials are warranted. Current clinical evidence possesses a high risk of bias.},
}
@article {pmid39377544,
year = {2024},
author = {Formato, A and Salbini, M and Orecchini, E and Pellegrini, M and Buccarelli, M and Vitiani, LR and Giannetti, S and Pallini, R and D'Alessandris, QG and Lauretti, L and Martini, M and De Falco, V and Levi, A and Falchetti, ML and Mongiardi, MP},
title = {N-Acetyl-L-Cysteine (NAC) Blunts Axitinib-Related Adverse Effects in Preclinical Models of Glioblastoma.},
journal = {Cancer medicine},
volume = {13},
number = {19},
pages = {e70279},
pmid = {39377544},
issn = {2045-7634},
support = {A0375-2020-36524//Gruppi di Ricerca 2020-POR-FESR Lazio 2014-2020/ ; IG 2021#25664//Associazione Italiana per la Ricerca sul Cancro/ ; RF-2019-12368786//Ministero della Salute/ ; },
mesh = {*Axitinib/pharmacology/therapeutic use ; Animals ; *Glioblastoma/drug therapy/pathology/metabolism ; Humans ; Mice ; *Acetylcysteine/pharmacology/therapeutic use ; *Xenograft Model Antitumor Assays ; *Brain Neoplasms/drug therapy/pathology/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Protein Kinase Inhibitors/pharmacology/adverse effects/therapeutic use ; Cellular Senescence/drug effects ; },
abstract = {OBJECTIVE: Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH-wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo-angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib-dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells.<br><br>METHODS: We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N-Acetyl-L-Cysteine (NAC) might be used to reduce senescence-associated adverse effects of axitinib treatment without altering its anti-tumor activity.<br><br>RESULTS: We demonstrate that the use of the antioxidant molecule N-Acetyl-Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib-dependent toxicity.<br><br>CONCLUSION: Overall, we found that NAC co-treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib-dependent toxicity.},
}
@article {pmid39376972,
year = {2024},
author = {Eghdami, S and Eissazade, N and Heidari Mokarar, M and Boroon, M and Orsolini, L and Shalbafan, M},
title = {The safety and efficacy of N-acetylcysteine as an augmentation in the treatment of obsessive-compulsive disorder in adults: a systematic review and meta-analysis of randomized clinical trials.},
journal = {Frontiers in psychiatry},
volume = {15},
number = {},
pages = {1421150},
pmid = {39376972},
issn = {1664-0640},
abstract = {BACKGROUND: Obsessive-compulsive disorder (OCD) ranks as the fourth most prevalent psychiatric disorder, with selective serotonin reuptake inhibitors (SSRIs) as its mainstay pharmacological treatment. However, approximately 40 to 60% of patients do not adequately respond to initial treatment, highlighting the need for alternative options. N-acetylcysteine (NAC) is one of the several medications that have been used in augmentation with SSRIs to enhance their efficacy.<br><br>OBJECTIVES: We aimed to investigate the safety and efficacy of NAC, a glutamate-modulating agent, as an augmentation in the treatment of moderate to severe OCD.<br><br>METHOD: We conducted a thorough search across PubMed, Scopus, Web of science, and ProQuest to identify relevant trials published until December 2023. The primary outcome of interest was the mean difference between the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores before and after administrating augmented NAC among patients with moderate to severe OCD. Furthermore, we compared the occurrence of adverse drug events between the experimental and control groups.<br><br>RESULTS: We included six randomized controlled trials with 195 patients. The results of our study indicated a positive outcome for the experimental group in terms of the total Y-BOCS score when using the medication for a period of five to eight weeks (p-Value = 0.05). However, no significant difference was observed for durations shorter than five weeks or longer than 12 weeks. Additionally, no significant difference was found between the two groups in terms of the obsession and compulsion Y-BOCS scores. Furthermore, no significant differences were observed in terms of adverse events.<br><br>CONCLUSION: Augmentation of NAC with SSRIs may benefit patients with moderate to severe OCD. However, it is necessary to conduct additional multi-center trials over extended periods to develop a comprehensive strategy for action.<br><br>https://www.crd.york.ac.uk/prospero/, identifier CRD42023463683.},
}
@article {pmid39371865,
year = {2024},
author = {Gupta, M and Sharma, A and Kumaran, MS},
title = {An Insight Into Adolescent Dermatitis Artefacta: A Case Report.},
journal = {Cureus},
volume = {16},
number = {9},
pages = {e68682},
pmid = {39371865},
issn = {2168-8184},
abstract = {Dermatitis artefacta (DA) is a rare and challenging-to-diagnose factitious dermatological disorder, most commonly affecting late adolescents and young adults. This case report presents a 17-year-old girl with a history of unexplained linear lesions on her face and abdomen persisting for 11 months, leading to significant school absenteeism. The dermatological examination was otherwise unremarkable except for multiple well-defined excoriations, erosions, and scarring, suggestive of DA. Dermoscopic examination supported this diagnosis, showing characteristic features. The patient was treated with N-acetyl cysteine and referred for psychiatric evaluation, highlighting the intricate nature of managing DA, particularly in young individuals who may have underlying psychological distress. The case underscores the importance of a multidisciplinary approach in diagnosing and treating DA, given its overlap with other neuropsychiatric and dermatological disorders.},
}
@article {pmid39366552,
year = {2024},
author = {Ishtiaq, A and Mushtaq, I and Rehman, H and Mushtaq, I and Mushtaq, I and Abbasi, SW and Liaqat, F and Rasheed, A and Ahmad, S and Akhtar, Z and Murtaza, I},
title = {Tetra aniline-based polymers ameliorate BPA-induced cardiotoxicity in Sprague Dawley rats, in silico and in vivo analysis.},
journal = {Life sciences},
volume = {358},
number = {},
pages = {123104},
doi = {10.1016/j.lfs.2024.123104},
pmid = {39366552},
issn = {1879-0631},
mesh = {Animals ; *Phenols/pharmacology/toxicity ; *Rats, Sprague-Dawley ; *Benzhydryl Compounds/toxicity ; Rats ; *Cardiotoxicity/metabolism/prevention &amp; control ; *Aniline Compounds/pharmacology/toxicity ; *Molecular Docking Simulation ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Polymers ; Male ; MicroRNAs/metabolism/genetics ; Antioxidants/pharmacology ; Computer Simulation ; Apoptosis/drug effects ; Bisphenol A Compounds ; },
abstract = {AIMS: Bisphenol A (BPA), xenoestrogen, is an environmental toxicant, that generates oxidative stress leading to cardiotoxicity. The oxidative stress can be neutralized by natural and synthetic antioxidants. The present study elucidates the highly selective antioxidative potential of synthetic tetra aniline polymers Es-37 and L-37 against Bisphenol A-induced cardiac cellular impairments and the role of miRNA-15a-5p in the regulation of different apoptotic proteins.<br><br>MATERIALS AND METHODS: The molecular docking of L-37 and Es-37 with three proteins (p53, Cytochrome c, and Bcl-2) were performed. The dose of 1&#xa0;mg/kg BW of BPA, 1&#xa0;mg/kg BW Es-37 and L-37 and 50&#xa0;mg/kg BW N-acetyl cysteine (NAC) was administered to Sprague Dawley rats. The miRNA and target gene expression were confirmed by qRt-PCR and Immunoblotting.<br><br>KEY FINDINGS: In our results, BPA administration significantly elevated the reactive oxygen species (ROS), p53, cytochrome c, and particularly miRNA-15a-5p expression; however: these changes were notably reversed by Es-37 and L-37 treatment. Additionally, molecular docking of synthetic polymers validated that L-37 has a greater binding affinity with the target proteins compared to Es-37, with the highest binding values reported for the enzymatic protein cytochrome c.<br><br>SIGNIFICANCE: These results suggest that both synthetic polymers Es-37 and L-37 have the potential to scavenge free radicals, boost-up antioxidant enzyme activities, and avert (BPA-induced) toxicity, thus, may serve as cardioprotective agents. Moreover, this study first time proposes that miRNA-15a-5p overexpression is associated with oxidative stress and coincides with BPA induced cardiotoxicity, thus may serve as potential therapeutic target in future.},
}
@article {pmid39365130,
year = {2024},
author = {Ram Kiran, KS and Trivedi, V and Rajesh, VSP and Sharma, M and Haranal, M and Pandya, H},
title = {Role of Prophylactic N-Acetylcysteine Supplementation on Postoperative Outcomes in Patients Undergoing Elective Double-Valve Replacement (Aortic and Mitral Valve).},
journal = {Annals of cardiac anaesthesia},
volume = {27},
number = {4},
pages = {324-329},
pmid = {39365130},
issn = {0974-5181},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Double-Blind Method ; Female ; Male ; Prospective Studies ; *Postoperative Complications/prevention &amp; control/epidemiology ; *Heart Valve Prosthesis Implantation/methods ; Middle Aged ; *Mitral Valve/surgery ; *Aortic Valve/surgery ; Treatment Outcome ; Adult ; Free Radical Scavengers/therapeutic use ; Length of Stay/statistics &amp; numerical data ; Liver Function Tests ; Aged ; Elective Surgical Procedures ; Liver Diseases/prevention &amp; control ; },
abstract = {AIMS AND OBJECTIVES: The incidence of postoperative liver dysfunction is high in patients undergoing double-valve replacement - mitral and aortic valve replacement (DVR). This study aims to evaluate N-acetylcysteine's free radical scavenging property (NAC) to prevent postoperative liver dysfunction in these patients, thus affecting overall clinical outcomes.<br><br>METHODS: A single-center, prospective, randomized, double-blinded interventional study of 60 patients divided into two groups of 30 each. Group N received prophylactic intravenous NAC, and Group C received volume-matched 5% dextrose. Data comprised demographics, liver function tests (LFT), renal function tests (RFT), vasoactive-inotropic scores (VIS) score, and C-reactive protein (CRP) at various time intervals. Postoperative parameters such as ventilation duration, length of stay in ICU (LOS-ICU), length of hospital stay (LOHS), atrial fibrillation (AF), acute kidney injury (AKI) requiring hemodialysis, and mortality were noted. Statistical analysis was performed with the Student's t-test and Chi-square test (SPSS 22 software).<br><br>RESULTS: All postoperative LFT parameters (total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), and alkaline phosphatase (ALP)) were significantly lower (P < 0.05) at 24, 48, and 72 hours in Group N compared to Group C. RFT and VIS scores were lower in Group N; however, were not statistically significant except for Serum Creatinine at 48 hours (P = 0.0478). Ventilation duration (P = 0.0465) and LOS-ICU (P = 0.0431) were significantly lower in Group N. Other outcomes like AF, LOHS, and mortality were lower in Group N but were not statistically significant.<br><br>CONCLUSION: Our study showed that prophylactic administration of NAC in patients undergoing DVR is associated with a reduction in the incidence of postoperative liver dysfunction with a positive impact on postoperative outcomes.},
}
@article {pmid39365126,
year = {2024},
author = {Kapoor, MC},
title = {N-acetyl Cysteine to Mitigate Liver Damage in Patients with Deranged Liver Function Undergoing Surgery on Cardiopulmonary Bypass.},
journal = {Annals of cardiac anaesthesia},
volume = {27},
number = {4},
pages = {299-300},
pmid = {39365126},
issn = {0974-5181},
mesh = {Female ; Humans ; Male ; *Acetylcysteine/therapeutic use ; *Cardiopulmonary Bypass/adverse effects ; Liver/drug effects ; Liver Diseases ; Liver Function Tests ; },
}
@article {pmid39363690,
year = {2024},
author = {Li, K and Jiang, L and Wei, Y and Li, Z},
title = {Identification of the metabolites of nimbolide in rat by liquid chromatography combined with quadrupole/orbitrap mass spectrometry.},
journal = {Biomedical chromatography : BMC},
volume = {38},
number = {12},
pages = {e6012},
doi = {10.1002/bmc.6012},
pmid = {39363690},
issn = {1099-0801},
mesh = {Animals ; Rats ; Male ; *Microsomes, Liver/metabolism ; *Rats, Sprague-Dawley ; *Limonins/metabolism/pharmacokinetics/chemistry/urine/analysis ; Chromatography, High Pressure Liquid/methods ; Tandem Mass Spectrometry/methods ; Bile/chemistry/metabolism ; },
abstract = {Nimbolide is a major furanoid compound isolated from Azadirachta indica. The aim of this study was to characterize the metabolites of nimbolide in rats and to propose the metabolic pathways. The metabolites were generated by incubating nimbolide (10 μM) with rat liver microsomes, nicotinamide adenine dinucleotide phosphate (NADPH), and nucleophiles (glutathione [GSH] or N-acetyl-lysine [NAL]) at 37°C for 60 min. For the in vivo study, nimbolide was intravenously administered to rats at a single dose of 10 mg/kg, and the bile and urine were collected. The metabolites were identified by ultra-high-performance liquid chromatography-quadrupole/orbitrap mass spectrometry (UPLC-Q/Orbitrap-MS) using electrospray ionization in positive ion mode. Totally, nine metabolites were detected, and their identities were characterized by accurate MS and MS/MS data. In GSH-supplemented liver microsomes, GSH conjugation was the primary elimination pathway. The furan ring was bioactivated into cis-butene-1,4-dial that can be trapped by GSH. In NAL-supplemented liver microsomes, two NAL conjugates (M4 and M5) derived from cis-butene-1,4-dial were observed. In rat bile and urine, N-acetyl-cysteine, cysteine-glycine, and GSH conjugate were also found. The current study provides an overview of the metabolism and the bioactivation profiles of nimbolide in rats, which aids in understanding its safety and activity.},
}
@article {pmid39360368,
year = {2024},
author = {D'Agostino Gennari, J and Deveza, GBH and Ribeiro, CT and Seguro, AC and Aikawa, NE and Shimizu, MHM and Leon, EP and Guedes, LKN and Kupa, LVK and Silva, CAA and Bonfa, E and Pasoto, SG},
title = {Efficacy of N-acetylcysteine for treating dryness symptoms of Sjögren's disease: randomised placebo-controlled double-blind clinical study.},
journal = {Clinical and experimental rheumatology},
volume = {42},
number = {12},
pages = {2427-2436},
doi = {10.55563/clinexprheumatol/dmd5dv},
pmid = {39360368},
issn = {0392-856X},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Sjogren's Syndrome/drug therapy/complications/diagnosis/blood ; Double-Blind Method ; Female ; Middle Aged ; Adult ; Treatment Outcome ; *Xerostomia/drug therapy/etiology ; Glutathione/blood ; Thiobarbituric Acid Reactive Substances/metabolism ; Aged ; Biomarkers/blood ; Time Factors ; },
abstract = {OBJECTIVES: N-acetylcysteine (NAC) is used in Sjögren's disease (SjD) based on limited evidence. The aim of this study was to assess the efficacy of NAC for relieving dryness symptoms in SjD.<br><br>METHODS: In this placebo-controlled double-blind trial, 60 adult SjD females (with low disease activity) were randomised to receive NAC (1,200 mg/day orally) or placebo. At baseline (D0), 30 days (D30) and 90 days (D90), all participants underwent the following evaluations: EULAR Sj&#xf6;gren's Syndrome Patient Reported Index (ESSPRI), Ocular Surface Disease Index (OSDI), Xerostomia Inventory (XI), Leicester Cough Questionnaire (LCQ), unstimulated/stimulated salivary flow, Schirmer's test, and plasma levels of thiobarbituric acid reactive substances (TBARS), glutathione and NAC.<br><br>RESULTS: At inclusion, both groups were balanced for age, ethnicity, disease duration, ESSPRI, OSDI, XI, Schirmer's test, salivary flow, ESSDAI and topical/systemic treatments (p>0.05). No significant differences were observed between NAC and placebo groups on D30 and D90 regarding ESSPRI, XI, OSDI, LCQ, Schirmer's test, stimulated salivary flow, ESSDAI and topical/systemic treatments (p>0.05). Unstimulated salivary flow was significantly higher in the placebo group on D90 (p=0.018). NAC blood concentrations were significantly higher in the NAC group on D30 (p=0.018) and D90 (p<0.001), however, no differences were found in TBARS and glutathione. Further analysis showed decrease&#x2265;1 in ESSPRI in the NAC compared with placebo group on D30 (p=0.045), a result not found on D90 (p=0.696).<br><br>CONCLUSIONS: NAC is recommended as a rescue therapy for SjD. However, our well-designed study provides novel evidence demonstrating its inefficacy for improving dryness symptoms or reducing oxidative stress.<br><br>CLINICALTRIALS: gov-NCT04793646.},
}
@article {pmid39357253,
year = {2025},
author = {Huang, W and He, M and Chen, S and Yin, G and Gan, Y and Li, H and Wu, C and Yin, P},
title = {Dual-Channel fluorescent detection of Biothiols: A novel probe for Distinguishing Cysteine, Homocysteine, Glutathione, and N-Acetylcysteine in cellular environments.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {326},
number = {},
pages = {125221},
doi = {10.1016/j.saa.2024.125221},
pmid = {39357253},
issn = {1873-3557},
mesh = {*Fluorescent Dyes/chemistry ; *Acetylcysteine/chemistry ; *Glutathione/analysis/blood ; *Homocysteine/analysis/blood ; Humans ; *Cysteine/analysis/blood ; *Spectrometry, Fluorescence/methods ; Sulfhydryl Compounds/analysis/chemistry/blood ; Limit of Detection ; Optical Imaging ; Coumarins/chemistry ; },
abstract = {Biothiols, including cysteine (Cys), homocysteine (Hcy), glutathione (GSH), and N-acetylcysteine (NAC), possess similar chemical structures and properties but play crucial, distinct roles in biological cells and blood serum. Imbalances in the concentrations of these biothiols are associated with various diseases, highlighting the importance of precise discrimination, especially between Cys and other biothiols. Owing to the similarity of the chemical properties of Cys, Hcy, GSH, and NAC, developing an effective methodology to differentiate these thiol compounds is challenging. In this study, we designed and synthesized a novel dual-channel fluorescent probe, hereafter referred to as CNTC, by integrating coumarin and acrylonitrile. This probe enabled the simultaneous discrimination of Cys from Hcy, GSH, and NAC, producing distinct fluorescent signals: blue for Cys and green for Hcy, GSH, and NAC. CNTC exhibited rapid response kinetics (within 30 min) and impressive detection limits of 0.31, 0.11, 0.029, and 0.032 μM for Cys, Hcy, GSH, and NAC, respectively. Furthermore, CNTC was successfully applied in the fluorescence imaging of both exogenous and endogenous Cys, Hcy, GSH, and NAC in living cells. The remarkable analytical and bioimaging capabilities of CNTCin vivo establish it as a promising tool for elucidating the pathophysiological roles of biothiols, particularly Cys, Hcy, GSH, and NAC.},
}
@article {pmid39353794,
year = {2024},
author = {Rajaratnam, G and Baldwin, AJ},
title = {"To BAL or not to BAL, that is the question": Variations in smoke inhalation injury guidelines from burn units and centres in England, Scotland and Wales.},
journal = {Burns : journal of the International Society for Burn Injuries},
volume = {50},
number = {9},
pages = {107273},
doi = {10.1016/j.burns.2024.09.012},
pmid = {39353794},
issn = {1879-1409},
mesh = {Humans ; *Smoke Inhalation Injury/therapy ; Cross-Sectional Studies ; *Practice Guidelines as Topic ; Wales ; Scotland ; England ; *Burn Units ; *Bronchoscopy/methods ; Bronchoalveolar Lavage/methods ; Adult ; Carbon Monoxide Poisoning/therapy ; Carboxyhemoglobin/analysis ; Guideline Adherence/statistics &amp; numerical data ; Acetylcysteine/therapeutic use ; },
abstract = {AIM: To evaluate variations in diagnostic criteria and management recommendations for smoke inhalation injury (SII) amongst the burn networks of England, Scotland, and Wales.<br><br>METHODS: A descriptive cross-sectional study examining SII guidelines provided by adult burn units and centres in England, Scotland and Wales.<br><br>RESULTS: All 16 adult burn units and centres responded. Fourteen (87.5&#xa0;%) had guidelines. Due to sharing of guidelines, ten unique guidelines were assessed. Diagnostic criteria showed variability with no universal criterion shared amongst guidelines. Bronchoscopy was recommended by 90&#xa0;% of guidelines, but the timing varied. The use of bronchoscopic scoring systems was recommended by four guidelines. Bronchoalveolar lavage (BAL) was recommended by four, with considerable variation in frequency and choice of lavage fluid. All guidelines advised at least one nebulised agent: heparin (n&#xa0;=&#xa0;8); N-acetyl cysteine (NAC) (n&#xa0;=&#xa0;8); or salbutamol (n&#xa0;=&#xa0;8). All guidelines included advice on carbon monoxide poisoning; however, carboxyhaemoglobin (COHb) cut-off levels for treatment varied (5&#xa0;% [n-4], 10&#xa0;% [n&#xa0;=&#xa0;3], 15&#xa0;% [n&#xa0;=&#xa0;1]). All recommended high-flow oxygen. Seven (70&#xa0;%) guidelines offered guidance on cyanide poisoning. Reduced/altered consciousness was the only consistent diagnostic criterion. Five (50&#xa0;%) guidelines provided intubation guidance, emphasising the role of a 'senior clinician' as the intubator. Ventilatory guidance appeared in eight guidelines, focusing on lung protective ventilation (n&#xa0;=&#xa0;8); oxygenation goals (n&#xa0;=&#xa0;3); and permissive hypercapnia (n&#xa0;=&#xa0;3). Within lung-protective ventilation, advice on tidal volume (6, or 6-8&#xa0;ml/kg) and plateau pressures (>30 cmH2O) were presented most commonly (n&#xa0;=&#xa0;7).<br><br>CONCLUSION: This study has outlined the substantial variations in guidance for the management of SII. The results underscore the need for a national guideline outlining a standardised approach to the diagnosis and management of SII, within the limitations of the current evidence.},
}
@article {pmid39351494,
year = {2024},
author = {Li, P and Zhou, H and Yang, Y and Wu, M and Zhao, D and Wang, L and Yi, D and Hou, Y},
title = {Dietary supplementation with N-acetylcysteine confers a protective effect on muscle and liver in lipopolysaccharide-challenged piglets.},
journal = {Frontiers in nutrition},
volume = {11},
number = {},
pages = {1458912},
pmid = {39351494},
issn = {2296-861X},
abstract = {N-acetylcysteine (NAC) is a well-established antioxidant that offers exciting opportunities for intestinal health in weaned piglets, while the effects of NAC on muscle and liver has not been fully characterized. Therefore, the present study was performed to investigate the effects of dietary supplementation with NAC on muscle and liver in weaned piglets challenged with lipopolysaccharide (LPS). Twenty-four piglets (24-day-old) were randomly assigned to three treatment groups, the piglets in the control (CTR) and LPS- challenged (LPS) groups were fed the basal diet and those in the LPS+ NAC group was fed the basal diet supplemented with 500 mg/kg NAC. The animal trial lasted for 21 days. At the end of the trial, piglets in the LPS and LPS+ NAC groups were injected intraperitoneally with LPS (100 μg/kg body weight) and piglets in the CTR group were administrated with an equal volume of normal saline. 3 h later, the blood was collected and tissue samples were obtained after 6 h of LPS or normal saline treatment. The results showed that the level of IL-1β, and the mRNA levels of C-X-C motif chemokine receptor 3 (CXCR3) and interferon-γ (IFN-γ) in the liver were up-regulated, and the mRNA levels of insulin-like growth factor 1 (IGF-1), total glutathione (T-GSH), and the ratio of total protein to DNA in the liver were decreased under LPS challenge (P < 0.05). At the same time, LPS increased the level of H2O2 and decreased the content of T-GSH and DNA in the longissimus dorsi and gastrocnemius muscles (P < 0.05). In addition, the percentage of monocytes and the level of epidermal growth factor (EGF) were down-regulated in the LPS treatment (P < 0.05). Interestingly, dietary NAC supplementation reversed the above changes induced by LPS (P < 0.05). Furthermore, NAC might alleviate the muscle and liver injury in LPS-challenged piglets by regulating the expression of genes related to the type I interferon signaling pathway, as well as hypoxia inducible factor 1 (HIF1) and nuclear factor erythroid-2 related factor 2 (Nrf-2). Our findings suggested that dietary supplementation with NAC could benefit the health of muscle and liver in LPS-challenged weaned piglets.},
}
@article {pmid39349423,
year = {2024},
author = {Wang, SH and Lee, DS and Kim, TH and Kim, JE and Kang, TC},
title = {Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.},
journal = {Cell death &amp; disease},
volume = {15},
number = {9},
pages = {707},
pmid = {39349423},
issn = {2041-4889},
support = {2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; 2021R1A2C4002003//National Research Foundation of Korea (NRF)/ ; },
mesh = {Animals ; *Mitochondrial Dynamics/drug effects ; *Oxidative Stress/drug effects ; *Dynamins/metabolism/genetics ; *Glutathione Peroxidase GPX1 ; *NF-kappa B/metabolism ; *Signal Transduction ; *Parvalbumins/metabolism ; *Cyclin-Dependent Kinase 5/metabolism/genetics ; *Glutathione Peroxidase/metabolism/genetics ; *Down-Regulation/drug effects ; Neurons/metabolism/drug effects ; Male ; Mice ; Quinazolinones/pharmacology ; Phosphorylation/drug effects ; Buthionine Sulfoximine/pharmacology ; Mitochondria/metabolism/drug effects ; },
abstract = {Loss of parvalbumin (PV) expressing neurons (PV neurons) is relevant to the underlying mechanisms of the pathogenesis of neurological and psychiatric diseases associated with the dysregulation of neuronal excitatory networks and brain metabolism. Although PV modulates mitochondrial morphology, volume and dynamics, it is largely unknown whether mitochondrial dynamics affect PV expression and what the molecular events are responsible for PV neuronal degeneration. In the present study, L-buthionine sulfoximine (BSO, an inhibitor of glutathione synthesis) did not degenerate PV neurons under physiological condition. However, BSO-induced oxidative stress decreased PV expression and facilitated cyclin-dependent kinase 5 (CDK5) tyrosine (Y) 15 phosphorylation, dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and glutathione peroxidase-1 (GPx1) downregulation in PV neurons. Co-treatment of roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission) attenuated BSO-induced PV downregulation. WY14643 (an inducer of mitochondrial fission) reduced PV expression without affecting CDK5 Y15 phosphorylation. Following status epilepticus (SE), CDK5 Y15 phosphorylation and mitochondrial fission were augmented in PV neurons. These were accompanied by reduced GPx1-mediated inhibition of NF-κB p65 serine (S) 536 phosphorylation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.},
}
@article {pmid39348347,
year = {2024},
author = {Komal, W and Fatima, S and Minahal, Q and Liaqat, R and Hussain, AS},
title = {Assessing the effects of N-acetyl cysteine on growth, antioxidant and immune response in tilapia (Oreochromis niloticus) under different regimes of stocking densities.},
journal = {PloS one},
volume = {19},
number = {9},
pages = {e0307212},
pmid = {39348347},
issn = {1932-6203},
mesh = {Animals ; *Antioxidants/metabolism/pharmacology ; *Acetylcysteine/pharmacology ; *Dietary Supplements ; Hydrocortisone/metabolism ; Cichlids/growth &amp; development/immunology/metabolism ; Superoxide Dismutase/metabolism ; Animal Feed/analysis ; Catalase/metabolism ; Tilapia/growth &amp; development/immunology/metabolism ; Aquaculture/methods ; Glutathione Peroxidase/metabolism ; },
abstract = {The study investigated the impact of N-acetyl cysteine on growth, immune response, and antioxidant activity in tilapia (Oreochromis niloticus). Fish were reared at three densities (1.50, 3.00, and 4.50 kg/m3) with four levels of N-acetyl cysteine supplementation (0, 2, 4, and 6 mg/kg) over 60 days. Better growth was observed at low density, but at all densities, fish fed the highest N-acetyl cysteine level (6 mg/kg) showed improved growth. Chemical composition of fish and activity of amylase, lipase and protease in all treatments were noted to be insignificant. The levels of antioxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) and cortisol in HD treatments were high as compared to LD and MD treatment. However, fish fed with N3 diet in each density treatment showed the lowest level of antioxidant enzymes as well as cortisol. Similarly, the levels of malondialdehyde were noted to be high at HD treatments as compared to that in LD and MD. Its levels were lower in fish fed with N3 diets in all density treatments. Expression of somatostatins-1 did not increase in MD and HD treatments in response to high stocking density when compared with LD treatment. However, pro-opiomelanocortin-α level was reduced after N3 diet in HD treatment and interleukin 1-β expression increased after N3 supplement in HD treatment. In conclusion, N-acetyl cysteine supplementation improved growth and antioxidant response in tilapia. The most optimum dose of N-acetyl cysteine was noted to be 6 mg/kg at high stocking, suggesting the potential role of this nutraceutical in tilapia intensive culture.},
}
@article {pmid39342748,
year = {2024},
author = {Zhang, S and Wang, D and Ding, Y and Li, Y and Wang, Y and Zeng, J},
title = {Inhibition of calpain reduces oxidative stress and attenuates pyroptosis and ferroptosis in Clostridium perfringens Beta-1 toxin-induced macrophages.},
journal = {Microbiological research},
volume = {289},
number = {},
pages = {127916},
doi = {10.1016/j.micres.2024.127916},
pmid = {39342748},
issn = {1618-0623},
mesh = {*Pyroptosis/drug effects ; *Ferroptosis/drug effects ; *Macrophages/drug effects/metabolism ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Bacterial Toxins/metabolism/toxicity ; Mice ; Animals ; *Calpain/metabolism ; Humans ; Clostridium perfringens/drug effects/metabolism ; Hydrogen Peroxide/metabolism ; Mitochondrial Proton-Translocating ATPases/metabolism ; RAW 264.7 Cells ; Acetylcysteine/pharmacology/metabolism ; Inflammation/metabolism ; },
abstract = {Clostridium perfringens Beta-1 toxin (CPB1) is a lethal toxin, which can lead to necrotic enteritis, but the pathological mechanism has not been elucidated. We investigated whether reactive oxygen species (ROS) participated in CPB1-induced pyroptosis and ferroptosis, and investigated the effects of calpain on CPB1-induced oxidative stress and inflammation. Scavenging ROS by N-Acetyl-L cysteine (NAC) led to the reduction of ROS, inhibited the death of macrophages, cytoplasmic swelling and membrane rupture, the expression of pyroptosis-related proteins and proinflammatory factor, while increased the expression of anti-inflammatory factors in cells treated with rCPB1. Adenosine triphosphate (ATP) synthase, H[+] transporting, mitochondrial F1 complex, alpha subunit 1 (ATP5A1) was identified specifically interact with rCPB1. Silencing ATP5A1 inhibited accumulation of ATP and ROS, leaded to less cytoplasmic swelling and membrane rupture, attenuated pyroptosis and inflammation in rCPB1-treated cells. We also found that rCPB1 induces ferroptosis in macrophages, and the level of ferroptosis was similar with H2O2. Of note, H2O2 is a major ROS source, indicated that ROS production may play a major role in the regulation of ferroptosis in macrophages treated with rCPB1. This finding was further corroborated in rCPB1- induced human acute monocytic leukemia cells, which were treated with NAC. In addition, the inhibition of ferroptosis using liproxstatin-1 inhibited the shriveled mitochondrial morphology, increased the expression of glutathione peroxidase 4, nicotinamide adenine dinucleotide (phosphate) hydrogen: quinone oxidoreductase 1 and cysteine/glutamic acid reverse transport solute carrier family 7 members 11, decreased the expression of heme oxygenase 1, nuclear receptor coactivator 4 and transferrin receptor proteins, reduced malondialdehyde and lipid peroxidation levels, and increased intracellular L-glutathione levels in cells treated with rCPB1. Furthermore, calpain inhibitor PD151746 was used to investigate how pyroptosis and ferroptosis were involved simultaneously in rCPB1-treated macrophages. We showed that PD151746 inhibited ATP and ROS production, reversed the representative pyroptosis/ferroptosis indicators and subsequently reduced inflammation. The above findings indicate that rCPB1 might lead to macrophage pyroptosis and ferroptosis through the large and sustained increase in intracellular calpain and oxidative stress, further lead to inflammation.},
}
@article {pmid39339978,
year = {2024},
author = {Wang, Y and Luan, T and Wang, L and Feng, D and Dong, Y and Li, S and Yang, H and Chen, Y and Fei, Y and Lin, L and Pan, J and Zhong, Z and Zhao, W},
title = {N-Acetylcysteine Inhibits Coxsackievirus B3 Replication by Downregulating Eukaryotic Translation Elongation Factor 1 Alpha 1.},
journal = {Viruses},
volume = {16},
number = {9},
pages = {},
pmid = {39339978},
issn = {1999-4915},
mesh = {Animals ; Humans ; Male ; Mice ; *Acetylcysteine/pharmacology ; Antiviral Agents/pharmacology ; Cell Line ; *Coxsackievirus Infections/drug therapy/virology ; *Down-Regulation/drug effects ; *Enterovirus B, Human/drug effects/physiology ; Myocarditis/virology/drug therapy ; *Peptide Elongation Factor 1/metabolism/genetics ; *Virus Replication/drug effects ; },
abstract = {Group B Coxsackieviruses (CVB) are one of the causative pathogens of myocarditis, which may progress to cardiomyopathy. The pathogenesis of CVB is not fully understood, and effective antiviral therapy is not available. N-acetylcysteine (NAC), the classic antioxidant, has been used in clinical practice for several decades to treat various medical conditions. In this study, the anti-CVB effect of NAC was investigated. We show that NAC dramatically suppressed viral replication and alleviated cardiac injury induced by CVB3. To further study the antiviral mechanism of NAC, RNA-sequencing was performed for CVB3-infected cells with NAC treatment. We found that eukaryotic elongation factor 1 alpha 1 (EEF1A1) is one of the most upregulated genes in CVB3-infected cells. However, EEF1A2, the highly homologous isoform of EEF1A1, remains unchanged. EEF1A1 expression was significantly suppressed by NAC treatment in CVB3-infected cells, while EEF1A2 was not affected. eEF1A1 knockdown significantly inhibited CVB3 replication, implicating that eEF1A1 facilitates viral replication. Importantly, we show that eEF1A1, which was not expressed in the myocardia of newborn mice, was significantly upregulated by CVB3 infection. NAC markedly downregulated the expression of eEF1A1 but not eEF1A2 in the myocardia of CVB3-infected mice. Furthermore, NAC accelerated eEF1A1 degradation by promoting autophagy in CVB3-infected cells. We show that p62, one of the critical adaptors of autophagic targets, interacts with eEF1A1 and was downregulated in CVB3-infected cells upon NAC treatment. Taken together, this study demonstrated that NAC shows a potent anti-CVB effect through the downregulation of eEF1A1.},
}
@article {pmid39339161,
year = {2024},
author = {Alam, MI and Paget, T and Moosa, NY and Alghurairy, H and Elkordy, AA},
title = {Liposomal Drug Delivery against Helicobacter pylori Using Furazolidone and N-Acetyl Cysteine in Augmented Therapy.},
journal = {Pharmaceutics},
volume = {16},
number = {9},
pages = {},
pmid = {39339161},
issn = {1999-4923},
abstract = {Helicobacter pylori (H. pylori) infection is a significant global health concern, affecting approximately 50% of the world's population and leading to gastric ulcers, gastritis, and gastric cancer. The increase in antibiotic resistance has compromised the efficacy of existing therapeutic regimens, necessitating novel approaches for effective eradication. This study aimed to develop a targeted liposomal drug delivery system incorporating furazolidone and N-acetylcysteine (NAC) to enhance mucopenetration and improve Helicobacter pylori eradication. Liposomes were formulated with furazolidone, NAC, and Pluronic F-127 using a modified reverse-phase evaporation technique. The formulations were categorized based on charge as neutral, negative, and positive and tested for mucopenetration using a modified silicon tube method with coumarin-6 as a fluorescent marker. The encapsulation efficiency and particle size were analyzed using HPLC and an Izon q-nano particle size analyzer. The results indicated that charged liposomes showed a higher encapsulation efficiency than neutral liposomes with Pluronic F-127. Notably, combining furazolidone with 1% NAC achieved complete eradication of H. pylori in 2.5 h, compared to six hours without NAC. The findings of this study suggest that incorporating NAC and Pluronic F-127 into liposomal formulations significantly enhances mucopenetration and antimicrobial efficacy.},
}
@article {pmid39337681,
year = {2024},
author = {Zhang, M and Chai, ZH and Zhang, C and Chen, L},
title = {Unbalanced Expression of Structural Genes in Carotenoid Pathway Contributes to the Flower Color Formation of the Osmanthus Cultivar 'Yanzhi Hong'.},
journal = {International journal of molecular sciences},
volume = {25},
number = {18},
pages = {},
pmid = {39337681},
issn = {1422-0067},
support = {BK20200786//Natural Science Foundation of Jiangsu Province/ ; 2019M651839//China Postdoctoral Science Foundation/ ; CX2019029//Innovation Fund for Young Scholars of Nanjing Forestry University/ ; 32071782//National Natural Science Foundation of China/ ; },
mesh = {*Carotenoids/metabolism ; *Flowers/genetics/metabolism/growth &amp; development ; *Gene Expression Regulation, Plant ; *Pigmentation/genetics ; *Oleaceae/genetics/metabolism/growth &amp; development ; Plant Proteins/genetics/metabolism ; Gene Expression Profiling/methods ; },
abstract = {Carotenoids are important natural pigments that are responsible for the fruit and flower colors of many plants. The composition and content of carotenoid can greatly influence the color phenotype of plants. However, the regulatory mechanism underling the divergent behaviors of carotenoid accumulation, especially in flower, remains unclear. In this study, a new cultivar Osmanthus fragrans 'Yanzhi Hong' was used to study the regulation of carotenoid pigmentation in flower. Liquid chromatograph-mass spectrometer (LC-MS) analysis showed that β-carotene, phytoene, lycopene, γ-carotene, and lutein were the top five pigments enriched in the petals of 'Yanzhi Hong'. Through transcriptome analysis, we found that the expression of the structural genes in carotenoid pathway was imbalanced: most of the structural genes responsible for lycopene biosynthesis were highly expressed throughout the flower developmental stages, while those for lycopene metabolism kept at a relatively lower level. The downregulation of LYCE, especially at the late developmental stages, suppressed the conversion from lycopene to α-carotene but promoted the accumulation of β-carotene, which had great effect on the carotenoid composition of 'Yanzhi Hong'. Ethylene response factor (ERF), WRKY, basic helix-loop-helix (bHLH), v-myb avian myeloblastosis viral oncogene homolog (MYB), N-Acetylcysteine (NAC), auxin response factor (ARF), and other transcription factors (TFs) have participated in the flower color regulation of 'Yanzhi Hong', which formed co-expression networks with the structural genes and functioned in multiple links of the carotenoid pathway. The results suggested that the cyclization of lycopene is a key link in determining flower color. The modification of the related TFs will break the expression balance between the upstream and downstream genes and greatly influence the carotenoid profile in flowers, which can be further used for creating colorful plant germplasms.},
}
@article {pmid39337474,
year = {2024},
author = {Stachura, A and Sobczak, M and Kędra, K and Kopka, M and Kopka, K and Włodarski, PK},
title = {The Influence of N-Acetylcysteine-Enriched Hydrogels on Wound Healing in a Murine Model of Type II Diabetes Mellitus.},
journal = {International journal of molecular sciences},
volume = {25},
number = {18},
pages = {},
pmid = {39337474},
issn = {1422-0067},
support = {1MN/2/MG/N/20//Medical University of Warsaw/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Hydrogels/chemistry ; *Wound Healing/drug effects ; Mice ; *Diabetes Mellitus, Type 2/drug therapy ; *Disease Models, Animal ; Skin/drug effects/pathology ; Male ; Cell Proliferation/drug effects ; Antioxidants/pharmacology ; Diabetes Mellitus, Experimental/drug therapy ; },
abstract = {Diabetes mellitus (DM) severely impairs skin wound healing capacity, yet few treatment options exist to enhance this process. N-acetylcysteine (NAC) is an antioxidant that improves cellular proliferation and enhances wound healing in healthy animals, yet its use in the context of type II DM has not been studied. The aim of our research was to investigate the effect of topically applied NAC-enriched hydrogels on wound healing in a leptin-deficient murine wound model. Four excisional wounds were created on the backs of 20 db/db mice and were subsequently treated with hydrogels containing NAC at concentrations of 5%, 10% and 20% or placebo (control). Healing was monitored for 28 days; photographs of the wounds were taken on every third day. Wound tissues were harvested on days 3, 7, 14 and 28 to undergo histological examinations. Wounds treated with 5% NAC showed improved wound closure speed accompanied by an increased dermal proliferation area on microscopic assessment compared with other groups. Higher concentrations of NAC failed to show a beneficial effect on wound healing. 5% NAC improved early stages of wound healing in a murine model of type II DM by increasing wound closure speed, likely mediated by improved dermal proliferation.},
}
@article {pmid39337344,
year = {2024},
author = {Morabito, C and Di Sinno, N and Mariggiò, MA and Guarnieri, S},
title = {Impact of Extremely Low-Frequency Electromagnetic Fields on Skeletal Muscle of Sedentary Adult Mice: A Pilot Study.},
journal = {International journal of molecular sciences},
volume = {25},
number = {18},
pages = {},
pmid = {39337344},
issn = {1422-0067},
mesh = {Animals ; *Electromagnetic Fields/adverse effects ; Mice ; Male ; Pilot Projects ; *Muscle, Skeletal/metabolism/radiation effects ; *Oxidative Stress/radiation effects ; *Mice, Inbred C57BL ; *Superoxide Dismutase-1/metabolism ; Acetylcysteine/pharmacology ; Myosin Heavy Chains/metabolism ; Antioxidants/metabolism ; PAX7 Transcription Factor/metabolism ; Sedentary Behavior ; Muscle Strength/radiation effects ; Catalase/metabolism ; },
abstract = {Extremely low-frequency electromagnetic fields (ELF-EMFs) are ubiquitous in industrialized environments due to the continuous use of electrical devices. Our previous studies demonstrated that ELF-EMFs affect muscle cells by modulating oxidative stress and enhancing myogenesis. This pilot study investigated these effects on the skeletal muscles of sedentary adult mice, assessing physiological responses to ELF-EMF exposure and potential modulation by antioxidant supplementation. Male C57BL/6 mice were exposed to ELF-EMFs (0.1 or 1.0 mT) for 1 h/day for up to 5 weeks and fed a standard diet without or with N-acetyl-cysteine (NAC). The results showed transient increases in muscle strength (after 2 weeks of exposure at 1.0 mT), potentially linked to muscle fiber recruitment and activation, revealed by higher PAX7 and myosin heavy chain (MyH) expression levels. After ELF-EMF exposure, oxidative status assessment revealed transient increases in the expression levels of SOD1 and catalase enzymes, in total antioxidant capacity, and in protein carbonyl levels, markers of oxidative damage. These effects were partially reduced by NAC. In conclusion, ELF-EMF exposure affects skeletal muscle physiology and NAC supplementation partially mitigates these effects, highlighting the complex interactions between ELF-EMFs and antioxidant pathways in vivo. Further investigations on ELF-EMFs as a therapeutic modality for muscle health are necessary.},
}
@article {pmid39332540,
year = {2024},
author = {Yao, Z and Xue, K and Chen, J and Zhang, Y and Zhang, G and Zheng, Z and Li, Z and Li, Z and Wang, F and Sun, X and Shen, L and Mao, C and Lin, C},
title = {Biliverdin improved angiogenesis and suppressed apoptosis via PI3K/Akt-mediated Nrf2 antioxidant system to promote ischemic flap survival.},
journal = {Free radical biology &amp; medicine},
volume = {225},
number = {},
pages = {35-52},
doi = {10.1016/j.freeradbiomed.2024.09.042},
pmid = {39332540},
issn = {1873-4596},
mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; Humans ; *Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; *Apoptosis/drug effects ; Animals ; *Phosphatidylinositol 3-Kinases/metabolism/genetics ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects ; *Neovascularization, Physiologic/drug effects ; *Surgical Flaps ; *Ischemia/metabolism/drug therapy/pathology ; *Biliverdine/metabolism/pharmacology ; *Antioxidants/pharmacology ; Hydrogen Peroxide/metabolism ; Mice ; Reactive Oxygen Species/metabolism ; Cell Proliferation/drug effects ; Oxidative Stress/drug effects ; Male ; Angiogenesis ; },
abstract = {Plastic and reconstructive surgeons frequently utilize random skin flap transplantation to repair skin defects. However, the procedure carries a substantial risk of necrosis. Previous research has suggested that Biliverdin (Bv), the main component of Calculus Bovis, possessed potent anti-ischemic properties, making it a potential therapeutic agent for skin flap survival. Hence, in this study, the potential of Bv in promoting flap survival has been comprehensively investigated. Network pharmacology analysis revealed that the pharmacological effects of Bv on ischemic diseases may be attributed to its modulation of various signaling molecules, including the PI3K-Akt pathway. In vitro results demonstrated that Bv treatment significantly promoted angiogenesis in human umbilical vein endothelial cells (HUVEC), even in the presence of H2O2. This was evident by the increased cell proliferation, enhanced migration, and improved tube formation. Bv also effectively attenuated the intracellular generation of reactive oxygen species (ROS) induced by H2O2, which was achieved by suppressing mitochondrial ROS production through the PI3K/Akt-mediated activation of Nrf2/HO-1 signaling pathway. Consequently, Bv treatment led to a significant reduction in apoptosis and an increase in cell viability of HUVEC. Furthermore, in vivo experiment demonstrated that Bv treatment vastly elevated flap survival through enhancing angiogenesis while decreasing oxidative stress and apoptosis, which was comparable to the results of positive control of N-acetylcysteine (Nac). In conclusion, this study not only established a solid foundation for future study on therapeutic potential of Bv, but also proposed a promising treatment approach for enhancing the success rate of flap transplants and other ischemic-related tissue repair.},
}
@article {pmid39331828,
year = {2025},
author = {Moraes, LGDS and Oliveira, VC and Macedo, AP and Freiria de Oliveira, CA and Watanabe, E and Pagnano, VO},
title = {Enhancing Removable Partial Denture Hygiene: Investigating Mucolytic Agents and Biocides for Disrupting Biofilms and Improving Antimicrobial Efficacy.},
journal = {The International journal of prosthodontics},
volume = {38},
number = {5},
pages = {559-569},
doi = {10.11607/ijp.9133},
pmid = {39331828},
issn = {1942-4426},
mesh = {*Biofilms/drug effects ; Candida albicans/drug effects ; Streptococcus mutans/drug effects ; Cetylpyridinium/pharmacology ; *Denture, Partial, Removable/microbiology ; Peracetic Acid/pharmacology ; Staphylococcus aureus/drug effects ; Acetylcysteine/pharmacology ; Candida glabrata/drug effects ; Acrylic Resins/chemistry ; *Denture Cleansers/pharmacology ; *Anti-Infective Agents/pharmacology ; Surface Properties ; },
abstract = {PURPOSE: To evaluate the antibiofilm action of 2.5 mg/mL peracetic acid (PA), 0.5 mg/mL cetylpyridinium chloride (CPC), and 160 mg/mL N-acetylcysteine (NAC) against multispecies biofilm of Streptococcus mutans, Staphylococcus aureus, Candida albicans, and Candida glabrata developed on surfaces of heat-polymerizing acrylic resin (AR) and cobalt-chromium (Co-Cr) alloy.<br><br>MATERIALS AND METHODS: A multispecies biofilm was grown on the surface of AR and Co-Cr specimens (&#xd8; 12 &#xd7; 3 mm). After biofilm maturation, the specimens were immersed in experimental solutions and evaluated through biofilm viability (CFU; n = 9), biofilm metabolic activity (XTT; n = 9), biofilm-covered areas (live/dead; n = 2), effects on the extracellular polymeric substance (EPS; n = 2), and biofilm morphology (n = 1). Data were analyzed by ANOVA and Tukey post-hoc test or Kruskal-Wallis followed by Dunn post-hoc test (&#x3b1; = .05).<br><br>RESULTS: Overall, all evaluated solutions impacted biofilm viability. PA presented wider activity by reducing CFU of all microorganisms on both surfaces, XTT (P < .001) and live/dead (P < .001). NAC had a notorious effect in reducing the viability of bacteria without affecting the yeasts. NAC reduced XTT on AR (P = .006) and Co-Cr (P = .003) but did not reduce the aggregated biofilm layer. CPC had a distinct effect, being most effective in reducing CFU on AR compared to the Co-Cr surface. However, it did not influence XTT or the amount of residual aggregated biofilm.<br><br>CONCLUSIONS: PA provided the greatest antibiofilm action, while CPC and NAC showed intermediate action. Nonetheless, no solution was able to completely remove the biofilm adhered to the surfaces of heat-polymerizing AR and Co-Cr alloy.},
}
@article {pmid39319193,
year = {2024},
author = {Attiq, A and Afzal, S and Wahab, HA and Ahmad, W and Kandeel, M and Almofti, YA and Alameen, AO and Wu, YS},
title = {Cytokine Storm-Induced Thyroid Dysfunction in COVID-19: Insights into Pathogenesis and Therapeutic Approaches.},
journal = {Drug design, development and therapy},
volume = {18},
number = {},
pages = {4215-4240},
pmid = {39319193},
issn = {1177-8881},
mesh = {Humans ; *COVID-19/complications ; *Cytokine Release Syndrome/drug therapy/etiology ; *SARS-CoV-2 ; *COVID-19 Drug Treatment ; Cytokines/metabolism ; Thyroid Diseases/drug therapy/metabolism ; Angiotensin-Converting Enzyme 2/metabolism ; Thyroid Gland/metabolism/physiopathology ; },
abstract = {Angiotensin-converting enzyme 2 receptors (ACE2R) are requisite to enter the host cells for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). ACE2R is constitutive and functions as a type I transmembrane metallo-carboxypeptidase in the renin-angiotensin system (RAS). On thyroid follicular cells, ACE2R allows SARS-CoV-2 to invade the thyroid gland, impose cytopathic effects and produce endocrine abnormalities, including stiff back, neck pain, muscle ache, lethargy, and enlarged, inflamed thyroid gland in COVID-19 patients. Further damage is perpetuated by the sudden bursts of pro-inflammatory cytokines, which is suggestive of a life-threatening syndrome known as a "cytokine storm". IL-1β, IL-6, IFN-γ, and TNF-α are identified as the key orchestrators of the cytokine storm. These inflammatory mediators upregulate transcriptional turnover of nuclear factor-kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and mitogen-activated protein kinase (MAPK), paving the pathway for cytokine storm-induced thyroid dysfunctions including euthyroid sick syndrome, autoimmune thyroid diseases, and thyrotoxicosis in COVID-19 patients. Targeted therapies with corticosteroids (dexamethasone), JAK inhibitor (baricitinib), nucleotide analogue (remdesivir) and N-acetyl-cysteine have demonstrated effectiveness in terms of attenuating the severity and frequency of cytokine storm-induced thyroid dysfunctions, morbidity and mortality in severe COVID-19 patients. Here, we review the pathogenesis of cytokine storms and the mechanisms and pathways that establish the connection between thyroid disorder and COVID-19. Moreover, cross-talk interactions of signalling pathways and therapeutic strategies to address COVID-19-associated thyroid diseases are also discussed herein.},
}
@article {pmid39313073,
year = {2025},
author = {Fort, TD and Azuma, MC and Laux, DA and Cain, ME},
title = {Environmental enrichment and sex, but not n-acetylcysteine, alter extended-access amphetamine self-administration and cue-seeking.},
journal = {Behavioural brain research},
volume = {476},
number = {},
pages = {115261},
pmid = {39313073},
issn = {1872-7549},
support = {P20 GM113109/GM/NIGMS NIH HHS/United States ; R15 DA035435/DA/NIDA NIH HHS/United States ; },
mesh = {Animals ; *Cues ; Male ; Female ; *Amphetamine/pharmacology/administration &amp; dosage ; *Self Administration ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Rats, Sprague-Dawley ; *Central Nervous System Stimulants/pharmacology/administration &amp; dosage ; *Environment ; Drug-Seeking Behavior/drug effects/physiology ; Rats ; Nucleus Accumbens/drug effects/metabolism ; Astrocytes/drug effects/metabolism ; Sex Characteristics ; Prefrontal Cortex/drug effects/metabolism ; },
abstract = {There are no approved therapeutics for psychostimulant use and recurrence of psychostimulant use. However, in preclinical rodent models environmental enrichment can decrease psychostimulant self-administration of low unit doses and cue-induced amphetamine seeking. We have previously demonstrated that glutamate-dependent therapeutics are able to alter amphetamine seeking to amphetamine-associated cues only in enriched rats. In the current experiment, we will determine if enrichment can attenuate responding and cue-induced amphetamine seeking during extended access to a high dose of intravenous amphetamine. We will also determine if N-acetylcysteine (NAC), a glutamate dependent therapeutic, can attenuate amphetamine seeking in differentially reared rats. Female and male Sprague-Dawley rats were reared in enriched, isolated, or standard conditions from postnatal day 21-51. Rats were trained to self-administer intravenous amphetamine (0.1 mg/kg/infusion) during twelve 6-hour sessions. During the abstinence period, NAC (100 mg/kg) or saline was administered daily. Following a cue-induced amphetamine-seeking test, astrocyte densities within regions of the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb) were quantified using immunohistochemistry. Environmental enrichment decreased responding for amphetamine and during the cue-induced amphetamine-seeking test. NAC did not attenuate cue-induced amphetamine seeking or alter astrocyte density. Across all groups, female rats self-administered less amphetamine but responded more during cue-induced amphetamine seeking than male rats. While amphetamine increased astrocyte densities within the ACb and mPFC, it did not alter mPFC astrocyte densities in female rats. The results suggest that enrichment can attenuate responding during extended access to a high dose of amphetamine and the associated cues. Sex alters amphetamine-induced changes to astrocyte densities in a regionally specific matter.},
}
@article {pmid39312385,
year = {2024},
author = {Dinç, M and Soydemir, &#xd6;C},
title = {Efficacy of N-acetylcysteine in reducing inflammation and oxidative stress to prevent complex regional pain syndrome type 1.},
journal = {Medicine},
volume = {103},
number = {38},
pages = {e39742},
pmid = {39312385},
issn = {1536-5964},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Female ; Male ; *Oxidative Stress/drug effects ; Middle Aged ; *Reflex Sympathetic Dystrophy/drug therapy/blood ; Retrospective Studies ; Aged ; Inflammation/blood/prevention &amp; control ; Radius Fractures ; Antioxidants/therapeutic use ; Biomarkers/blood ; Cytokines/blood ; Tumor Necrosis Factor-alpha/blood ; },
abstract = {This study aimed to evaluate the effectiveness of N-acetylcysteine (NAC) in preventing complex regional pain syndrome type 1 (CRPS-1) by reducing proinflammatory cytokines and oxidative stress markers in patients with distal radius fractures. A retrospective single-center study at Bursa City Hospital involves patients over 50 years of age with distal radius fractures treated between January 2021 and December 2023. A total of 60 patients (mean age, 62.8 ± 5.1 years; 26 males and 34 females) were analyzed. Patients were divided into 2 groups: the NAC group (31 patients receiving 600-mg NAC daily for 3 months) and the control group (29 patients with no prophylactic medication). CRPS-1 diagnosis was based on Budapest criteria during multiple follow-up visits. Serum levels of interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha (TNF-α), total oxidant status (TOS), and total antioxidant status (TAS) were measured at baseline and study end point. CRPS-1 positive patients had significantly higher levels of IL-6, TNF-α, and IL-1 (P < .001 for all), higher TOS (P < .001) and oxidative stress index (P < .001), and lower TAS (P < .001) compared with CRPS-1 negatives. The incidence of CRPS-1 was significantly lower in the NAC group (9.7%) compared with the control group (31.0%; P = .039). Logistic regression indicated a 78% reduction in CRPS-1 odds ratio with NAC treatment (odds ratio, 0.219 [95% confidence interval, 0.053-0.895]; P = .0322). NAC significantly reduced end-point levels and changes in IL-6 (P < .001), TNF-α (P < .001), and IL-1 (P = .038) and improved oxidative stress markers, showing higher TAS (P < .001), lower TOS (P < .001), and oxidative stress index (P < .001) compared with controls. NAC significantly reduced the risk of developing CRPS-1 by decreasing levels of proinflammatory cytokines and oxidative stress. This study highlights NAC's potential as a preventive treatment for CRPS-1 and emphasizes the importance of early intervention.},
}
@article {pmid39312076,
year = {2024},
author = {Xue, Y and Bian, H and Bai, S and Bao, Z and Wang, L and Wang, S and Zhao, B and Wu, X and Chen, Y},
title = {N-acetylcysteine mitigates oxidative damage to the ovary in D-galactose-induced ovarian failure in rabbits.},
journal = {Molecular biology reports},
volume = {51},
number = {1},
pages = {1008},
pmid = {39312076},
issn = {1573-4978},
support = {CARS-43-A-1//China Agriculture Research System of MOF and MARA/ ; 2022//Qing Lan Project of Yangzhou university/ ; },
mesh = {Animals ; Rabbits ; Female ; *Acetylcysteine/pharmacology ; *Galactose/adverse effects/pharmacology ; *Oxidative Stress/drug effects ; *Ovary/drug effects/metabolism/pathology ; Primary Ovarian Insufficiency/chemically induced/metabolism/pathology ; Granulosa Cells/metabolism/drug effects ; Antioxidants/pharmacology/metabolism ; Superoxide Dismutase/metabolism ; Glutathione/metabolism ; Catalase/metabolism ; Disease Models, Animal ; },
abstract = {BACKGROUND: Oxidative damage to the ovaries is the primary cause of impaired reproductive functions in female animals. This study aimed to investigate the protective role of N-Acetyl-L-cysteine (NAC) in reducing oxidative damage in the ovaries of female rabbits.<br><br>METHODS AND RESULTS: Female rabbit ovaries were treated in vitro with varying concentrations of D-galactose (D-gal): 0, 5, 10, and 15 mg/mL, and it was found that 10 mg/mL D-gal significantly disrupted follicular structures, causing disarray in granulosa cell arrangements and significantly reducing T-SOD and GSH levels (p&#x2009;<&#x2009;0.01). Consequently, we selected 10 mg/mL D-gal to establish an ovarian failure model. These models were treated with multiple doses of NAC (0, 0.1, 0.3, 0.5 mg/mL). The results revealed that the disruption in granulosa cell arrangement caused by 10 mg/mL D-gal was effectively alleviated by 0.1&#xa0;mg/mL NAC compared to the D-gal treatment group. Furthermore, 10 mg/mL D-gal significantly (p&#x2009;<&#x2009;0.01) reduced GSH, T-SOD, and catalase (CAT) levels in the ovaries. However, 0.1 mg/mL NAC effectively (p&#x2009;<&#x2009;0.01) suppressed these adverse effects. Moreover, the current results showed that 10 mg/mL D-gal alone significantly (p&#x2009;<&#x2009;0.01) downregulated the expression of Nrf2, GPX, PRDX4, GSR, SOD1, and TAF4B, whereas 0.1 mg/mL NAC counteracted these suppressive effects (p&#x2009;<&#x2009;0.01).<br><br>CONCLUSIONS: It could be concluded that NAC may delay ovarian failure by reducing D-gal-induced ovarian oxidative damage in female rabbit, suggested NAC could be a promising therapeutic agent for protecting against ovarian failure and potentially delaying ovarian failure in female rabbits.},
}
@article {pmid39309000,
year = {2024},
author = {Cuocina, M and Aiello, G and Cutrufelli, P and Rampello, M and Rapisarda, L and Rodolico, A and Cantarella, G and Signorelli, MS and Bernardini, R},
title = {Effect of N-acetylcysteine on craving in substance use disorders (SUD): a meta-analysis of randomized controlled trials.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1462612},
pmid = {39309000},
issn = {1663-9812},
abstract = {BACKGROUND: N-acetyl cysteine (NAC) appears promising as a treatment in patients with substance use disorder (SUD) as it helps rebalance glutamate levels in the central nervous system (CNS). Basal concentrations of glutamate are indeed reduced in SUD patients but increased during craving.<br><br>MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We assessed whether NAC reduce craving rating as compared to a placebo in SUD patients. Secondary outcomes were withdrawal symptoms (WS), side effects (SE) and drop-outs. Estimates are presented as standardized mean differences (SMD) or risk ratio (RR) with 95% confidence interval (CI).<br><br>RESULTS: Eleven RCTs were included. NAC reduced craving rating (SMD -0.61 (-1.17, -0.06), p = 0.03, I2 = 85%), with no differences in the subgroup analysis according to the drug addiction (alcohol, cocaine, poly-drugs, amphetamine, nicotine) (p = 0.98). Among the secondary outcomes, for WS data showed no significant difference between groups (SMD -0.18 (-0.43, 0.08), p = 0.17); for SE no substantial difference was observed between the two treatment groups (RR = 1.06 (0.89-1.27), p = 0.52, I2 = 0%); for dropouts the results are in favor of the placebo but no statistically significant (RR 1.17 (0.85, 1.61), p = 0.34; I2 = 0%).<br><br>CONCLUSION: NAC seem to reduce craving rating in SUD patients, but evidence is weak. More studies are needed to confirm this finding.},
}
@article {pmid39302378,
year = {2024},
author = {Park, J and Oh, JP and Ku, K and Jin, Y and Kim, EJ and Lee, JH},
title = {Preventing Donepezil-Induced Adverse Effects Through N-acetylcysteine Co-Administration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {101},
number = {4},
pages = {1281-1292},
doi = {10.3233/JAD-240709},
pmid = {39302378},
issn = {1875-8908},
mesh = {*Donepezil/pharmacology ; Animals ; *Acetylcysteine/pharmacology ; *Rats, Sprague-Dawley ; Male ; *Cholinesterase Inhibitors/pharmacology ; Female ; Rats ; *Reactive Oxygen Species/metabolism ; Calcium/metabolism ; Indans/pharmacology ; Piperidines/pharmacology ; },
abstract = {BACKGROUND: Drug-induced adverse symptoms affect patients' quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer's disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL.<br><br>OBJECTIVE: Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and investigate the underlying mechanisms.<br><br>METHODS: Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes.<br><br>RESULTS: High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2+]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2+]i levels in muscle cells.<br><br>CONCLUSIONS: Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2+]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients.},
}
@article {pmid39301637,
year = {2024},
author = {Jin, J and Nan, J and Si, Y and Chen, X and Wang, H and Wang, X and Huang, J and Guo, T},
title = {Exploring the therapeutic potential of rabdoternin E in lung cancer treatment: Targeting the ROS/p38 MAPK/JNK signaling pathway.},
journal = {Molecular medicine reports},
volume = {30},
number = {5},
pages = {},
pmid = {39301637},
issn = {1791-3004},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; Animals ; *Lung Neoplasms/drug therapy/metabolism/pathology ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *MAP Kinase Signaling System/drug effects ; Mice ; A549 Cells ; *Apoptosis/drug effects ; Xenograft Model Antitumor Assays ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Ferroptosis/drug effects ; Mice, Nude ; Antineoplastic Agents/pharmacology/therapeutic use ; },
abstract = {Lung cancer has the highest incidence and mortality rates of all cancer types in China and therefore represents a serious threat to human health. In the present study, the mechanism of rabdoternin E against the proliferation of the lung cancer cell line A549 was explored. It was found that rabdoternin E caused the accumulation of large amounts of reactive oxygen species (ROS), promoted cell S phase arrest by reducing the expression of CDK2 and cyclin A2, induced apoptosis by increasing the Bax/Bcl‑2 ratio and promoted the phosphorylation of proteins in the ROS/p38 MAPK/JNK signaling pathway, which is associated with apoptosis and ferroptosis. In addition, it was also found that Z‑VAD‑FMK (an apoptosis inhibitor), ferrostatin‑1 (ferroptosis inhibitor) and N‑acetylcysteine (a ROS inhibitor) could partially or greatly reverse the cytotoxicity of rabdoternin E to A549 cells. Similarly, NAC (N‑acetylcysteine) treatment notably inhibited the rabdoternin E‑stimulated p38 MAPK and JNK activation. Furthermore, in vivo experiments in mice revealed that Rabdoternin E markedly reduced tumor volume and weight and regulated the expression levels of apoptosis and ferroptosis‑related proteins (including Ki67, Bcl‑2, Bax, glutathione peroxidase 4, solute carrier family 7 member 11 and transferrin) in the tumor tissues of mice. Histopathological observation confirmed that the number of tumor cells decreased markedly after administration of rabdoternin E. Taken together, rabdoternin E induced apoptosis and ferroptosis of A549 cells by activating the ROS/p38 MAPK/JNK signaling pathway. Therefore, the results of the present study showed that rabdoternin E is not toxic to MCF‑7 cells (normal lung cells), had no significant effect on body weight and was effective and therefore may be a novel therapeutic treatment for lung cancer.},
}
@article {pmid39299599,
year = {2024},
author = {da Silva, AM and Murillo, DM and Anbumani, S and von Zuben, AA and Cavalli, A and Obata, HT and Fischer, ER and de Souza E Silva, M and Bakkers, E and Souza, AA and Carvalho, HF and Cotta, MA},
title = {N-acetylcysteine effects on extracellular polymeric substances of Xylella fastidiosa: A spatiotemporal investigation with implications for biofilm disruption.},
journal = {International journal of antimicrobial agents},
volume = {64},
number = {5},
pages = {107340},
doi = {10.1016/j.ijantimicag.2024.107340},
pmid = {39299599},
issn = {1872-7913},
mesh = {*Biofilms/drug effects ; *Xylella/drug effects/physiology ; *Acetylcysteine/pharmacology ; *Extracellular Polymeric Substance Matrix/drug effects/metabolism ; Bacterial Adhesion/drug effects ; Anti-Bacterial Agents/pharmacology ; Spatio-Temporal Analysis ; },
abstract = {BACKGROUND: The matrix of extracellular polymeric substances (EPS) present in biofilms greatly amplifies the problem of bacterial infections, protecting bacteria against antimicrobial treatments and eventually leading to bacterial resistance. The need for alternative treatments that destroy the EPS matrix becomes evident. N-acetylcysteine (NAC) is one option that presents diverse effects against bacteria; however, the different mechanisms of action of NAC in biofilms have yet to be elucidated.<br><br>OBJECTIVES: In this work, we performed microscopy studies at micro and nano scales to address the effects of NAC at single cell level and early-stage biofilms of the Xylella fastidiosa phytopathogen.<br><br>METHODS: We show the physical effects of NAC on the adhesion surface and the different types of EPS, as well as the mechanical response of individual bacteria to NAC concentrations between 2 and 20 mg/mL.<br><br>RESULTS: NAC modified the conditioning film on the substrate, broke down the soluble EPS, resulting in the release of adherent bacteria, decreased the volume of loosely bound EPS, and disrupted the biofilm matrix. Tightly bound EPS suffered structural alterations despite no solid evidence of its removal. In addition, bacterial force measurements upon NAC action performed with InP nanowire arrays showed an enhanced momentum transfer to the nanowires due to increased cell mobility resulting from EPS removal.<br><br>CONCLUSIONS: Our results clearly show that conditioning film and soluble EPS play a key role in cell adhesion control and that NAC alters EPS structure, providing solid evidence that NAC actuates mainly on EPS removal, both at single cell and biofilm levels.},
}
@article {pmid39295440,
year = {2024},
author = {Brand, F and Bale, E and Tsiachristas, A and Hawton, K},
title = {Self-poisoning with paracetamol in England: short report of characteristics of individuals and their overdoses according to source of tablets.},
journal = {BJPsych open},
volume = {10},
number = {5},
pages = {e155},
pmid = {39295440},
issn = {2056-4724},
support = {//Department of Health and Social Care/ ; //National Institute for Health and Care Research Applied Research Collaboration Oxford and Thames Valley/ ; },
abstract = {Self-poisoning with paracetamol is the most frequently used overdose method in the UK. Psychosocial assessments were conducted by mental health clinicians with 127 consecutive individuals who presented with pure paracetamol overdoses to a large general hospital over 8 months, including asking about the source of the tablets and scoring the patients' acts on the Beck Suicide Intent scale (BSI). Patients were predominantly female (86%) and young (79% aged 12-24 years). Most had used paracetamol which was available in the home (77%). Those who purchased paracetamol for the act took double the number of tablets compared with those who used paracetamol available in the home (37 v. 18), had higher suicidal intent (mean BSI: 11 v. 7) and more often required treatment with N-acetyl cysteine (71% v. 43%). These results highlight the need for safer home storage of paracetamol and consideration of reducing pack size limits on paracetamol that can be purchased.},
}
@article {pmid39281865,
year = {2024},
author = {Bishop, A and Romero, JC and Tonapi, S and Parihar, M and Loranc, E and Miller, H and Lawrence, L and Bassani, N and Robledo, D and Cao, L and Nie, J and Kanda, K and Stoja, A and Garcia, N and Gorthi, A and Stoveken, B and Lane, A and Fan, T and Cassel, T and Zha, S and Musi, N},
title = {ATM phosphorylation of CD98HC increases antiporter membrane localization and prevents chronic toxic glutamate accumulation in Ataxia telangiectasia.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {39281865},
issn = {2693-5015},
support = {T32 AG021890/AG/NIA NIH HHS/United States ; R01 CA241554/CA/NCI NIH HHS/United States ; F31 AG072902/AG/NIA NIH HHS/United States ; TL1 TR002647/TR/NCATS NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; K22 ES012264/ES/NIEHS NIH HHS/United States ; P30 CA177558/CA/NCI NIH HHS/United States ; T32 CA148724/CA/NCI NIH HHS/United States ; },
abstract = {Ataxia telangiectasia (A-T) is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in A-T, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of A-T is not understood. CD98HC chaperones cystine/glutamate (xc [-]) and cationic/neutral amino acid (y[+]L) antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on SLC family antiporters relevant to A-T phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes) with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance both in ATM-deficient cells and mouse models. These findings provide new insight into the long-known benefits of N-acetyl cysteine to A-T cells beyond oxidative stress through removing excess glutamate by production of glutathione.},
}
@article {pmid39278392,
year = {2024},
author = {Wang, Z and Guo, L and Zhu, C and Li, J and Guo, J and Zhu, X and Li, J and Cui, L and Dong, J and Liu, K and Meng, X and Zhu, G and Wang, H},
title = {NLRP3 targets HMGB1 to exacerbate the pyroptosis of canine corneal epithelial cells infected with Staphylococcus pseudintermedius.},
journal = {Experimental eye research},
volume = {248},
number = {},
pages = {110096},
doi = {10.1016/j.exer.2024.110096},
pmid = {39278392},
issn = {1096-0007},
mesh = {Animals ; *Pyroptosis ; *HMGB1 Protein/metabolism/genetics ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; Dogs ; *Epithelium, Corneal/metabolism/microbiology/drug effects ; *Reactive Oxygen Species/metabolism ; *Staphylococcus ; Staphylococcal Infections/microbiology/metabolism ; Eye Infections, Bacterial/microbiology/metabolism ; Cells, Cultured ; Blotting, Western ; Gene Expression Regulation ; RNA, Messenger/genetics/metabolism ; },
abstract = {PURPOSE: This study focused on the mechanisms of pyroptosis and oxidative damage exacerbation by NOD-like receptor thermal protein domain associated protein 3 (NLRP3) during the infection of canine corneal epithelial cells (CCECs) with Staphylococcus pseudintermedius.<br><br>METHODS: The CCECs treated with dimethyl fumarate (DMF), recombinant high mobility group protein 1 (HMGB1), or N-acetylcysteine (NAC). The gasdermin (GSDM) family and HMGB1 mRNA expression levels were detected using quantitative reverse transcription polymerase chain reaction. Lactate dehydrogenase activity, bacterial counts, the pyroptosis rate, reactive oxygen species (ROS) content, and antioxidant enzyme activity were used to reflect pyroptosis and oxidation level.<br><br>RESULTS: Regulation of NLRP3 significantly affected the pyroptosis rate and GSDMD-N expression levels during S. pseudintermedius infection. Inhibition of GSDMD-N protein activation by DMF reversed the exacerbation of pyroptosis induced by NLRP3 overexpression and reduced the levels of cleaved interleukin-1&#x3b2; (IL-1&#x3b2;), cleaved cysteinyl aspartate-specific protease-1, and NLRP3. In addition, NLRP3 was found to target the HMGB1 promoter and regulate its protein expression, to increase ROS accumulation and GSDMD-N expression levels, and activate the NLRP3-HMGB1-ROS-GSDMD signaling axis to aggravate pyroptosis during infection.<br><br>CONCLUSIONS: NLRP3 aggravates pyroptosis and oxidative damage associated with the activation of NLRP3-GSDMD and NLRP3-HMGB1-ROS-GSDMD signaling pathways during the infection of CCECs with S. pseudintermedius.},
}
@article {pmid39276051,
year = {2024},
author = {Cong, X and Chen, T and Li, S and Wang, Y and Zhou, L and Li, X and Zhang, P and Sun, X and Zhao, S},
title = {[Dihydroartemisinin enhances sensitivity of nasopharyngeal carcinoma HNE1/DDP cells to cisplatin-induced apoptosis by promoting ROS production].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {44},
number = {8},
pages = {1553-1560},
pmid = {39276051},
issn = {1673-4254},
mesh = {Humans ; *Cisplatin/pharmacology ; *Artemisinins/pharmacology ; *Apoptosis/drug effects ; *Nasopharyngeal Carcinoma/metabolism/pathology/drug therapy ; *Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; *Nasopharyngeal Neoplasms/metabolism/pathology/drug therapy ; *Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Resistance, Neoplasm/drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Antineoplastic Agents/pharmacology ; },
abstract = {OBJECTIVE: To investigate the effect of dihydroartemisinin (DHA) for enhancing the inhibitory effect of cisplatin (DDP) on DDP-resistant nasopharyngeal carcinoma cell line HNE1/DDP and explore the mechanism.<br><br>METHODS: CCK-8 method was used to assess the survival rate of HNE1/DDP cells treated with DHA (0, 5, 10, 20, 40, 80, and 160 &#x3bc;mol/L) and DDP (0, 4, 8, 16, 32, 64, 128 &#x3bc;mol/L) for 24 or 48 h, and the combination index of DHA and DDP was calculated using Compusyn software. HNE1/DDP cells treated with DHA, DDP, or their combination for 24 h were examined for cell viability, proliferation and colony formation ability using CCK-8, EdU and colony-forming assays. Flow cytometry was used to detect cell apoptosis and intracellular reactive oxygen species (ROS). The expression levels of apoptosis-related proteins cleaved PARP, cleaved caspase-9 and cleaved caspase-3 were detected by Western blotting. The effects of N-acetyl-cysteine (a ROS inhibitor) on proliferation and apoptosis of HNE1/DDP cells with combined treatment with DHA and DDP were analyzed.<br><br>RESULTS: Different concentrations of DHA and DDP alone both significantly inhibited the viability of HNE1/DDP cells. The combination index of DHA (5 &#x3bc;mol/L) combined with DDP (8, 16, 32, 64, 128 &#x3bc;mol/L) were all below 1. Compared with DHA or DDP alone, their combined treatment more potently decreased the cell viability, colony-forming ability and the number of EdU-positive cells, and significantly increased the apoptotic rate, intracellular ROS level, and the expression levels of cleaved PARP, cleaved caspase-9 and cleaved caspase-3 in HNE1/DDP cells. N-acetyl-cysteine pretreatment obviously attenuated the inhibitory effect on proliferation and apoptosis-inducing effect of DHA combined with DDP in HNE1/DDP cells (P<0.01).<br><br>CONCLUSION: DHA enhances the growth-inhibitory and apoptosis-inducing effect of DDP on HNE1/DDP cells possibly by promoting accumulation of intracellular ROS.},
}
@article {pmid39275957,
year = {2024},
author = {},
title = {RETRACTION "Protective effects of N-acetyl cysteine on lipid peroxide metabolism on isoproterenol-induced myocardial infarcted rats,".},
journal = {Journal of biochemical and molecular toxicology},
volume = {38},
number = {10},
pages = {e23852},
doi = {10.1002/jbt.23852},
pmid = {39275957},
issn = {1099-0461},
abstract = {M. F. Nagoor Meeran and P. S. Mainzen Prince, Journal of Biochemical and Molecular Toxicology 25, no. 3 (2011): 151-157, https://doi.org/10.1002/jbt.20371. The above article, published online on 23 November 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Hari K. Bhat; and Wiley Periodicals, LLC. The retraction has been agreed due to duplication of several Western blot bands observed in Figure 2. The authors did not provide an explanation or their raw data. The editors consider the results and conclusion reported in this article unreliable.},
}
@article {pmid39272966,
year = {2024},
author = {Gupta, KB and Taylor, TL and Panda, SS and Thangaraju, M and Lokeshwar, BL},
title = {Curcumin-Dichloroacetate Hybrid Molecule as an Antitumor Oral Drug against Multidrug-Resistant Advanced Bladder Cancers.},
journal = {Cancers},
volume = {16},
number = {17},
pages = {},
pmid = {39272966},
issn = {2072-6694},
support = {HT9425-23-1-0761//US Department of Defense Army Research program/ ; },
abstract = {Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.},
}
@article {pmid39268103,
year = {2024},
author = {Zheng, J and Zhao, L and Liu, Y and Chen, M and Guo, X and Wang, J},
title = {N-acetylcysteine, a small molecule scavenger of reactive oxygen species, alleviates cardiomyocyte damage by regulating OPA1-mediated mitochondrial quality control and apoptosis in response to oxidative stress.},
journal = {Journal of thoracic disease},
volume = {16},
number = {8},
pages = {5323-5336},
pmid = {39268103},
issn = {2072-1439},
abstract = {BACKGROUND: Oxidative stress-induced mitochondrial damage is the major cause of cardiomyocyte dysfunction. Therefore, the maintenance of mitochondrial function, which is regulated by mitochondrial quality control (MQC), is necessary for cardiomyocyte homeostasis. This study aimed to explore the underlying mechanisms of N-acetylcysteine (NAC) function and its relationship with MQC.<br><br>METHODS: A hydrogen peroxide-induced oxidative stress model was established using H9c2 cardiomyocytes treated with or without NAC prior to oxidative stress stimulation. Autophagy with light chain 3 (LC3)-green fluorescent protein (GFP) assay, reactive oxygen species (ROS) with the 2',7'-dichlorodi hydrofluorescein diacetate (DCFH-DA) fluorescent, lactate dehydrogenase (LDH) release assay, adenosine triphosphate (ATP) content assay, and a mitochondrial membrane potential detection were used to evaluate mitochondrial dynamics in H2O2-treated H9c2 cardiomyocytes, with a focus on the involvement of MQC regulated by NAC. Cell apoptosis was analyzed using caspase-3 activity assay and Annexin V-fluorescein isothiocyanate (V-FITC)/propidium iodide (PI) double staining.<br><br>RESULTS: We observed that NAC improved cell viability, reduced ROS levels, and partially restored optic atrophy 1 (OPA1) protein expression under oxidative stress. Following transfection with a specific OPA1-small interfering RNA, the mitophagy, mitochondrial dynamics, mitochondrial functions, and cardiomyocyte apoptosis were evaluated to further explore the mechanisms of NAC. Our results demonstrated that NAC attenuated cardiomyocyte apoptosis via the ROS/OPA1 axis and protected against oxidative stress-induced mitochondrial damage via the regulation of OPA1-mediated MQC.<br><br>CONCLUSIONS: NAC ameliorated the injury to H9c2 cardiomyocytes caused by H2O2 by promoting the expression of OPA1, consequently improving mitochondrial function and decreasing apoptosis.},
}
@article {pmid39265983,
year = {2025},
author = {Sun, J and Ding, J and Yue, H and Xu, B and Sodhi, A and Xue, K and Ren, H and Qian, J},
title = {Hypoxia-induced BNIP3 facilitates the progression and metastasis of uveal melanoma by driving metabolic reprogramming.},
journal = {Autophagy},
volume = {21},
number = {1},
pages = {191-209},
pmid = {39265983},
issn = {1554-8635},
mesh = {*Melanoma/pathology/metabolism ; *Membrane Proteins/metabolism ; Humans ; *Uveal Neoplasms/pathology/metabolism ; *Mitophagy/physiology ; Animals ; *Disease Progression ; *Proto-Oncogene Proteins/metabolism ; Cell Line, Tumor ; *Neoplasm Metastasis ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mitochondria/metabolism ; Oxidative Phosphorylation ; Reactive Oxygen Species/metabolism ; Mice ; Glycolysis ; Cell Hypoxia ; Mice, Nude ; Metabolic Reprogramming ; Uveal Melanoma ; },
abstract = {Uveal melanoma (UM) is an aggressive intraocular malignancy derived from melanocytes in the uvea tract of the eye. Up to 50% of patients with UM develop distant metastases which is usually fatal within one year; preventing metastases is therefore essential. Metabolic reprogramming plays a critical role in UM progression and metastasis. However, the metabolic phenotype of UM cells in the hypoxic tumor is not well understood. Here, we report that hypoxia-induced BNIP3 reprograms tumor cell metabolism, promoting their survival and metastasis. In response to hypoxia, BNIP3-mediated mitophagy alleviates mitochondrial dysfunction and enhances mitochondrial oxidative phosphorylation (OXPHOS) while simultaneously reducing mitochondrial reactive oxygen species (mtROS) production. This, in turn, impairs HIF1A/HIF-1α protein stability and inhibits glycolysis. Inhibition of mitophagy significantly suppresses BNIP3-induced UM progression and metastasis in vitro and in vivo. Collectively, these observations demonstrate a novel mechanism whereby BNIP3 promotes UM metabolic reprogramming and malignant progression by mediating hypoxia-induced mitophagy and suggest that BNIP3 could be an important therapeutic target to prevent metastasis in patients with UM.Abbreviations: AOD: average optical density; BNIP3: BCL2/adenovirus E1B interacting protein 3; CQ: chloroquine; CoCl2: cobalt chloride; GEPIA: Gene Expression Profiling Interactive Analysis; HIF1A: hypoxia inducible factor 1, alpha subunit; IHC: immunohistochemistry; mtROS: mitochondrial reactive oxygen species; NAC: N-acetylcysteine; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species; TCGA: The Cancer Genome Atlas; UM: uveal melanoma.},
}
@article {pmid39265812,
year = {2024},
author = {Pazarci, &#xd6; and Hümeyra Taşkin Kafa, A and Taş, A and Keklikcioğlu Çakmak, N and Hasbek, M and Kilinç, S and Tunçbilek, Z},
title = {Assessment of the antimicrobial and antibiofilm activity of the combination of N-acetyl cysteine and carvacrol against Staphylococcus aureus, the most common orthopedic infectious agent.},
journal = {Microbial pathogenesis},
volume = {196},
number = {},
pages = {106934},
doi = {10.1016/j.micpath.2024.106934},
pmid = {39265812},
issn = {1096-1208},
mesh = {*Biofilms/drug effects ; *Cymenes/pharmacology ; *Acetylcysteine/pharmacology ; *Microbial Sensitivity Tests ; *Staphylococcus aureus/drug effects ; *Drug Synergism ; *Anti-Bacterial Agents/pharmacology ; Staphylococcal Infections/drug therapy/microbiology ; Monoterpenes/pharmacology ; Humans ; Methicillin-Resistant Staphylococcus aureus/drug effects ; Cell Line ; },
abstract = {BACKGROUND: The increasing prevalence of antibiotic-resistant bacterial infections has led to the search for new approaches.<br><br>OBJECTIVE: This study aimed to evaluate the effects of carvacrol and N-acetyl cysteine, both individually and in combination, on the planktonic cells and biofilm formations of Staphylococcus aureus, including methicillin-resistant and methicillin-sensitive strains. Additionally, the study sought to perform cytotoxicity tests and chemical characterization to further understand the properties and potential applications of these substances.<br><br>METHODS: A total of 19&#xa0;S. aureus strains were included in the study. Minimum inhibitory concentration and minimum bactericidal concentration were determined by assays. Synergy analysis tests were carried out. Cytotoxicity tests were conducted on the fibroblast cell line. Characterization test was performed.<br><br>RESULTS: While Minimum inhibitory concentration and minimum bactericidal concentration values for carvacrol varied between 250 and 500&#xa0;&#x3bc;g/ml, these values were in the range of 32-64&#xa0;mg/ml for N-acetyl cysteine. Biofilm formation activities were identified. A total of eight strains, including six clinical and two standard strains with the highest biofilm-forming ability, were selected for combination studies. The combination of Carvacrol and N-acetyl cysteine exhibited synergistic and partially synergistic effects on the tested planktonic and biofilm strains, and these effects were dose-dependent. Carvacrol was found to be the most active drug at the end of 24, 48, and 72&#xa0;h. Regarding the synergistic effect of N-acetyl cysteine&#xa0;+&#xa0;carvacrol, it was revealed to exhibit higher activity than N-acetyl cysteine and lower activity than carvacrol.<br><br>CONCLUSION: The combination of carvacrol and N-acetyl cysteine demonstrated synergistic and partially synergistic effects against both planktonic and biofilm forms of Staphylococcus aureus. These results suggest potential for novel approaches in managing orthopedic infections, warranting further research to explore their therapeutic applications.},
}
@article {pmid39263473,
year = {2024},
author = {Li, YL and Wang, G and Wang, BW and Li, YH and Ma, YX and Huang, Y and Yan, WT and Xie, P},
title = {The potential treatment of N-acetylcysteine as an antioxidant in the radiation-induced heart disease.},
journal = {Cardiovascular diagnosis and therapy},
volume = {14},
number = {4},
pages = {509-524},
pmid = {39263473},
issn = {2223-3652},
abstract = {BACKGROUND: Radiation-induced heart disease (RIHD) is a serious complication of thoracic tumor radiotherapy that substantially affects the quality of life of cancer patients. Oxidative stress plays a pivotal role in the occurrence and progression of RIHD, which prompted our investigation of an innovative approach for treating RIHD using antioxidant therapy.<br><br>METHODS: We used 8-week-old male Sprague-Dawley (SD) rats as experimental animals and H9C2 cells as experimental cells. N-acetylcysteine (NAC) was used as an antioxidant to treat H9C2 cells after X-ray irradiation in this study. In the present study, the extent of cardiomyocyte damage caused by X-ray exposure was determined, alterations in oxidation/antioxidation levels were assessed, and changes in the expression of genes related to mitochondria were examined. The degree of myocardial tissue and cell injury was also determined. Dihydroethidium (DHE) staining, reactive oxygen species (ROS) assays, and glutathione (GSH) and manganese superoxide dismutase (Mn-SOD) assays were used to assess cell oxidation/antioxidation. Flow cytometry was used to determine the mitochondrial membrane potential and mitochondrial permeability transition pore (mPTP) opening. High-throughput transcriptome sequencing and bioinformatics analysis were used to elucidate the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure. Polymerase chain reaction (PCR) was used to verify the expression of differentially expressed genes.<br><br>RESULTS: X-ray irradiation damaged myocardial tissue and cells, resulting in an imbalance of oxidative and antioxidant substances and mitochondrial damage. NAC treatment increased cell counting kit-8 (CCK-8) levels (P=0.02) and decreased lactate dehydrogenase (LDH) release (P=0.02) in cardiomyocytes. It also reduced the level of ROS (P=0.002) and increased the levels of GSH (P=0.04) and Mn-SOD (P=0.01). The mitochondrial membrane potential was restored (P<0.001), and mPTP opening was inhibited (P<0.001). Transcriptome sequencing and subsequent validation analyses revealed a decrease in the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure, but antioxidant therapy did not reverse the related DNA damage.<br><br>CONCLUSIONS: Antioxidants mitigated radiation-induced myocardial damage to a certain degree, but these agents did not reverse the associated DNA damage. These findings provide a new direction for future investigations by our research group, including exploring the treatment of RIHD-related DNA damage.},
}
@article {pmid39262205,
year = {2025},
author = {González-Guzmán, D and Andrade-Castellanos, CA and Ponce-Gallegos, MA and Mesina-Estarrón, I and Mora-Almanza, JG and Ruelas-Moreno, HE and Rodríguez-González, D and Eguia-Ortega, O and Colunga-Lozano, LE},
title = {N-acetyl-cysteine in Intensive Care Unit Patients with Acute Respiratory Distress Syndrome due to COVID-19: A Retrospective Cohort Study.},
journal = {Journal of intensive care medicine},
volume = {40},
number = {3},
pages = {284-293},
doi = {10.1177/08850666241281281},
pmid = {39262205},
issn = {1525-1489},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Respiratory Distress Syndrome/mortality/drug therapy/etiology/virology/therapy ; Male ; Female ; Middle Aged ; *COVID-19/complications/mortality ; Retrospective Studies ; Intensive Care Units ; Aged ; Respiration, Artificial ; Critical Illness ; SARS-CoV-2 ; *COVID-19 Drug Treatment ; Administration, Oral ; },
abstract = {COVID-19-related acute respiratory distress syndrome (ARDS) is linked to mortality, primarily due to a cytokine storm, oxidative stress imbalance, and pro-thrombotic state.PurposeWe assessed the potential association between N-acetyl-cysteine (NAC) and clinical outcomes in critically ill subjects with COVID-19-related ARDS.Material and MethodsWe included subjects with confirmed COVID-19 who were admitted to our ICU between March 1, 2020, and January 31, 2021, due to ARDS and necessitating invasive mechanical ventilation (IMV). Subjects who received standard of care (SOC) were compared with subjects who additionally received NAC 600 mg bid orally.ResultsA total of 243 subjects were included in this study. The results indicate significantly improved survival rates in the NAC plus SOC group, both in the unadjusted analysis and after adjusting for confounding factors such as ARDS severity (HR 0.48, 95% CI 0.32-0.70).ConclusionsWe found that oral administration of NAC was associated with reduced mortality in critically ill patients with COVID-19 related ARDS.},
}
@article {pmid39260547,
year = {2024},
author = {Das, S and Mukherjee, U and Biswas, S and Banerjee, S and Karmakar, S and Maitra, S},
title = {Unravelling bisphenol A-induced hepatotoxicity: Insights into oxidative stress, inflammation, and energy dysregulation.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {362},
number = {},
pages = {124922},
doi = {10.1016/j.envpol.2024.124922},
pmid = {39260547},
issn = {1873-6424},
mesh = {Animals ; *Phenols/toxicity ; *Benzhydryl Compounds/toxicity ; Mice ; Male ; *Oxidative Stress/drug effects ; *Inflammation/chemically induced/metabolism ; Endocrine Disruptors/toxicity ; Reactive Oxygen Species/metabolism ; Liver/metabolism/drug effects ; NF-kappa B/metabolism ; Inflammasomes/metabolism ; Chemical and Drug Induced Liver Injury/metabolism ; Energy Metabolism/drug effects ; Bisphenol A Compounds ; },
abstract = {Bisphenol A (BPA), a prevalent plastic monomer and endocrine disruptor, negatively impacts metabolic functions. This study examines the chronic effects of eco-relevant BPA concentrations on hepatotoxicity, focusing on redox balance, inflammatory response, cellular energy sensors, and metabolic homeostasis in male Swiss albino mice. Chronic BPA exposure resulted in reactive oxygen species (ROS) accumulation, altered hepatic antioxidant defense, lipid peroxidation, and NOX4 expression, leading to reduced cell viability. Additionally, BPA exposure significantly upregulated hepatic pro-inflammatory cytokine genes (Tnf-α, Il-1β, Il-6), NOS2, and arginase II, correlating with increased TLR4 expression, NF-κB phosphorylation, and a dose-dependent decrease in IκBα levels. BPA-induced NF-κB nuclear localization and inflammasome activation (NLRP3, cleaved caspase-1, IL-1β) established an inflammatory milieu. Perturbations in hepatic AMPKα phosphorylation, SIRT1, and PGC-1α, along with elevated p38 MAPK phosphorylation and ERα expression, indicated BPA-induced energy dysregulation. Furthermore, increased PLA2G4A, COX1, COX2, and PTGES2 expression in BPA-treated liver correlated with hyperlipidemia, hepatic FASN expression, steatosis, and visceral adiposity, likely due to disrupted energy sensors, oxidative stress, and inflammasome activation. Elevated liver enzymes (ALP, AST, ALT) and apoptotic markers indicated liver damage. Notably, N-acetylcysteine (NAC) priming reversed BPA-induced hepatocellular ROS accumulation, NF-κB-inflammasome activation, and intracellular lipid accumulation, while upregulating cellular energy sensors and attenuating ERα expression, suggesting NAC's protective effects against BPA-induced hepatotoxicity. Pharmacological inhibition of the NF-κB/NLRP3 cascade in BAY11-7082 pretreated, or NLRP3 immunodepleted hepatocytes reversed BPA's negative impact on SIRT1/p-AMPKα/PGC-1α and intracellular lipid accumulation, providing mechanistic insights into BPA-induced metabolic disruption.},
}
@article {pmid39258904,
year = {2024},
author = {Chae, IG and Jung, J and Kim, DH and Choi, JS and Chun, KS},
title = {EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells.},
journal = {Free radical research},
volume = {58},
number = {10},
pages = {596-605},
doi = {10.1080/10715762.2024.2396909},
pmid = {39258904},
issn = {1029-2470},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Colorectal Neoplasms/metabolism/drug therapy/pathology ; *Receptors, Prostaglandin E, EP4 Subtype/agonists/metabolism ; *HSP90 Heat-Shock Proteins/metabolism ; Mice ; Animals ; Up-Regulation/drug effects ; HCT116 Cells ; Mice, Nude ; },
abstract = {Prostaglandin E2 (PGE2) interacts with four specific G protein-coupled receptors, namely EP1, EP2, EP3, and EP4, playing a pivotal role in determining the fate of cells. Our previous findings highlighted that stimulating the EP4 receptor with its agonist, CAY10598, triggers apoptosis in colon cancer HCT116 cells via the production of reactive oxygen species (ROS). This process also reduces the phosphorylation of the oncogenic protein JAK2 and leads to its degradation in these cells. In this study, our goal was to explore the pathways through which CAY10598 leads to JAK2 degradation. We focused on Hsp90, a heat shock protein family member known for its role as a molecular chaperone maintaining the stability of several key proteins including EGFR, MET, Akt, and JAK2. Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N-acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS. Furthermore, we observed that CAY10598 cleaves both α and β isoforms of Hsp90, the process inhibited by NAC. Inhibition of EP4 with the antagonist GW627368x not only prevented the degradation of Hsp90 client proteins but also the cleavage of Hsp90 itself in CAY10598-treated HCT116 cells. Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.},
}
@article {pmid39257692,
year = {2024},
author = {De Felice, M and Szkudlarek, HJ and Uzuneser, TC and Rodríguez-Ruiz, M and Sarikahya, MH and Pusparajah, M and Galindo Lazo, JP and Whitehead, SN and Yeung, KK and Rushlow, WJ and Laviolette, SR},
title = {The Impacts of Adolescent Cannabinoid Exposure on Striatal Anxiety- and Depressive-Like Pathophysiology Are Prevented by the Antioxidant N-Acetylcysteine.},
journal = {Biological psychiatry global open science},
volume = {4},
number = {6},
pages = {100361},
pmid = {39257692},
issn = {2667-1743},
abstract = {BACKGROUND: Exposure to Δ[9]-tetrahydrocannabinol (THC) is an established risk factor for later-life neuropsychiatric vulnerability, including mood- and anxiety-related symptoms. The psychotropic effects of THC on affect and anxiogenic behavioral phenomena are known to target the striatal network, particularly the nucleus accumbens, a neural region linked to mood and anxiety disorder pathophysiology. THC may increase neuroinflammatory responses via the redox system and dysregulate inhibitory and excitatory neural balance in various brain circuits, including the striatum. Thus, interventions that can induce antioxidant effects may counteract the neurodevelopmental impacts of THC exposure.<br><br>METHODS: In the current study, we used an established preclinical adolescent rat model to examine the impacts of adolescent THC exposure on various behavioral, molecular, and neuronal biomarkers associated with increased mood and anxiety disorder vulnerability. Moreover, we investigated the protective properties of the antioxidant N-acetylcysteine against THC-related pathology.<br><br>RESULTS: We demonstrated that adolescent THC exposure induced long-lasting anxiety- and depressive-like phenotypes concomitant with differential neuronal and molecular abnormalities in the two subregions of the nucleus accumbens, the shell and the core. In addition, we report for the first time that N-acetylcysteine can prevent THC-induced accumbal pathophysiology and associated behavioral abnormalities.<br><br>CONCLUSIONS: The preventive effects of this antioxidant intervention highlight the critical role of redox mechanisms underlying cannabinoid-induced neurodevelopmental pathology and identify a potential intervention strategy for the prevention and/or reversal of these pathophysiological sequelae.},
}
@article {pmid39251120,
year = {2024},
author = {Wood, JPM and Chidlow, G and Wall, GM and Casson, RJ},
title = {N-acetylcysteine amide and di- N-acetylcysteine amide protect retinal cells in culture via an antioxidant action.},
journal = {Experimental eye research},
volume = {248},
number = {},
pages = {110074},
doi = {10.1016/j.exer.2024.110074},
pmid = {39251120},
issn = {1096-0007},
mesh = {Animals ; *Acetylcysteine/pharmacology/analogs &amp; derivatives ; Rats ; *Oxidative Stress/drug effects ; Cells, Cultured ; *Retinal Ganglion Cells/drug effects/metabolism ; *Antioxidants/pharmacology ; *Reactive Oxygen Species/metabolism ; Glutathione/metabolism ; Cell Survival/drug effects ; Neuroglia/drug effects/metabolism ; Retina/drug effects/metabolism ; Dose-Response Relationship, Drug ; },
abstract = {Reactive oxygen species (ROS) play a significant role in toxicity to the retina in a variety of diseases. N-acetylcysteine (NAC), N-acetylcysteine amide (NACA) and the dimeric di-N-acetylcysteine amide (diNACA) were evaluated in terms of protecting retinal cells, in vitro, in a variety of stress models. Three types of rat retinal cell cultures were utilized in the study: macroglial-only cell cultures, neuron-only retinal ganglion cell (RGC) cultures, and mixed cultures containing retinal glia and neurons. Ability of test agents to attenuate oxidative stress in all cultures was ascertained. In addition, capability of agents to protect against a variety of alternate clinically-relevant stressors, including excitotoxins and mitochondrial electron transport chain inhibitors, was also evaluated. Capacity of test agents to elevate cellular levels of reduced glutathione under normal and compromised conditions was also determined. NAC, NACA and diNACA demonstrated concentration-dependent cytoprotection against oxidative stress in all cultures. These three compounds, however, had differing effects against a variety of alternate insults to retinal cells. The most protective agent was NACA, which was most potent against the most stressors (including oxidative stress, mitochondrial impairment by antimycin A and azide, and glutamate-induced excitotoxicity). Similar to NAC, NACA increased glutathione levels in non-injured cells, although diNACA did not, suggesting a different, unknown mechanism of antioxidant activity for the latter. In support of this, diNACA was the only agent to attenuate rotenone-induced toxicity in mitochondria. NAC, NACA and diNACA exhibited varying degrees of antioxidant activity, i.e., protected cultured rat retinal cells from a variety of stressors which were designed to mimic aspects of the pathology of different retinal diseases. A general rank order of activity was observed: NACA ≥ diNACA > NAC. These results warrant further exploration of NACA and diNACA as antioxidant therapeutics for the treatment of retinal diseases, particularly those involving oxidative stress. Furthermore, we have defined the battery of tests carried out as the "Wood, Chidlow, Wall and Casson (WCWC) Retinal Antioxidant Indices"; we believe that these are of great value for screening molecules for potential to reduce retinal oxidative stress in a range of retinal diseases.},
}
@article {pmid39251036,
year = {2024},
author = {Moyano, P and Flores, A and San Juan, J and García, J and Anadón, MJ and Plaza, JC and Naval, MV and Fernández, MC and Guerra-Menéndez, L and Del Pino, J},
title = {Imidacloprid unique and repeated treatment produces cholinergic transmission disruption and apoptotic cell death in SN56 cells.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {193},
number = {},
pages = {114988},
doi = {10.1016/j.fct.2024.114988},
pmid = {39251036},
issn = {1873-6351},
mesh = {Animals ; *Apoptosis/drug effects ; *Acetylcholinesterase/metabolism ; *Neonicotinoids/toxicity ; *tau Proteins/metabolism/genetics ; Mice ; NF-E2-Related Factor 2/metabolism/genetics ; Synaptic Transmission/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism/genetics ; Insecticides/toxicity ; Reactive Oxygen Species/metabolism ; HSP70 Heat-Shock Proteins/metabolism/genetics ; Cholinergic Neurons/drug effects/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; Oxidative Stress/drug effects ; Cell Line ; Proteasome Endopeptidase Complex/metabolism/drug effects ; Amyloid Precursor Protein Secretases/metabolism/genetics ; Aspartic Acid Endopeptidases/metabolism/genetics ; Nitro Compounds ; },
abstract = {Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), β-amyloid-precursor-protein (βAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3β), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 μM-800 μM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aβ and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aβ and Tau accumulation through BACE1, GSK3β, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools.},
}
@article {pmid39248027,
year = {2024},
author = {Thakkar, Y and Kobets, T and Api, AM and Duan, JD and Williams, GM},
title = {Assessment of genotoxic potential of fragrance materials in the chicken egg assays.},
journal = {Environmental and molecular mutagenesis},
volume = {65},
number = {8},
pages = {261-274},
doi = {10.1002/em.22627},
pmid = {39248027},
issn = {1098-2280},
mesh = {Animals ; *Chickens ; *Micronucleus Tests/methods ; *Mutagenicity Tests/methods ; *DNA Damage/drug effects ; *Perfume/toxicity ; Mutagens/toxicity ; Aldehydes/toxicity ; Ovum/drug effects ; Acrolein/toxicity/analogs &amp; derivatives ; },
abstract = {The genotoxic and clastogenic/aneugeneic potentials of four α,β-unsaturated aldehydes, 2-phenyl-2-butenal, nona-2-trans-6-cis-dienal, 2-methyl-2-pentenal, and p-methoxy cinnamaldehyde, which are used as fragrance materials, were assessed using the Chicken Egg Genotoxicity Assay (CEGA) and the Hen's egg micronucleus (HET-MN) assay, respectively. Selection of materials was based on their chemical structures and the results of their previous assessment in the regulatory in vitro and/or in vivo genotoxicity test battery. Three tested materials, 2-phenyl-2-butenal, nona-2-trans-6-cis-dienal, and 2-methyl-2-pentenal, were negative in both, CEGA and HET-MN assays. These findings were congruent with the results of regulatory in vivo genotoxicity assays. In contrast, p-methoxy cinnamaldehyde, which was also negative in the in vivo genotoxicity assays, produced evidence of DNA damage, including DNA strand breaks and DNA adducts in CEGA. However, no increase in the micronucleus formation in blood was reported in the HET-MN study. Such variation in responses between the CEGA and HET-MN assay can be attributed to differences in the dosing protocols. Pretreatment with a glutathione precursor, N-acetyl cysteine, negated positive outcomes produced by p-methoxy cinnamaldehyde in CEGA, indicating that difference in response observed in the chicken egg and rodent models can be attributed to rapid glutathione depletion. Overall, our findings support the conclusion that CEGA and/or HET-MN can be considered as a potential alternative to animal testing as follow-up strategies for assessment of genotoxic potential of fragrance materials with evidence of genotoxicity in vitro.},
}
@article {pmid39246710,
year = {2024},
author = {Abolfazli, S and Foroumand, S and Mohammadi, E and Ahangar, N and Kheirandish, A and Fathi, H and Mohammadi, H},
title = {Brain mitochondrial damage attenuation by quercetin and N-acetyl cysteine: peripheral and central antiemetic effects.},
journal = {Toxicology research},
volume = {13},
number = {5},
pages = {tfae139},
pmid = {39246710},
issn = {2045-452X},
abstract = {Nausea serves as a protective mechanism in organisms to prevent excessive consumption of toxic substances. Due to the adverse effects of chemical anti-nausea drugs, there is a growing interest in using herbal remedies and natural antioxidants. In this study, we evaluated the neuroprotective effects of quercetin (QU) and N-acetylcysteine (NAC) against oxidative damage induced by nausea. Emesis was induced in chickens using ipecac and copper sulfate (600 and 60 mg/kg, orally, respectively). QU and NAC (with doses of 50, 100, 200 mg/kg), and their combination were administered, along with a standard therapy (metoclopramide; MET 2 mg/kg) for one-time. Mitochondrial function, lipid peroxidation (LPO), protein carbonyl (PC), glutathione level (GSH), and reactive oxygen species (ROS) as oxidative damage biomarkers were evaluated in the chicken's brain mitochondria. QU and NAC significantly reduced emesis induced by copper sulfate and ipecac compared to the control group (P < 0.001). Significant differences in oxidative damage were observed in the groups received of copper sulfate and ipecac compared with control group. Levels of LPO, ROS, and PC were significantly decreased after the administration of QU and NAC in emesis induced by copper sulfate and ipecac. While, mitochondrial function and GSH levels were increased after the administration of QU and NAC. Combination therapy with QU and NAC yielded the most effective results. This study suggests that QU and NAC possess antiemetic effects through both peripheral and central mechanisms and exhibit neuroprotective effects against oxidative brain damage induced by emesis by increasing plasma antioxidants or scavenging free radicals.},
}
@article {pmid39245438,
year = {2025},
author = {Lee, TL and Shen, WC and Chen, YC and Lai, TC and Lin, SR and Lin, SW and Yu, IS and Yeh, YH and Li, TK and Lee, IT and Lee, CW and Chen, YL},
title = {Mir221- and Mir222-enriched adsc-exosomes mitigate PM exposure-exacerbated cardiac ischemia-reperfusion injury through the modulation of the BNIP3-MAP1LC3B-BBC3/PUMA pathway.},
journal = {Autophagy},
volume = {21},
number = {2},
pages = {374-393},
pmid = {39245438},
issn = {1554-8635},
mesh = {Animals ; *MicroRNAs/metabolism/genetics ; *Myocardial Reperfusion Injury/metabolism/pathology/genetics ; *Exosomes/metabolism ; Microtubule-Associated Proteins/metabolism ; Myocytes, Cardiac/metabolism/drug effects/pathology ; *Membrane Proteins/metabolism ; Mice ; Mitophagy/drug effects ; Signal Transduction/drug effects ; *Particulate Matter/toxicity/adverse effects ; *Mitochondrial Proteins/metabolism ; *Apoptosis Regulatory Proteins/metabolism ; Apoptosis/drug effects ; Male ; Rats ; Mice, Inbred C57BL ; Proto-Oncogene Proteins/metabolism ; Mice, Transgenic ; Cell Line ; Autophagy ; },
abstract = {Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion (I/R) injury, and the related mechanisms are unclear. Our previous study has shown that adipose stem cell-derived exosomes (ADSC-Exos) contain high levels of Mir221 and Mir222. The present study investigated the effects of PM exposure on I/R-induced cardiac injury through mitophagy and apoptosis, as well as the potential role of Mir221 and Mir222 in ADSC-Exos. Wild-type, mir221- and mir222-knockout (KO), and Mir221- and Mir222-overexpressing transgenic (TG) mice were intratracheally injected with PM (10 mg/kg). After 24 h, mice underwent left coronary artery ligation for 30 min, followed by 3 h of reperfusion (I/R). H9c2 cardiomyocytes were cultured under 1% O2 for 6 h, then reoxygenated for 12 h (hypoxia-reoxygenation [H/R]). PM aggravated I/R (or H/R) cardiac injury by increasing ROS levels and causing mitochondrial dysfunction, which increased the expression of mitochondrial fission-related proteins (DNM1L/Drp1 and MFF) and mitophagy-related proteins (BNIP3 and MAP1LC3B/LC3B) in vivo and in vitro. Treatment with ADSC-Exos or Mir221- and Mir222-mimics significantly reduced PM+I/R-induced cardiac injury. Importantly, ADSC-Exos contain Mir221 and Mir222, which directly targets BNIP3, MAP1LC3B/LC3B, and BBC3/PUMA, decreasing their expression and ultimately reducing cardiomyocyte mitophagy and apoptosis. The present data showed that ADSC-Exos treatment regulated mitophagy and apoptosis through the Mir221 and Mir222-BNIP3-MAP1LC3B-BBC3/PUMA pathway and significantly reduced the cardiac damage caused by PM+I/R. The present study revealed the novel therapeutic potential of ADSC-Exos in alleviating PM-induced exacerbation of myocardial I/R injury.Abbreviation: ADSC-Exos: adipose-derived stem cell exosomes; AL: autolysosome; ATP: adenosine triphosphate; BBC3/PUMA: BCL2 binding component 3; BNIP3: BCL2/adenovirus E1B interacting protein 3; CASP3: caspase 3; CASP9: caspase 9; CDKN1B/p27: cyclin dependent kinase inhibitor 1B; CVD: cardiovascular disease; DCFH-DA: 2',7'-dichlorodihydrofluorescein diacetate; DHE: dihydroethidium; DNM1L/Drp1: dynamin 1-like; EF: ejection fraction; FS: fractional shortening; H/R: hypoxia-reoxygenation; I/R: ischemia-reperfusion; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFF: mitochondrial fission factor; miRNA: microRNA; NAC: N-acetylcysteine; OCR: oxygen consumption rate; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PM: particulate matter; PRKAA1/AMPK: protein kinase AMP-activated catalytic subunit alpha 1; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TRP53/p53: transformation related protein 53; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.},
}
@article {pmid39245103,
year = {2024},
author = {Mondal, S and Hazra, A and Paul, P and Saha, B and Roy, S and Bhowmick, P and Bhowmick, M},
title = {Formulation and evaluation of n-acetyl cysteine loaded bi-polymeric physically crosslinked hydrogel with antibacterial and antioxidant activity for diabetic wound dressing.},
journal = {International journal of biological macromolecules},
volume = {279},
number = {Pt 4},
pages = {135418},
doi = {10.1016/j.ijbiomac.2024.135418},
pmid = {39245103},
issn = {1879-0003},
mesh = {*Acetylcysteine/pharmacology/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Wound Healing/drug effects ; *Antioxidants/pharmacology/chemistry ; *Hydrogels/chemistry/pharmacology ; *Bandages ; Animals ; Humans ; Alginates/chemistry ; Microbial Sensitivity Tests ; Candida albicans/drug effects ; Drug Liberation ; Plant Gums/chemistry ; Escherichia coli/drug effects ; Rats ; Drug Compounding ; Mannans/chemistry/pharmacology ; },
abstract = {Diabetic wounds have become a serious global health concern, with a growing number of patients each year. Diabetic altered wound healing physiology, as well as resulting complications, make therapy difficult. Hence, diabetic wound healing necessitates a multidisciplinary strategy. This study focused on the formulation, statistical optimization, ex vivo, and in vitro evaluation of a diabetic wound healing by n-acetyl cysteine (NAC) loaded hydrogel. The objective of the study is to formulate n-acetyl loaded hydrogel with different ratio (1:1, 1:2, 1:3, 2:1) of sodium alginate and guar gum. The antibacterial and antifungal assessment against the viability of Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), and Staphylococcus aureus (S.aureus) and Candida albicans (C. albicans) was conducted after determining the in vitro drug release profile. The results of the experiment demonstrated that the formulation F3 was an optimal formulation on triplicate measurement with a pH of 6.2 ± 0.168, and a density of 1.026 ± 0.21. In vitro cell line study exhibited F3 has potential role in cell adhesion and proliferation might be beneficial to tissue regeneration and wound healing. The results imply that F3 may be helpful for the quick healing of diabetic wounds by promoting angiogenesis and also by scavenging free oxygen radicals.},
}
@article {pmid39239906,
year = {2024},
author = {Guo, J and Xu, Q and Zhong, Y and Su, Y},
title = {N-acetylcysteine promotes doxycycline resistance in the bacterial pathogen Edwardsiella tarda.},
journal = {Virulence},
volume = {15},
number = {1},
pages = {2399983},
pmid = {39239906},
issn = {2150-5608},
mesh = {*Edwardsiella tarda/drug effects/genetics ; *Doxycycline/pharmacology ; *Anti-Bacterial Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Drug Resistance, Bacterial ; Reactive Oxygen Species/metabolism ; Enterobacteriaceae Infections/microbiology/drug therapy ; Animals ; Glutathione/metabolism ; Proteomics ; Bacterial Proteins/genetics/metabolism ; Humans ; Microbial Sensitivity Tests ; },
abstract = {Bacterial resistance poses a significant threat to both human and animal health. N-acetylcysteine (NAC), which is used as an anti-inflammatory, has been shown to have distinct and contrasting impacts on bacterial resistance. However, the precise mechanism underlying the relationship between NAC and bacterial resistance remains unclear and requires further investigation. In this study, we study the effect of NAC on bacterial resistance and the underlying mechanisms. Specifically, we examine the effects of NAC on Edwardsiella tarda ATCC15947, a pathogen that exhibits resistance to many antibiotics. We find that NAC can promote resistance of E. tarda to many antibiotics, such as doxycycline, resulting in an increase in the bacterial survival rate. Through proteomic analysis, we demonstrate that NAC activates the amino acid metabolism pathway in E. tarda, leading to elevated intracellular glutathione (GSH) levels and reduced reactive oxygen species (ROS). Additionally, NAC reduces antibiotic influx while enhancing efflux, thus maintaining low intracellular antibiotic concentrations. We also propose that NAC promotes protein aggregation, thus contributing to antibiotic resistance. Our study describes the mechanism underlying E. tarda resistance to doxycycline and cautions against the indiscriminate use of metabolite adjuvants.},
}
@article {pmid39232832,
year = {2024},
author = {Duan, H and Wang, F and Wang, K and Yang, S and Zhang, R and Xue, C and Zhang, L and Ma, X and Du, X and Kang, J and Zhang, Y and Zhao, X and Hu, J and Xiao, L},
title = {Quercetin ameliorates oxidative stress-induced apoptosis of granulosa cells in dairy cow follicular cysts by activating autophagy via the SIRT1/ROS/AMPK signaling pathway.},
journal = {Journal of animal science and biotechnology},
volume = {15},
number = {1},
pages = {119},
pmid = {39232832},
issn = {1674-9782},
abstract = {BACKGROUND: Follicular cysts contribute significantly to reproductive loss in high-yield dairy cows. This results from the death of follicular granulosa cells (GCs) caused by oxidative stress. Quercetin is known to have significant antioxidant and anti-apoptotic effects. However, the effect of quercetin on follicular cysts has yet been elucidated. Therefore, this study aimed to explore the anti-oxidant and anti-apoptosis effects and potential molecular mechanisms of quercetin in H2O2-induced primary cow GCs and 3-nitropropionic acid (3-NPA)-induced mouse model of oxidative stress and thus treat ovarian cysts in dairy cows.<br><br>RESULTS: In this study, compared with estrus cows, cows with follicular cysts showed heightened levels of oxidative stress and increased follicular cell apoptosis, while autophagy levels were reduced. A model of oxidative stress was induced in vitro by H2O2 and showed significant increases in apoptosis together with reduced autophagy. These effects were significantly ameliorated by quercetin. Effects similar to those of quercetin were observed after treatment of cells with the reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC). Further investigations using chloroquine (autophagy inhibitor), rapamycin (autophagy activator), selisistat (SIRT1 inhibitor), and compound C (AMPK inhibitor) showed that chloroquine counteracted the effects of quercetin on oxidative stress-induced apoptosis, while rapamycin had the same effect as quercetin. In addition, the SIRT1/AMPK pathway inhibitors antagonized quercetin-mediated mitigation of the effects of oxidative stress on increased apoptosis and reduced autophagy. Consistent with the results in vitro, in mouse ovarian oxidative stress model induced by 3-NPA, quercetin activated autophagy through the SIRT1/AMPK signaling pathway, while alleviating oxidative stress damage and inhibiting apoptosis in mouse ovaries.<br><br>CONCLUSIONS: These findings indicate that quercetin can inhibit apoptosis in GCs and restore ovarian function by activating autophagy through the SIRT1/ROS/AMPK signaling pathway, suggesting a new direction for the treatment of ovarian follicular cysts in high-yield dairy cows.},
}
@article {pmid39225404,
year = {2025},
author = {Chinnapaka, S and Bakthavachalam, V and Dasari, S and Kannan, J and Sapkota, S and Kumar, R and Munirathinam, G},
title = {Vitamin K3 derivative inhibits androgen receptor signaling in targeting aggressive prostate cancer cells.},
journal = {BioFactors (Oxford, England)},
volume = {51},
number = {1},
pages = {e2117},
doi = {10.1002/biof.2117},
pmid = {39225404},
issn = {1872-8081},
mesh = {Humans ; Male ; *Apoptosis/drug effects ; Black or African American/genetics ; Cell Line, Tumor ; *Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; *Prostatic Neoplasms/pathology/drug therapy/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Receptors, Androgen/metabolism/genetics ; *Signal Transduction/drug effects ; Thioredoxin Reductase 2/metabolism/genetics ; *Vitamin K 3/pharmacology ; },
abstract = {Prostate cancer (PCa) is the second critical cause of cancer-related deaths, with African Americans dying at higher rates in the U.S. The main reasons for the higher mortality rate are ethnic differences and lack of understanding of prostate cancer biology and affordable treatments, as well as the financial burden of African American men to obtain the most effective and safe treatments. The effect of micronutrients, including Vitamin K, on various cancer cell lines has been widely studied, but the potential anticancer effect of VK3-OCH3, an analog of vitamin K3 (Menadione), on African American prostate cancer has not been evaluated. In this study, we compared the anticancer effect of VK3-OCH3 on targeting African American derived PCa cell lines namely RC77-T and MDA-PCa-2b. Our results show that VK3-OCH3 significantly inhibits the proliferation of both RC77-T and MDA-PCa-2b African American PCa cells and promotes apoptosis, and the underlying mechanism of cell death appears to be similar in both the cell lines. Notably, VK3-OCH3 inhibits colony-forming ability and induces apoptosis by blocking the cell cycle at G0 in African American PCa cells. VK3-OCH3 also acts as an anti-metastatic agent by inhibiting the migration ability of the metastatic properties of African American PCa cells. The cell death of African American PCa cells mediated by VK3-OCH3 is associated with the production of free radicals, such as intracellular and mitochondrial reactive oxygen species (ROS). Interestingly, antioxidants such as N-Acetylcysteine (NAC) and Glutathione (GSH) effectively negated the oxidative stress induced by VK3-OCH3 on PCa cell lines derived from African American patients. Of note, VK3-OCH3 reduces androgen receptor and prostate-specific antigen expression in these PCa cells. Furthermore, molecular dynamic studies reiterated that VK3-OCH3 strongly binds to the androgen receptor, suggesting that the androgen receptor is the potential molecular target of VK3-OCH3. In addition, Western blot analysis showed that VK3-OCH3 reduces the expression of androgen receptor, TRX2, and anti-apoptotic signaling molecules such as Bcl-2 and TCTP in the MDA-PCa-2b metastatic PCa cellular model. In conclusion, our results suggested that VK3-OCH3 is a promising anticancer agent that could potentially reduce the mortality rates of African American PCa patients, warranting further preclinical and translational studies.},
}
@article {pmid39223526,
year = {2024},
author = {Rhee, CK and Lim, SY and Lee, WY and Jung, JY and Park, YB and Lee, CY and Hwang, YI and Song, JW and Choi, WI and Yoo, KH and Kim, KU and Kim, YI and Kim, TH and Park, SJ and Shin, KC and Um, SJ and Yoon, HK and Lee, HS and Kim, DK and Leem, AY and , },
title = {The effect of nebulized N-acetylcysteine on the phlegm of chronic obstructive pulmonary disease: the NEWEST study.},
journal = {BMC pulmonary medicine},
volume = {24},
number = {1},
pages = {434},
pmid = {39223526},
issn = {1471-2466},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage ; *Pulmonary Disease, Chronic Obstructive/drug therapy/physiopathology ; Male ; Female ; Aged ; Prospective Studies ; *Nebulizers and Vaporizers ; Middle Aged ; Forced Expiratory Volume/drug effects ; Administration, Inhalation ; Vital Capacity/drug effects ; Expectorants/administration &amp; dosage/adverse effects ; Treatment Outcome ; },
abstract = {BACKGROUND: Phlegm is prevalent symptom in patients with chronic obstructive pulmonary disease (COPD). Few studies have investigated the effectiveness of N-acetylcysteine (NAC) nebulizer therapy in COPD patients. We evaluated the effect of nebulized NAC on the improvement of phlegm symptom in COPD patients.<br><br>METHODS: This was a 12-week, prospective, single-arm, open-label, phase IV multi-center trial (NCT05102305, Registration Date: 20-October-2021). We enrolled patients aged&#x2009;&#x2265;&#x2009;40 years with post bronchodilator forced expiratory volume in one second/forced vital capacity (FEV1/FVC)&#x2009;<&#x2009;0.7 and COPD assessment test (CAT) phlegm score&#x2009;&#x2265;&#x2009;2; the patients were current or ex-smoker with smoking pack-years&#x2009;&#x2265;&#x2009;10. The primary endpoint was to determine the change in CAT phlegm score at 12 weeks compared to the baseline. Patients were assessed at baseline, 4, 8, and 12 weeks of treatment using the CAT score.<br><br>RESULTS: In total, 100 COPD patients were enrolled from 10 hospitals. The mean age of the patients was 71.42&#x2009;&#xb1;&#x2009;8.20 years, with 19.78% being current-smokers and 80.22% being ex-smokers. The mean smoking pack-years was 40.32&#x2009;&#xb1;&#x2009;35.18. The mean FVC, FEV1, and FEV1/FVC were 3.94&#xa0;L (75.44%), 2.22&#xa0;L (58.50%), and 0.53, respectively. The CAT phlegm score at baseline was 3.47&#x2009;&#xb1;&#x2009;1.06, whereas after 12 weeks of nebulized NAC it significantly decreased to 2.62&#x2009;&#xb1;&#x2009;1.30 (p&#x2009;<&#x2009;0.01). More than half (53.5%) of the patients expressed satisfaction with the effects of nebulized NAC therapy. Adverse events occurred in 8 (8.0%) patients. Notably, no serious adverse drug reactions were reported.<br><br>CONCLUSION: In this study, we have established the effectiveness and safety of nebulized NAC over 12 weeks.},
}
@article {pmid39214451,
year = {2024},
author = {Kim, JE and Lee, DS and Wang, SH and Kim, TH and Kang, TC},
title = {GPx1-ERK1/2-CREB pathway regulates the distinct vulnerability of hippocampal neurons to oxidative stress via modulating mitochondrial dynamics following status epilepticus.},
journal = {Neuropharmacology},
volume = {260},
number = {},
pages = {110135},
doi = {10.1016/j.neuropharm.2024.110135},
pmid = {39214451},
issn = {1873-7064},
mesh = {Animals ; *Oxidative Stress/drug effects/physiology ; Male ; *Neurons/metabolism/drug effects ; *Glutathione Peroxidase/metabolism ; *Glutathione Peroxidase GPX1 ; *Hippocampus/metabolism/drug effects/pathology ; *Mitochondrial Dynamics/drug effects/physiology ; *Status Epilepticus/chemically induced/metabolism/pathology ; *Cyclic AMP Response Element-Binding Protein/metabolism ; Rats ; *MAP Kinase Signaling System/drug effects/physiology ; *Rats, Sprague-Dawley ; },
abstract = {Glutathione peroxidase-1 (GPx1) and cAMP/Ca[2+] responsive element (CRE)-binding protein (CREB) regulate neuronal viability by maintaining the redox homeostasis. Since GPx1 and CREB reciprocally regulate each other, it is likely that GPx1-CREB interaction may play a neuroprotective role against oxidative stress, which are largely unknown. Thus, we investigated the underlying mechanisms of the reciprocal regulation between GPx1 and CREB in the male rat hippocampus. Under physiological condition, L-buthionine sulfoximine (BSO)-induced oxidative stress increased GPx1 expression, extracellular signal-regulated kinase 1/2 (ERK1/2) activity and CREB serine (S) 133 phosphorylation in CA1 neurons, but not dentate granule cells (DGC), which were diminished by GPx1 siRNA, U0126 or CREB knockdown. GPx1 knockdown inhibited ERK1/2 and CREB activations induced by BSO. CREB knockdown also decreased the efficacy of BSO on ERK1/2 activation. BSO facilitated dynamin-related protein 1 (DRP1)-mediated mitochondrial fission in CA1 neurons, which abrogated by GPx1 knockdown and U0126. CREB knockdown blunted BSO-induced DRP1 upregulation without affecting DRP1 S616 phosphorylation ratio. Following status epilepticus (SE), GPx1 expression was reduced in CA1 neurons and DGC. SE also decreased CREB activity CA1 neurons, but not DGC. SE degenerated CA1 neurons, but not DGC, accompanied by mitochondrial elongation. These post-SE events were ameliorated by N-acetylcysteine (NAC, an antioxidant), but deteriorated by GPx1 knockdown. These findings indicate that a transient GPx1-ERK1/2-CREB activation may be a defense mechanism to protect hippocampal neurons against oxidative stress via maintenance of proper mitochondrial dynamics.},
}
@article {pmid39208656,
year = {2024},
author = {Xue, A and Zhang, H and Song, S and Yu, X},
title = {Effects of N-Acetylcysteine combined with Ambroxol Hydrochloride on clinical symptoms, CRP, and PCT in children with pneumonia.},
journal = {Clinics (Sao Paulo, Brazil)},
volume = {79},
number = {},
pages = {100476},
pmid = {39208656},
issn = {1980-5322},
mesh = {Humans ; *Ambroxol/therapeutic use/administration &amp; dosage ; *C-Reactive Protein/analysis ; *Acetylcysteine/therapeutic use ; Female ; Male ; *Procalcitonin/blood ; Child, Preschool ; *Expectorants/therapeutic use/adverse effects ; *Drug Therapy, Combination ; *Pneumonia/drug therapy ; Child ; Treatment Outcome ; Infant ; Blood Gas Analysis ; },
abstract = {OBJECTIVE: This study investigated the effects of N-Acetylcysteine (NAC) combined with Ambroxol Hydrochloride (AH) on clinical symptoms, C-Reactive Protein (CRP), and Procalcitonin (PCT) levels in children with pneumonia.<br><br>METHODS: A total of 98 children with pneumonia were assigned to the control group and observation group by random number table method. NAC was administered to the observation group and AH was given to the control group. The therapeutic effect was observed, the disappearance time of clinical symptoms and levels of inflammatory factors, lung function parameters, blood gas analysis parameters, and immunoglobulin were measured. The incidence of adverse reactions was statistically analyzed.<br><br>RESULTS: A higher effective rate was observed in the observation group than in the control group (p < 0.05). Antipyretic time, cough disappearance time, and lung rale disappearance time in the observation group were shorter than those in the control group (p < 0.05). After treatment, CRP and PCT were lower (p < 0.05), FVC, FEV1, and FEV1/FVC were higher, PaCO2 was lower, PaO2 and SaO2 were higher, and IgA, IgG, IgM, and C3 were higher in the observation group than those in the control group (p < 0.05). The incidence of adverse reactions between the two groups was not significantly different (p > 0.05).<br><br>CONCLUSION: NAC combined with AH is effective in the treatment of pediatric pneumonia by effectively alleviating clinical symptoms, reducing inflammatory factors, and improving lung function and immune function.},
}
@article {pmid39208572,
year = {2024},
author = {Chen, C and Chen, Y and Zhai, H and Xiao, Y and Xu, J and Gu, Y and Han, X and Wang, C and Chen, Q and Lu, H},
title = {Cadmium exposure induces skeletal muscle insulin resistance through the reactive oxygen species-mediated PINK1/Parkin pathway.},
journal = {Ecotoxicology and environmental safety},
volume = {284},
number = {},
pages = {116954},
doi = {10.1016/j.ecoenv.2024.116954},
pmid = {39208572},
issn = {1090-2414},
mesh = {Animals ; Male ; Rats ; *Cadmium/toxicity ; *Insulin Resistance ; Mitophagy/drug effects ; Muscle Fibers, Skeletal/drug effects/pathology ; *Muscle, Skeletal/drug effects ; Oxidative Stress/drug effects ; Protein Kinases/metabolism ; Rats, Sprague-Dawley ; *Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; Ubiquitin-Protein Ligases/metabolism ; PTEN-Induced Putative Kinase ; },
abstract = {Epidemiological studies have suggested a positive association between environmental cadmium (Cd) exposure and type 2 diabetes mellitus (T2DM). Skeletal muscle insulin resistance (IR) plays a critical role in the pathogenesis of T2DM. This study aimed to investigate the effects of chronic low-level Cd exposure on skeletal muscle IR and its potential mechanism. Rats were exposed to drinking water containing 2 or 10 mg/L Cd for 24 weeks. Differentiated L6 myotubes were treated with Cd for 72 h. Immunofluorescence, flow cytometry assay, RNA-sequencing, and Seahorse analysis were conducted to determine the effects of Cd and its underlying mechanism on relevant parameters, including insulin sensitivity, glucose uptake, oxidative stress, mitophagy, and mitochondrial function in skeletal muscle and L6 myotubes. N-acetyl-cysteine (NAC), a scavenger of reactive oxygen species (ROS), and mitophagy inhibitor Cyclosporin A (CsA) were used to confirm the role of oxidative stress in mitophagy and mitochondrial dysfunction caused by Cd. We found that rats exposed to 10 mg/L Cd exhibited hyperglycemia and skeletal muscle IR. Cd markedly increased IRS-1 phosphorylation at Ser612, while decreased levels of phosphorylated PI3K, Akt, AS160, inhibited GLUT4 translocation and glucose uptake. Mechanistically, Cd increased the intracellular ROS, hydrogen peroxide, and malondialdehyde levels and decreased antioxidase activity in L6 myotubes. Furthermore, Cd upregulated the mRNA and protein levels of LC3II/I, PINK1, and Parkin. In addition, Cd induced the formation of mitophagosomes, reduced the mitochondrial membrane potential, decreased the adenosine triphosphate content, and impaired the mitochondrial respiratory capacity. Strikingly, NAC ameliorated oxidative stress, excessive mitophagy, and the associated reduction in myotube insulin sensitivity, while inhibition of mitophagy by CsA alleviated skeletal muscle IR. In conclusion, this study reveals a previously unrecognized mechanism that chronic low-level Cd exposure may induce mitophagy by activating the PINK1/Parkin signal pathway by increasing ROS, thus causing skeletal muscle IR and elevated blood glucose.},
}
@article {pmid39204746,
year = {2024},
author = {Carlucci, V and Ponticelli, M and Russo, D and Labanca, F and Costantino, V and Esposito, G and Milella, L},
title = {Nutraceutical Valorization of Exhausted Olive Pomace from Olea europaea L. Using Advanced Extraction Techniques.},
journal = {Plants (Basel, Switzerland)},
volume = {13},
number = {16},
pages = {},
pmid = {39204746},
issn = {2223-7747},
support = {CUP: G49J19001350004//Regione Basilicata/ ; CUP: C31G18000210002//Regione Basilicata/ ; },
abstract = {Exhausted olive pomace (EOP) represents the principal residue of olive pomace. Several studies have optimized the extraction of specialized metabolites from the EOP of Olea europaea L., but a comparison between different extractive methods has not been made. For this reason, the present investigation aims to compare four different extractive methods by using water and 15% ethanol/water as extractive solvents. Specifically, based on extract antioxidant activity, the methods compared were maceration (MAC), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), and Accelerated Solvent Extraction (ASE). Between these, the UAE and ASE hydroalcoholic EOP extracts were demonstrated to have the highest antioxidant activity. Subsequently, these extracts were investigated for their hypoglycemic and antiradical activity using in vitro cell-free and cell-based assays, respectively. ASE hydroalcoholic EOP extract demonstrated the greatest ability to inhibit the α-amylase enzyme and an in vitro antioxidant activity comparable to N-acetyl cysteine in HepG2 cells. UAE and ASE extracts' phytochemical characterization was also performed, identifying seven phenolic compounds, including 3-hydroxytyrosol, tyrosol, and, for the first time, salidroside. The ASE hydroalcoholic EOP extract was the richest from a phytochemical point of view, thus confirming its major biological activity. Therefore, ASE and 15% ethanol/water may represent the best extractive method for EOP nutraceutical valorization.},
}
@article {pmid39196852,
year = {2024},
author = {Zhao, Q and Hu, Z and Wang, A and Ding, Z and Zhao, G and Wang, X and Li, W and Peng, Y and Zheng, J},
title = {Correlation of Vanillin-Induced Cytotoxicity with CYP3A-Mediated Metabolic Activation.},
journal = {Journal of agricultural and food chemistry},
volume = {72},
number = {36},
pages = {20064-20076},
doi = {10.1021/acs.jafc.4c03060},
pmid = {39196852},
issn = {1520-5118},
mesh = {Animals ; *Benzaldehydes/metabolism/pharmacology ; *Hepatocytes/metabolism/drug effects ; Rats ; Male ; *Cytochrome P-450 CYP3A/metabolism/genetics ; *Microsomes, Liver/metabolism/drug effects ; *Rats, Sprague-Dawley ; *Activation, Metabolic ; Glutathione/metabolism ; Flavoring Agents/metabolism/chemistry/toxicity ; },
abstract = {Vanillin (VAN) is a common flavoring agent that can cause liver damage when ingested in large amounts. Nevertheless, the precise processes responsible for its toxicity remain obscure. The present research aimed to examine the metabolic activation of VAN and establish a potential correlation between its reactive metabolites and its cytotoxicity. In rat liver microsomes incubated with VAN, reduced glutathione/N-acetylcysteine (GSH/NAC), and nicotinamide adenine dinucleotide phosphate (NADPH), two conjugates formed from GSH and one conjugate derived from NAC were identified. We also discovered one GSH conjugate in both the bile obtained from rats and the rat primary hepatocytes that were subjected to VAN exposure. Additionally, the NAC conjugate exerted in the urine of VAN-treated rats was observed. These results indicate that a quinone intermediate was produced from VAN both in vitro and in vivo. Next, we identified CYP3A as the main enzyme that initiated the bioactive pathway of VAN. After the activity of CYP3A was selectively inhibited by ketoconazole (KTZ), the generation of the GSH conjugate declined in hepatocytes exposed to VAN. Furthermore, the vulnerability to VAN-induced toxicity was alleviated by KTZ in hepatocytes. Thus, we propose that the cytotoxicity of VAN may derive from metabolic activation triggered by CYP3A.},
}
@article {pmid39195722,
year = {2024},
author = {Wang, Z and Wang, Q and Gong, X},
title = {Unveiling the Mysteries of Contrast-Induced Acute Kidney Injury: New Horizons in Pathogenesis and Prevention.},
journal = {Toxics},
volume = {12},
number = {8},
pages = {},
pmid = {39195722},
issn = {2305-6304},
support = {No.82074387//National Natural Science Foundation of China/ ; No.81873280//National Natural Science Foundation of China/ ; No.20Y21902200//Shanghai Science and Technology Development Foundation/ ; },
abstract = {The utilization of contrast media (CM) in clinical diagnostic imaging and interventional procedures has escalated, leading to a gradual increase in the incidence of contrast-induced acute kidney injury (CI-AKI). Presently, the scarcity of effective pharmacological treatments for CI-AKI poses significant challenges to clinical management. Firstly, we explore the pathogenesis of CI-AKI in this review. Beyond renal medullary ischemia and hypoxia, oxidative stress, cellular apoptosis, and inflammation, emerging mechanisms such as ferroptosis, release of neutrophil extracellular traps (NETs), and nitrosative stress, which offer promising avenues for the management of CI-AKI, are identified. Secondly, a comprehensive strategy for the early prevention of CI-AKI is introduced. Investigating the risk factors associated with CI-AKI is essential for the timely identification of high-risk groups. Additionally, exploring early sensitive biomarkers is crucial for early diagnosis. A synergistic approach that combines these sensitive biomarkers, CI-AKI risk factors, and disease risk prediction models enhances both the accuracy and efficiency of early diagnostic processes. Finally, we explore recent pharmacological and non-pharmacological interventions for the management of Cl-AKI. Beyond the traditional focus on the antioxidant N-acetylcysteine (NAC), we look at active compounds from traditional Chinese medicine, including tetramethylpyrazine (TMP), salvianolic acid B (Sal B), as well as emerging preventive medications like N-acetylcysteine amide (NACA), alprostadil, and others, which all showed potential benefits in animal and clinical studies for CI-AKI prevention. Furthermore, innovative strategies such as calorie restriction (CR), enhanced external counterpulsation (EECP), and mesenchymal stem cell therapy are highlighted as providing fresh insights into Cl-AKI prevention and management.},
}
@article {pmid39195687,
year = {2024},
author = {Podobnik, B and Demšar, L and Šarc, L and Jerin, A and Osredkar, J and Trontelj, J and Roškar, R and Brvar, M},
title = {N-Acetylcysteine Ineffective in Alleviating Hangover from Binge Drinking: A Clinical Study.},
journal = {Toxics},
volume = {12},
number = {8},
pages = {},
pmid = {39195687},
issn = {2305-6304},
support = {P3-0019//Slovenian Research Agency grants/ ; 20200175//University Medical Centre Ljubljana/ ; },
abstract = {Alcohol hangover (veisalgia) is a fairly common phenomenon. The pathogenesis of veisalgia is not understood and treatment has not yet been established. Occasionally, students take N-acetylcysteine (NAC) before binge drinking to alleviate hangover. The aim of this study was to evaluate the effect of NAC on serum levels of electrolytes, enzymes, oxidative stress biomarkers and symptoms of veisalgia in binge drinking. In this randomized, double-blind, placebo-controlled study, healthy students were randomly assigned into two groups: one receiving NAC and the other receiving a placebo. Blood samples were taken before drinking, 30 min after a 1.5 h long drinking session, and the subsequent morning. Serum levels of electrolytes, urea, enzymes, ethanol, 8-Hydroxydeoxyguanosine (8-OHdG) and N-epsilon-hexanoyl-lysine were measured. The participants completed the Acute Hangover Severity Scale (AHSS) assessment based on symptoms, and 40 students (20 male), aged 23 ± 2 years, were included in the study. Their mean blood ethanol concentration was 1.4 g/kg. Serum sodium levels were increased after drinking, and urea decreased the following morning compared to their levels before drinking in both groups. Serum 8-OHdG levels were increased after drinking and remained elevated until the following morning, compared to the levels before drinking, in both groups. NAC had no effect on sodium, urea and 8-OHdG levels or the symptoms of veisalgia. In conclusion, binge drinking causes a transient increase in serum sodium and as a prolonged increase in oxidative marker 8-OHdG levels. NAC had no effect on the sodium and 8-OHdG levels.},
}
@article {pmid39192169,
year = {2025},
author = {Sun, C and Wang, Q and Li, P and Dong, R and Lei, Y and Hu, Y and Yan, Y and Song, G},
title = {The ROS Mediates MCUb in Mitochondria-Regulated Apoptosis of TM4 Cells Induced by Titanium Dioxide Nanoparticles.},
journal = {Biological trace element research},
volume = {203},
number = {5},
pages = {2760-2775},
pmid = {39192169},
issn = {1559-0720},
support = {2023AB049//Corps Science and Technology Planning Project/ ; 21966027, 81560536, and 32060125//National Natural Science Foundation of China/ ; 2023CB008-18//Youth Science and Technology Innovation Talents Project of Xinjiang Production and Construction Corps/ ; },
mesh = {*Titanium/pharmacology/chemistry ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; *Mitochondria/metabolism/drug effects ; Animals ; Mice ; *Nanoparticles/chemistry ; Cell Survival/drug effects ; Calcium/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Cell Line ; },
abstract = {Titanium dioxide nanoparticles (TiO2 NPs) can cause mitochondrial apoptosis of TM4 cells associated with reactive oxygen species (ROS) accumulation and Ca[2+] overload, but the relations among these processes remain unclear. This study aimed to evaluate whether the accumulation of ROS caused by TiO2 NPs inhibits MCUb expression, leading to mitochondrial calcium overload and subsequent cell apoptosis through the mitochondrial pathway. TM4 cells were exposed to different concentrations of TiO2 NPs (0, 25, 50, 75, 100 μg/mL) for 24 h. We assessed cell viability, ROS level, MCUb and VDAC1 expression, mitochondrial and cytoplasmic Ca[2+] levels, mitochondrial membrane potential (MMP), apoptosis rate, and key proteins related to mitochondrial apoptosis (Bcl-2, Bax, Caspase 3, Caspase 9, p53 and Cyt c). Additionally, the effect of N-acetylcysteine (NAC) on MCUb expression, calcium homeostasis, and cell apoptosis was evaluated. Compared to control group, TiO2 NPs significantly increased ROS level, downregulated MCUb expression, elevated Ca[2+] levels in mitochondria and cytoplasm, and enhanced mitochondria-regulated apoptosis, starting from the 50 μg/mL TiO2 NPs group. However, NAC significantly increased MCUb expression, attenuated Ca[2+] levels in mitochondria and cytoplasm, and reduced mitochondria-related apoptosis. In conclusion, TiO2 NPs induced ROS accumulation, which inhibited the expression of MCUb. The decreased MCUb level led to Ca[2+] overload in mitochondria, causing TM4 cell apoptosis via the mitochondrial pathway. This research elucidates, for the first time, the role of MCUb and its relation with ROS in apoptosis of TM4 cells induced by TiO2 NPs, which supplementing the molecular mechanism of cell apoptosis caused by TiO2 NPs.},
}
@article {pmid39189858,
year = {2024},
author = {Wallis, RS and Sabi, I and Lalashowi, J and Bakuli, A and Mapamba, D and Olomi, W and Siyame, E and Ngaraguza, B and Chimbe, O and Charalambous, S and Rachow, A and Ivanova, O and Zurba, L and Myombe, B and Kunambi, R and Hoelscher, M and Ntinginya, N and Churchyard, G},
title = {Adjunctive N-Acetylcysteine and Lung Function in Pulmonary Tuberculosis.},
journal = {NEJM evidence},
volume = {3},
number = {9},
pages = {EVIDoa2300332},
doi = {10.1056/EVIDoa2300332},
pmid = {39189858},
issn = {2766-5526},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/therapeutic use ; Male ; *Tuberculosis, Pulmonary/drug therapy ; Female ; Adult ; Prospective Studies ; *Antitubercular Agents/therapeutic use/administration &amp; dosage ; *Glutathione/blood ; Middle Aged ; Lung/drug effects/microbiology/physiopathology ; Sputum/microbiology ; Treatment Outcome ; Respiratory Function Tests ; Young Adult ; },
abstract = {BACKGROUND: Tuberculosis remains a global health concern, and half of cured patients have permanent lung injury. N-acetylcysteine (NAC) has shown beneficial antimicrobial, antioxidant, and immunomodulatory effects in preclinical tuberculosis models. We examined its effects on tuberculosis treatment outcomes.<br><br>METHODS: This prospective, randomized, controlled trial nested within the TB SEQUEL cohort study enrolled 140 adults with moderate or far-advanced tuberculosis. Participants were randomly assigned 1:1 to standard therapy with or without 1200&#x2009;mg of oral NAC twice daily for days 1 to 112. Clinical evaluations, sputum culture, and spirometry were performed at specified intervals through day 168, after which participants returned to the TB SEQUEL cohort. The primary outcome was culture conversion. Secondary outcomes included whole-blood glutathione levels and lung function.<br><br>RESULTS: Participants were predominantly young, male, and human immunodeficiency virus 1-negative and had heavy sputum Mycobacterium tuberculosis (MTB) infection burdens. NAC increased glutathione levels (NAC &#xd7; day interaction, 8.48; 95% confidence interval [CI], 1.93 to 15.02) but did not increase stable culture conversion (hazard ratio, 0.84; 95% CI, 0.59 to 1.20; P=0.33). NAC treatment was associated with improved recovery of lung function (NAC &#xd7; month, 0.49 [95% CI, 0.02 to 0.95] and 0.42 [95% CI, -0.06 to 0.91] for forced vital capacity and forced expiratory volume in the first second, respectively, as percentages of predicted values). The effects of NAC on lung function were greatest in participants with severe baseline lung impairment and appeared to persist beyond the period of NAC administration. Rates of serious or grade 3 to 4 nonserious adverse events did not differ between the groups.<br><br>CONCLUSIONS: Despite increasing whole-blood glutathione levels, NAC did not affect eradication of MTB infection in adults with pulmonary tuberculosis that was moderate to far advanced. Secondary outcomes of lung function showed changes that merit further investigation. (Funded by TB SEQUEL grant 01KA1613 of the German Ministry for Education and Research, the Health Africa Project, and the German Center for Infection Research; ClinicalTrials.gov number, NCT03702738.).},
}
@article {pmid39189572,
year = {2024},
author = {Sarıtaş, TB and Ertürk, C and Büyükdoğan, H and Yıldırım, B and Gündüz, N and Selek, &#x15e;},
title = {Effects of N-acetylcysteine on sciatic nerve healing: A histopathological, functional, and biochemical study of the rat sciatic nerve.},
journal = {Joint diseases and related surgery},
volume = {35},
number = {3},
pages = {618-627},
pmid = {39189572},
issn = {2687-4792},
mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Rats, Wistar ; Male ; *Sciatic Nerve/drug effects/pathology/injuries ; *Nerve Regeneration/drug effects ; Rats ; Antioxidants/pharmacology ; Disease Models, Animal ; Wound Healing/drug effects ; Peripheral Nerve Injuries/drug therapy/pathology ; Recovery of Function/drug effects ; },
abstract = {OBJECTIVES: This study aims to evaluate the histopathological, biochemical, and functional effects of N-acetylcysteine (NAC), which has antioxidant, anti-inflammatory, and cytoprotective activity, on nerve regeneration in rats with sciatic nerve crush (axonotmesis) injury.<br><br>MATERIALS AND METHODS: This study used 16 male Wistar rats, which were divided into treatment and control groups. A standard axonotmesis-type surgical injury was induced in the left sciatic nerves of all rats. The treatment group was given 300 mg/kg of intraperitoneal NAC once a day, whereas the control group received an equal volume of saline solution. After conducting gait analyses, the sciatic functional index (SFI) was used for functional assessment. After gait analysis, all animals were euthanized. Blood samples were examined biochemically. The left sciatic nerves and left triceps surae muscles were examined histopathologically.<br><br>RESULTS: Histopathologically, the thickness of the perineurium, axonal degeneration, axonolysis, edema, inflammation, muscle atrophy, and muscle degeneration were all significantly lower in the treatment group (p<0.05). Functionally, SFI-1, SFI-2, and SFI-3 were significantly higher in the treatment group (p<0.05). Biochemically, while the native thiol level and native thiol/total thiol ratio were significantly higher in the treatment group (p<0.003), the disulfide/total thiol ratio was significantly higher in the control group (p<0.005). Significant correlations were found between six of the seven gait parameters and the histopathological findings (p<0.05).<br><br>CONCLUSION: Our study results suggest that NAC may contribute positively to the histopathological and functional recovery of sciatic nerve injury in rats. Furthermore, NAC may have an antioxidant effect on thiol-disulfide homeostasis at a biochemical level. We believe that NAC has a stimulatory effect on healing following nerve injuries.},
}
@article {pmid39189388,
year = {2024},
author = {Adel, O and El-Sherbiny, HR and M Shahat, A and Ismail, ST},
title = {N-Acetylcysteine Supplementation Improves Testicular Haemodynamics, Testosterone Levels, Seminal Antioxidant Capacity and Semen Quality in Heat-Stressed Goat Bucks.},
journal = {Reproduction in domestic animals = Zuchthygiene},
volume = {59},
number = {8},
pages = {e14709},
doi = {10.1111/rda.14709},
pmid = {39189388},
issn = {1439-0531},
mesh = {Male ; Animals ; *Goats/physiology ; *Testis/drug effects ; *Testosterone/blood ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Antioxidants/pharmacology ; *Semen Analysis/veterinary ; *Hemodynamics/drug effects ; *Dietary Supplements ; *Semen/drug effects ; Nitric Oxide/metabolism ; Hot Temperature ; },
abstract = {Heat stress (HS) disrupts testicular homeostasis because of oxidative stress. N-acetylcysteine (NAC) is a thiol compound with antioxidants, anti-inflammatory and anti-apoptotic properties. As a sequel, this research aimed to assess the ameliorative effects of NAC supplementation on the reproductive performance of goat bucks kept under environmental HS. Primarily, Doppler examination as well as semen collection and evaluation were conducted on 12 mature bucks for 2 weeks (W) as pre-heat stress control (W1 and W2) during winter (February 2023). The temperature-humidity index (THI) was 63.4-64.3 (winter season). Then during summer HS conditions (from the beginning of July till the end of August 2023) bucks were assessed before NAC supplementation (W0), afterwards they were arbitrarily assigned into two groups. The control group (CON; n = 6) received the basal diet while the NAC group (n = 6) received the basal diet in addition to oral NAC daily for 7 weeks (W1-W7). The THI was 78.1-81.6 (summer season). Testicular blood flow parameters, serum concentration of nitric oxide (NO) and testosterone were measured. Additionally, total antioxidant capacity (TAC) and malondialdehyde (MDA) content in seminal plasma and semen quality parameters were evaluated. There were marked reductions (p < 0.05) in the resistive index (RI; W1, W4 and W5), pulsatility index (PI; W2 and W4-W7), and systolic/diastolic ratio (S/D; W4-W7) in the NAC group compared to the CON group. Furthermore, testosterone and NO levels were higher (p < 0.01 and p < 0.05, respectively) in the NAC group (W2, W3, W5 and W3-W5, respectively). Seminal plasma TAC increased (p < 0.05) and MDA decreased (p < 0.05) in the NAC group (W2, W4 and W5) compared to the CON group. Moreover, there were marked improvements (p < 0.05) in semen quality parameters (mass motility, total motility, viability and normal morphology) in the NAC group. In conclusion, oral NAC supplementation could be used to enhance the reproductive performance of goat bucks during HS conditions which is supported by remarkable enhancement in testicular haemodynamics, NO, testosterone levels and semen quality parameters.},
}
@article {pmid39182712,
year = {2024},
author = {Jiang, P and Hu, S and Zheng, C and Liu, Y and Zhang, Q and Dou, L},
title = {Cryopreservation of human teeth using vitrification method with cryoprotectant cocktails and N-acetylcysteine for banking and clinical applications.},
journal = {Cryobiology},
volume = {117},
number = {},
pages = {104959},
doi = {10.1016/j.cryobiol.2024.104959},
pmid = {39182712},
issn = {1090-2392},
mesh = {Humans ; *Cryopreservation/methods ; *Cryoprotective Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Periodontal Ligament/cytology/drug effects ; *Vitrification/drug effects ; *Cell Survival/drug effects ; Animals ; Rats ; Tooth/drug effects ; Cell Differentiation/drug effects ; Male ; Superoxide Dismutase/metabolism ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Cells, Cultured ; Catalase/metabolism/genetics ; Osteogenesis/drug effects ; Female ; Superoxide Dismutase 2 ; },
abstract = {Preserving freshly-extracted healthy human teeth offers an optional resource for potential tooth transplantation and cell therapy. This study aimed to assess the impact of vitrification, utilizing a blend of cryoprotectant agents and N-acetylcysteine (NAC), on the cryopreservation of periodontal ligament tissues, and investigate the underlying mechanisms of NAC on the tooth cryopreservation. Periodontal ligament cells were isolated from freshly-extracted healthy human permanent teeth, and cell sheets of PDLCs were fabricated. The samples including cell sheets, freshly-extracted human and rat teeth were cryopreserved with or without NAC for three months. The viability, ROS level, gene expressions and microstructure of PDLCs within cell sheets were assessed. The expression of SOD-2, Caspase3, LC3A/B and Catalase were evaluated through western blotting. Histological assessments of cryopreserved cell sheets and teeth were conducted. PDLCs were isolated from cryopreserved teeth, and their immunophenotype and differentiation ability were evaluated. The data was analyzed using one-way analysis of variance. The vitrification method showed good performance in preserving the viability and differentiation potential of PDLCs. Cryopreservation supplemented with NAC improved the survival rate of PDLCs, enhanced osteogenic differentiation ability, upregulated the expression of SOD-2 and Catalase, and inhibited cell apoptosis. Additionally, mRNA sequencing analysis revealed a significant activation of the PI3K-AKT pathway following cryopreservation via vitrification. Adding a PI3K-AKT activator improved the survival rates of PDLCs post-cryopreservation. The vitrification strategy combining various CPAs and NAC proved to be feasible for tooth cryopreservation. Targeting the PI3K-AKT pathway may improve the efficacy of tooth cryopreservation.},
}
@article {pmid39182421,
year = {2024},
author = {Lu, J and Zhao, P and Ding, X and Li, H},
title = {N-acetylcysteine stimulates the proliferation and differentiation in heat-stressed skeletal muscle cells.},
journal = {Journal of thermal biology},
volume = {124},
number = {},
pages = {103958},
doi = {10.1016/j.jtherbio.2024.103958},
pmid = {39182421},
issn = {0306-4565},
mesh = {*Acetylcysteine/pharmacology ; Animals ; *Heat-Shock Response/drug effects ; *Cell Proliferation/drug effects ; *Cell Differentiation/drug effects ; Mice ; *Oxidative Stress/drug effects ; Cell Line ; Apoptosis/drug effects ; HSP70 Heat-Shock Proteins/metabolism/genetics ; Muscle, Skeletal/drug effects/cytology/metabolism ; Antioxidants/pharmacology ; },
abstract = {N-acetylcysteine (NAC) is known for its beneficial effects on health due to its antioxidant and antiapoptotic properties. This study explored the protective effects of NAC against oxidative stress in heat-stressed (HS) skeletal muscle cells and its role in promoting muscle development. NAC reduced the heat shock response by decreasing the expression of heat shock protein 70 (HSP70) in HS-induced muscle cells during proliferation and differentiation. NAC also mitigated HS-induced oxidative stress via increasing the antioxidant enzyme levels and reducing oxidant enzyme levels. Treatment with NAC at 2 mM increased cell viability from 43.68% ± 5.14%-66.69% ± 14.43% and decreased the apoptosis rate from 7.89% ± 0.53%-5.17% ± 0.11% in skeletal muscle cells. Additionally, NAC promoted the proliferation and differentiation of HS-induced skeletal muscle cells by upregulating the expression of PAX7, MYF5, MRF4 and MYHC. These findings suggest that NAC alleviates HS-induced oxidative damage in skeletal muscle cells and support muscle development.},
}
@article {pmid39182400,
year = {2025},
author = {Feng, Y and Yuan, J and Yang, X and Ma, X and Cheng, Z},
title = {Developing an off-on fluorescence sensor based on red copper nanoclusters wrapped by sulfhydryl and polymer double ligands for sensitive detection of N-acetyl-L-cysteine.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {324},
number = {},
pages = {125008},
doi = {10.1016/j.saa.2024.125008},
pmid = {39182400},
issn = {1873-3557},
mesh = {*Acetylcysteine/chemistry/urine ; *Copper/chemistry/analysis ; *Spectrometry, Fluorescence/methods ; *Sulfhydryl Compounds/chemistry/analysis ; Ligands ; *Metal Nanoparticles/chemistry ; *Limit of Detection ; Mercury/analysis/urine ; Humans ; Fluorescent Dyes/chemistry ; Povidone/chemistry ; Benzoates/chemistry ; Polymers/chemistry ; },
abstract = {N-acetyl-L-cysteine (NAC) as a class of thiols is commonly used in the treatment of lung diseases, detoxification and prevention of liver damage. In this paper, 4-mercaptobenzoic acid (4-MBA) coated and polyvinylpyrrolidone (PVP) attached copper nanoclusters (4-MBA@PVP-CuNCs) were successfully synthesized using a simple one-pot method with an absolute quantum yield of 10.98 %, and its synthetic conditions (like effects of single/double ligands and temperature) were studied intensively. Then Hg[2+] could quench the fluorescence of the 4-MBA@PVP-CuNCs and its fluorescence was restored with the addition of NAC. Based on the above principles, an off-on switching system was established to detect NAC. That is, the 4-MBA@PVP-CuNCs-Hg probe was prepared by adding Hg[2+] to switch off the fluorescence of the CuNCs by static quenching, and then NAC was added to switch on the fluorescence of the probe based on the chelation of NAC and Hg[2+]. Moreover, the effects of metal ion types and mercury ion doses for the probe construction were also further discussed. The method showed excellent linearity in the range of 0.05-1.25 µM and low detection limit of 16 nM. Meanwhile, good recoveries in real urine, tablets and pellets were observed, which proved the reliability of the method and provided a convenient, fast and sensitive method for NAC detection.},
}
@article {pmid39180519,
year = {2024},
author = {Yang, H and Liu, Y and Wang, C and Hussain, M and Ettayri, K and Chen, Y and Wang, K and Long, L and Qian, J},
title = {Ultrastable NAC-Capped CdZnTe Quantum Dots Encapsulated within Dendritic Mesoporous Silica As an Exceptional Tag for Anti-Interference Fluorescence Aptasensor with Signal Amplification.},
journal = {Analytical chemistry},
volume = {96},
number = {36},
pages = {14550-14559},
doi = {10.1021/acs.analchem.4c02826},
pmid = {39180519},
issn = {1520-6882},
mesh = {*Quantum Dots/chemistry ; *Silicon Dioxide/chemistry ; *Tellurium/chemistry ; *Cadmium Compounds/chemistry ; *Biosensing Techniques/methods ; *Aptamers, Nucleotide/chemistry ; Porosity ; Acetylcysteine/chemistry ; Fluorescence ; Spectrometry, Fluorescence ; Limit of Detection ; Cadmium ; Zinc ; },
abstract = {In this work, we explored the potential of thiol-capped CdZnTe quantum dots (QDs) as an exceptional signal tag for fluorescence aptasensing applications. Employing a one-pot hydrothermal approach, we modulated the terminal functional groups of CdZnTe QDs using l-cysteine (Lcys), 3-mercaptopropionic acid (MPA), and N-acetyl-l-cysteine (NAC) as ligands. Our comparative analysis revealed that NAC-capped CdZnTe QDs (NAC-CdZnTe QDs) exhibited superior anti-interference capabilities and storage stability across various temperatures, pH levels, and storage durations. Encouraged by these promising results, we further optimized the use of ultrastable NAC-CdZnTe QDs encapsulated in dendritic mesoporous silica nanoparticles (DMSN@QDs) as an exceptional tag for the development of an advanced anti-interference fluorescence aptasensor for aflatoxin B1 (AFB1) detection. The developed aptasensor using DMSN@QDs as signal tags achieved a remarkable signal amplification of approximately 10.2 fold compared to the NAC-CdZnTe QDs coated silica (SiO2@QDs) labeled fluorescence aptasensor. This aptasensor was able to detect AFB1 within a wide range of 1 pg mL[-1] to 200 ng mL[-1], achieving a limit of detection as low as 0.41 pg mL[-1] (S/N = 3). Crucially, the specific binding affinity between the aptamer and the target enabled the aptasensor to be easily customized for various targets by simply replacing the aptamer sequence with the desired one. The exceptional potential of NAC-CdZnTe QDs, particularly when encapsulated in DMSNs, leads to the development of highly sensitive and selective anti-interference fluorescence aptasensors for various targets, thereby, paving the way for advancements in a diverse range of applications.},
}
@article {pmid39178962,
year = {2024},
author = {Zhao, Z and Yi, S and E, H and Jiang, L and Zhou, C and Zhao, X and Yang, L},
title = {α-amanitin induce inflammatory response by activating ROS/NF-κB-NLRP3 signaling pathway in human hepatoma HepG2 cells.},
journal = {Chemosphere},
volume = {364},
number = {},
pages = {143157},
doi = {10.1016/j.chemosphere.2024.143157},
pmid = {39178962},
issn = {1879-1298},
mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; *Reactive Oxygen Species/metabolism ; Hep G2 Cells ; *Alpha-Amanitin/toxicity ; *Inflammation/chemically induced/metabolism ; Inflammasomes/metabolism ; Carcinoma, Hepatocellular/metabolism ; Liver Neoplasms/metabolism ; Oxidative Stress/drug effects ; Cytokines/metabolism ; Malondialdehyde/metabolism ; },
abstract = {α-amanitin (AMA) is a hepatotoxic mushroom toxin responsible for over 90% of mushroom poisoning fatalities worldwide, seriously endangering human life and health. Few evidences have indicated that AMA leads to inflammatory responses and inflammatory infiltration in vitro and in vivo. However, the molecular mechanism remains unknown. In this study, human hepatocellular carcinomas cells (HepG2) were exposed to AMA at various concentrations for short period of times. Results revealed that AMA increased ROS production and elevated the releases of malondialdehyde (MDA) and lactate dehydrogenase (LDH), resulting in oxidative damage in HepG2 cells. Also, AMA exposure significantly increased the secreted levels of inflammatory cytokines and activated the NLRP3 inflammasome. The inflammatory responses were reversed by NLRP3 inhibitor MCC950 and NF-κB inhibitor Bay11-7082. Additionally, N-acetylcysteine (NAC) blocked the upregulation of the NF-κB/NLRP3 signaling pathway and remarkably alleviated the inflammatory response. These results demonstrated that AMA could induce inflammation through activating the NLRP3 inflammasome triggered by ROS/NF-κB signaling pathway. Our research provides new insights into the molecular mechanism of AMA-induced inflammation damage and may contribute to establish new prevention strategies for AMA hepatotoxicity.},
}
@article {pmid39178616,
year = {2024},
author = {Zhang, C and Sun, X and Wu, D and Wang, G and Lan, H and Zheng, X and Li, S},
title = {IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.},
journal = {Theriogenology},
volume = {229},
number = {},
pages = {147-157},
doi = {10.1016/j.theriogenology.2024.08.023},
pmid = {39178616},
issn = {1879-3231},
mesh = {Animals ; *Inositol 1,4,5-Trisphosphate Receptors/metabolism/genetics ; Swine ; *Mitochondria/metabolism/physiology ; *Meiosis/physiology ; *Oxidative Stress ; *Calcium/metabolism ; *Embryonic Development/physiology ; Reactive Oxygen Species/metabolism ; Oocytes/physiology ; Female ; },
abstract = {Calcium ions (Ca[2+]) regulate cell proliferation and differentiation and participate in various physiological activities of cells. The calcium transfer protein inositol 1,4,5-triphosphate receptor (IP3R), located between the endoplasmic reticulum (ER) and mitochondria, plays an important role in regulating Ca[2+] levels. However, the mechanism by which IP3R1 affects porcine meiotic progression and embryonic development remains unclear. We established a model in porcine oocytes using siRNA-mediated knockdown of IP3R1 to investigate the effects of IP3R1 on porcine oocyte meiotic progression and embryonic development. The results indicated that a decrease in IP3R1 expression significantly enhanced the interaction between the ER and mitochondria. Additionally, the interaction between the ER and the mitochondrial Ca[2+] ([Ca[2+]]m) transport network protein IP3R1-GRP75-VDAC1 was disrupted. The results of the Duolink II in situ proximity ligation assay (PLA) revealed a weakened pairwise interaction between IP3R1-GRP75 and VDAC1 and a significantly increased interaction between GRP75 and VDAC1 after IP3R1 interference, resulting in the accumulation of large amounts of [Ca[2+]]m. These changes led to mitochondrial oxidative stress, increased the levels of reactive oxygen species (ROS) and reduced ATP production, which hindered the maturation and late development of porcine oocytes and induced apoptosis. Nevertheless, after treat with [Ca[2+]]m chelating agent ruthenium red (RR) or ROS scavenger N-acetylcysteine (NAC), the oocytes developmental abnormalities, oxidative stress and apoptosis caused by Ca[2+] overload were improved. In conclusion, our results indicated IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.},
}
@article {pmid39175643,
year = {2024},
author = {Sabbaghziarani, F and Soleimani, P and Eynshikh, FR and Zafari, F and Aali, E},
title = {Reduced ischemia-reperfusion oxidative stress injury by melatonin and N-acetylcysteine in the male rat brain.},
journal = {IBRO neuroscience reports},
volume = {17},
number = {},
pages = {131-137},
pmid = {39175643},
issn = {2667-2421},
abstract = {Middle cerebral artery occlusion (MCAO) is a model for inducing ischemic stroke in rodents, leading to devastating brain damage. Oxidative stress (OS) plays a crucial role in the pathogenesis of ischemia. In this study, the effect of melatonin and N-acetylcysteine on ischemia-reperfusion-induced oxidative stress injury in the cerebral cortex of male rats was investigated. 30 male Wistar rats were divided into sham, ischemic, NAC, melatonin and NAC + melatonin groups. All groups, except the sham group, underwent MCAO on the left side, and the treatment groups received intraperitoneal injections of either 50 mg/kg N-acetylcysteine (NAC) or 5 mg/kg melatonin or a combination of both 24 and 48 hours later. At 24 and 72 hours after surgery, the animals were examined for sensory and motor activity. The cerebral cortex was dissected after sacrificing the rats, infarct volume estimated and the concentrations of glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and nuclear factor erythroid-2 related factor 2 (Nrf2) were analyzed by enzyme-linked immunosorbent assay (ELISA). The results indicate that the NAC + melatonin group exhibited elevated sensory-motor activity and a reduced infarct volume rate in comparison to the ischemic group (p≤ 0.05). Compared to the ischemic group, the NAC + melatonin group showed a significant increase in SOD concentration and a significant decrease in MDA (p≤ 0.05). It can therefore be concluded that the simultaneous administration of NAC and melatonin can reduce the cerebral infarction volume, and improve neurological functions by modulating SOD and MDA.},
}
@article {pmid39166871,
year = {2024},
author = {Wilson, PR and Bridges, KH and Scofield, M and Wilson, SH},
title = {Perioperative N-acetylcysteine: evidence and indications.},
journal = {Pain management},
volume = {14},
number = {7},
pages = {385-396},
pmid = {39166871},
issn = {1758-1877},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage ; *Perioperative Care/methods ; Postoperative Pain/drug therapy/prevention &amp; control ; Analgesics, Non-Narcotic/adverse effects/administration &amp; dosage/pharmacology ; },
abstract = {Nonopioid analgesics serve to improve analgesia and limit side effects and risks of perioperative opioids. N-acetylcysteine (NAC), the primary treatment of acetaminophen toxicity, may have perioperative indications, including analgesia. NAC impacts glutathione synthesis, oxidant scavenging, glutamate receptor modulation and neuroinflammation. Potential perioperative benefits include arrhythmia prevention after cardiac surgery, decreased contrast-induced nephropathy, improved post-transplant liver function and superior pulmonary outcomes with general anesthesia. NAC may improve perioperative analgesia, with some studies displaying a reduction in postoperative opioid use. NAC is generally well tolerated with an established safety profile. NAC administration may predispose to gastrointestinal effects, while parenteral administration may carry a risk of anaphylactoid reactions, including bronchospasm. Larger randomized trials may clarify the impact of NAC on perioperative analgesic outcomes.},
}
@article {pmid39159553,
year = {2024},
author = {Kim, NY and Dukanya, D and Sethi, G and Girimanchanaika, SS and Yang, J and Nagaraja, O and Swamynayaka, A and Vishwanath, D and Venkantesha, K and Basappa, S and Chinnathambi, A and Alharbi, SA and Madegowda, M and Sukhorukov, A and Pandey, V and Lobie, PE and Basappa, B and Ahn, KS},
title = {Oxazine drug-seed induces paraptosis and apoptosis through reactive oxygen species/JNK pathway in human breast cancer cells.},
journal = {Translational oncology},
volume = {49},
number = {},
pages = {102101},
pmid = {39159553},
issn = {1936-5233},
abstract = {Small molecule-driven JNK activation has been found to induce apoptosis and paraptosis in cancer cells. Herein pharmacological effects of synthetic oxazine (4aS, 7aS)-3-((4-(4‑chloro-2-fluorophenyl)piperazin-1-yl)methyl)-4-phenyl-4, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[e] [1,2]oxazine (FPPO; BSO-07) on JNK-driven apoptosis and paraptosis has been demonstrated in human breast cancer (BC) MDA-MB231 and MCF-7 cells respectively. BSO-07 imparted significant cytotoxicity in BC cells, induced activation of JNK, and increased intracellular reactive oxygen species (ROS) levels. It also enhanced the expression of apoptosis-associated proteins like PARP, Bax, and phosphorylated p53, while decreasing the levels of Bcl-2, Bcl-xL, and Survivin. Furthermore, the drug altered the expression of proteins linked to paraptosis, such as ATF4 and CHOP. Treatment with N-acetyl-cysteine (antioxidant) or SP600125 (JNK inhibitor) partly reversed the effects of BSO-07 on apoptosis and paraptosis. Advanced in silico bioinformatics, cheminformatics, density Fourier transform and molecular electrostatic potential analysis further demonstrated that BSO-07 induced apoptosis and paraptosis via the ROS/JNK pathway in human BC cells.},
}
@article {pmid39158930,
year = {2024},
author = {Li, J and Jiang, L and Zhao, K and Tang, Y and Yuan, X and Xu, Y},
title = {MYELOID-DERIVED TLR4-TRIF SIGNALING PATHWAY MEDIATES OXIDATIVE STRESS IN LPS/D-GALN-INDUCED ACUTE LIVER FAILURE.},
journal = {Shock (Augusta, Ga.)},
volume = {62},
number = {4},
pages = {582-587},
doi = {10.1097/SHK.0000000000002438},
pmid = {39158930},
issn = {1540-0514},
mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; *Adaptor Proteins, Vesicular Transport/metabolism ; *Oxidative Stress ; *Liver Failure, Acute/metabolism ; *Signal Transduction/drug effects ; Mice ; *Lipopolysaccharides/toxicity ; *Galactosamine ; *Mice, Knockout ; Male ; Mice, Inbred C57BL ; },
abstract = {Background: Acute liver failure (ALF) is a severe clinical syndrome characterized by massive hepatocyte death in a short time due to viruses, drugs, alcohol, or other factors. Oxidative stress is an important pathogenic mechanism of ALF. LPS-induced internalization of toll-like receptor 4 (TLR4) and the subsequent activation of the toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF) signaling pathway widely mediate inflammatory responses in a series of diseases. However, whether the TLR4-TRIF signaling pathway contributes to ALF by mediating oxidative stress processes remains unclear. Methods: An ALF mouse model was induced by lipopolysaccharide (LPS)/D-galactosamine (D-GalN). TLR4-TRIF systemic knockout mice and TLR4 conditional knockout mice were used to determine the role of the TLR4-TRIF signaling pathway in ALF. The effects of TLR4 or TRIF deficiency on oxidative stress were investigated. In addition, we examined the protective role of the clodronate liposomes (macrophage scavengers) and the antioxidant N-acetylcysteine (NAC) in ALF. Results: TLR4 or TRIF deficiency significantly alleviated LPS/D-GalN-induced lethality, hepatic dysfunction, and hepatic pathologic injury, which was dependent on myeloid-derived TLR4. Hence, macrophage clearance exhibits a similar protective effect. Mechanically, TLR4 or TRIF deficiency was observed to inhibit oxidative stress by increasing glutathione, while decreasing malondialdehyde, 8-hydroxy-2-deoxyguanosine, and γ-H2AX. Therefore, the pharmacologic antioxidant NAC exhibited significant hepato-protective effects. Conclusions: Targeting myeloid-derived TLR4-TRIF signaling pathway or antioxidant therapy may be a potential therapeutic direction to treat ALF.},
}
@article {pmid39148391,
year = {2024},
author = {Yang, K and Wu, Y and Zhang, R and Lei, XP and Kang, L and Dong, WB},
title = {[Role of reactive oxygen species/silent information regulator 1 in hyperoxia-induced bronchial epithelial cell injury].},
journal = {Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics},
volume = {26},
number = {8},
pages = {852-860},
pmid = {39148391},
issn = {1008-8830},
mesh = {*Sirtuin 1/metabolism/physiology/genetics ; Humans ; *Reactive Oxygen Species/metabolism ; *Hyperoxia/complications/metabolism ; *Epithelial Cells/metabolism ; *Bronchi/metabolism ; Mitochondria/metabolism ; Cells, Cultured ; Cell Line ; },
abstract = {OBJECTIVES: To investigate the effect of reactive oxygen species (ROS)/silent information regulator 1 (SIRT1) on hyperoxia-induced mitochondrial injury in BEAS-2B cells.<br><br>METHODS: The experiment was divided into three parts. In the first part, cells were divided into H0, H6, H12, H24, and H48 groups. In the second part, cells were divided into control group, H48 group, H48 hyperoxia+SIRT1 inhibitor group (H48+EX 527 group), and H48 hyperoxia+SIRT1 agonist group (H48+SRT1720 group). In the third part, cells were divided into control group, 48-hour hyperoxia+N-acetylcysteine group (H48+NAC group), and H48 group. The ROS kit was used to measure the level of ROS. Western blot and immunofluorescent staining were used to measure the expression levels of SIRT1 and mitochondria-related proteins. Transmission electron microscopy was used to observe the morphology of mitochondria.<br><br>RESULTS: Compared with the H0 group, the H6, H12, H24, and H48 groups had a significantly increased fluorescence intensity of ROS (P<0.05), the H48 group had significant reductions in the expression levels of SIRT1 protein and mitochondria-related proteins (P<0.05), and the H24 and H48 groups had a significant reduction in the fluorescence intensity of mitochondria-related proteins (P<0.05). Compared with the H48 group, the H48+SRT1720 group had significant increases in the expression levels of mitochondria-related proteins and the mitochondrial aspect ratio (P<0.05), and the H48+EX 527 group had a significant reduction in the mitochondrial area (P<0.05). Compared with the H48 group, the H48+NAC group had a significantly decreased fluorescence intensity of ROS (P<0.05) and significantly increased levels of SIRT1 protein, mitochondria-related proteins, mitochondrial area, and mitochondrial aspect ratio (P<0.05).<br><br>CONCLUSIONS: The ROS/SIRT1 axis is involved in hyperoxia-induced mitochondrial injury in BEAS-2B cells.},
}
@article {pmid39148029,
year = {2024},
author = {Wu, C and Li, Y and Liu, S and Wang, L and Wang, X},
title = {Catalpol inhibits HHcy-induced EndMT in endothelial cells by modulating ROS/NF-κB signaling.},
journal = {BMC cardiovascular disorders},
volume = {24},
number = {1},
pages = {431},
pmid = {39148029},
issn = {1471-2261},
support = {SB201901060&#xff1b;YJSCX202290Y//Medical Science and Technology Tackling Program of Henan Province (SB201901060) and Postgraduate research innovation program (YJSCX202290Y)./ ; SB201901060&#xff1b;YJSCX202290Y//Medical Science and Technology Tackling Program of Henan Province (SB201901060) and Postgraduate research innovation program (YJSCX202290Y)./ ; },
mesh = {Animals ; Humans ; Antigens, CD/metabolism ; Antioxidants/pharmacology ; *Atherosclerosis/drug therapy/etiology/pathology ; Cadherins/metabolism ; Cells, Cultured ; Disease Models, Animal ; *Endothelial-Mesenchymal Transition/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism/drug effects/pathology ; *Hyperhomocysteinemia/drug therapy/metabolism/complications ; *Iridoid Glucosides/pharmacology/therapeutic use ; Mice, Inbred C57BL ; *NF-kappa B/metabolism ; Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Transcription Factor RelA/metabolism ; Mice ; },
abstract = {BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis (AS). Endothelial mesenchymal transition (EndMT) refers to the process in which endothelial cells lose endothelial cell morphology and characteristic gene expression, and acquire phenotypic characteristics and gene expression related to mesenchymal cells. Numerous studies have confirmed that EndMT is involved in the formation of atherosclerosis. Catalpol is one of the active components of Rehmannia, which has antioxidant, anti-inflammatory, anti-tumor, neuroprotective and other biological activities. Studies have shown that catalpol can reduce atherosclerotic plaque induced by high sugar or fat. However, the effect of catalpol on HHCY-induced EndMT is unclear.<br><br>METHODS AND RESULTS: In vitro HHcy-treated primary human umbilical vein endothelial cells (HUVECs) were used to construct a cell model, and the antioxidants N-acetylcysteine (NAC) and catalase alcohol were administered. In vivo C57BL/6N mice were given a diet fed with 4.4% high methionine chow to construct a HHcy mice model and were treated with catalpol. The results showed that hhcy could induce morphological transformation of endothelial cells into mesenchymal cells, increase intracellular ROS content, up-regulate &#x3b1;-SMA, N-cadherin, p-p65 protein expression, down-regulate VE-cadherin, CD31 protein expression, induce pathological changes of aortic root endothelium, and increase aortic endothelial ROS content. Catalpol reversed these hhcy induced outcomes.<br><br>CONCLUSIONS: Catalpol inhibits HHcy-induced EndMT, and the underlying mechanism may be related to the ROS/NF-&#x3ba;B signaling pathway. Catalpol may be a potential drug for the treatment of HHcy-related AS.},
}
@article {pmid39146674,
year = {2024},
author = {Wu, H and Huo, H and Li, H and Zhang, H and Li, X and Han, Q and Liao, J and Tang, Z and Guo, J},
title = {N-acetylcysteine combined with insulin therapy can reduce myocardial injury induced by type 1 diabetes through the endoplasmic reticulum pathway.},
journal = {Tissue &amp; cell},
volume = {90},
number = {},
pages = {102515},
doi = {10.1016/j.tice.2024.102515},
pmid = {39146674},
issn = {1532-3072},
mesh = {Animals ; *Diabetes Mellitus, Type 1/drug therapy/metabolism/pathology/complications ; *Insulin/pharmacology/metabolism ; Dogs ; *Endoplasmic Reticulum/metabolism/drug effects ; *Acetylcysteine/pharmacology ; *Myocardium/metabolism/pathology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects ; Apoptosis/drug effects ; Male ; Signal Transduction/drug effects ; },
abstract = {With the development of Type 1 diabetes mellitus (T1DM), various complications can be caused. Hyperglycemia affects the microenvironment of cardiomyocytes, changes endoplasmic reticulum homeostasis, triggers unfolding protein response and eventually promotes myocardial apoptosis. However, insulin therapy alone cannot effectively combat the complications caused by T1DM. Forty adult beagles were randomly divided into five groups: control group, diabetes mellitus group, insulin group, insulin combined with NAC group, and NAC group. 24-hour blood glucose, 120-day blood glucose, 120-day body weight, and serum FMN content were observed, furthermore, hematoxylin-eosin staining, Periodic acid Schiff reagent staining, and Sirius red staining of the myocardium were evaluated. The protein expressions of GRP78, ATF6, IRE1, PERK, JNK, CHOP, caspase 3, Bcl2, and Bax were detected. Results of the pathological section of myocardial tissue indicated that insulin combined with NAC therapy could improve myocardial pathological injury and glycogen deposition. Additionally, insulin combined with NAC therapy down-regulates the expression of GRP78, ATF6, IRE1, PERK, JNK, CHOP, caspase3, and Bax. These findings suggest that NAC has a phylactic effect on myocardial injury in beagles with T1DM, and the mechanism may be related to the improvement of endoplasmic reticulum stress-induced apoptosis.},
}
@article {pmid39144112,
year = {2024},
author = {Husain, MO and Chaudhry, IB and Khoso, AB and Husain, MI and Ansari, MA and Mehmood, N and Naqvi, HA and Nizami, AT and Talib, U and Rajput, AH and Bassett, P and Foussias, G and Deakin, B and Husain, N},
title = {Add-on Sodium Benzoate and N-Acetylcysteine in Patients With Early Schizophrenia Spectrum Disorder: A Multicenter, Double-Blind, Randomized Placebo-Controlled Feasibility Trial.},
journal = {Schizophrenia bulletin open},
volume = {5},
number = {1},
pages = {sgae004},
pmid = {39144112},
issn = {2632-7899},
abstract = {BACKGROUND AND HYPOTHESIS: Oxidative stress pathways may play a role in schizophrenia through direct neuropathic actions, microglial activation, inflammation, and by interfering with NMDA neurotransmission. N-acetylcysteine (NAC) has been shown to improve negative symptoms of schizophrenia, however, results from trials of other compounds targeting NMDA neurotransmission have been mixed. This may reflect poor target engagement but also that risk mechanisms act in parallel. Sodium Benzoate (NaB) could have an additive with NAC to act on several pathophysiological mechanisms implicated in schizophrenia.<br><br>STUDY DESIGN: A multicenter, 12 weeks, 2&#x2005;&#xd7;&#x2005;2 factorial design, randomized double-blind placebo-controlled feasibility trial of NaB and NAC added to standard treatment in 68 adults with early schizophrenia. Primary feasibility outcomes included recruitment, retention, and completion of assessments as well as acceptability of the study interventions. Psychosis symptoms, functioning, and cognitive assessments were also assessed.<br><br>STUDY RESULTS: We recruited our desired sample (n&#x2005;=&#x2005;68) and retained 78% (n&#x2005;=&#x2005;53) at 12 weeks, supporting the feasibility of recruitment and retention. There were no difficulties in completing clinical outcome schedules. Medications were well tolerated with no dropouts due to side effects. This study was not powered to detect clinical effect and as expected no main effects were found on the majority of clinical outcomes.<br><br>CONCLUSIONS: We demonstrated feasibility of conducting a clinical trial of NaB and NAC. Given the preliminary nature of this study, we cannot draw firm conclusions about the clinical efficacy of either agent, and a large-scale trial is needed to examine if significant differences between treatment groups emerge.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT03510741.},
}
@article {pmid39144108,
year = {2024},
author = {Wasserthal, S and Muthesius, A and Hurlemann, R and Ruhrmann, S and Schmidt, SJ and Hellmich, M and Schultze-Lutter, F and Klosterkötter, J and Müller, H and Meyer-Lindenberg, A and Poeppl, TB and Walter, H and Hirjak, D and Koutsouleris, N and Fallgatter, AJ and Bechdolf, A and Brockhaus-Dumke, A and Mulert, C and Philipsen, A and Kambeitz, J},
title = {N-Acetylcysteine and a Specialized Preventive Intervention for Individuals at High Risk for Psychosis: A Randomized Double-Blind Multicenter Trial.},
journal = {Schizophrenia bulletin open},
volume = {5},
number = {1},
pages = {sgae005},
pmid = {39144108},
issn = {2632-7899},
abstract = {BACKGROUND AND HYPOTHESIS: Clinical high risk for psychosis (CHR-P) offers a window of opportunity for early intervention and recent trials have shown promising results for the use of N-acetylcysteine (NAC) in schizophrenia. Moreover, integrated preventive psychological intervention (IPPI), applies social-cognitive remediation to aid in preventing the transition to the psychosis of CHR-P patients.<br><br>STUDY DESIGN: In this double-blind, randomized, controlled multicenter trial, a 2&#x2005;&#xd7;&#x2005;2 factorial design was applied to investigate the effects of NAC compared to placebo (PLC) and IPPI compared to psychological stress management (PSM). The primary endpoint was the transition to psychosis or deterioration of CHR-P symptoms after 18 months.<br><br>STUDY RESULTS: While insufficient recruitment led to early trial termination, a total of 48 participants were included in the study. Patients receiving NAC showed numerically higher estimates of event-free survival probability (IPPI&#x2005;+&#x2005;NAC: 72.7&#x2005;&#xb1;&#x2005;13.4%, PSM&#x2005;+&#x2005;NAC: 72.7&#x2005;&#xb1;&#x2005;13.4%) as compared to patients receiving PLC (IPPI&#x2005;+&#x2005;PLC: 56.1&#x2005;&#xb1;&#x2005;15.3%, PSM&#x2005;+&#x2005;PLC: 39.0&#x2005;&#xb1;&#x2005;17.4%). However, a log-rank chi-square test in Kaplan-Meier analysis revealed no significant difference of survival probability for NAC vs control (point hazard ratio: 0.879, 95% CI 0.281-2.756) or IPPI vs control (point hazard ratio: 0.827, 95% CI 0.295-2.314). The number of adverse events (AE) did not differ significantly between the four groups.<br><br>CONCLUSIONS: The superiority of NAC or IPPI in preventing psychosis in patients with CHR-P compared to controls could not be statistically validated in this trial. However, results indicate a consistent pattern that warrants further testing of NAC as a promising and well-tolerated intervention for CHR patients in future trials with adequate statistical power.},
}
@article {pmid39142116,
year = {2024},
author = {Wang, Y and Guo, AL and Xu, Y and Xu, X and Yang, L and Yang, Y and Chao, L},
title = {EHDPP induces proliferation inhibition and apoptosis to spermatocyte: Insights from transcriptomic and metabolomic profiles.},
journal = {Ecotoxicology and environmental safety},
volume = {284},
number = {},
pages = {116878},
doi = {10.1016/j.ecoenv.2024.116878},
pmid = {39142116},
issn = {1090-2414},
mesh = {Male ; Animals ; *Apoptosis/drug effects ; Mice ; *Cell Proliferation/drug effects ; *Spermatocytes/drug effects ; *Transcriptome/drug effects ; Cell Line ; Humans ; Oxidative Stress/drug effects ; Metabolome/drug effects ; Sperm Motility/drug effects ; Reactive Oxygen Species/metabolism ; DNA Damage ; Spermatogenesis/drug effects ; Testis/drug effects/metabolism ; },
abstract = {BACKGROUND: 2-ethylhexyldiphenyl phosphate (EHDPP) was used widespread in recent years and it was reported to impair reproductive behaviors and decrease fertility in male Japanese medaka. However, whether EHDPP causes spermatogenesis disturbance remains uncertain.<br><br>OBJECTIVES: We aimed to study the male reproductive toxicity of EHDPP and its related mechanism.<br><br>METHODS: Human spermatocyte cell line GC-2 was treated with 10&#x202f;&#xb5;M, 50&#x202f;&#xb5;M or 100&#x202f;&#xb5;M EHDPP for 24&#x202f;h. Male CD-1 mice aged 6 weeks were given 1, 10, or 100&#x202f;mg/kg/d EHDPP daily for 42 days and then euthanized to detect sperm count and motility. Proliferation, apoptosis, oxidative stress was detected in mice and cell lines. Metabolome and transcriptome were used to detect the related mechanism. Finally, anti-oxidative reagent N-Acetylcysteine was used to detect whether it could reverse the side-effect of EHDPP both in vivo and in vitro.<br><br>RESULTS: Our results showed that EHDPP inhibited proliferation and induced apoptosis in mice testes and spermatocyte cell line GC-2. Metabolome and transcriptome showed that nucleotide metabolism disturbance and DNA damage was potentially involved in EHDPP-induced reproductive toxicity. Finally, we found that excessive ROS production caused DNA damage and mitochondrial dysfunction; NAC supplement reversed the side effects of EHDPP such as DNA damage, proliferation inhibition, apoptosis and decline in sperm motility.<br><br>CONCLUSION: ROS-evoked DNA damage and nucleotide metabolism disturbance mediates EHDPP-induced germ cell proliferation inhibition and apoptosis, which finally induced decline of sperm motility.},
}
@article {pmid39139444,
year = {2024},
author = {Hanafy, DA and Willim, HA and Suwatri, WT and Sani, AA and Khouw, H and Susanti, EI and Sugisman, },
title = {Efficacy of N-acetylcysteine for Prevention of Postoperative Atrial Fibrillation Following Coronary Artery Bypass Grafting: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.},
journal = {Reviews in cardiovascular medicine},
volume = {25},
number = {7},
pages = {243},
pmid = {39139444},
issn = {2153-8174},
abstract = {BACKGROUND: As the prevalence of coronary artery disease rises, the demand for coronary artery bypass grafting (CABG) increases. A common complication after CABG is postoperative atrial fibrillation (POAF), which is linked to adverse clinical outcomes. N-acetylcysteine (NAC), an antioxidant, may mitigate oxidative stress and reduce the incidence of POAF. This meta-analysis aims to investigate the efficacy of NAC in preventing POAF after CABG.<br><br>METHODS: The meta-analysis was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched multiple databases, including PubMed, Cochrane Library, ProQuest, and ScienceDirect, to identify relevant randomized controlled trials (RCTs). The intervention groups received perioperative NAC therapy, while the control groups received a placebo. The outcomes assessed were POAF incidence, all-cause mortality, and hospital length of stay (LOS). Review Manager 5.3 was used to conduct the meta-analysis.<br><br>RESULTS: Eleven RCTs involving 648 patients were included. The NAC group comprised 326 patients, while the control group comprised 322 patients. In the pooled analysis, patients in the NAC group had a significantly lower incidence of POAF (odds ratios (OR) = 0.57; 95% confidence intervals (CI) = 0.33 to 0.97; p = 0.04) and a shorter hospital LOS (weighted mean differences (WMD) = -0.66; 95% CI = -1.22 to -0.10; p = 0.02) compared to the control group. However, there was no significant difference in all-cause mortality.<br><br>CONCLUSIONS: The perioperative administration of NAC can effectively reduce the incidence of POAF and hospital LOS in CABG patients. However, larger RCTs are needed to confirm these findings.},
}
@article {pmid39139367,
year = {2024},
author = {Tasci, T and Orta-Yilmaz, B and Aydin, Y and Caliskan, M},
title = {N-acetylcysteine attenuates sodium arsenite-induced oxidative stress and apoptosis in embryonic fibroblast cells.},
journal = {Toxicology research},
volume = {13},
number = {4},
pages = {tfae128},
pmid = {39139367},
issn = {2045-452X},
abstract = {In recent years, the increase in environmental pollutants has been one of the most important factors threatening human and environmental health. Arsenic, a naturally occurring element found in soil, water, and air, easily enters the human body and leads to many metabolic disorders. In this study, we focused on the possible protective effects of N-acetylcysteine (NAC) against sodium arsenite (As)-induced toxic effects on embryonic fibroblast cells. The effects of As and NAC treatment on cells were evaluated, including cytotoxicity, oxidative stress, and apoptosis. Embryonic fibroblast cells were exposed to As (ranging from 0.01 μM to 10 μM) and NAC (at a concentration of 2 mM) for 24 h. The assessment of cytotoxicity markers, such as cell viability and lactate dehydrogenase (LDH), showed that As significantly reduced cell viability and increased LDH levels. Furthermore, we observed that As increased the amount of reactive oxygen species (ROS) in the cell, decreased the activity of antioxidant enzymes, and triggered apoptosis in cells. Additionally, our research revealed that the administration of NAC mitigates the detrimental effects of As. The results showed that As exerted hazardous effects on embryonic fibroblast cells through the induction of oxidative stress and apoptosis. In this context, our study provides evidence that NAC may have a protective effect against the toxicity of As in embryonic fibroblast cells.},
}
@article {pmid39131009,
year = {2024},
author = {Roghani, SH and Arif, MA and Niazi, R and Mansoor, S},
title = {Naphthalene or Mothball Poisoning Manifesting as Acute Intravascular Hemolysis and Acquired Methemoglobinemia.},
journal = {Cureus},
volume = {16},
number = {7},
pages = {e64325},
pmid = {39131009},
issn = {2168-8184},
abstract = {Naphthalene is a major component of mothballs. Domestically, people use mothballs as an insect repellent. Its deliberate or accidental ingestion leading to toxicity has rarely been reported in the medical literature, despite its widespread use in Southeast Asia. Naphthalene, or mothball poisoning, is a rare but serious condition that can have detrimental effects on human health. This case report presents the clinical course of a 22-year-old male who ingested six naphthalene balls, resulting in severe symptoms including fever, abdominal pain, vomiting, jaundice, and dark-colored urine. Laboratory investigations were suggestive of acute intravascular hemolysis and methemoglobinemia. The patient was promptly admitted to the hospital, where he received supportive care along with specific treatment in the form of red blood cell transfusions, intravenous methylene blue, ascorbic acid, and N-acetyl cysteine. Through this report, the importance of raising awareness about the dangers of naphthalene poisoning and the specific treatment options available is highlighted.},
}
@article {pmid39128732,
year = {2024},
author = {Lu, X and Wu, S and Ai, H and Wu, R and Cheng, Y and Yun, S and Chang, M and Liu, J and Meng, J and Cheng, F and Feng, C and Cao, J},
title = {Sparassis latifolia polysaccharide alleviated lipid metabolism abnormalities in kidney of lead-exposed mice by regulating oxidative stress-mediated inflammation and autophagy based on multi-omics.},
journal = {International journal of biological macromolecules},
volume = {278},
number = {Pt 1},
pages = {134662},
doi = {10.1016/j.ijbiomac.2024.134662},
pmid = {39128732},
issn = {1879-0003},
mesh = {Animals ; *Oxidative Stress/drug effects ; Mice ; *Autophagy/drug effects ; *Lipid Metabolism/drug effects ; *Polysaccharides/pharmacology ; *Kidney/drug effects/metabolism/pathology ; *Inflammation/drug therapy/metabolism ; *Lead/toxicity ; Male ; Lipidomics ; Multiomics ; },
abstract = {Lead is a common environmental pollutant which can accumulate in the kidney and cause renal injury. However, regulatory effects and mechanisms of Sparassis latifolia polysaccharide (SLP) on lipid metabolism abnormality in kidney exposed to lead are not clarified. In this study, mice were used to construct an animal model to observe the histopathological changes in kidney, measure lead content, damage indicators, differentially expressed metabolites (DEMs) and genes (DEGs) in key signaling pathways that cause lipid metabolism abnormalities based on lipidomics and transcriptomics, which were later validated using qPCR and western blotting. Co-treatment of Pb and N-acetylcysteine (NAC) were used to verify the link between SLP and oxidative stress. Our results indicated that treatment with SLP identified 276 DEMs (including metabolism of glycerophospholipid, sphingolipid, glycerolipid and fatty acid) and 177 DEGs (including genes related to oxidative stress, inflammation, autophagy and lipid metabolism). Notably, regulatory effects of SLP on abnormal lipid metabolism in kidney were mainly associated with oxidative stress, inflammation and autophagy; SLP could regulate abnormal lipid metabolism in kidney by reducing oxidative stress and affecting its downstream-regulated autophagy and inflammatory to alleviate renal injury caused by lead exposure. This study provides a theoretical basis for SLP intervention in lead injury.},
}
@article {pmid39128490,
year = {2025},
author = {Isaguliants, M and Zhitkevich, A and Petkov, S and Gorodnicheva, T and Mezale, D and Fridrihsone, I and Kuzmenko, Y and Kostyushev, D and Kostyusheva, A and Gordeychuk, I and Bayurova, E},
title = {Enzymatic activity of HIV-1 protease defines migration of tumor cells in vitro and enhances their metastatic activity in vivo.},
journal = {Biochimie},
volume = {228},
number = {},
pages = {32-43},
doi = {10.1016/j.biochi.2024.08.009},
pmid = {39128490},
issn = {1638-6183},
mesh = {Animals ; *Cell Movement ; Mice ; Female ; Cell Line, Tumor ; *Mice, Inbred BALB C ; *Neoplasm Metastasis ; HIV Protease/metabolism/genetics ; Epithelial-Mesenchymal Transition ; Reactive Oxygen Species/metabolism ; HIV-1 ; Humans ; Breast Neoplasms/pathology/metabolism/enzymology ; },
abstract = {Overexpression of aspartic proteases, as cathepsin D, is an independent marker of poor prognosis in breast cancer, correlated with the incidence of clinical metastasis. We aimed to find if HIV-1 aspartic protease (PR) can play a similar role. Murine adenocarcinoma 4T1luc2 cells were transduced with lentivirus encoding inactivated drug-resistant PR, generating subclones PR20.1 and PR20.2. Subclones were assessed for production of reactive oxygen species (ROS), expression of epithelial-mesenchymal transition (EMT) factors, and in vitro migratory activity in the presence or absence of antioxidant N-acetyl cysteine and protease inhibitors. Tumorigenic activity was evaluated by implanting cells into BALB/c mice and following tumor growth by calipering and bioluminescence imaging in vivo, and metastases, by organ imaging ex vivo. Both subclones expressed PR mRNA, and PR20.2, also the protein detected by Western blotting. PR did not induce production of ROS, and had no direct effect on cell migration rate, however, treatment with inhibitors of drug-resistant PR suppressed the migratory activity of both subclones. Furthermore, expression of N-cadherin and Vimentin in PR20.2 cells and their migration were enhanced by antioxidant treatment. Sensitivity of in vitro migration to protease inhibitors and to antioxidant, known to restore PR activity, related the effects to the enzymatic activity of PR. In vivo, PR20.2 cells demonstrated higher tumorigenic and metastatic activity than PR20.1 or parental cells. Thus, HIV-1 protease expressed in breast cancer cells determines their migration in vitro and metastatic activity in vivo. This effect may aggravate clinical course of cancers in people living with HIV-1.},
}
@article {pmid39125554,
year = {2024},
author = {Wee, JH and Park, JH and Park, MW and Choi, YS and Jung, HJ},
title = {Sinus Irrigation with N-Acetylcysteine after Endoscopic Sinus Surgery for Chronic Rhinosinusitis: A Preliminary Report of a Single-Blind Randomized Controlled Trial.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {14},
number = {15},
pages = {},
pmid = {39125554},
issn = {2075-4418},
support = {2022101232//Chungbuk National University/ ; },
abstract = {Nasal irrigation is crucial following endoscopic sinus surgery (ESS), especially for managing chronic rhinosinusitis (CRS). This study assessed the effectiveness of N-acetylcysteine (NAC) irrigation during the post-ESS period of patients with CRS without nasal polyposis. In this prospective, single-blind randomized controlled trial, 49 patients (NAC, n = 24; saline, n = 25) undergoing ESS were assigned to receive either NAC or saline irrigations twice daily for a month. The preoperative and postoperative assessments conducted included Lund-Macka (LM) and Lund-Kennedy (LK) endoscopic scores, the Nasal Obstruction Symptom Evaluation (NOSE) scale, and the Sino-Nasal Outcome Test-20 (SNOT-20). At 2 weeks, 1 month, and 3 months after the operation, endoscopic findings and symptoms were evaluated. Both groups showed no differences in age, sex, LM and LK scores, NOSE scale, and SNOT-20 preoperatively. In terms of the endoscopic findings regarding the sinonasal mucosa after ESS, the NAC group had slightly lower scores 2 weeks, 1 month, and 3 months after the operation, but this difference was not statistically significant. The NAC group showed significant improvement in VAS scores, namely, postnasal drip (1.0, p = 0.041), smell dysfunction (0.8, p = 0.003), and crust (1.5, p = 0.034), compared to the control group's scores of 2.6, 4.7, and 3.6, respectively, 2 weeks after the operation, although no significant differences were observed in VAS scores for any symptoms 1 and 3 months after the operation. NAC was well tolerated, and no adverse events were reported. NAC irrigation showed benefits over saline irrigation in terms of improving postnasal drip, smell dysfunction, and crust after ESS for CRS without nasal polyposis in the immediate postoperative period.},
}
@article {pmid39121982,
year = {2024},
author = {Liu, DD and Liu, XL and Zheng, TF and Li, X and Zhao, YC and Pan, JC and Yuan, C and Wang, QQ and Zhang, M},
title = {Dapagliflozin alleviates right heart failure by promoting collagen degradation by reducing ROS levels.},
journal = {European journal of pharmacology},
volume = {981},
number = {},
pages = {176875},
doi = {10.1016/j.ejphar.2024.176875},
pmid = {39121982},
issn = {1879-0712},
mesh = {Animals ; *Glucosides/pharmacology/therapeutic use ; *Benzhydryl Compounds/pharmacology/therapeutic use ; *Heart Failure/drug therapy/metabolism/physiopathology ; *Reactive Oxygen Species/metabolism ; Rats ; *Collagen/metabolism ; Male ; *Rats, Sprague-Dawley ; *Fibrosis ; Fibroblasts/drug effects/metabolism/pathology ; Matrix Metalloproteinase 9/metabolism ; Hypertension, Pulmonary/drug therapy/metabolism/pathology ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology/therapeutic use ; Matrix Metalloproteinase 2/metabolism ; Disease Models, Animal ; },
abstract = {BACKGROUND: Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms.<br><br>METHODS: We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-&#x3b2;) to investigate the effect of DAPA.<br><br>RESULTS: In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels.<br><br>CONCLUSIONS: In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.},
}
@article {pmid39113878,
year = {2024},
author = {Wong, G and Wu, SY and Chen, WM and Hsu, PJ and Chou, TC and Chiang, MF and Wu, MS and Lee, MC and Soong, RS},
title = {Effects of N-acetylcysteine on hepatocellular carcinoma in chronic hepatitis C.},
journal = {American journal of cancer research},
volume = {14},
number = {7},
pages = {3533-3544},
pmid = {39113878},
issn = {2156-6976},
abstract = {Hepatitis C virus (HCV) infection significantly contributes to global hepatocellular carcinoma (HCC) incidence. N-Acetylcysteine (NAC), known for its antioxidant properties, is a potential therapeutic agent. However, evidence on its efficacy in reducing HCC risk among HCV patients is limited. A retrospective cohort analysis using Taiwan's National Health Insurance Research Database (2008-2018) included ≥18-year-old HCV patients. NAC usage (≥28 cumulative defined daily doses [cDDDs]) was assessed for its association with HCC risk using Cox regression models and propensity score matching. The study comprised 269,647 HCV patients, with detailed NAC dosage characterization and hazard ratios (HRs) for HCC risk. Post-matching, NAC usage emerged as the significant predictor of reduced HCC risk (adjusted HR: 0.39, 95% CI: 0.37-0.41, P<0.0001). Dose-response analysis showed reduced HCC risk with increasing cDDDs of NAC (P<0.0001). Higher daily NAC dosage (≥1 DDD) was associated with significantly lower HCC risk (adjusted HR: 0.33, 95% CI: 0.31-0.36, P<0.0001). The study provides compelling evidence for NAC's potential in reducing HCC risk among HCV patients. Insights into dose-dependent effects and optimal daily intensity thresholds offer valuable directions for future therapeutic strategies and clinical trials targeting HCC burden in HCV-infected individuals.},
}
@article {pmid39113864,
year = {2024},
author = {Wu, SY and Chen, WM and Hsu, PJ and Chou, TC and Chiang, MF and Wu, MS and Lee, MC and Soong, RS},
title = {Protective effect of N-acetylcysteine against hepatocellular carcinoma in hepatitis B virus carriers.},
journal = {American journal of cancer research},
volume = {14},
number = {7},
pages = {3639-3651},
pmid = {39113864},
issn = {2156-6976},
abstract = {Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC), contributing to cancer development through direct genomic integration and chronic inflammation. N-acetylcysteine (NAC), known for its antioxidant properties, is widely utilized in cancer prevention. However, clinical evidence regarding its protective effect against HCC in HBV carriers remains sparse. In this retrospective cohort study spanning 2008 to 2018, we utilized Taiwan's National Health Insurance Research Database (NHIRD) to include 1,061,174 chronic HBV carriers. Participants were stratified into NAC users and non-users using Propensity Score Matching. We assessed the incidence of HCC in both cohorts, examining the relationship between NAC usage duration and HCC incidence, and evaluating the dose-response effect. NAC users exhibited a significantly lower risk of developing HCC (adjusted hazard ratio [aHR]: 0.38; 95% confidence interval [CI]: 0.36-0.40; P < 0.0001). A dose-response relationship was evident, with higher cumulative defined daily doses (cDDDs) of NAC correlating with reduced HCC risk, revealing a significant trend (P < 0.0001). Notably, a daily NAC intensity of > 1.4 DDDs was associated with a decreased risk of HCC in HBV patients. Our results demonstrate that the use of NAC, in a dose-dependent manner, is intricately linked with a diminished incidence of HCC in individuals chronically infected with the HBV.},
}
@article {pmid39112929,
year = {2024},
author = {Xu, X and Wu, Y and Zhao, Y and Liu, A and Yi, C and Zhang, A and Wang, X},
title = {Inhibition of Macrophage Pyroptosis─A New Therapeutic Strategy to Alleviate T-2 Toxin-Induced Subacute Liver Injury by Directly Competing with the Key Target.},
journal = {Journal of agricultural and food chemistry},
volume = {72},
number = {33},
pages = {18670-18681},
doi = {10.1021/acs.jafc.4c03340},
pmid = {39112929},
issn = {1520-5118},
mesh = {*Pyroptosis/drug effects ; Animals ; Mice ; *T-2 Toxin/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/genetics ; *Macrophages/drug effects/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; Humans ; NF-kappa B/genetics/metabolism ; Cell Line ; Male ; Berberine/pharmacology ; Mice, Inbred C57BL ; Liver/drug effects/metabolism ; },
abstract = {Multiple compounds are related to the development of liver injury, such as toxins, drugs, and environmental pollutants. Although there are reports that the T-2 toxin can cause liver injury, its toxic mechanism remains unclear, which further impedes the development of effective antidotes. In this study, CRISPR-Cas9 genome-wide screening technology was used to identify transformation-related protein 53 inducible nuclear protein 1 (trp53inp1) as a toxic target of the T-2 toxin. Mechanism studies have shown that the T-2 toxin induced pyroptosis of macrophages (J774A.1 cells) by activating the trp53inp1/NF-κB/NLRP3/GSDMD-N pathway, leading to a subacute liver injury. Also, the new drug berberine (BER) identified through virtual screening significantly alleviated the subacute liver injury by competitively binding trp53inp1 via His224; the effect was better than those of the positive control drugs N-acetylcysteine (NAC) and disulfiram (DSF). In summary, the above results indicate that trp53inp1 is a key target for T-2 toxin to induce subacute liver injury and that inhibiting macrophage pyroptosis is a new method for treating liver injury. In addition, this study provides a new method and strategy for the discovery of key disease targets and the search for effective drugs.},
}
@article {pmid39108325,
year = {2024},
author = {Kwok, WC and Chan, SKS and Chiang, KY and Ho, CMJ},
title = {A double-blind randomized controlled trial of N-acetylcysteine (NAC) for the treatment of acute exacerbation of chronic obstructive pulmonary disease.},
journal = {Respirology case reports},
volume = {12},
number = {8},
pages = {e01449},
pmid = {39108325},
issn = {2051-3380},
abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with acute exacerbation (AECOPD) being a common sequalae which negatively impact health status, rates of hospitalization and readmission, and disease progression. N-acetylcysteine (NAC) has been studied in COPD in both stable state and acute exacerbations, which has been shown to have small beneficial effects in stable COPD, as well as AECOPD. Yet, there has been lack of study with well-designed protocol to assess the role of NAC in more objective outcomes in AECOPD.<br><br>METHODS: This is a double-blind randomized controlled trial. Patients will be randomized in 1:1 ratio to receive oral NAC at 600&#x2009;mg twice daily or placebo twice daily with standard of care. Partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2) and the ratio of partial pressure arterial oxygen and fraction of inspired oxygen (PaO2/FiO2) will be measured on days 1 and 7. The following will be measure at baseline and on day 4 and 7: Forced expiratory volume in one second (FEV1), 24-hour sputum volume, oxygen saturation (SaO2), end-tidal CO2, Leicester Cough Questionnaire (LCQ) score, COPD Assessment Test (CAT) score, grading of wheeze and grade of dyspnoea; blood inflammatory markers (leucocyte count, neutrophil count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and high sensitivity CRP (hs-CRP)). Patients will be randomized to oral NAC at 600&#x2009;mg twice daily or placebo for 7&#x2009;days. The main outcome measures include: The difference in PaO2 on day 7. Secondary outcome: Change in following parameters on day 4/7 from baseline: FEV1, sputum volume, CAT score, LCQ score, SaO2, grade of wheeze; mMRC Dyspnoea Scale, end-tidal CO2, blood inflammatory marker, change in PaO2/FiO2 ratio from baseline to day 7, PaCO2 on day 7, 28 and 90&#x2009;days' mortality, time to wean off supplemental oxygen, length of stay.Primary and secondary outcomes will be compared among the two treatment groups with two-sample t-test.<br><br>DISCUSSION: We hypothesize that NAC use in COPD exacerbation can provide benefits in clinical and laboratory parameters.<br><br>TRIAL REGISTRATION: Name of the registry : ClinicalTrials.gov Trial registration number : NCT05706402. URL of the trial registry record for this trial : https://classic.clinicaltrials.gov/ct2/show/NCT05706402 Date of registration : Registered on 11th January 2023 Funding of the trial : The Health and Medical Research Fund (HMRF). Name and contact information for the trial sponsor : Wang Chung Kwok, Clinical Assistant Professor, Honorary Associate Consultant, Queen Mary Hospital, The University of Hong Kong, Hong Kong. Role of sponsor : The funder is not involved in the planning of the study, gathering, analysing, and interpreting the data, or in preparing the manuscript.},
}
@article {pmid39103770,
year = {2024},
author = {Junqueira, A and Gomes, MJ and Lima, ARR and Pontes, THD and Rodrigues, EA and Damatto, FC and Depra, I and Paschoareli, GL and Pagan, LU and Fernandes, AAH and Oliveira-Jr, SA and Pacagnelli, FL and Okoshi, MP and Okoshi, K},
title = {Effects of concurrent training and N-acetylcysteine supplementation on cardiac remodeling and oxidative stress in middle-aged spontaneously hypertensive rats.},
journal = {BMC cardiovascular disorders},
volume = {24},
number = {1},
pages = {409},
pmid = {39103770},
issn = {1471-2261},
support = {307703/2022-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 307280/2022-5//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 2021/10923-5//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; },
mesh = {Animals ; *Rats, Inbred SHR ; Male ; *Oxidative Stress/drug effects ; *Acetylcysteine/pharmacology ; *Ventricular Remodeling/drug effects ; *Hypertension/physiopathology/drug therapy/metabolism ; *NADPH Oxidases/metabolism/genetics ; Rats ; Antioxidants/pharmacology ; Physical Conditioning, Animal ; Disease Models, Animal ; NADPH Oxidase 2/metabolism/genetics ; NADPH Oxidase 4/metabolism/genetics ; Membrane Glycoproteins/metabolism/genetics ; Myocardium/metabolism/pathology ; Lipid Peroxides/metabolism ; Ventricular Function, Left/drug effects ; Dietary Supplements ; Hypertrophy, Left Ventricular/physiopathology/prevention &amp; control/metabolism ; },
abstract = {BACKGROUND: This study evaluated the effects of concurrent isolated training (T) or training combined with the antioxidant N-acetylcysteine (NAC) on cardiac remodeling and oxidative stress in spontaneously hypertensive rats (SHR).<br><br>METHODS: Six-month-old male SHR were divided into sedentary (S, n&#x2009;=&#x2009;12), concurrent training (T, n&#x2009;=&#x2009;13), sedentary supplemented with NAC (SNAC, n&#x2009;=&#x2009;13), and concurrent training with NAC supplementation (TNAC, n&#x2009;=&#x2009;14) groups. T and TNAC rats were trained three times a week on a treadmill and ladder; NAC supplemented groups received 120&#xa0;mg/kg/day NAC in rat chow for eight weeks. Myocardial antioxidant enzyme activity and lipid hydroperoxide concentration were assessed by spectrophotometry. Gene expression of NADPH oxidase subunits Nox2, Nox4, p22 phox, and p47 phox was evaluated by real time RT-PCR. Statistical analysis was performed using ANOVA and Bonferroni or Kruskal-Wallis and Dunn.<br><br>RESULTS: Echocardiogram showed concentric remodeling in TNAC, characterized by increased relative wall thickness (S 0.40&#x2009;&#xb1;&#x2009;0.04; T 0.39&#x2009;&#xb1;&#x2009;0.03; SNAC 0.40&#x2009;&#xb1;&#x2009;0.04; TNAC 0.43&#x2009;&#xb1;&#x2009;0.04 *; * p&#x2009;<&#x2009;0.05 vs T and SNAC) and diastolic posterior wall thickness (S 1.50&#x2009;&#xb1;&#x2009;0.12; T 1.52&#x2009;&#xb1;&#x2009;0.10; SNAC 1.56&#x2009;&#xb1;&#x2009;0.12; TNAC 1.62&#x2009;&#xb1;&#x2009;0.14 * mm; * p&#x2009;<&#x2009;0.05 vs T), with improved contractile function (posterior wall shortening velocity: S 39.4&#x2009;&#xb1;&#x2009;5.01; T 36.4&#x2009;&#xb1;&#x2009;2.96; SNAC 39.7&#x2009;&#xb1;&#x2009;3.44; TNAC 41.6&#x2009;&#xb1;&#x2009;3.57 * mm/s; * p&#x2009;<&#x2009;0.05 vs T). Myocardial lipid hydroperoxide concentration was lower in NAC treated groups (S 210&#x2009;&#xb1;&#x2009;48; T 182&#x2009;&#xb1;&#x2009;43; SNAC 159&#x2009;&#xb1;&#x2009;33 *; TNAC 110&#x2009;&#xb1;&#x2009;23 *[#] nmol/g tissue; * p&#x2009;<&#x2009;0.05 vs S, [#] p&#x2009;<&#x2009;0.05 vs T and SNAC). Nox 2 and p22 phox expression was higher and p47 phox lower in T than S [S 1.37 (0.66-1.66); T 0.78 (0.61-1.04) *; SNAC 1.07 (1.01-1.38); TNAC 1.06 (1.01-1.15) arbitrary units; * p&#x2009;<&#x2009;0.05 vs S]. NADPH oxidase subunits did not differ between TNAC, SNAC, and S groups.<br><br>CONCLUSION: N-acetylcysteine supplementation alone reduces oxidative stress in untreated spontaneously hypertensive rats. The combination of N-acetylcysteine and concurrent exercise further decreases oxidative stress. However, the lower oxidative stress does not translate into improved cardiac remodeling and function in untreated spontaneously hypertensive rats.},
}
@article {pmid39103611,
year = {2024},
author = {Leite, G and Rezaie, A and Morales, W and Weitsman, S and de Freitas Germano, J and Barlow, GM and Parodi, G and Pimentel, ML and Villanueva-Millan, MJ and Sanchez, M and Ayyad, S and Mathur, R and Pimentel, M},
title = {Low dose rifaximin combined with N-acetylcysteine is superior to rifaximin alone in a rat model of IBS-D: a randomized trial.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {18140},
pmid = {39103611},
issn = {2045-2322},
mesh = {Animals ; *Rifaximin/pharmacology/therapeutic use ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Rats ; *Escherichia coli/drug effects ; *Disease Models, Animal ; *Diarrhea/drug therapy/microbiology ; *Irritable Bowel Syndrome/drug therapy/microbiology ; Male ; Rats, Sprague-Dawley ; Drug Therapy, Combination ; },
abstract = {Rifaximin is FDA-approved for treatment of irritable bowel syndrome with diarrhea (IBS-D), but poor solubility may limit its efficacy against microbes in the mucus layer, e.g. Escherichia coli. Here we evaluate adding the mucolytic N-acetylcysteine (NAC) to improve rifaximin efficacy. In a resazurin checkerboard assay, combining rifaximin with NAC had significant synergistic effects in reducing E. coli levels. The optimal rifaximin + NAC combination was then tested in a validated rat model of IBS-D (induced by cytolethal distending toxin [CdtB] inoculation). Rats were inoculated with vehicle and treated with placebo (Control-PBS) or rifaximin + NAC (Control-Rif + NAC, safety), or inoculated with CdtB and treated with placebo (CdtB-PBS), rifaximin (CdtB-Rifaximin), or rifaximin + NAC (CdtB-Rif + NAC) for 10 days. CdtB-inoculated rats (CdtB-PBS) developed wide variability in stool consistency (P = 0.0014) vs. controls (Control-PBS). Stool variability normalized in rats treated with rifaximin + NAC (CdtB-Rif + NAC) but not rifaximin alone (CdtB-Rifaximin). Small bowel bacterial levels were elevated in CdtB-PBS rats but normalized in CdtB-Rif + NAC but not CdtB-Rifaximin rats. E. coli and Desulfovibrio spp levels (each associated with different IBS-D microtypes) were also elevated in CdtB-inoculated (CdtB-PBS) but normalized in CdtB-Rif + NAC rats. Cytokine levels normalized only in CdtB-Rif + NAC rats, in a manner predicted to be associated with reduced diarrhea driven by reduced E. coli. These findings suggest that combining rifaximin with NAC may improve the percentage of IBS-D patients responding to treatment.},
}
@article {pmid39102049,
year = {2025},
author = {Logge, WB and Haber, PS and Hurzeler, TP and Towers, EE and Morley, KC},
title = {The effects of N-acetyl cysteine on intrinsic functional connectivity and neural alcohol cue reactivity in treatment-seeking individuals with alcohol use disorder: a preliminary study.},
journal = {Psychopharmacology},
volume = {242},
number = {1},
pages = {149-160},
pmid = {39102049},
issn = {1432-2072},
mesh = {Humans ; Female ; Male ; *Alcoholism/drug therapy/physiopathology ; *Acetylcysteine/pharmacology/administration &amp; dosage/therapeutic use ; Cues ; Magnetic Resonance Imaging/methods ; Adult ; Middle Aged ; Craving/drug effects ; *Brain/drug effects/diagnostic imaging ; Double-Blind Method ; },
abstract = {N-acetyl cysteine (NAC) is a potential pharmacotherapy for alcohol use disorder (AUD), but it is not known whether it modulates neural activation to alcohol cues or intrinsic functional connectivity. We investigated whether NAC attenuates (i) alcohol cue-elicited activation, and (ii) intrinsic functional connectivity compared to placebo in patients with AUD. In this preliminary study, twenty-three individuals (7 females) with moderate-severe AUD received daily NAC (2400 mg/day, n = 9), or a placebo (n = 14) for at least 2 weeks. Participants completed a pre-treatment functional magnetic resonance imaging session (T0) and a post-treatment session (T1) comprising resting-state and visual alcohol cue reactivity task acquisitions. Activation differences between sessions, treatment, and session-by-treatment interaction were assessed. Resting-state functional connectivity examined using 377 node ROI-to-ROIs evaluated whether NAC reduced intrinsic functional connectivity after treatment. There were no differences in alcohol cue reactivity for brain activation or subjective craving between NAC and placebo during treatment or across sessions, or significant interaction. A significant treatment-by-time interaction, with reduced intrinsic connectivity was observed after treatment (T1) for NAC-treated compared to placebo-treated patients in the posterior cingulate node (9, left hemisphere) of the dorsal attentional network and connections to salience, ventral-attentional, somatosensory, and visual-peripheral networks implicated in AUD. NAC reduced intrinsic functional connectivity in patients with moderate-severe AUD after treatment compared to placebo, but did not attenuate alcohol cue-elicited activation. However, the absence of cue reactivity findings may result from low power, rather than the absence of cue reactivity findings associated with NAC. These results provide preliminary evidence that NAC treatment may modulate intrinsic functional connectivity brain activation in patients with alcohol use disorder, but replication in larger studies are required to determine the strength of this effect and any associations with clinical outcomes. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT03879759.},
}
@article {pmid39101446,
year = {2024},
author = {Cavalcanti, BC and Magalhães, IL and Rodrigues, DS and Cabral, VPF and Barbosa, AD and Valente Sá, LGDA and da Silva, LJ and de Andrade Neto, JB and da Silva, CR and de Moraes, MO and Dos Santos, CC and Nobre Júnior, HV},
title = {Anticandidal activity of Croton heliotropiifolius Kunth essential oil is enhanced by N-acetylcysteine and itraconazole.},
journal = {Future microbiology},
volume = {19},
number = {15},
pages = {1309-1320},
pmid = {39101446},
issn = {1746-0921},
mesh = {*Croton/chemistry ; *Oils, Volatile/pharmacology/chemistry ; *Itraconazole/pharmacology ; *Antifungal Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Microbial Sensitivity Tests ; *Biofilms/drug effects ; *Candida/drug effects ; Drug Synergism ; Animals ; Cell Line ; Fluconazole/pharmacology ; Cricetinae ; },
abstract = {Aim: Evaluate the anticandidal effect of Croton heliotropiifolius Kunth essential oil and its interaction with azoles and N-acetylcysteine (NAC) against planktonic cells and biofilms.Materials &amp; methods: Broth microdilution and checkerboard methods were used to evaluate the individual and combined activity with fluconazole and itraconazole (ITRA). The antibiofilm effect of the oil was assessed in 96-well plates alone and combined with ITRA and NAC, and cytotoxicity determined by MTT.Results: The oil inhibited all Candida species growth. The activity was enhanced when associated with ITRA and NAC for planktonic cells and biofilms in formation. The effective concentrations were lower than the toxic ones to V79 cells.Conclusion: C. heliotropiifolius Kunth essential oil is an anticandidal alternative, and can be associated with ITRA and NAC.},
}
@article {pmid39101362,
year = {2024},
author = {Koh, A and Wong, T and Adiamah, A and Sanyal, S},
title = {Systematic review and meta-analysis of the effect of N-acetylcysteine on outcomes after liver resection.},
journal = {ANZ journal of surgery},
volume = {94},
number = {10},
pages = {1693-1701},
doi = {10.1111/ans.19183},
pmid = {39101362},
issn = {1445-2197},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage ; Blood Transfusion/statistics &amp; numerical data ; *Hepatectomy/adverse effects ; Length of Stay/statistics &amp; numerical data ; *Postoperative Complications/epidemiology/prevention &amp; control ; Randomized Controlled Trials as Topic ; Reperfusion Injury/epidemiology/prevention &amp; control ; Treatment Outcome ; },
abstract = {BACKGROUND: N-Acetylcysteine (NAC) is a recognized antioxidative agent that facilitates the conjugation of toxic metabolites. In recent years, NAC has been routinely used to limit ischaemia-reperfusion injury in liver transplantation. There remains, however, contradictory evidence on its effectiveness in liver resection. This meta-analysis examines the effectiveness of NAC in improving outcomes following hepatectomy.<br><br>METHODS: A comprehensive search of the MEDLINE, EMBASE, and Cochrane databases was performed to identify relevant randomized controlled trials (RCTs) published since database inception until November 2023. The outcomes of Day 1 biochemical markers (lactate, ALT, bilirubin, and INR), length of stay, transfusion rates, and morbidity were extracted. Quantitative pooling of data was based on a random-effects model. The study protocol was registered on PROSPERO (Registration no: CRD42023442429).<br><br>RESULTS: Five RCTs reporting on 388 patients undergoing hepatectomy were included in the analysis. There were no significant differences in patient demographics between groups. Post-operative lactate was lower in patients receiving NAC (WMD -0.61, 95% CI -1.19 to -0.04, I[2]&#x2009;=&#x2009;67%). There were, however, no differences in the post-operative INR (WMD -0.04, 95% CI -0.19 to 0.12, I[2]&#x2009;=&#x2009;96%) and ALT (WMD -94.94, 95% CI -228.46 to 40.38; I[2]&#x2009;=&#x2009;67%). More importantly, there were no statistically significant differences in length of stay, transfusion rates, and morbidity between the two groups.<br><br>CONCLUSION: The administration of NAC in liver resection did not alter important biochemical parameters suggesting any real effectiveness in reducing hepatic dysfunction. There were no improvements in the clinical outcomes of length of stay, transfusion rates, and overall morbidity.},
}
@article {pmid39100861,
year = {2024},
author = {Zhang, R and Yang, A and Fu, J and Zhang, L and Yin, L and Xu, T and Dai, C and Su, W and Shen, W},
title = {Budesonide and N-acetylcysteine inhibit activation of the NLRP3 inflammasome by regulating miR-381 to alleviate acute lung injury caused by the pyroptosis-mediated inflammatory response.},
journal = {Toxicology research},
volume = {13},
number = {4},
pages = {tfae115},
pmid = {39100861},
issn = {2045-452X},
abstract = {BACKGROUND: The anti-inflammatory effects of budesonide (BUN) and N-acetylcysteine (NAC) attenuate acute lung injury (ALI). The aim of this study was to investigate the effects of combination therapy consisting of BUN and NAC on ALI and the underlying mechanisms.<br><br>METHODS: In vitro and in vivo models of ALI were generated by LPS induction. Western blotting was used to detect the expression levels of pyroptosis-related proteins and inflammation-related factors, and RT-qPCR was used to detect the expression of miR-381. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry, respectively. ELISA was used to detect the levels of inflammation-related factors. HE staining was used to detect lung injury.<br><br>RESULTS: The results showed that LPS effectively induced pyroptosis in cells and promoted the expression of pyroptosis-related proteins (Caspase1, Gasdermin D and NLRP3) and inflammatory cytokines (TNF-&#x3b1;, IL-6 and IL-1&#x3b2;). The combination of BUN and NAC significantly alleviated LPS-induced pyroptosis and inflammation. In addition, the combination of BUN and NAC effectively promoted miR-381 expression. Transfection of miR-381 mimics effectively alleviated LPS-induced pyroptosis and inflammation, while transfection of miR-381 inhibitors had the opposite effect. miR-381 negatively regulates NLRP3 expression. Treatment with a miR-381 inhibitor or pc-NLRP3 reversed the effects of the combination of BUN and NAC. In a mouse model of ALI, the combination of BUN and NAC effectively improved lung injury, while treatment with a miR-381 inhibitor or pc-NLRP3 effectively reversed this effect.<br><br>CONCLUSION: Overall, this study revealed that BUN&#xa0;+&#xa0;NAC inhibits the activation of NLRP3 by regulating miR-381, thereby alleviating ALI caused by pyroptosis-mediated inflammation.},
}
@article {pmid39094650,
year = {2024},
author = {Ma, N and Liu, X and Zhao, L and Liu, Y and Peng, X and Ma, D and Ma, L and Kiyama, R and Dong, S},
title = {Bisphenol P induces increased oxidative stress in renal tissues of C57BL/6 mice and human renal cortical proximal tubular epithelial cells, resulting in kidney injury.},
journal = {The Science of the total environment},
volume = {949},
number = {},
pages = {175159},
doi = {10.1016/j.scitotenv.2024.175159},
pmid = {39094650},
issn = {1879-1026},
mesh = {Animals ; Humans ; Mice ; Apoptosis/drug effects ; Benzhydryl Compounds/toxicity ; Endocrine Disruptors/toxicity ; *Epithelial Cells/drug effects ; Kidney/cytology/drug effects/pathology ; Kidney Tubules, Proximal/cytology/drug effects/pathology ; *Mice, Inbred C57BL ; *Oxidative Stress/drug effects ; *Phenols/toxicity ; Reactive Oxygen Species/metabolism ; Bisphenols ; },
abstract = {Bisphenol P (BPP) has been detected in human biological samples; however studies on its nephrotoxicity are scarce. Given the susceptibility of kidneys to endocrine-disrupting chemicals, there is an urgent need to investigate the renal toxicity of BPP. This study aimed to evaluate the effects of different concentrations of BPPs on the kidneys of C57BL/6 mice and elucidate the underlying mechanisms of renal damage using a combination of mouse renal transcriptomic data and human renal proximal tubular epithelial cells (HK-2). Mice were exposed to BPP (0, 0.3, 30, 3000 μg/kg bw/d) via gavage for 5 weeks. Renal injury was assessed based on changes in body and kidney weights, serum renal function indices, and histopathological examination. Transcriptomic analysis identified differentially expressed genes and pathways, whereas cellular assays were used to measure cell viability, reactive oxygen species (ROS), apoptosis, and the expression of key genes and proteins. The results show that BPP exposure induces renal injury, as evidenced by increased body weight, abnormal renal function indices, and renal tissue damage. Transcriptomic analysis revealed alterations in genes and pathways related to oxidative stress, p53 signaling, autophagy, and apoptosis. Cellular experiments confirmed that BPP induces oxidative stress and apoptosis. Furthermore, BPP exposure significantly inhibits autophagy, potentially exacerbating apoptosis and contributing to kidney injury. Treatment with a ROS inhibitor (N-Acetylcysteine, NAC) mitigated BPP-induced autophagy inhibition and apoptosis, implicating oxidative stress as a key factor. BPP exposure may lead to renal injury through excessive ROS accumulation, oxidative stress, inflammatory responses, autophagy inhibition, and increased apoptosis. The effects of NAC highlight the role of oxidative stress in BPP-induced nephrotoxicity. These findings enhance our understanding of BPP-induced nephrotoxicity and underscore the need to control BPP exposure to prevent renal disease. This study emphasized the importance of evaluating the safety of new Bisphenol A analogs, including BPP, in environmental toxicology.},
}
@article {pmid39094233,
year = {2024},
author = {Lu, WM and Ji, HN and Yang, RH and Cheng, KL and Yang, XL and Zeng, HL and Tao, K and Yin, DM and Wu, DH},
title = {A rat model of cerebral small vascular disease induced by ultrasound and protoporphyrin.},
journal = {Biochemical and biophysical research communications},
volume = {735},
number = {},
pages = {150451},
doi = {10.1016/j.bbrc.2024.150451},
pmid = {39094233},
issn = {1090-2104},
mesh = {Animals ; *Cerebral Small Vessel Diseases/pathology/diagnostic imaging ; *Disease Models, Animal ; *Protoporphyrins/pharmacology ; Male ; Rats ; *Rats, Sprague-Dawley ; Brain/pathology/drug effects/metabolism/diagnostic imaging ; Ultrasonic Waves ; Acetylcysteine/pharmacology ; Microspheres ; },
abstract = {Cerebral small vascular disease (CSVD) has a high incidence worldwide, but its pathological mechanisms remain poorly understood due to the lack of proper animal models. The current animal models of CSVD have several limitations such as high mortality rates and large-sized lesions, and thus it is urgent to develop new animal models of CSVD. Ultrasound can activate protoporphyrin to produce reactive oxygen species in a liquid environment. Here we delivered protoporphyrin into cerebral small vessels of rat brain through polystyrene microspheres with a diameter of 15 μm, and then performed transcranial ultrasound stimulation (TUS) on the model rats. We found that TUS did not affect the large vessels or cause large infarctions in the brain of model rats. The mortality rates were also comparable between the sham and model rats. Strikingly, TUS induced several CSVD-like phenotypes such as cerebral microinfarction, white matter injuries and impaired integrity of endothelial cells in the model rats. Additionally, these effects could be alleviated by antioxidant treatment with N-acetylcysteine (NAC). As control experiments, TUS did not lead to cerebral microinfarction in the rat brain when injected with the polystyrene microspheres not conjugated with protoporphyrin. In sum, we generated a rat model of CSVD that may be useful for the mechanistic study and drug development for CSVD.},
}
@article {pmid39089892,
year = {2024},
author = {Canbaz, FA and Yurtçu, M and Oltulu, P and Taştekin, G and Kocabaş, R and Doğan, M},
title = {Investigation of the Effects of N-acetylcysteine and Selenium on Vesicoureteral Reflux Nephropathy: An Experimental Study.},
journal = {Journal of pediatric surgery},
volume = {59},
number = {11},
pages = {161616},
doi = {10.1016/j.jpedsurg.2024.06.024},
pmid = {39089892},
issn = {1531-5037},
mesh = {*Vesico-Ureteral Reflux/complications/drug therapy ; Animals ; *Acetylcysteine/therapeutic use/pharmacology ; Rabbits ; *Selenium/therapeutic use ; Disease Models, Animal ; Kidney/drug effects ; Kidney Diseases/etiology/drug therapy/prevention &amp; control ; Malondialdehyde/metabolism/analysis/urine ; Technetium Tc 99m Dimercaptosuccinic Acid ; Antioxidants/therapeutic use/administration &amp; dosage/pharmacology ; Escherichia coli Infections/drug therapy/complications ; Male ; Cicatrix/prevention &amp; control/etiology ; },
abstract = {INTRODUCTION: This study aimed to investigate the effects of N-acetylcysteine (NAC) and selenium (Se) on vesicoureteral reflux (VUR) nephropathy.<br><br>METHODS: A total of 44 rabbits in 7 groups, namely group 1 (Control), group 2 (VUR&#xa0;+&#xa0;sterile urine), group 3 (VUR&#xa0;+&#xa0;sterile urine&#xa0;+&#xa0;NAC), group 4 (VUR&#xa0;+&#xa0;sterile urine&#xa0;+&#xa0;Se), group 5 (VUR&#xa0;+&#xa0;infected urine), group 6 (VUR&#xa0;+&#xa0;infected urine&#xa0;+&#xa0;NAC) and group 7 (VUR&#xa0;+&#xa0;infected urine&#xa0;+&#xa0;Se), were used. [99m]Tc Dimercaptosuccinic acid renal scan (DMSA), cystogram and urine culture were performed both at the beginning and end of the study. Left VUR was created surgically, and E.&#xa0;coli was inoculated in infected urine groups. NAC and Se were administered daily for 21 days. Malondialdehyde (MDA) measurement, inflammatory response scores (IRSs), and cicatrization response scores (CRSs) in renal tissues were evaluated.<br><br>RESULTS: VUR did not reduce left renal uptake values in neither group 2 nor group 5. MDA levels of the left kidney were significantly higher in group 5 compared to group 1 (p&#xa0;=&#xa0;0.001). There was no significant difference in MDA levels between group 5 and group 6, and between group 5 and group 7. Left kidney IRSs were found to be higher in all other groups except group 2 compared to the control group (p&#xa0;<&#xa0;0.001). Left kidney CRSs were significantly higher in group 5 compared to group 2 (p&#xa0;=&#xa0;0.026), group 6 (p&#xa0;<&#xa0;0.001) and group 7 (p&#xa0;=&#xa0;0.006).<br><br>CONCLUSION: A decrease in renal functions was not observed in VUR, even if there was infection. When CRSs were evaluated, NAC and Se had protective effects in terms of scar formation in VUR nephropathy.<br><br>TYPE OF STUDY: Experimental animal study.<br><br>LEVELS OF EVIDENCE: N/A.},
}
@article {pmid39089052,
year = {2024},
author = {Zhang, X and Qiu, W and Huang, J and Pang, X and Su, Y and Ye, J and Zhou, S and Tang, Z and Wang, R and Su, R},
title = {Insulin combined with N-acetylcysteine attenuates type 1 diabetes-induced splenic inflammatory injury in canines by inhibiting the MAPKs-NF-κB signaling pathway and pyroptosis.},
journal = {Journal of diabetes and its complications},
volume = {38},
number = {9},
pages = {108805},
doi = {10.1016/j.jdiacomp.2024.108805},
pmid = {39089052},
issn = {1873-460X},
mesh = {Animals ; Dogs ; *Acetylcysteine/pharmacology/therapeutic use ; *Diabetes Mellitus, Type 1/complications/drug therapy ; *Insulin ; *NF-kappa B/metabolism ; *Pyroptosis/drug effects ; *Diabetes Mellitus, Experimental/complications/drug therapy ; *Signal Transduction/drug effects ; Male ; *Drug Therapy, Combination ; *Spleen/drug effects/pathology ; Hypoglycemic Agents/pharmacology/therapeutic use ; Splenic Diseases/drug therapy/etiology/complications ; MAP Kinase Signaling System/drug effects ; },
abstract = {PURPOSE: Type 1 diabetes (T1DM) is a chronic metabolic disorder that can cause damage to multiple organs including the spleen. Sole insulin therapy is not satisfactory. This study aims to investigate the effects and mechanisms of combined treatment with insulin and N-acetylcysteine (NAC) on spleen damage in T1DM canines, in order to identify drugs that may better assist patients in the management of diabetes and its complications.<br><br>METHODS: The canine model of T1DM was established by intravenous injection of alloxan (ALX) and streptozotocin (STZ). The therapeutic effects of insulin and NAC were evaluated by clinical manifestations, spleen protein and mRNA expression.<br><br>RESULTS: The results indicate that the combined treatment of insulin and NAC can alleviate hyperglycemia and hematologic abnormalities, improve splenic histopathological changes, prevent fibrous tissue proliferation, and glycogen deposition. In addition, we observed that this combination treatment significantly suppressed the protein expression of p-P65/P65 (17.6&#xa0;%, P&#xa0;<&#xa0;0.05), NLRP3 (46.8&#xa0;%, P&#xa0;<&#xa0;0.05), and p-P38/P38 (37.1&#xa0;%, P&#xa0;<&#xa0;0.05) induced by T1DM when compared to insulin treatment alone. Moreover, it also significantly decreased the mRNA expression of TLR4 (45.0&#xa0;%, P&#xa0;<&#xa0;0.01), TNF-&#x3b1; (30.3&#xa0;%, P&#xa0;<&#xa0;0.05), and NLRP3 (43.3&#xa0;%, P&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: This combination has the potential to mitigate splenic inflammatory injury in T1DM canines by suppressing the activation of MAPKs-NF-&#x3ba;B pathway and pyroptosis. These findings provide a reference for the treatment strategies of diabetes and its complications.},
}
@article {pmid39073694,
year = {2024},
author = {Cheng, R and Jiang, Y and Zhang, Y and Ismail, M and Zhang, L and Jiang, Z and Yu, Q},
title = {Proteasome activity inhibition mediates endoplasmic reticulum stress-apoptosis in triptolide/lipopolysaccharide-induced hepatotoxicity.},
journal = {Cell biology and toxicology},
volume = {40},
number = {1},
pages = {60},
pmid = {39073694},
issn = {1573-6822},
support = {81973562//The research was supported by National Natural Science Foundation of China/ ; 82274200//The research was supported by National Natural Science Foundation of China/ ; CPU2018GY33//"Double First-Class" University project/ ; },
mesh = {*Phenanthrenes/pharmacology/toxicity ; *Diterpenes/pharmacology/toxicity ; *Endoplasmic Reticulum Stress/drug effects ; *Apoptosis/drug effects ; *Lipopolysaccharides/toxicity ; *Epoxy Compounds/toxicity/pharmacology ; Animals ; *Reactive Oxygen Species/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; *Endoplasmic Reticulum Chaperone BiP ; *Proteasome Inhibitors/pharmacology ; *Acetylcysteine/pharmacology ; Activating Transcription Factor 4/metabolism ; Phenylbutyrates/pharmacology ; Mice ; Chemical and Drug Induced Liver Injury/metabolism/pathology ; Liver/drug effects/pathology/metabolism ; Caspase 3/metabolism ; Male ; Leupeptins ; },
abstract = {Triptolide (TP) is a major active and toxic composition of the Chinese medicine Tripterygium wilfordii Hook. F. (TWHF), exhibiting various therapeutic bioactivities. Among the toxic effects, the hepatotoxicity of TP deserves serious attention. Previously, our research group proposed a new view of TP-related hepatotoxicity: hepatic hypersensitivity under lipopolysaccharide (LPS) stimulation. However, the mechanism of TP/LPS-induced hepatic hypersensitivity remains unclear. In this study, we investigated the mechanism underlying TP/LPS-induced hypersensitivity from the perspective of the inhibition of proteasome activity, activated endoplasmic reticulum stress (ERS)-related apoptosis, and the accumulation of reactive oxygen species (ROS). Our results showed that N-acetylcysteine (NAC), a common ROS inhibitor, decreased the expression of cleaved caspase-3 and cleaved PARP, which are associated with FLIP enhancement. Moreover, 4-phenylbutyric acid (4-PBA), an ERS inhibitor, was able to alleviate TP/LPS-induced hepatotoxicity by reducing ERS-related apoptosis protein expression (GRP78, p-eIF2α/eIF2α, ATF4, CHOP, cleaved caspase-3 and cleaved PARP) and ROS levels, with ATF4 being an indispensable mediator. In addition, the proteasome activity inhibitor MG-132 further aggravated ERS-related apoptosis, which indicated that the inhibition of proteasome activity also plays an important role in TP/LPS-related liver injuries. In summary, we propose that TP/LPS may upregulate the activation of ERS-associated apoptosis by inhibiting proteasome activity and enhancing ROS production through ATF4.},
}
@article {pmid39072707,
year = {2024},
author = {Dino, P and Giuffrè, MR and Buscetta, M and Di Vincenzo, S and La Mensa, A and Cristaldi, M and Bucchieri, F and Lo Iacono, G and Bertani, A and Pace, E and Cipollina, C},
title = {Release of IL-1β and IL-18 in human primary bronchial epithelial cells exposed to cigarette smoke is independent of NLRP3.},
journal = {European journal of immunology},
volume = {54},
number = {10},
pages = {e2451053},
doi = {10.1002/eji.202451053},
pmid = {39072707},
issn = {1521-4141},
support = {G78I18000930007//Progetto "SeNSO/ ; //P.O. FESR Regione Siciliana/ ; //Fondazione Ri.MED./ ; },
mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Interleukin-18/metabolism ; *Interleukin-1beta/metabolism ; *Epithelial Cells/metabolism ; *Bronchi/cytology/pathology/metabolism ; *Inflammasomes/metabolism ; Cells, Cultured ; Smoke/adverse effects ; Caspase 1/metabolism ; Cigarette Smoking/adverse effects ; },
abstract = {Cigarette smoke (CS) is a major risk factor for chronic lung diseases and promotes activation of pattern recognition receptors in the bronchial epithelium. NOD-like receptor family, pyrin domain-containing 3 (NLRP3) is a pattern recognition receptor whose activation leads to caspase-1 cleavage, maturation/release of IL-1β and IL-18, and eventually pyroptosis. Whether the NLRP3 inflammasome participates in CS-induced inflammation in bronchial epithelial cells is still unclear. Herein, we evaluated the involvement of NLRP3 in CS-induced inflammatory responses in human primary bronchial epithelial cells. To this purpose, human primary bronchial epithelial cells were stimulated with CS extracts (CSE) and lytic cell death, caspase activation (-1, -8, -3/7), cytokine release (IL-1β, IL-18, and IL-8), NLRP3, pro-IL-1β/pro-IL-18 mRNA, and protein expression were measured. The impact of inhibitors of NLRP3 (MCC950), caspases, and the effect of the antioxidant N-acetyl cysteine were evaluated. We found that CSE increased pro-IL-1β expression and induced activation of caspase-1 and release of IL-1β and IL-18. These events were independent of NLRP3 and we found that NLRP3 was not expressed. N-acetyl cysteine reverted CSE-induced caspase-1 activation. Overall, our findings support that the bronchial epithelium may play a central role in the release of IL-1 family cytokines independently of NLRP3 in the lungs of smokers.},
}
@article {pmid39070434,
year = {2024},
author = {Awaji, AA and Bakhamees, BH and Alalshaikh, NK and Albelwi, NM and Al-Zahrani, MM and Alshammari, KF and Almutairi, SD and Siraj, IM and Aljaber, TN and Alnajdi, RS and Al-Majnooni, SS and Alserhani, AS},
title = {Vitamin E for the Prevention of Contrast-Induced Nephropathy: A Systematic Review and Meta-Analysis.},
journal = {Cureus},
volume = {16},
number = {6},
pages = {e63256},
pmid = {39070434},
issn = {2168-8184},
abstract = {Contrast-induced nephropathy (CIN) is a serious condition that may develop in patients undergoing diagnostic radiologic procedures. Several treatments have been assessed to prevent CIN development. This study aims to assess the efficacy and safety of vitamin E in the prevention of CIN compared to intravenous (IV) saline hydration. The literature search included MEDLINE/PubMed, Cochrane Central Register of Controlled Trials, the Web of Science, ProQuest, and Scopus for articles published until May 11, 2024, without language or time limits. The outcomes included the incidence of CIN, new-onset dialysis, and death (primary), as well as the change in serum creatinine and glomerular filtration rate (GFR) (secondary). Numerical and dichotomous outcomes were presented as standardized mean difference (SMD) and risk ratio (RR), respectively, with 95% confidence intervals (CI). Six clinical trials were included. Vitamin E was administered orally in varying doses, but one study used IV infusion. Vitamin E decreased the risk of developing CIN by 59% (n=5; pooled RR: 0.41; 95% CI: 0.25, 0.65; P<0.001) compared to IV hydration. None of the patients required renal replacement therapy. One patient on vitamin E died due to the occurrence of acute coronary syndrome. Vitamin E is a promising effective prophylaxis against CIN. However, the number of included studies and their sample sizes are small. The studies showed several limitations. There is a need for further high-quality clinical trials to ascertain the effectiveness of vitamin E compared to IV hydration and to compare vitamin E to other therapies, such as N-acetyl cysteine.},
}
@article {pmid39066381,
year = {2024},
author = {Bufan, B and Arsenović-Ranin, N and Živković, I and Ćuruvija, I and Blagojević, V and Dragačević, L and Kovačević, A and Kotur-Stevuljević, J and Leposavić, G},
title = {Modulation of T-Cell-Dependent Humoral Immune Response to Influenza Vaccine by Multiple Antioxidant/Immunomodulatory Micronutrient Supplementation.},
journal = {Vaccines},
volume = {12},
number = {7},
pages = {},
pmid = {39066381},
issn = {2076-393X},
support = {451-03-65/2024-03/ 200161, 451-03-66/2024-03/ 200161, and 451-03-66/2024-03.//Ministry of Science, Technological Development and Innovation, Republic of Serbia/ ; },
abstract = {Notwithstanding prevalence gaps in micronutrients supporting immune functions, the significance of their deficits/supplementation for the efficacy of vaccines is underinvestigated. Thus, the influence of supplementation combining vitamins C and D, zinc, selenium, manganese, and N-acetyl cysteine on immune correlates/surrogates of protection conferred by a quadrivalent influenza vaccine (QIV) in mice was investigated. The supplementation starting 5 days before the first of two QIV injections given 28 days apart increased the serum titres of total and neutralizing IgG against each of four influenza strains from QIV. Accordingly, the frequencies of germinal center B cells, follicular CD4+ T helper (Th) cells, and IL-21-producing Th cells increased in secondary lymphoid organs (SLOs). Additionally, the supplementation improved already increased IgG response to the second QIV injection by augmenting not only neutralizing antibody production, but also IgG2a response, which is important for virus clearance, through favoring Th1 differentiation as indicated by Th1 (IFN-γ)/Th2 (IL-4) signature cytokine level ratio upon QIV restimulation in SLO cell cultures. This most likely partly reflected antioxidant action of the supplement as indicated by splenic redox status analyses. Thus, the study provides a solid scientific background for further research aimed at repurposing the use of this safe and inexpensive micronutrient combination to improve response to the influenza vaccine.},
}
@article {pmid39064168,
year = {2024},
author = {Santus, P and Signorello, JC and Danzo, F and Lazzaroni, G and Saad, M and Radovanovic, D},
title = {Anti-Inflammatory and Anti-Oxidant Properties of N-Acetylcysteine: A Fresh Perspective.},
journal = {Journal of clinical medicine},
volume = {13},
number = {14},
pages = {},
pmid = {39064168},
issn = {2077-0383},
abstract = {N-acetyl-L-cysteine (NAC) was initially introduced as a treatment for mucus reduction and widely used for chronic respiratory conditions associated with mucus overproduction. However, the mechanism of action for NAC extends beyond its mucolytic activity and is complex and multifaceted. Contrary to other mucoactive drugs, NAC has been found to exhibit antioxidant, anti-infective, and anti-inflammatory activity in pre-clinical and clinical reports. These properties have sparked interest in its potential for treating chronic lung diseases, including chronic obstructive pulmonary disease (COPD), bronchiectasis (BE), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF), which are associated with oxidative stress, increased levels of glutathione and inflammation. NAC's anti-inflammatory activity is noteworthy, and it is not solely secondary to its antioxidant capabilities. In ex vivo models of COPD exacerbation, the anti-inflammatory effects have been observed even at very low doses, especially with prolonged treatment. The mechanism involves the inhibition of the activation of NF-kB and neurokinin A production, resulting in a reduction in interleukin-6 production, a cytokine abundantly present in the sputum and breath condensate of patients with COPD and correlates with the number of exacerbations. The unique combination of mucolytic, antioxidant, anti-infective, and anti-inflammatory properties positions NAC as a safe, cost-effective, and efficacious therapy for a plethora of respiratory conditions.},
}
@article {pmid39063017,
year = {2024},
author = {Kenari, F and Pintér, Z and Molnár, S and Borges, ID and Camargo, AJ and Napolitano, HB and Perjési, P},
title = {(E)-2-Benzylidenecyclanones: Part XIX. Reaction of (E)-2-(4'-X-Benzylidene)-1-tetralones with Cellular Thiols: Comparison of Thiol Reactivities of Open-Chain Chalcones and Their Six- and Seven-Membered Cyclic Analogs.},
journal = {International journal of molecular sciences},
volume = {25},
number = {14},
pages = {},
pmid = {39063017},
issn = {1422-0067},
support = {EFOP-3.6.1.-16-2016-00004//European Union/ ; },
mesh = {Humans ; *Chalcones/chemistry/pharmacology ; *Sulfhydryl Compounds/chemistry ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology/chemistry ; Chromatography, High Pressure Liquid ; Glutathione/metabolism/chemistry ; Kinetics ; Benzylidene Compounds/chemistry ; },
abstract = {Non-enzyme-catalyzed thiol addition onto the α,β-unsaturated carbonyl system is associated with several biological effects. Kinetics and diastereoselectivity of non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) and N-acetylcysteine (NAC) to the six-membered cyclic chalcone analogs 2a and 2b were investigated at different pH values (pH 3.2, 7.4 and 8.0). The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended both on the substitution and the pH. The stereochemical outcome of the reactions was evaluated using high-pressure liquid chromatography with UV detection (HPLC-UV). The structures of the formed thiol-conjugates and the retro-Michael products (Z)-2a and (Z)-2b were confirmed by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Frontier molecular orbitals and the Fukui function calculations were carried out to investigate their effects on the six-membered cyclic analogs. Data were compared with those obtained with the open-chain (1) and the seven-membered (3) analogs. The observed reactivities do not directly relate to the difference in in vitro cancer cell cytotoxicity of the compounds.},
}
@article {pmid39062784,
year = {2024},
author = {Salanci, &#x160; and Vilková, M and Martinez, L and Mirossay, L and Michalková, R and Mojžiš, J},
title = {The Induction of G2/M Phase Cell Cycle Arrest and Apoptosis by the Chalcone Derivative 1C in Sensitive and Resistant Ovarian Cancer Cells Is Associated with ROS Generation.},
journal = {International journal of molecular sciences},
volume = {25},
number = {14},
pages = {},
pmid = {39062784},
issn = {1422-0067},
support = {VEGA 1/0539/21//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Repub-lic/ ; VEGA 1/0498/23//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Repub-lic/ ; APVV-16-0446//Slovak Research and Development Agency/ ; ITMS2014+: 313011V455//EDRF/ ; ITMS2014 + 313011D103//EDRF/ ; },
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; Female ; *Apoptosis/drug effects ; *Ovarian Neoplasms/metabolism/pathology/drug therapy ; *Drug Resistance, Neoplasm/drug effects ; *G2 Phase Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; *Chalcones/pharmacology ; Antineoplastic Agents/pharmacology ; Chalcone/pharmacology/analogs &amp; derivatives ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Signal Transduction/drug effects ; DNA Damage/drug effects ; },
abstract = {Ovarian cancer ranks among the most severe forms of cancer affecting the female reproductive organs, posing a significant clinical challenge primarily due to the development of resistance to conventional therapies. This study investigated the effects of the chalcone derivative 1C on sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines. Our findings revealed that 1C suppressed cell viability, induced cell cycle arrest at the G2/M phase, and triggered apoptosis in both cell lines. These effects are closely associated with generating reactive oxygen species (ROS). Mechanistically, 1C induced DNA damage, modulated the activity of p21, PCNA, and phosphorylation of Rb and Bad proteins, as well as cleaved PARP. Moreover, it modulated Akt, Erk1/2, and NF-κB signaling pathways. Interestingly, we observed differential effects of 1C on Nrf2 levels between sensitive and resistant cells. While 1C increased Nrf2 levels in sensitive cells after 12 h and decreased them after 48 h, the opposite effect was observed in resistant cells. Notably, most of these effects were suppressed by the potent antioxidant N-acetylcysteine (NAC), underscoring the crucial role of ROS in 1C-induced antiproliferative activity. Moreover, we suggest that modulation of Nrf2 levels can, at least partially, contribute to the antiproliferative effect of chalcone 1C.},
}
@article {pmid39062322,
year = {2024},
author = {De Rose, DU and Landolfo, F and Pugnaloni, F and Giliberti, P and Santisi, A and Columbo, C and Martini, L and Ronchetti, MP and Schingo, PM and Salvatori, G and Fusaro, F and Bagolan, P and Dotta, A and Capolupo, I and Conforti, A},
title = {Use of N-Acetylcysteine in Preterm Neonates with Enteral Feeding Intolerance and Intestinal Obstruction: A Case Series and Review of the Literature.},
journal = {Children (Basel, Switzerland)},
volume = {11},
number = {7},
pages = {},
pmid = {39062322},
issn = {2227-9067},
support = {Current Research funds//Ministero della Salute/ ; },
abstract = {(1) Background: The use of N-acetylcysteine (NAC) to relieve meconium obstruction of prematurity in the first days of life has been reported, with NAC reducing the viscosity of luminal contents by cleaving the disulfide bonds of mucoproteins. However, its use in this population should be further explored since it has been associated with hypernatremia and transient increase in transaminases and bilirubin. (2) Methods: In this retrospective study, we included neonates admitted because of enteral feeding intolerance and intestinal obstruction from 2019 to 2021 who received NAC as a rescue therapy before explorative laparotomy. (3) Results: We summarized the clinical presentation of six preterm neonates with enteral feeding intolerance and intestinal obstruction who received NAC as a rescue therapy. Four infants (66.7%) gradually improved without the need for explorative laparotomy, whereas two infants (33.3%) underwent the creation of an ileostomy. No cases of hypernatremia or hepatic derangement associated with NAC therapy were observed. (4) Conclusions: We described the use of NAC treatment by nasogastric tube and/or rectal enemas in preterm infants with enteral feeding intolerance and intestinal obstruction after a multidisciplinary assessment, but the limited sample size did not allow us to obtain definitive conclusions and further research is needed in this field, given the limited evidence about NAC treatment in preterm infants.},
}
@article {pmid39062036,
year = {2024},
author = {Orban, C and Agapie, M and Bratu, A and Jafal, M and Duțu, M and Popescu, M},
title = {No Significant Beneficial Effects of Intravenous N-Acetylcysteine on Patient Outcome in Non-Paracetamol Acute Liver Failure: A Meta-Analysis of Randomized Controlled Trials.},
journal = {Biomedicines},
volume = {12},
number = {7},
pages = {},
pmid = {39062036},
issn = {2227-9059},
abstract = {Acute liver failure is a life-threatening organ dysfunction with systemic organ involvement and is associated with significant mortality and morbidity unless specific management is undertaken. This meta-analysis aimed to assess the effects of intravenous N-acetylcysteine (NAC) on mortality and the length of hospital stay in patients with non-acetaminophen acute liver failure. Two hundred sixty-six studies from four databases were screened, and four randomized control trials were included in the final analysis. Our results could not demonstrate increased overall survival (OR 0.70, 95% CI [0.34, 1.44], p = 0.33) or transplant-free survival (OR 0.90, 95% CI [0.25, 3.28], p = 0.87) in patients treated with intravenous NAC. We observed an increased overall survival in adult patients treated with NAC (OR 0.59, 95% CI [0.35, 0.99], p = 0.05) compared to pediatric patients, but whether this is attributed to the age group or higher intravenous dose administered remains unclear. We did not observe a decreased length of stay in NAC-treated patients (OR -5.70, 95% CI [-12.44, 1.05], p = 0.10). In conclusion, our meta-analysis could not demonstrate any significant benefits on overall and transplant-free patient survival in non-acetaminophen ALF. Future research should also focus on specific etiologies of ALF that may benefit most from the use of NAC.},
}
@article {pmid39061932,
year = {2024},
author = {Ebbert, L and von Montfort, C and Wenzel, CK and Reichert, AS and Stahl, W and Brenneisen, P},
title = {A Combination of Cardamonin and Doxorubicin Selectively Affect Cell Viability of Melanoma Cells: An In Vitro Study.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {7},
pages = {},
pmid = {39061932},
issn = {2076-3921},
support = {BR1551/7-1//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Treatment of the most aggressive and deadliest form of skin cancer, the malignant melanoma, still has room for improvement. Its invasive nature and ability to rapidly metastasize and to develop resistance to standard treatment often result in a poor prognosis. While the highly effective standard chemotherapeutic agent doxorubicin (DOX) is widely used in a variety of cancers, systemic side effects still limit therapy. Especially, DOX-induced cardiotoxicity remains a big challenge. In contrast, the natural chalcone cardamonin (CD) has been shown to selectively kill tumor cells. Besides its anti-tumor activity, CD exhibits anti-oxidative, anti-inflammatory and anti-bacterial properties. In this study, we investigated the effect of the combinational treatment of DOX with CD on A375 melanoma cells compared to normal human dermal fibroblasts (NHDF) and rat cardiac myoblasts (H9C2 cells). DOX-induced cytotoxicity was unselective and affected all cell types, especially H9C2 cardiac myoblasts, demonstrating its cardiotoxic effect. In contrast, CD only decreased the cell viability of A375 melanoma cells, without harming normal (healthy) cells. The addition of CD selectively protected human dermal fibroblasts and rat cardiac myoblasts from DOX-induced cytotoxicity. While no apoptosis was induced by the combinational treatment in normal (healthy) cells, an apoptosis-mediated cytotoxicity was demonstrated in A375 melanoma cells. CD exhibited thiol reactivity as it was able to directly interact with N-acetylcysteine (NAC) in a cell-free assay and to induce heme oxygenase-1 (HO-1) in all cell types. And that took place in a reactive oxygen species (ROS)-independent manner. DOX decreased the mitochondrial membrane potential (Δψm) in all cell types, whereas CD selectively decreased mitochondrial respiration, affecting basal respiration, maximal respiration, spare respiratory capacity and ATP production in A375 melanoma cells, but not in healthy cardiac myoblasts. The DOX-induced cytotoxicity seen in melanoma cells was ROS-independent, whereas the cytotoxic effect of CD was associated with CD-induced ROS-formation and/or its thiol reactivity. This study highlights the beneficial properties of the addition of CD to DOX treatment, which might protect patients from DOX-induced cardiotoxicity. Future experiments with other tumor cell lines or a mouse model should substantiate this hypothesis.},
}
@article {pmid39061900,
year = {2024},
author = {Tsai, MS and Liou, GG and Liao, JW and Lai, PY and Yang, DJ and Wu, SH and Wang, SH},
title = {N-acetyl Cysteine Overdose Induced Acute Toxicity and Hepatic Microvesicular Steatosis by Disrupting GSH and Interfering Lipid Metabolisms in Normal Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {7},
pages = {},
pmid = {39061900},
issn = {2076-3921},
support = {NSTC 109-2320-B-040-005 and NSTC 110-2320-B-040-008//National Science and Technology Council Taiwan/ ; },
abstract = {N-acetyl cysteine (NAC) is a versatile drug used in various conditions, but the limitations and toxicities are not clear. The acute toxicity and toxicological mechanisms of an intraperitoneal injection of NAC in normal mice were deciphered. The LD50 for male and female BALB/cByJNarl mice were 800 mg/kg and 933 mg/kg. The toxicological mechanisms of 800 mg/kg NAC (N800) were investigated. The serum biomarkers of hepatic and renal indices dramatically increased, followed by hepatic microvesicular steatosis, renal tubular injury and necrosis, and splenic red pulp atrophy and loss. Thus, N800 resulted in mouse mortality mainly due to acute liver, kidney, and spleen damages. The safe dose (275 mg/kg) of NAC (N275) increased hepatic antioxidant capacity by increasing glutathione levels and catalase activity. N275 elevated the hepatic gene expressions of lipid transporter, lipid synthesis, β-oxidation, and ketogenesis, suggesting a balance between lipid production and consumption, and finally, increased ATP production. In contrast, N800 increased hepatic oxidative stress by decreasing glutathione levels through suppressing Gclc, and reducing catalase activity. N800 decreased the hepatic gene expressions of lipid transporter, lipid synthesis, and interferred β-oxidation, leading to lipid accumulation and increasing Cyp2E1 expression, and finally, decreased ATP production. Therefore, NAC doses are limited for normal individuals, especially via intraperitoneal injection or similar means.},
}
@article {pmid39061896,
year = {2024},
author = {Xie, B and Liu, Y and Chen, C and Velkov, T and Tang, S and Shen, J and Dai, C},
title = {Colistin Induces Oxidative Stress and Apoptotic Cell Death through the Activation of the AhR/CYP1A1 Pathway in PC12 Cells.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {7},
pages = {},
pmid = {39061896},
issn = {2076-3921},
support = {2023YFD1802300//National Key R&amp;D Program/ ; 32102724//National Natural Science Foundation of China/ ; },
abstract = {Colistin is commonly regarded as the "last-resort" antibiotic for combating life-threatening infections caused by multidrug-resistant (MDR) gram-negative bacteria. Neurotoxicity is a potential adverse event associated with colistin application in clinical settings, yet the exact molecular mechanisms remain unclear. This study examined the detrimental impact of colistin exposure on PC12 cells and the associated molecular mechanisms. Colistin treatment at concentrations of 0-400 μM decreased cell viability and induced apoptotic cell death in both time- and concentration-dependent manners. Exposure to colistin triggered the production of reactive oxygen species (ROS) and caused oxidative stress damage in PC12 cells. N-acetylcysteine (NAC) supplementation partially mitigated the cytotoxic and apoptotic outcomes of colistin. Evidence of mitochondrial dysfunction was observed through the dissipation of membrane potential. Additionally, colistin treatment upregulated the expression of AhR and CYP1A1 mRNAs in PC12 cells. Pharmacological inhibition of AhR (e.g., using α-naphthoflavone) or intervention with the CYP1A1 gene significantly decreased the production of ROS induced by colistin, subsequently lowering caspase activation and cell apoptosis. In conclusion, our findings demonstrate, for the first time, that the activation of the AhR/CYP1A1 pathway contributes partially to colistin-induced oxidative stress and apoptosis, offering insights into the cytotoxic effects of colistin.},
}
@article {pmid39061830,
year = {2024},
author = {Carles, L and Gibaja, A and Scheper, V and Alvarado, JC and Almodovar, C and Lenarz, T and Juiz, JM},
title = {Efficacy and Mechanisms of Antioxidant Compounds and Combinations Thereof against Cisplatin-Induced Hearing Loss in a Rat Model.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {7},
pages = {},
pmid = {39061830},
issn = {2076-3921},
support = {PID2020-117266RB-C22-1, EXC 2177/1, ID:390895286, SBPLY/17/180501/000544.//Ministerio de Ciencia Innovaci&#xf3;n, MCINN, Gobierno de Espa&#xf1;a, Plan Estatal de I+D+i, PID2020-117266RB-C22-1, Cluster of Excellence "Hearing4All" EXC 2177/1, ID:390895286, part of the Germany&#xb4;s Excellence Strategy of the German Research Foundation, DFG. Co/ ; },
abstract = {Cisplatin is an election chemotherapeutic agent used for many cancer treatments. Its cytotoxicity against neoplastic cells is mirrored by that taking place in healthy cells and tissues, resulting in serious adverse events. A very frequent one is ototoxicity, causing hearing loss which may permanently affect quality of life after successful oncologic treatments. Exacerbated oxidative stress is a main cytotoxic mechanism of cisplatin, including ototoxicity. Previous reports have shown antioxidant protection against cisplatin ototoxicity, but there is a lack of comparative studies on the otoprotectant activity and mechanism of antioxidant formulations. Here, we show evidence that a cocktail of vitamins A, C, and E along with Mg[++] (ACEMg), previously shown to protect against noise-induced hearing loss, reverses auditory threshold shifts, promotes outer hair cell survival, and attenuates oxidative stress in the cochlea after cisplatin treatment, thus protecting against extreme cisplatin ototoxicity in rats. The addition of 500 mg N-acetylcysteine (NAC), which, administered individually, also shows significant attenuation of cisplatin ototoxicity, to the ACEMg formulation results in functional degradation of ACEMg otoprotection. Mg[++] administered alone, as MgSO4, also prevents cisplatin ototoxicity, but in combination with 500 mg NAC, otoprotection is also greatly degraded. Increasing the dose of NAC to 1000 mg also results in dramatic loss of otoprotection activity compared with 500 mg NAC. These findings support that single antioxidants or antioxidant combinations, particularly ACEMg in this experimental series, have significant otoprotection efficacy against cisplatin ototoxicity. However, an excess of combined antioxidants and/or elevated doses, above a yet-to-be-defined "antioxidation threshold", results in unrecoverable redox imbalance with loss of otoprotectant activity.},
}
@article {pmid39060756,
year = {2024},
author = {Doi, K and Inoue, J and Ninomiya, M and Sano, A and Tsuruoka, M and Sato, K and Onuki, M and Sawahashi, S and Ouchi, K and Masamune, A},
title = {Three consecutive cases of acute liver failure in young women due to acetaminophen overdose: insights into Japanese social issues and transplantation landscape.},
journal = {Clinical journal of gastroenterology},
volume = {17},
number = {5},
pages = {948-954},
pmid = {39060756},
issn = {1865-7265},
mesh = {Humans ; Female ; *Acetaminophen/poisoning ; *Liver Failure, Acute/chemically induced/surgery ; *Drug Overdose ; Japan ; Young Adult ; *Liver Transplantation ; *Nonprescription Drugs/poisoning ; Analgesics, Non-Narcotic/poisoning ; Acetylcysteine/therapeutic use/administration &amp; dosage ; Chemical and Drug Induced Liver Injury/etiology ; East Asian People ; },
abstract = {Acetaminophen (APAP) is an over-the-counter (OTC) drug known worldwide for its safety and efficacy. However, in Japan, OTC drug overdose has become a prominent social problem in recent years due to stricter regulations for other drugs, especially among young people, and APAP is an increasing cause of acute liver injury due to overdose. This report describes three consecutive cases of acute liver failure in young women (22, 22 and 19 years old) due to APAP overdose in December 2023. Despite severe liver injury, indicated by high ALT levels and coagulopathy, these cases recovered without requiring liver transplantation. This report discusses three cases of acute liver failure in young Japanese women following APAP overdose, reflecting a national increase in such cases due to increased misuse of OTC drugs and societal factors. Key findings include the need for early treatment with N-acetylcysteine (NAC) and the importance of mental health assessment in the management of overdose patients. The cases underscore the need for prompt team-based care to prevent serious outcomes and highlight the complexity of liver transplantation decisions in Japan, highlighting the need for comprehensive strategies to address the escalating problem of APAP overdose.},
}
@article {pmid39055649,
year = {2024},
author = {Zheng, H and Liu, J and Sun, L and Meng, Z},
title = {The role of N-acetylcysteine in osteogenic microenvironment for bone tissue engineering.},
journal = {Frontiers in cell and developmental biology},
volume = {12},
number = {},
pages = {1435125},
pmid = {39055649},
issn = {2296-634X},
abstract = {Bone defect is a common clinical symptom which can arise from various causes. Currently, bone tissue engineering has demonstrated positive therapeutic effects for bone defect repair by using seeding cells such as mesenchymal stem cells and precursor cells. N-acetylcysteine (NAC) is a stable, safe and highly bioavailable antioxidant that shows promising prospects in bone tissue engineering due to the ability to attenuate oxidative stress and enhance the osteogenic potential and immune regulatory function of cells. This review systematically introduces the antioxidant mechanism of NAC, analyzes the advancements in NAC-related research involving mesenchymal stem cells, precursor cells, innate immune cells and animal models, discusses its function using the classic oral microenvironment as an example, and places particular emphasis on the innovative applications of NAC-modified tissue engineering biomaterials. Finally, current limitations and future prospects are proposed, with the aim of providing inspiration for targeted readers in the field.},
}
@article {pmid39053861,
year = {2024},
author = {Yu, H and Xie, Y and Lan, L and Ma, S and Mok, SWF and Wong, IN and Wang, Y and Zhong, G and Yuan, L and Zhao, H and Hu, X and Macrae, VE and He, S and Chen, G and Zhu, D},
title = {Sirt7 protects against vascular calcification via modulation of reactive oxygen species and senescence of vascular smooth muscle cells.},
journal = {Free radical biology &amp; medicine},
volume = {223},
number = {},
pages = {30-41},
doi = {10.1016/j.freeradbiomed.2024.07.021},
pmid = {39053861},
issn = {1873-4596},
mesh = {Animals ; *Vascular Calcification/pathology/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; *Muscle, Smooth, Vascular/metabolism/pathology ; Mice ; *Cellular Senescence ; *Sirtuins/metabolism/genetics ; *Myocytes, Smooth Muscle/metabolism/pathology ; *Oxidative Stress ; Humans ; NF-E2-Related Factor 2/metabolism/genetics ; Male ; Cholecalciferol/pharmacology ; Renal Insufficiency, Chronic/pathology/metabolism/genetics ; Mice, Inbred C57BL ; Cells, Cultured ; },
abstract = {Vascular calcification is frequently seen in patients with chronic kidney disease (CKD), and significantly increases cardiovascular mortality and morbidity. Sirt7, a NAD[+]-dependent histone deacetylases, plays a crucial role in cardiovascular disease. However, the role of Sirt7 in vascular calcification remains largely unknown. Using in vitro and in vivo models of vascular calcification, this study showed that Sirt7 expression was significantly reduced in calcified arteries from mice administered with high dose of vitamin D3 (vD3). We found that knockdown or inhibition of Sirt7 promoted vascular smooth muscle cell (VSMC), aortic ring and vascular calcification in mice, whereas overexpression of Sirt7 had opposite effects. Intriguingly, this protective effect of Sirt7 on vascular calcification is dependent on its deacetylase activity. Unexpectedly, Sirt7 did not alter the osteogenic transition of VSMCs. However, our RNA-seq and subsequent studies demonstrated that knockdown of Sirt7 in VSMCs resulted in increased intracellular reactive oxygen species (ROS) accumulation, and induced an Nrf-2 mediated oxidative stress response. Treatment with the ROS inhibitor N-acetylcysteine (NAC) significantly attenuated the inhibitory effect of Sirt7 on VSMC calcification. Furthermore, we found that knockdown of Sirt7 delayed cell cycle progression and accelerated cellular senescence of VSMCs. Taken together, our results indicate that Sirt7 regulates vascular calcification at least in part through modulation of ROS and cellular senescence of VSMCs. Sirt7 may be a potential therapeutic target for vascular calcification.},
}
@article {pmid39046019,
year = {2024},
author = {Varela, ELP and Gomes, ARQ and Santos, ASBD and Cruz, JND and Carvalho, EP and Prazeres, BAPD and Dolabela, MF and Percario, S},
title = {Lycopene supplementation promoted increased survival and decreased parasitemia in mice with severe malaria: comparison with N-acetylcysteine.},
journal = {Anais da Academia Brasileira de Ciencias},
volume = {96},
number = {3},
pages = {e20230347},
doi = {10.1590/0001-3765202420230347},
pmid = {39046019},
issn = {1678-2690},
mesh = {Animals ; *Lycopene/therapeutic use/administration &amp; dosage/pharmacology ; *Parasitemia/drug therapy ; Mice ; *Malaria/drug therapy ; *Acetylcysteine/administration &amp; dosage/therapeutic use/pharmacology ; *Plasmodium berghei/drug effects ; *Antioxidants/therapeutic use/administration &amp; dosage ; *Dietary Supplements ; Oxidative Stress/drug effects ; Carotenoids/therapeutic use/administration &amp; dosage ; Male ; Disease Models, Animal ; Random Allocation ; },
abstract = {Oxidative stress is involved in the pathogenesis of malaria, causing anemia, respiratory complications, and cerebral malaria. To mitigate oxidative stress, we investigated the effect of nutritional supplementation whit lycopene (LYC) on the evolution of parasitemia and survival rate in mice infected with Plasmodium berghei ANKA (Pb), comparing to the effects promoted by N-acetylcysteine (NAC). Therefore, 175 mice were randomly distributed into 4 groups; Sham: untreated and uninfected animals; Pb: animals infected with Pb; LYC+Pb: animals treated with LYC and infected with Pb; NAC+Pb: animals treated with NAC and infected with Pb. The animals were followed for 12 days after infection, and survival and parasitemia rates were evaluated. There was a 40.1% increase in parasitemia in the animals of the Pb group on the 12th day, and a survival rate of 45%. LYC supplementation slowed the development of parasitemia to 19% and promoted a significative increase in the survival rate of 80% on the 12th day after infection, compared to the Pb group, effects superior to those promoted by NAC, providing strong evidence of the beneficial effect of LYC on in vivo malaria and stressing the importance of antioxidant supplementation in the treatment of this disease.},
}
@article {pmid39045541,
year = {2024},
author = {Wu, X and Zhang, G and Du, X},
title = {Cigarette Smoke Extract Induces MUC5AC Expression Through the ROS/ IP3R/Ca[2+] Pathway in Calu-3 Cells.},
journal = {International journal of chronic obstructive pulmonary disease},
volume = {19},
number = {},
pages = {1635-1647},
pmid = {39045541},
issn = {1178-2005},
mesh = {Humans ; Acetylcysteine/pharmacology ; Calcium/metabolism ; *Calcium Signaling/drug effects ; Cell Line, Tumor ; Cigarette Smoking/adverse effects ; Endoplasmic Reticulum Stress/drug effects ; Endoribonucleases ; Epithelial Cells/metabolism/drug effects ; *Inositol 1,4,5-Trisphosphate Receptors/metabolism/genetics ; *Mucin 5AC/metabolism/genetics ; *Mucin-5B/metabolism/genetics ; Oxidative Stress/drug effects ; Protein Serine-Threonine Kinases/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; RNA Interference ; *Smoke/adverse effects ; Up-Regulation ; X-Box Binding Protein 1 ; Tobacco Products ; },
abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is caused by exposure to noxious external particles, air pollution, and the inhalation of cigarette smoke. Airway mucus hypersecretion particularly mucin5AC (MUC5AC), is a crucial pathological feature of COPD and is associated with its initiation and progression. In this study, we aimed to investigate the effects of cigarette smoke extract (CSE) on MUC5AC expression, particularly the mechanisms by which reactive oxygen species (ROS) induce MUC5AC expression.<br><br>METHODS: The effects of CSE on the expression of MUC5AC and mucin5B (MUC5B) were investigated in vitro in Calu-3 cells. MUC5AC and MUC5B expression levels were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). Total cellular levels of ROS and Ca[2+] were determined using DCFH-DA and Fluo-4 AM. Subsequently, the expression levels of IP3R, IRE1&#x3b1;, p-IRE1&#x3b1; and XBP1s were measured by Western blotting. Gene silencing was achieved by using small-interfering RNAs.<br><br>RESULTS: Our findings revealed that exposure to CSE increased MUC5AC levels and upregulated ROS, IP3R/Ca[2+] and unfolded protein response (UPR)-associated factors. In addition, knockdown of IP3R using siRNA decreased CSE-induced Ca[2+] production, UPR-associated factors, and MUC5AC expression. Furthermore, 10 mM N-acetyl-l-cysteine (NAC) treatment suppressed the effects of CSE, including ROS generation, IP3R/ Ca[2+], UPR activation, and MUC5AC overexpression.<br><br>CONCLUSION: Our results suggest that ROS regulates CSE-induced UPR and MUC5AC overexpression through IP3R/ Ca[2+] signaling. Additionally, we identified NAC as a promising therapeutic agent for mitigating CSE-induced MUC5AC overexpression.},
}
@article {pmid39044301,
year = {2024},
author = {Hao, WY and Wang, JX and Xu, XY and Chen, JL and Chen, Q and Li, YH and Zhu, GQ and Chen, AD},
title = {Chemerin in caudal division of nucleus tractus solitarius increases sympathetic activity and blood pressure.},
journal = {The European journal of neuroscience},
volume = {60},
number = {5},
pages = {4830-4842},
doi = {10.1111/ejn.16475},
pmid = {39044301},
issn = {1460-9568},
support = {32071106//National Natural Science Foundation of China/ ; 31871148//National Natural Science Foundation of China/ ; 31571168//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Solitary Nucleus/drug effects/physiology/metabolism ; Male ; *Rats, Sprague-Dawley ; *Chemokines/metabolism ; *Blood Pressure/drug effects/physiology ; *Sympathetic Nervous System/physiology/drug effects ; Rats ; Receptors, Chemokine/metabolism ; Heart Rate/drug effects/physiology ; Intercellular Signaling Peptides and Proteins/pharmacology/administration &amp; dosage ; NADPH Oxidases/metabolism ; Superoxides/metabolism ; },
abstract = {Chemerin is an adipokine that contributes to metabolism regulation. Nucleus tractus solitarius (NTS) is the first relay station in the brain for accepting various visceral afferent activities for regulating cardiovascular activity. However, the roles of chemerin in the NTS in regulating sympathetic activity and blood pressure are almost unknown. This study aimed to determine the role and potential mechanism of chemerin in the NTS in modulating sympathetic outflow and blood pressure. Bilateral NTS microinjections were performed in anaesthetized adult male Sprague-Dawley rats. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were highly expressed in caudal NTS (cNTS). Microinjection of chemerin-9 to the cNTS increased RSNA, MAP and HR, which were prevented by CMKLR1 antagonist α-NETA, superoxide scavenger tempol or N-acetyl cysteine, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium or apocynin. Chemerin-9 increased superoxide production and NADPH oxidase activity in the cNTS. The increased superoxide production induced by chemerin-9 was inhibited by α-NETA. The effects of cNTS microinjection of chemerin-9 on the RSNA, MAP and HR were attenuated by the pretreatment with paraventricular nucleus (PVN) microinjection of NMDA receptor antagonist MK-801 rather than AMPA/kainate receptor antagonist CNQX. These results indicate that chemerin-9 in the NTS increases sympathetic outflow, blood pressure and HR via CMKLR1-mediated NADPH oxidase activation and subsequent superoxide production in anaesthetized normotensive rats. Glutamatergic inputs in the PVN are needed for the chemerin-9-induced responses.},
}
@article {pmid39042563,
year = {2024},
author = {Jeon, M and Bae, S},
title = {In vitro effects of N-acetylcysteine in combination with antifungal agents against Malassezia pachydermatis isolated from canine otitis externa.},
journal = {Veterinary medicine and science},
volume = {10},
number = {5},
pages = {e1479},
pmid = {39042563},
issn = {2053-1095},
mesh = {Animals ; Dogs ; *Malassezia/drug effects ; *Otitis Externa/veterinary/drug therapy/microbiology ; *Dog Diseases/drug therapy/microbiology ; *Antifungal Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Drug Therapy, Combination/veterinary ; *Microbial Sensitivity Tests/veterinary ; Male ; Female ; },
abstract = {BACKGROUND: Many clinicians prescribe antifungal agents to treat canine otitis externa (OE). However, studies evaluating the antifungal effects of N-acetylcysteine (NAC) and its combinations are limited.<br><br>HYPOTHESIS/OBJECTIVES: The aim of this study was to evaluate the antifungal effects of NAC alone and in combination with other antifungal agents against Malassezia pachydermatis isolated from canine OE.<br><br>MATERIALS AND METHODS: M. pachydermatis samples were collected from 13 dogs with OE. The final concentration of the inoculum suspensions of M. pachydermatis was 1-5&#xa0;&#xd7;&#xa0;10[6] colony forming units/mL. The concentrations of the test compounds ketoconazole (KTZ), terbinafine (TER), nystatin (NYS) and NAC were 0.02-300&#xa0;&#xb5;g/mL, 0.04-80&#xa0;&#xb5;g/mL, 0.16-40&#xa0;&#xb5;g/mL and 1.25-20&#xa0;mg/mL, respectively. The minimum inhibitory concentration (MIC) was measured to evaluate the susceptibility of the M. pachydermatis to KTZ, TER, NYS and NAC. The checkerboard testing method and fractional inhibitory concentration index were used to evaluate the effect of NAC in combination with KTZ, TER and NYS against M. pachydermatis.<br><br>RESULTS: The MIC90 values of M. pachydermatis were 4.6875-9.375&#xa0;&#xb5;g/mL, 1.25&#xa0;&#xb5;g/mL, 5-10&#xa0;&#xb5;g/mL and 10&#xa0;mg/mL for KTZ, TER, NYS and NAC, respectively. The synergistic effects of KTZ, TER and NYS with NAC were identified in 0/13, 2/13 and 0/13 isolates, respectively.<br><br>NAC had an antifungal effect against M. pachydermatis but did not exert synergistic effects when used with KTZ, TER and NYS. Thus, the use of NAC alone as a topical solution could be considered an effective treatment option for canine OE involving M. pachydermatis.},
}
@article {pmid39040524,
year = {2024},
author = {Tomimoto, N and Takasaki, T and Sugiura, R},
title = {Arsenite treatment induces Hsp90 aggregatesdistinct from conventional stress granules in fission yeast.},
journal = {Microbial cell (Graz, Austria)},
volume = {11},
number = {},
pages = {242-253},
pmid = {39040524},
issn = {2311-2638},
abstract = {Various stress conditions, such as heat stress (HS) and oxidative stress, can cause biomolecular condensates represented by stress granules (SGs) via liquid-liquid phase separation. We have previously shown that Hsp90 forms aggregates in response to HS and that Hsp90 aggregates transiently co-localize with SGs as visualized by Pabp. Here, we showed that arsenite, one of the well-described SG-inducing stimuli, induces Hsp90 aggregates distinct from conventional SGs in fission yeast. Arsenite induced Hsp90 granules in a dose-dependent manner, and these granules were significantly diminished by the co-treatment with a ROS scavenger N-acetyl cysteine (NAC), indicating that ROS are required for the formation of Hsp90 granules upon arsenite stress. Notably, Hsp90 granules induced by arsenite do not overlap with conventional SGs as represented by eIF4G or Pabp, while HS-induced Hsp90 granules co-localize with SGs. Nrd1, an RNA-binding protein known as a HS-induced SG component, was recruited into Hsp90 aggregates but not to the conventional SGs upon arsenite stress. The non-phosphorylatable eIF2α mutants significantly delayed the Hsp90 granule formation upon arsenite treatment. Importantly, inhibition of Hsp90 by geldanamycin impaired the Hsp90 granule formation and reduced the arsenite tolerance. Collectively, arsenite stimulates two types of distinct aggregates, namely conventional SGs and a novel type of aggregates containing Hsp90 and Nrd1, wherein Hsp90 plays a role as a center for aggregation, and stress-specific compartmentalization of biomolecular condensates.},
}
@article {pmid39039898,
year = {2024},
author = {Yifu, P},
title = {A review of antioxidant N-acetylcysteine in addressing polycystic ovary syndrome.},
journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology},
volume = {40},
number = {1},
pages = {2381498},
doi = {10.1080/09513590.2024.2381498},
pmid = {39039898},
issn = {1473-0766},
mesh = {*Polycystic Ovary Syndrome/drug therapy/metabolism ; *Acetylcysteine/therapeutic use/pharmacology ; Humans ; Female ; *Antioxidants/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; },
abstract = {N-acetylcysteine (NAC), a compound known for its cysteine and glutathione precursor properties, has been used in therapeutic applications for many years. Recently, there has been increasing interest in exploring the potential benefits of NAC in addressing polycystic ovary syndrome (PCOS). However, the exact mechanisms underlying NAC's therapeutic and clinical uses remain not fully understood. This review aims to specifically investigate how NAC offers protection against PCOS. This involved an extensive systematic review of the literature, and it made use of PubMed, Embase, and Web of Science databases. By analyzing key findings from over 100 research papers, the potential mechanisms through which NAC produces its effects were explored and summarized. Most studies suggest that NAC, whether used on its own or in combination with other medications, has the potential to counteract oxidative stress, utilize its anti-inflammatory and anti-apoptotic properties, and offer benefits in managing PCOS. Moreover, NAC might have the potential to influence specific signaling pathways in insulin target cells and β cells. Diverse biological effects of NAC indicate its potential usefulness as a supplementary or therapeutic approach for managing PCOS. As a result, additional research is required to explore its potential in addressing PCOS.},
}
@article {pmid39039306,
year = {2024},
author = {Chen, Y and Luo, X and Deng, C and Zhao, L and Gao, H and Zhou, J and Peng, L and Yang, H and Li, M and Zhang, W and Zhao, Y and Fei, Y},
title = {Immunometabolic alteration of CD4[+] T cells in the pathogenesis of primary Sjögren's syndrome.},
journal = {Clinical and experimental medicine},
volume = {24},
number = {1},
pages = {163},
pmid = {39039306},
issn = {1591-9528},
support = {3332022105//Fundamental Research Funds for the Central Universities/ ; 82172343//National Natural Science Foundation of China/ ; 81971545//National Natural Science Foundation of China/ ; 7242103//Beijing Natural Science Foundation Program/ ; 2022-PUMCH-C-039//National High Level Hospital Clinical Research Funding/ ; CIFMS 2023-I2M-C &amp; T-B-006//Chinese Academy of Medical Science Innovation Fund/ ; },
mesh = {Humans ; *Sjogren's Syndrome/immunology/metabolism/pathology ; *CD4-Positive T-Lymphocytes/immunology/metabolism ; *Glycolysis ; *Reactive Oxygen Species/metabolism ; Female ; Middle Aged ; Male ; Adult ; Th17 Cells/immunology ; Cell Differentiation ; Interferon-gamma/metabolism ; Interleukin-17/metabolism ; Th1 Cells/immunology ; },
abstract = {Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder wherein CD4[+] T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4[+] T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4[+] T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4[+] T cells, conducted flow cytometry to assess the effector function and differentiation of CD4[+] T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4[+] T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4[+] T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4[+] T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4[+] T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4[+] T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4[+] T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS.},
}
@article {pmid39038059,
year = {2024},
author = {Bandekar, M and Panda, D},
title = {Microtubule depolymerization induces ferroptosis in neuroblastoma cells.},
journal = {IUBMB life},
volume = {76},
number = {12},
pages = {1186-1198},
doi = {10.1002/iub.2899},
pmid = {39038059},
issn = {1521-6551},
support = {JCB/2019/000016//Department of Science and Technology, Ministry of Science and Technology, India (The J.C. Bose fellowship)/ ; },
mesh = {*Ferroptosis/drug effects ; Humans ; *Neuroblastoma/pathology/metabolism/drug therapy ; *Microtubules/metabolism/drug effects ; *Reactive Oxygen Species/metabolism ; *Lipid Peroxidation/drug effects ; Cell Line, Tumor ; Deferoxamine/pharmacology ; Iron/metabolism ; Cell Proliferation/drug effects ; Glutathione/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; Nocodazole/pharmacology ; Vinblastine/pharmacology ; },
abstract = {Estramustine (EM), a clinically successful hormone-refractory anti-prostate cancer drug, exhibited potent anti-proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH-SY5Y and IMR-32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre-treatment of neuroblastoma cells with ROS scavengers (N-acetyl cysteine and dithiothreitol) reduced the anti-proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin-1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule-depolymerizing agents may be considered for developing pro-ferroptosis chemotherapeutics.},
}
@article {pmid39037665,
year = {2025},
author = {Gao, C and Wang, L and Fu, K and Cheng, S and Wang, S and Feng, Z and Yu, S and Yang, Z},
title = {N-Acetylcysteine Alleviates Necrotizing Enterocolitis by Depressing SESN2 Expression to Inhibit Ferroptosis in Intestinal Epithelial Cells.},
journal = {Inflammation},
volume = {48},
number = {1},
pages = {464-482},
pmid = {39037665},
issn = {1573-2576},
support = {GSWS2021036//Gusu Talent Program/ ; SKY2022181//Science and Technology Project of Suzhou/ ; LGY2020045//Jiangsu Commission of Health/ ; SYH-32034-0103(2024007)//Jiangsu Medical Association Pediatric Medical Research Special Fund Project/ ; },
mesh = {*Enterocolitis, Necrotizing/drug therapy/metabolism/pathology ; *Ferroptosis/drug effects/physiology ; *Acetylcysteine/pharmacology/therapeutic use ; Animals ; Humans ; *Intestinal Mucosa/drug effects/metabolism/pathology ; *Epithelial Cells/drug effects/metabolism/pathology ; Mice ; *Nuclear Proteins/antagonists &amp; inhibitors/biosynthesis/metabolism ; *Peroxidases ; Infant, Newborn ; Sestrins ; },
abstract = {Abstract-Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in neonates, and effective strategies to prevent and treat NEC are still lacking. Studies have shown that N-acetylcysteine (NAC) has protective effects against NEC, however, the specific mechanism underlying its effects on intestinal functions remains unclear. Recently, NAC has been shown to suppress ferroptosis in many diseases, while it is unclear whether the beneficial effects of NAC on NEC are related to ferroptosis. In this study, we revealed that ferroptosis was significantly induced in intestinal samples from infants with NEC. NAC alleviated intestinal inflammation, barrier damage and ferroptosis in multifactorial NEC models in vivo and in vitro. Sestrin2 (SESN2) was identified as an important mediator of NAC-induced ferroptosis resistance in intestinal epithelial cells. Furthermore, SESN2 knockdown inhibited the inflammatory response, alleviated barrier damage and ferroptosis in intestinal epithelial cells and enhanced the protective effects of NAC to a certain extent. Conversely, cells overexpressing SESN2 showed the opposite changes. In summary, our study demonstrated that NAC attenuates NEC progression by decreasing SESN2 expression to inhibit ferroptosis in intestinal epithelial cells, suggesting that NAC might be an effective clinical treatment for NEC.},
}
@article {pmid40236464,
year = {2024},
author = {Wu, J and Maller, B and Kaul, R and Galabow, A and Bryan, A and Neuwelt, A},
title = {High-Dose Acetaminophen as a Treatment for Cancer.},
journal = {Livers},
volume = {4},
number = {1},
pages = {84-91},
pmid = {40236464},
issn = {2673-4389},
support = {IK2 BX004914/BX/BLRD VA/United States ; },
abstract = {The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity-in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent "reverse translational" studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted.},
}
@article {pmid40395300,
year = {2023},
author = {Campos-Blázquez, JP and Flores-Maldonado, C and Gallardo, JM and Bonilla-Delgado, J and Pedraza-Ramírez, AA and López-Méndez, O and Cortés-Malagón, EM and Contreras, RG},
title = {Ouabain promotes claudin-1, -2, and -4 autophagic degradation through oxidative stress and AMPK activation in MDCK cells.},
journal = {Autophagy reports},
volume = {2},
number = {1},
pages = {2256146},
pmid = {40395300},
issn = {2769-4127},
abstract = {Epithelial cells transport substances through the cellular and paracellular pathways. The last one depends on tight junctions, particularly on claudins, the family of integral membrane proteins responsible for the permeability and selectivity of these junctions. 300 nM ouabain (OUA) induces endocytosis and lysosomal degradation of claudin-2 and -4 in an Src and ERK1/2 kinases-dependent manner. Here we investigate whether OUA-induced lysosomal degradation of claudins implicates autophagy in renal epithelial Madin-Darby canine kidney cells. During autophagy, LC3 protein binds phosphatidylethanolamine and incorporates, together with protein p62, into the phagophore. Subsequently, the autolysosome degrades both LC3 and p62 proteins. OUA's occupancy of its site in the Na[+]/K[+]ATPase (300 nM, 10 h) increases autophagic flux because of degradation of LC3 and p62 and an increase in the number of autophagosomes, as detected by fluorescent LC3 and p62 puncta and the rise in autolysosomes seen by the GFP-LC3-RFP probe. Finally, OUA increases the colocalisation of claudin-1, -2, or -4 with p62 in these puncta. OUA induces autophagy increasing reactive oxygen species generation that activates AMP-activated protein kinase, phosphorylating ULK1 at S555. The autophagy inducer rapamycin causes a degradation of the studied claudins comparable to the one generated by OUA. Furthermore, the autophagy inhibitor dorsomorphin blocks OUA-induced autophagy and claudin-1, -2, and -4 degradation. These results demonstrated that OUA induces claudin-1, -2, and -4 autophagy through oxidative stress. Abbreviations: AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: Adenosine triphosphate; DM: dorsomorphin; EGFR: epidermal growth factor receptor; ERK: extracellular signal-regulated kinase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; LC3: microtubule-associated protein 1A/1B-light chain 3; MDCK: Madin-Darby canine kidney; mTOR: mammalian target of rapamycin; NAC: N-acetylcysteine; OUA: ouabain; PCC: Pearson's correlation coefficient; PE: phosphatidylethanolamine, Rapa: rapamycin; ROS: reactive oxygen species; SNK: Student-Newman-Keuls; TER: transepithelial electrical resistance; TJs: tight junctions; ULK1: Unc-51-like kinase 1.},
}
@article {pmid39872876,
year = {2023},
author = {McLaughlin, RM and Top, I and Laguna, A and Hernandez, C and Katz, H and Livi, LL and Kramer, L and Zambuto, SG and Hoffman-Kim, D},
title = {Cortical Spheroid Model for Studying the Effects of Ischemic Brain Injury.},
journal = {In vitro models},
volume = {2},
number = {1-2},
pages = {25-41},
pmid = {39872876},
issn = {2731-3441},
support = {T32 HL134625/HL/NHLBI NIH HHS/United States ; T32 MH020068/MH/NIMH NIH HHS/United States ; U01 ES028184/ES/NIEHS NIH HHS/United States ; },
abstract = {PURPOSE: Ischemic brain injury occurs when there is reduced or complete disruption of blood flow to a brain region, such as in stroke or severe traumatic brain injury. Even short interruptions can lead to devastating effects including excitotoxicity and widespread cell death. Despite many decades of research, there are still very few therapeutic options for patients suffering from brain ischemia.<br><br>METHODS: We developed an in vitro brain ischemia model using our previously established 3D spheroids derived from primary postnatal rat cortex. These spheroids provide an in vivo-relevant model containing a similar cellular composition to the native cortex and a cell-synthesized extracellular matrix. This model is cost-effective, highly reproducible, and can be produced in a high-throughput manner, making it an ideal candidate for screening potential therapeutics. To study the cellular and molecular mechanisms of stroke in this model, spheroids were deprived of glucose, oxygen, or both oxygen and glucose for 24&#xa0;h.<br><br>RESULTS: Both oxygen and oxygen-glucose deprived spheroids demonstrated many of the hallmarks of ischemic brain injury, including a decrease in metabolism, an increase in neural dysfunction, breakdown in the neurovascular unit, and an increase in reactive astrocytes. Pretreatment of spheroids with the antioxidant agent N-acetylcysteine (NAC) mitigated the decrease in ATP after oxygen-glucose deprivation, was partially neuroprotective, and enhanced the expression of laminin.<br><br>CONCLUSION: This 3D cortical spheroid model provides a platform for studying ischemic injury and has the potential for screening therapeutics.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44164-023-00046-z.},
}
@article {pmid39360158,
year = {2024},
author = {Liu, L and Pang, W and Liu, J and Xu, S and Zhang, Z and Hao, R and Wan, J and Xie, W and Tao, X and Yang, P and Zhao, L and Zhai, Z and Wang, C},
title = {Inhibition of heterogeneous nuclear ribonucleoproteins A1 and oxidative stress reduces glycolysis via pyruvate kinase M2 in chronic thromboembolic pulmonary hypertension.},
journal = {Journal of translational internal medicine},
volume = {12},
number = {4},
pages = {437-451},
pmid = {39360158},
issn = {2450-131X},
abstract = {BACKGROUND AND OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a lethal complication of pulmonary embolism involving pulmonary artery occlusion and microvascular disease. The glucose metabolism and reactive oxygen species (ROS) production may be perturbed in CTEPH, but the precise mechanisms are unclear. This study investigated glucose metabolism in CTEPH employing pulmonary endarterectomy (PEA)-derived pulmonary artery smooth muscle cells (PASMCs) and characterized the roles of pyruvate kinase M2 (PKM2) and its regulation by heterogeneous nuclear ribonucleoproteins A1 (hnRNPA1) and ROS in CTEPH.<br><br>METHODS: PEA tissues and blood samples of CTEPH patients were collected to study the levels of PKM2. Primary PASMCs were isolated from PEA tissues. We used small interfering RNAs to knock down PKM2 and hnRNPAI, and applied antioxidant N-acetylcysteine (NAC) and mito-TEMPO to reduce ROS production. The expression of glucometabolic genes, ROS production, glycolysis rate and proliferative and migratory activities were analyzed in PEA-derived PASMCs.<br><br>RESULTS: PKM2 levels in serum and PEA tissues of CTEPH patients were higher than that of the healthy controls. Compared to the control PASMCs, PEA-derived PASMCs showed increased PKM2 expression and ROS production. The rates of glycolysis, proliferation and migration were increased in PEA-PASMCs and could be mitigated by PKM2 downregulation through hnRNPA1 or ROS inhibition.<br><br>CONCLUSIONS: Increased glycolysis and PKM2 expression were found in PEA-PASMCs. Inhibition of hnRNPA1 or ROS corrected the aberrant glycolysis, cell proliferation and migration by downregulating PKM2. Regulation of the hnRNPA1/PKM2 axis represents a potential therapeutic target for the treatment of CTEPH.},
}
@article {pmid39554835,
year = {2023},
author = {Ferguson, M and Mebane, CM and Reddy, A},
title = {Prophylactic Effect of N-Acetylcysteine in an Adolescent With Trichotillomania After Acetaminophen Overdose.},
journal = {JAACAP open},
volume = {1},
number = {1},
pages = {74-75},
pmid = {39554835},
issn = {2949-7329},
abstract = {N-Acetylcysteine (NAC) is an essential drug for the treatment of acetaminophen overdose, with nearly 100% efficacy if delivered within 8 hours of ingestion. In addition to preventing hepatotoxicity following an overdose, there is some evidence that NAC may be effective in the treatment of trichotillomania, onychophagia, onychotillomania, and excoriation disorder. Here we report a 16-year-old female patient with an acetaminophen overdose who presented to the emergency department with normal liver function testing, despite ingesting approximately 100 tablets of acetaminophen 500 mg. The patient also had a history of trichotillomania and had been taking 600 mg twice daily of over-the-counter NAC for the week before the overdose. Therefore, the over-the-counter NAC treatment regimen may have serendipitously served as a prophylactic measure against hepatoxicity in her acetaminophen overdose.},
}
@article {pmid39193224,
year = {2023},
author = {Rodrigues, K and Hussain, R and Cooke, S and Zhang, G and Zhang, D and Yin, L and Tong, X},
title = {Fructose as a novel nutraceutical for acetaminophen (APAP)-induced hepatotoxicity.},
journal = {Metabolism and target organ damage},
volume = {3},
number = {4},
pages = {},
pmid = {39193224},
issn = {2769-6375},
support = {R25 HL108842/HL/NHLBI NIH HHS/United States ; R01 DK121170/DK/NIDDK NIH HHS/United States ; P30 DK089503/DK/NIDDK NIH HHS/United States ; P60 DK020572/DK/NIDDK NIH HHS/United States ; R01 DK099593/DK/NIDDK NIH HHS/United States ; },
abstract = {Acetaminophen (APAP) is the most widely used analgesic in the world. APAP overdose can cause severe hepatotoxicity and therefore is the most common cause of drug-induced liver injury. The only approved treatment for APAP overdose is N-acetyl-cysteine (NAC) supplementation. However, the narrow efficacy window of the drug severely limits its clinical use, prompting the search for other therapeutic options to counteract APAP toxicity. Recent research has pointed to fructose as a novel nutraceutical for APAP-induced liver injury. This review summarizes the current understanding of the molecular mechanisms underlying APAP-induced liver injury, introduces how fructose supplementation could prevent and treat APAP liver toxicity with a focus on the ChREBPα-FGF21 pathway, and proposes possible future directions of study.},
}
@article {pmid39034050,
year = {2024},
author = {Liyanage, W and Kale, N and Kannan, S and Kannan, RM},
title = {Journey from lab to clinic: Design, preclinical, and clinical development of systemic, targeted dendrimer-N-acetylcysteine (D-NAC) nanomedicines.},
journal = {Advances in pharmacology (San Diego, Calif.)},
volume = {100},
number = {},
pages = {119-155},
doi = {10.1016/bs.apha.2024.05.003},
pmid = {39034050},
issn = {1557-8925},
support = {R01 EY025304/EY/NEI NIH HHS/United States ; R01 NS093416/NS/NINDS NIH HHS/United States ; P30 EY001765/EY/NEI NIH HHS/United States ; },
mesh = {*Dendrimers/chemistry ; *Acetylcysteine/pharmacology/therapeutic use/chemistry ; Humans ; Animals ; *Nanomedicine/methods ; COVID-19 Drug Treatment ; Drug Delivery Systems/methods ; Drug Development/methods ; },
abstract = {Drug discovery is challenging task with numerous obstacles in translating drug candidates into clinical products. Dendrimers are highly adaptable nanostructured polymers with significant potential to improve the chances of clinical success for drugs. Yet, dendrimer-based drug products are still in their infancy. However, Hydroxyl polyamidoamine (PAMAM) dendrimers showed significant promise in drug discovery efforts, owning their remarkable potential to selectively target and deliver drugs specifically to activated microglia and astrocytes at the site of brain injury in several preclinical models. After a decade's worth of academic research and pre-clinical efforts, the hydroxyl PAMAM dendrimer-N-acetyl cysteine conjugate (OP-101) nanomedicine has made a significant advancement in the field of nanomedicine and targeted delivery. The OP-101 conjugate, primarily developed and validated in academic labs, has now entered clinical trials as a potential treatment for hyperinflammation in hospitalized adults with severe COVID-19 through Ashvattha Therapeutics. This chapter, we delve into the journey of the hydroxyl PAMAM dendrimer-N-acetylcysteine (NAC) OP-101 formulation from the laboratory to the clinic. It will specifically focus on the design, synthesis, preclinical, and clinical development of OP-101, highlighting the potential it holds for the future of medicine and the positive Phase 2a results for treating severe COVID-19.},
}
@article {pmid39031462,
year = {2024},
author = {Hsu, CS and Chang, SH and Yang, RC and Lee, CH and Lee, MS and Kao, JK and Shieh, JJ},
title = {Lipopolysaccharide-Induced Lysosomal Cell Death Through Reactive Oxygen Species in Rat Liver Cell Clone 9.},
journal = {Environmental toxicology},
volume = {39},
number = {11},
pages = {5008-5018},
doi = {10.1002/tox.24377},
pmid = {39031462},
issn = {1522-7278},
support = {NCHU-CCH-11007//National Chung Hsing University/Changhua Christian Hospital Joint Research Program/ ; TCVGH-1107304D//Taichung Veterans General Hospital Research Program/ ; MOST-109-2320-B-371-003//Ministry of Science and Technology, Taiwan/ ; },
mesh = {Animals ; *Lipopolysaccharides/pharmacology/toxicity ; *Reactive Oxygen Species/metabolism ; Rats ; *Lysosomes/drug effects/metabolism ; *Hepatocytes/drug effects/metabolism ; Cell Line ; Cathepsin D/metabolism ; Caspase 3/metabolism ; Caspase 8/metabolism ; Cell Survival/drug effects ; Apoptosis/drug effects ; Lysosomal-Associated Membrane Protein 2/metabolism ; Cell Death/drug effects ; },
abstract = {In sepsis, bacterial components, particularly lipopolysaccharide (LPS), trigger organ injuries such as liver dysfunction. Although sepsis induces hepatocyte damage, the mechanisms underlying sepsis-related hepatic failure remain unclear. In this study, we demonstrated that the LPS-treated rat hepatocyte cell line Clone 9 not only induced reactive oxygen species (ROS) generation and apoptosis but also increased the expression of the autophagy marker proteins LC3-II and p62, and decreased the expression of intact Lamp2A, a lysosomal membrane protein. Additionally, LPS increased lysosomal membrane permeability and galectin-3 puncta formation, and promoted lysosomal alkalization in Clone 9 cells. Pharmacological inhibition of caspase-8 and cathepsin D (CTSD) suppressed the activation of caspase-3 and rescued the viability of LPS-treated Clone 9 cells. Furthermore, LPS induced CTSD release associated with lysosomal leakage and contributed to caspase-8 activation. Pretreatment with the antioxidant N-acetylcysteine (NAC) not only diminished ROS generation and increased the cell survival rate, but also decreased the expression of activated caspase-8 and caspase-3 and increased the protein level of Lamp2A in LPS-treated Clone 9 cells. These results demonstrate that LPS-induced ROS causes lysosomal membrane permeabilization and lysosomal cell death, which may play a crucial role in hepatic failure in sepsis. Our results may facilitate the development of new strategies for sepsis management.},
}
@article {pmid39028629,
year = {2024},
author = {Ye, JJ and Chen, ZY and Wang, QH and Liao, XY and Wang, XY and Zhang, CC and Liu, LR and Wei, Q and Bao, YG},
title = {Current treatment for male infertility: an umbrella review of systematic reviews and meta-analyses.},
journal = {Asian journal of andrology},
volume = {26},
number = {6},
pages = {645-652},
pmid = {39028629},
issn = {1745-7262},
mesh = {Humans ; Male ; Antioxidants/therapeutic use ; *Infertility, Male/diagnosis/therapy ; Meta-Analysis as Topic ; Sperm Count ; Sperm Motility ; Systematic Reviews as Topic ; },
abstract = {This umbrella review aimed to summarize and provide a general evaluation of the effectiveness of current treatments for male infertility and assess the quality of evidence and possible biases. An umbrella review of systematic reviews and meta-analyses available in PubMed, Web of Science, and Scopus, covering studies published up to October 2023, was conducted. Sperm concentration, morphology, and motility were used as endpoints to evaluate the effectiveness of the treatments. Of 2998 studies, 18 published meta-analyses were extracted, yielding 90 summary effects on sperm concentration (n = 36), sperm morphology (n = 26), and sperm motility (n = 28) on 28 interventions. None of the meta-analyses were classified as having low methodological quality, whereas 12 (66.7%) and 6 (33.3%) had high and moderate quality, respectively. Of the 90 summary effects, none were rated high-evidence quality, whereas 53.3% (n = 48), 25.6% (n = 23), and 21.1% (n = 19) were rated moderate, low, and very low, respectively. Significant improvements in sperm concentration, morphology, and motility were observed with pharmacological interventions (N-acetyl-cysteine, antioxidant therapy, aromatase inhibitors, selective estrogen receptor modulators, hormones, supplements, and alpha-lipoic acid) and nonpharmacological interventions (varicocele repair and redo varicocelectomy). In addition, vitamin supplementation had no significant positive effects on sperm concentration, motility, or morphology. Treatments for male infertility are increasingly diverse; however, the current evidence is poor because of the limited number of patients. Further well-designed studies on single treatment and high-quality meta-analysis of intertreatment comparisons are recommended.},
}
@article {pmid39028412,
year = {2025},
author = {Zolnourian, A and Garland, P and Holton, P and Arora, M and Rhodes, J and Uff, C and Birch, T and Howat, D and Franklin, S and Galea, I and Bulters, D},
title = {A Randomised Controlled Trial of SFX-01 After Subarachnoid Haemorrhage - The SAS Study.},
journal = {Translational stroke research},
volume = {16},
number = {4},
pages = {1031-1043},
pmid = {39028412},
issn = {1868-601X},
mesh = {Humans ; Middle Aged ; Male ; *Subarachnoid Hemorrhage/drug therapy/diagnostic imaging ; Female ; Adult ; Double-Blind Method ; Aged ; Aged, 80 and over ; *Sulfoxides/therapeutic use ; Young Adult ; *Isothiocyanates/therapeutic use/pharmacokinetics ; Treatment Outcome ; Adolescent ; Vasospasm, Intracranial/drug therapy/diagnostic imaging ; },
abstract = {SFX-01 is a novel drug for clinical delivery of sulforaphane (SFN). SFN is a potent nuclear factor erythroid 2-related factor 2 activator that reduces inflammation and oxidation, improving outcomes after subarachnoid haemorrhage (SAH) in animal models. This was a multi-centre, double-blind, placebo-controlled, parallel-group randomised clinical trial to evaluate the safety, pharmacokinetics and efficacy of 28 days of SFX-01 300 mg BD in patients aged 18-80 with spontaneous SAH and high blood load on CT. Primary outcomes were (1) safety, (2) plasma and CSF SFN and metabolite levels and (3) vasospasm on transcranial doppler ultrasound. Secondary outcomes included CSF haptoglobin and malondialdehyde and clinical outcome on the modified Rankin Scale (mRS) and SAH outcome tool (SAHOT). A total of 105 patients were randomised (54 SFX-01, 51 placebo). There were no differences in adverse events other than nausea (9 SFX-01 (16.7%), 1 placebo (2.0%)). SFN, SFN-glutathione and SFN-N-acetyl-cysteine AUClast were 16.2, 277 and 415 h × ng/ml. Plasma SFN was higher in GSTT1 null individuals (t = 2.40, p = 0.023). CSF levels were low with many samples below the lower limit of quantification and predicted by the CSF/serum albumin ratio (R[2] = 0.182, p = 0.039). There was no difference in CSF haptoglobin (1.981 95%CI 0.992-3.786, p = 0.052) or malondialdehyde (1.12 95%CI 0.7477-1.687, p = 0.572) or middle cerebral artery flow velocity (1.04 95%CI 0.903-1.211, p = 0.545) or functional outcome (mRS 1.647 95%CI 0.721-3.821, p = 0.237, SAHOT 1.082 95%CI 0.464-2.525, p = 0.855). SFX-01 is safe and effective for the delivery of SFN in acutely unwell patients. SFN penetrated CSF less than expected and did not reduce large vessel vasospasm or improve outcome. Trial registration: NCT02614742 clinicaltrials.gov.},
}
@article {pmid39028033,
year = {2024},
author = {Arenhoevel, J and Kuppe, A and Addante, A and Wei, LF and Boback, N and Butnarasu, C and Zhong, Y and Wong, C and Graeber, SY and Duerr, J and Gradzielski, M and Lauster, D and Mall, MA and Haag, R},
title = {Thiolated polyglycerol sulfate as potential mucolytic for muco-obstructive lung diseases.},
journal = {Biomaterials science},
volume = {12},
number = {17},
pages = {4376-4385},
doi = {10.1039/d4bm00381k},
pmid = {39028033},
issn = {2047-4849},
mesh = {Humans ; *Glycerol/chemistry ; *Polymers/chemistry/pharmacology ; *Sputum/metabolism/chemistry ; *Sulfhydryl Compounds/chemistry/pharmacology ; Cystic Fibrosis/metabolism/drug therapy ; Mucin 5AC/metabolism ; Lung Diseases, Obstructive/drug therapy/metabolism ; Mucin-5B/metabolism ; Sulfates/chemistry/pharmacology ; Expectorants/pharmacology/chemistry ; Mucus/metabolism/chemistry ; Rheology ; Acetylcysteine/pharmacology/chemistry ; Viscosity ; },
abstract = {Increased disulfide crosslinking of secreted mucins causes elevated viscoelasticity of mucus and is a key determinant of mucus dysfunction in patients with cystic fibrosis (CF) and other muco-obstructive lung diseases. In this study, we describe the synthesis of a novel thiol-containing, sulfated dendritic polyglycerol (dPGS-SH), designed to chemically reduce these abnormal crosslinks, which we demonstrate with mucolytic activity assays in sputum from patients with CF. This mucolytic polymer, which is based on a reportedly anti-inflammatory polysulfate scaffold, additionally carries multiple thiol groups for mucolytic activity and can be produced on a gram-scale. After a physicochemical compound characterization, we compare the mucolytic activity of dPGS-SH to the clinically approved N-acetylcysteine (NAC) using western blot studies and investigate the effect of dPGS-SH on the viscoelastic properties of sputum samples from CF patients by oscillatory rheology. We show that dPGS-SH is more effective than NAC in reducing multimer intensity of the secreted mucins MUC5B and MUC5AC and demonstrate significant mucolytic activity by rheology. In addition, we provide data for dPGS-SH demonstrating a high compound stability, low cytotoxicity, and superior reaction kinetics over NAC at different pH levels. Our data support further development of the novel reducing polymer system dPGS-SH as a potential mucolytic to improve mucus function and clearance in patients with CF as well as other muco-obstructive lung diseases.},
}
@article {pmid39019252,
year = {2024},
author = {Rivera-Ingraham, GA and Martínez-Alarcón, D and Theuerkauff, D and Nommick, A and Lignot, JH},
title = {Two faces of one coin: Beneficial and deleterious effects of reactive oxygen species during short-term acclimation to hypo-osmotic stress in a decapod crab.},
journal = {Comparative biochemistry and physiology. Part A, Molecular &amp; integrative physiology},
volume = {296},
number = {},
pages = {111700},
doi = {10.1016/j.cbpa.2024.111700},
pmid = {39019252},
issn = {1531-4332},
mesh = {Animals ; *Reactive Oxygen Species/metabolism ; *Brachyura/physiology/metabolism/drug effects ; *Salinity ; *Acclimatization ; Osmotic Pressure ; Acetylcysteine/pharmacology ; Seawater ; Antioxidants/metabolism ; Oxidative Stress/drug effects ; Gills/metabolism/drug effects ; Osmoregulation ; },
abstract = {Exposure to environmental changes often results in the production of reactive oxygen species (ROS), which, if uncontrolled, leads to loss of cellular homeostasis and oxidative distress. However, at physiological levels these same ROS are known to be key players in cellular signaling and the regulation of key biological activities (oxidative eustress). While ROS are known to mediate salinity tolerance in plants, little is known for the animal kingdom. In this study, we use the Mediterranean crab Carcinus aestuarii, highly tolerant to salinity changes in its environment, as a model to test the healthy or pathological role of ROS due to exposure to diluted seawater (dSW). Crabs were injected either with an antioxidant [N-acetylcysteine (NAC), 150 mg·kg[-1]] or phosphate buffered saline (PBS). One hour after the first injection, animals were either maintained in seawater (SW) or transferred to dSW and injections were carried out at 12-h intervals. After ≈48 h of salinity change, all animals were sacrificed and gills dissected for analysis. NAC injections successfully inhibited ROS formation occurring due to dSW transfer. However, this induced 55% crab mortality, as well as an inhibition of the enhanced catalase defenses and mitochondrial biogenesis that occur with decreased salinity. Crab osmoregulatory capacity under dSW condition was not affected by NAC, although it induced in anterior (non-osmoregulatory) gills a 146-fold increase in Na[+]/K[+]/2Cl[-] expression levels, reaching values typically observed in osmoregulatory tissues. We discuss how ROS influences the physiology of anterior and posterior gills, which have two different physiological functions and strategies during hyper-osmoregulation in dSW.},
}
@article {pmid39006976,
year = {2024},
author = {Sadeghinejad, S and Mousavi, M and Zeidooni, L and Mansouri, E and Mohtadi, S and Khodayar, MJ},
title = {Ameliorative effects of umbelliferone against acetaminophen-induced hepatic oxidative stress and inflammation in mice.},
journal = {Research in pharmaceutical sciences},
volume = {19},
number = {1},
pages = {83-92},
pmid = {39006976},
issn = {1735-5362},
abstract = {BACKGROUND AND PURPOSE: Acetaminophen (APAP) is a commonly used antipyretic and pain reliever that its overdose causes acute liver toxicity. Umbelliferone (UMB) has many pharmacological effects. In this study, the hepatoprotective effect of UMB on acute hepatotoxicity induced by APAP was investigated.<br><br>EXPERIMENTAL APPROACH: Forty-nine male mice were separated into seven groups. The control received vehicle (i.p.), UMB group received UMB (120 mg/kg, i.p.), APAP group was treated with a single dose of APAP (350 mg/kg, i.p.), and pretreated groups received N-acetylcysteine (NAC, 200 mg/kg, i.p.) or different doses of UMB (30, 60, and 120 mg/kg, i.p.), respectively before APAP. Twenty-four hours after APAP injection, mice were sacrificed and blood and liver samples were collected. Then, serum and tissue samples were investigated for biochemical and histological studies.<br><br>FINDINGS/RESULTS: A single dose of APAP caused elevation in the serum liver enzymes, including alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. The amounts of thiobarbituric acid reactive substances, tumor necrosis factor-alpha, and nitric oxide increased in the mice's liver tissue. Moreover, the amount of total thiol and the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) significantly diminished in the APAP group. Histological results confirmed the hepatotoxicity induced by APAP. However, UMB (more effective at 60 and 120 mg/kg) lessened APAP-induced hepatic injuries, which is comparable with NAC effects.<br><br>CONCLUSION AND IMPLICATIONS: The findings of this study provided evidence that UMB ameliorates liver injury induced by APAP through its antioxidant and anti-inflammatory effects.},
}
@article {pmid39005460,
year = {2024},
author = {Wellslager, B and Roberts, J and Chowdhury, N and Madan, L and Orellana, E and Yilmaz, &#xd6;},
title = {Porphyromonas gingivalis activates Heat-Shock-Protein 27 to drive a LC3C-specific probacterial form of select autophagy that is redox sensitive for intracellular bacterial survival in human gingival mucosa.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.01.601539},
pmid = {39005460},
issn = {2692-8205},
abstract = {Porphyromonas gingivalis , a major oral pathobiont, evades canonical host pathogen clearance in human primary gingival epithelial cells (GECs) by initiating a non-canonical variant of autophagy consisting of Microtubule-associated protein 1A/1B-light chain 3 (LC3)-rich autophagosomes, which then act as replicative niches. Simultaneously, P. gingivalis inhibits apoptosis and oxidative-stress, including extracellular-ATP (eATP)-mediated reactive-oxygen-species (ROS) production via phosphorylating Heat Shock Protein 27 (HSp27) with the bacterial nucleoside-diphosphate-kinase (Ndk). Here, we have mechanistically identified that P. gingivalis -mediated induction of HSp27 is crucial for the recruitment of the LC3 isoform, LC3C, to drive the formation of live P. gingivalis -containing Beclin1-ATG14-rich autophagosomes that are redox sensitive and non-degrading. HSp27 depletions of both infected GECs and gingiva-mimicking organotypic-culture systems resulted in the collapse of P. gingivalis -mediated autophagosomes, and abolished P. gingivalis -induced LC3C-specific autophagic-flux in a HSp27-dependent manner. Concurrently, HSp27 depletion accompanied by eATP treatment abrogated protracted Beclin 1-ATG14 partnering and decreased live intracellular P. gingivalis levels. These events were only partially restored via treatments with the antioxidant N-acetyl cysteine (NAC), which rescued the cellular redox environment independent of HSp27. Moreover, the temporal phosphorylation of HSp27 by the bacterial Ndk results in HSp27 tightly partnering with LC3C, hindering LC3C canonical cleavage, extending Beclin 1-ATG14 association, and halting canonical maturation. These findings pinpoint how HSp27 pleiotropically serves as a major platform-molecule, redox regulator, and stepwise modulator of LC3C during P. gingivalis -mediated non-canonical autophagy. Thus, our findings can determine specific molecular strategies for interfering with the host-adapted P. gingivalis ' successful mucosal colonization and oral dysbiosis.},
}
@article {pmid39004668,
year = {2024},
author = {Erichsen, PA and Dalhoff, K and Andersen, MA},
title = {Should high-dose N-acetylcysteine be given in cases of massive paracetamol overdoses: A narrative review.},
journal = {Basic &amp; clinical pharmacology &amp; toxicology},
volume = {135},
number = {3},
pages = {285-294},
pmid = {39004668},
issn = {1742-7843},
mesh = {*Acetylcysteine/administration &amp; dosage/therapeutic use ; Humans ; *Acetaminophen/poisoning/administration &amp; dosage ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury/etiology/prevention &amp; control ; Analgesics, Non-Narcotic/poisoning/administration &amp; dosage ; Antidotes/administration &amp; dosage/therapeutic use ; Dose-Response Relationship, Drug ; Observational Studies as Topic ; },
abstract = {N-acetylcysteine (NAC) is regarded as an effective treatment of paracetamol overdoses. However, in cases of "massive" paracetamol overdoses, recent studies indicate that patients may not be sufficiently treated with the standard dose of NAC (300 mg/kg over 20-21 h). The subject is further complicated because "massive overdoses" and "high-risk" are defined differently; some studies use the ingested amount (e.g., >40 g), and some studies use blood concentrations of paracetamol and transaminases. This narrative review investigates whether high-dose NAC significantly decreases the risk of hepatotoxicity in patients with massive paracetamol overdoses. Three observational studies were analysed; one study with 373 patients found no significant difference (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.49-3.29). One study with 79 patients found a significant difference (OR: 0.27, 95% CI: 0.08-0.94). The third study with 89 patients found a significant difference in hepatoxicity between the groups (p = 0.043). There are no solid evidence to support that treatment with high-dose NAC significantly reduces the rate of hepatotoxicity in patients presenting with massive paracetamol overdoses. Differences in inclusion criteria in the included studies make the studies incomparable. This paper shows that standardized inclusion is needed to determine whether a high-dose NAC regimen should be included in clinical practice.},
}
@article {pmid39004152,
year = {2024},
author = {Chen, Q and Hu, R and Qiu, H and Li, S and Xiang, P and Lu, Y and Wang, X and Wang, T and Zhou, L and Zhang, W and Wen, E and Ma, L and Yu, C},
title = {REDD1 knockdown ameliorates endothelial cell senescence through repressing TXNIP-mediated oxidative stress.},
journal = {Mechanisms of ageing and development},
volume = {221},
number = {},
pages = {111962},
doi = {10.1016/j.mad.2024.111962},
pmid = {39004152},
issn = {1872-6216},
mesh = {*Cellular Senescence/drug effects ; Animals ; *Oxidative Stress/drug effects ; Mice ; Humans ; *Transcription Factors/metabolism/genetics ; *Atherosclerosis/metabolism/pathology/genetics ; *Carrier Proteins/metabolism/genetics ; *Endothelial Cells/metabolism ; *Reactive Oxygen Species/metabolism ; Thioredoxins/metabolism/genetics ; Human Umbilical Vein Endothelial Cells/metabolism ; Gene Knockdown Techniques ; },
abstract = {Endothelial cell senescence characterized by reactive oxygen species (ROS) accumulation and chronic inflammation is widely recognized as a key contributor to atherosclerosis (AS). Regulated in development and DNA damage response 1 (REDD1), a conserved stress-response protein that regulates ROS production, is involved in the pathogenesis of various age-related diseases. However, the role of REDD1 in endothelial cell senescence is still unclear. Here, we screened REDD1 as a differentially expressed senescence-related gene in the AS progression using bioinformatics methods, and validated the upregulation of REDD1 expression in AS plaques, senescent endothelial cells, and aging aorta by constructing AS mice, D-galactose (DG)-induced senescent endothelial cells and DG-induced accelerated aging mice, respectively. siRNA against REDD1 could improve DG-induced premature senescence of endothelial cells and inhibit ROS accumulation, similar to antioxidant N-Acetylcysteine (NAC) treatment. Meanwhile, NAC reduced the upregulation of REDD1 induced by DG, supporting the positive feedback loop between REDD1 and ROS contributes to endothelial cell senescence. Mechanistically, the regulatory effect of REDD1 on ROS might be related to the TXNIP-REDD1 interaction in DG-induced endothelial cell senescence. Collectively, experiments above provide evidence that REDD1 participates in endothelial cell senescence through repressing TXNIP-mediated oxidative stress, which may be involved in the progression of atherosclerosis.},
}
@article {pmid39003685,
year = {2024},
author = {Dharshini, KS and Ameen, F and Anbazhagan, V},
title = {Mechanistic Investigation on the Antibacterial Activity of Biogenic Silver Nanoparticles Prepared Using Root Extract of Sarsaparilla and Demonstrated their In Vivo Efficacy in Zebrafish Model.},
journal = {Current microbiology},
volume = {81},
number = {9},
pages = {268},
pmid = {39003685},
issn = {1432-0991},
mesh = {Animals ; *Zebrafish ; *Silver/pharmacology/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Metal Nanoparticles/chemistry ; *Plant Extracts/pharmacology/chemistry ; *Microbial Sensitivity Tests ; *Plant Roots/chemistry/microbiology ; Reactive Oxygen Species/metabolism ; Bacteria/drug effects ; },
abstract = {Antibiotic success rates are decreasing as drug-resistant bacteria become more prevalent, prompting the development of new therapeutic drugs. Herein, we demonstrated the antimicrobial activity of sarsaparilla root extract fabricated silver nanoparticles (sAgNPs). The UV-Visible spectra revealed that the surface Plasmon resonance maxima of sAgNPs were at 415 nm. Transmission electron microscopy confirms that the particles are spherical with size of 12-35 nm. The minimum inhibitory concentration (MIC) of sAgNPs against Escherichia coli, uropathogenic Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus was 62.5, 62.5, 62.5, 62.5, 125 and 125 µM, respectively. At 1X MIC, sAgNPs induces excess reactive oxygen species (ROS) production and disturbs the bacteria membrane intergity, causing cytoplamic membrane depolarization. Interestingly, antibacterial activity of sAgNPs was considerably reduced in the presence of an antioxidant, N-acetyl cysteine, suggesting that ROS-induced membrane damage is a plausible cause of cell death. In contrast to many studies that only report the in vitro activity of NPs, we determined the in vivo antibacterial efficacy using the zebrafish model. It was found that sAgNPs protect fish from infection by inhibiting bacterial growth and eliminating them from the fish. In addition, the catalytic potential of sAgNPs for wastewater decontamination was demonstrated by degrading organic pollutants such as methyl orange, congo red, reactive black, and acid blue. The pollutants degraded in less than 10 min, and the reaction follows pseudo-first-order kinetics. As a proof of concept, the catalytic potential of sAgNPs in degrading mixed dyes to satisfy industrial wastewater treatment needs was established. In summary, sAgNPs have the potential to act as nanocatalysts and nano-drugs, addressing key challenges in medical and environmental research.},
}
@article {pmid38997833,
year = {2024},
author = {Shiozawa, A and Kajiwara, C and Ishii, Y and Tateda, K},
title = {Corrigendum to "N-acetyl-cysteine mediates protection against Mycobacterium avium through induction of human β-defensin-2" [Microb Infect 22 (10) (2020) 567-575].},
journal = {Microbes and infection},
volume = {26},
number = {8},
pages = {105388},
doi = {10.1016/j.micinf.2024.105388},
pmid = {38997833},
issn = {1769-714X},
}
@article {pmid38992233,
year = {2024},
author = {Glass, KA and Stoecker, ZR and LeRoy, J and Palmer, CL and Stipek, J and Boley, S},
title = {Investigating a Novel Two-Bag N-Acetylcysteine Regimen for Acetaminophen Toxicity.},
journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology},
volume = {20},
number = {4},
pages = {381-388},
pmid = {38992233},
issn = {1937-6995},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Acetaminophen ; Retrospective Studies ; Female ; Male ; Adult ; *Chemical and Drug Induced Liver Injury/etiology/prevention &amp; control ; Middle Aged ; *Medication Errors/prevention &amp; control ; Analgesics, Non-Narcotic ; Antidotes/administration &amp; dosage/adverse effects/therapeutic use ; Treatment Outcome ; Drug Administration Schedule ; Drug Packaging ; },
abstract = {BACKGROUND: Acetaminophen toxicity remains one of the most common causes of liver failure and is treated with a course of n-acetylcysteine (NAC). This exceptionally effective medication is traditionally administered using a complicated three-bag protocol that is prone to administration errors.<br><br>OBJECTIVE: We aimed to assess whether switching to a novel two-bag protocol (150&#xa0;mg/kg over 1&#xa0;h followed by 150&#xa0;mg/kg over 20&#xa0;h) reduced administration errors while not increasing liver injury or anaphylactoid reactions.<br><br>METHODS: This was a retrospective chart review of hospital encounters for patients with acetaminophen toxicity, comparing outcomes before and after the change from a three-bag protocol to a two-bag protocol at two affiliated institutions. The primary outcome was incidence of medication errors with secondary outcomes including acute liver injury (ALI) and incidence of non-anaphylactoid allergic reactions (NAAR). The study was approved by the health system's Institutional Review Board.<br><br>RESULTS: 483 encounters were included for analysis (239 in the three-bag and 244 in the two-bag groups). NAAR were identified in 11 patients with no difference seen between groups. Similarly, no differences were seen in ALI. Medication administration errors were observed significantly less often in the two-bag group (OR 0.24) after adjusting for confounders.<br><br>CONCLUSION: Transitioning to a novel two-bag NAC regimen decreased administration errors. This adds to the literature that two-bag NAC regimens are not only safe but also may have significant benefits over the traditional NAC protocol.},
}
@article {pmid38990380,
year = {2024},
author = {Lu, SH and Yun, TF and Kou, YR and Chang, YP},
title = {Preliminary evidence for therapeutic impact of intravesical glucosamine on protamine sulfate and potassium chloride-induced bladder overactivity in rat model.},
journal = {World journal of urology},
volume = {42},
number = {1},
pages = {405},
pmid = {38990380},
issn = {1433-8726},
support = {V105C-148//Taipei Veterans General Hospital/ ; },
mesh = {Animals ; *Urinary Bladder, Overactive/drug therapy ; Female ; *Rats, Sprague-Dawley ; Rats ; Administration, Intravesical ; *Protamines ; *Disease Models, Animal ; *Potassium Chloride ; *Glucosamine/pharmacology/therapeutic use/administration &amp; dosage ; },
abstract = {PURPOSE: To investigate the protective effect of intravesical glucosamine in treating overactive bladder (OAB).<br><br>METHODS: Ninety-two female Sprague-Dawley (SD) rats were divided into 4 groups i.e. protamine sulfate (PS), N-acetylcysteine (NAC), and glucosamine-treated PS (GPS), and normal saline control (NC) were used. We induced hyperactivity in rats via intravesical infusion of PS and potassium chloride (KCl), whereas the NC group underwent a sustained intravesical saline infusion for 1&#xa0;h. N-acetylcysteine (NAC), a potential antioxidant as well as anti-inflammatory agent was employed as positive control. Cystometrography (CMG) was then conducted to determine urodynamic parameters, i.e., leak point pressure (LPP, n&#x2009;=&#x2009;48) and inter-contractile interval, the duration between two voids (ICI, n&#x2009;=&#x2009;32).<br><br>RESULTS: LPP was significantly elevated in the GPS group (mean&#x2009;&#xb1;&#x2009;SD: 110.9&#x2009;&#xb1;&#x2009;6.2 mmHg) compared to the NC (81.0&#x2009;&#xb1;&#x2009;32.5 mmHg), PS (40.3&#x2009;&#xb1;&#x2009;10.9 mmHg), and NAC group (70.3&#x2009;&#xb1;&#x2009;19.4 mmHg). The cystometrogram data also reveals a prolonged ICI in the GPS group (241.3&#x2009;&#xb1;&#x2009;40.2&#xa0;s) compared to the NC group (216.0&#x2009;&#xb1;&#x2009;41.7&#xa0;s), PS group (128.8&#x2009;&#xb1;&#x2009;23.6&#xa0;s), and NAC group (193.8&#x2009;&#xb1;&#x2009;28.3&#xa0;s).<br><br>CONCLUSION: This preliminary study implies the ameliorative impact of GPS treatment on OAB in terms of improved urodynamic parameters, including LPP and ICI.},
}
@article {pmid38986690,
year = {2024},
author = {Li, Z and Li, H and Wang, D and Peng, X and Syed, BM and Liu, Q},
title = {S-glutathionylation in hepatocytes is involved in arsenic-induced liver fibrosis through activation of the NLRP3 inflammasome, an effect alleviated by NAC.},
journal = {The Science of the total environment},
volume = {947},
number = {},
pages = {174534},
doi = {10.1016/j.scitotenv.2024.174534},
pmid = {38986690},
issn = {1879-1026},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Liver Cirrhosis/chemically induced ; Mice ; *Hepatocytes/drug effects ; Animals ; *Inflammasomes/metabolism ; *Glutathione/metabolism ; *Arsenic/toxicity ; Acetylcysteine/pharmacology ; Reactive Oxygen Species/metabolism ; },
abstract = {Arsenic, a toxicant widely distributed in the environment, is considered as a risk factor for liver fibrosis. At present, the underlying mechanism still needs to be explored. In the present study, we found that, for mice, chronic exposure to arsenic induced liver fibrosis, activated the NLRP3 inflammasome, and increased the levels of reactive oxygen species (ROS). After hepatocytes were co-cultured with hepatic stellate cells (HSCs), we observed the arsenic-activated NLRP3 inflammasome in hepatocytes, and the co-cultured HSCs were activated. Further, we found that, in livers of mice, arsenic disturbed GSH metabolism and promoted protein S-glutathionylation. A 3D molecular docking simulation suggested that NLRP3 binds with GSH, which was confirmed by immunoprecipitation experiments. N-acetylcysteine (NAC) increased the levels of GSH in hepatocytes, which suppressed the S-glutathionylation of NLRP3 and blocked arsenic-induced activation of the NLRP3 inflammasome. Mechanistically, an imbalance of the redox state induced by arsenic promotes the S-glutathionylation of NLRP3, which regulates activation of the NLRP3 inflammasome, leading into the activation of HSCs. Moreover, NAC increases the levels of GSH to block arsenic-induced S-glutathionylation of NLRP3, thereby blocking arsenic-induced liver fibrosis. Thus, via activating HSCs, the S-glutathionylation of NLRP3 in hepatocytes is involved in arsenic-induced liver fibrosis, and, for hepatocytes, NAC alleviates these effects by increasing the levels of GSH. These results reveal a new mechanism and provide a possible therapeutic target for the liver fibrosis induced by environmental factors.},
}
@article {pmid38985827,
year = {2024},
author = {Krause, BJ and Paz, AA and Garrud, TAC and Peñaloza, E and Vega-Tapia, F and Ford, SG and Niu, Y and Giussani, DA},
title = {Epigenetic regulation by hypoxia, N-acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos.},
journal = {The Journal of physiology},
volume = {602},
number = {15},
pages = {3833-3852},
doi = {10.1113/JP286266},
pmid = {38985827},
issn = {1469-7793},
support = {1220421//Fondo Nacional de Desarrollo Cient&#xed;fico y Tecnol&#xf3;gico/ ; PG/10/99/28656/BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Animals ; *Hydrogen Sulfide/metabolism ; *Acetylcysteine/pharmacology ; Chick Embryo ; Humans ; *Epigenesis, Genetic ; Female ; Pregnancy ; *Fetal Growth Retardation/metabolism/genetics/physiopathology ; *Hypoxia/metabolism/physiopathology ; DNA Methylation ; Cystathionine gamma-Lyase/genetics/metabolism ; Vasodilation/drug effects ; Placenta/metabolism/blood supply ; Umbilical Arteries/metabolism ; },
abstract = {Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.},
}
@article {pmid38973318,
year = {2024},
author = {Babu Balagopal, P and Kohli, R and Uppal, V and Averill, L and Shah, C and McGoogan, K and Di Guglielmo, M and Goran, M and Hossain, MJ},
title = {Effect of N-acetyl cysteine in children with metabolic dysfunction-associated steatotic liver disease-A pilot study.},
journal = {Journal of pediatric gastroenterology and nutrition},
volume = {79},
number = {3},
pages = {652-660},
doi = {10.1002/jpn3.12312},
pmid = {38973318},
issn = {1536-4801},
support = {1-14-CE-04//American Diabetes Association/ ; //Nemours Biomedical Research/ ; },
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Pilot Projects ; Male ; Female ; Child ; Double-Blind Method ; *Non-alcoholic Fatty Liver Disease/drug therapy/complications/metabolism ; Adolescent ; *Oxidative Stress/drug effects ; *Insulin Resistance ; *Biomarkers/blood ; Liver/metabolism/diagnostic imaging/drug effects ; Pediatric Obesity/complications/drug therapy ; Treatment Outcome ; },
abstract = {BACKGROUND: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its sequelae of more severe forms such as metabolic dysfunction-associated steatohepatitis (MASH) is rapidly increasing in children with the rise in obesity. Successful and sustainable treatments for MASLD are lacking in children. We determined the therapeutic effect of N-acetyl cysteine (NAC) on biomarkers of oxidative stress, inflammation and insulin resistance (IR), liver enzymes, liver fat fraction (LFF) and liver stiffness (LS) in children with obesity and biopsy-confirmed MASLD.<br><br>METHODS: Thirteen children (n&#x2009;=&#x2009;13; age: 13.6&#x2009;&#xb1;&#x2009;2.8 years; NAS score >2) underwent a double-blind, placebo-controlled trial of NAC (either 600 or 1200&#x2009;mg NAC/day) or placebo for 16 weeks. Measurements included LFF (magnetic resonance imaging), LS (ultrasound elastography), and body composition. Erythrocyte glutathione (GSH), liver enzymes, insulin, glucose, adiponectin, high-sensitivity c-reactive protein (hs-CRP), and interleukin-6 (IL-6) were also measured. homeostasis model assessment for insulin resistance (HOMA-IR) was calculated.<br><br>RESULTS: Sixteen-week NAC treatment improved (baseline adjusted between-group p&#x2009;<&#x2009;.05 for all) markers of inflammation (IL-6 and hs-CRP), oxidative stress (GSH), and IR (HOMA-IR) and reduced liver enzymes, LFF and LS. Body weight and body composition did not show beneficial changes.<br><br>CONCLUSIONS: Sixteen-week NAC treatment was well tolerated in children with obesity and MASLD and led to improvements in oxidative stress, inflammation and IR and liver outcomes. The results from this pilot study support further investigation of NAC as a therapeutic agent in children with MASLD.},
}
@article {pmid38972409,
year = {2024},
author = {Huang, Y and Sun, Y and Huang, Q and Wu, S and Huang, Z and Hong, Y},
title = {Abamectin-induced behavioral alterations link to energy metabolism disorder and ferroptosis via oxidative stress in Chinese mitten crab, Eriocheir sinensis.},
journal = {The Science of the total environment},
volume = {947},
number = {},
pages = {174558},
doi = {10.1016/j.scitotenv.2024.174558},
pmid = {38972409},
issn = {1879-1026},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Ivermectin/toxicity/analogs &amp; derivatives ; *Brachyura/drug effects/physiology ; *Energy Metabolism/drug effects ; *Water Pollutants, Chemical/toxicity ; *Ferroptosis/drug effects ; Behavior, Animal/drug effects ; },
abstract = {The increasing application of abamectin (ABM) in agriculture has raised concerns regarding its environmental safety and potential adverse effects on aquatic environment safety. In the present study, the toxic effects of ABM exposure on the adult Chinese mitten crab, Eriocheir sinensis were investigated, with a focus on locomotion impairment, behavioral changes, oxidative stress, energy metabolism disruption, and ferroptosis. Crabs were exposed to sublethal concentrations of ABM at 2, 20 and 200 μg/L. After 21 d chronic exposure to 200 μg/L, residual ABM in hepatopancreas and muscles were detected as 12.24 ± 6.67 and 8.75 ± 5.42 μg/Kg, respectively. By using acute exposure experiments (96 h), we observed significant locomotion and behavioral alterations, alongside biochemical evidences of oxidative stress and energy metabolism impairment. The presence of ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, was notably identified in the hepatopancreas. Functional tests with N-acetylcysteine (NAC) supplementation showed restored behavioral responses and decrease of ferroptosis levels. It suggests that mitigating oxidative stress could counteract ABM-induced toxicity. Our findings highlight the critical roles of oxidative stress and ferroptosis in mediating the toxic effects of ABM on E. sinensis, underscoring the need for strategies to mitigate environmental exposure to pesticides.},
}
@article {pmid38971422,
year = {2024},
author = {Guo, Z and Wu, J and Hu, Y and Zhou, J and Li, Q and Zhang, Y and Zhang, J and Yang, L and Wang, S and Zhang, H and Yang, J},
title = {Exogenous iron caused osteocyte apoptosis, increased RANKL production, and stimulated bone resorption through oxidative stress in a murine model.},
journal = {Chemico-biological interactions},
volume = {399},
number = {},
pages = {111135},
doi = {10.1016/j.cbi.2024.111135},
pmid = {38971422},
issn = {1872-7786},
mesh = {Animals ; *Osteocytes/drug effects/metabolism ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *RANK Ligand/metabolism ; *Mice, Inbred C57BL ; *Bone Resorption/metabolism/pathology ; Mice ; *Iron/metabolism ; Disease Models, Animal ; Male ; Iron Overload/metabolism/pathology/chemically induced ; Osteoprotegerin/metabolism ; Acetylcysteine/pharmacology ; Adaptor Proteins, Signal Transducing ; },
abstract = {Iron overload is a risk factor for osteoporosis due to its oxidative toxicity. Previous studies have demonstrated that an excessive amount of iron increases osteocyte apoptosis and receptor activator of nuclear factor κ-B ligand (RANKL) production, which stimulates osteoclast differentiation in vitro. However, the effects of exogenous iron supplementation-induced iron overload on osteocytes in vivo and its role in iron overload-induced bone loss are unknown. This work aimed to develop an iron overloaded murine model of C57BL/6 mice by intraperitoneal administration of iron dextran for two months. The iron levels in various organs, bone, and serum, as well as the microstructure and strength of bone, apoptosis of osteocytes, oxidative stress in bone tissue, and bone formation and resorption, were assessed. The results showed that 2 months of exogenous iron supplementation significantly increased iron levels in the liver, spleen, kidney, bone tissue, and serum. Iron overload negatively affected bone microstructure and strength. Osteocyte apoptosis and empty lacunae rate were elevated by exogenous iron. Iron overload upregulated RANKL expression but had no significant impact on osteoprotegerin (OPG) and sclerostin levels. Static and dynamic histologic analyses and serum biochemical assay showed that iron overload increased bone resorption without significantly affecting bone formation. Exogenous iron promoted oxidative stress in osteocytes in vivo and in vitro. Additional supplementation of iron chelator (deferoxamine) or N-acetyl-l-cysteine (NAC) partially alleviated bone loss, osteocyte apoptosis, osteoclast formation, and oxidative stress due to iron overload. These findings, in line with prior in vitro studies, suggest that exogenous iron supplementation induces osteoclastogenesis and osteoporosis by promoting osteocyte apoptosis and RANKL production via oxidative stress.},
}
@article {pmid38969277,
year = {2024},
author = {Shi, W and Gao, Y and Yang, H and Li, H and Liu, T and Zhao, J and Wei, Z and Lin, L and Huang, Y and Guo, Y and Xu, A and Bai, Z and Xiao, X},
title = {Bavachinin, a main compound of Psoraleae Fructus, facilitates GSDMD-mediated pyroptosis and causes hepatotoxicity in mice.},
journal = {Chemico-biological interactions},
volume = {400},
number = {},
pages = {111133},
doi = {10.1016/j.cbi.2024.111133},
pmid = {38969277},
issn = {1872-7786},
mesh = {Animals ; *Pyroptosis/drug effects ; Mice ; *Phosphate-Binding Proteins/metabolism/genetics ; *Psoralea/chemistry ; *Inflammasomes/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Chemical and Drug Induced Liver Injury/metabolism/pathology ; Mice, Inbred C57BL ; Lipopolysaccharides/toxicity ; Liver/drug effects/metabolism/pathology ; Flavonoids/pharmacology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Caspase 1/metabolism ; Interleukin-1beta/metabolism ; Gasdermins ; },
abstract = {Psoraleae Fructus (PF, Psoralea corylifolia L.), a traditional medicine with a long history of application, is widely used clinically for the treatment of various diseases. However, the reports of PF-related adverse reactions, such as hepatotoxicity, phototoxic dermatitis, and allergy, are increasing year by year, with liver injury being the mostly common. Our previous studies have demonstrated that PF and its preparations can cause liver injury in lipopolysaccharide (LPS)-mediated susceptibility mouse model, but the mechanism of PF-related liver injury is unclear. In this study, we showed that PF and bavachinin, a major component of PF, can directly induce the expression of caspase-1 and interleukin-1β (IL-1β), indicating that PF and bavachinin can directly triggered the activation of inflammasome. Furthermore, pretreatment with NLR family pyrin domain-containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome inhibitors, containing MCC950, ODN TTAGGG (ODN) and carnosol, all significantly reversed bavachinin-induced inflammasome activation. Mechanistically, bavachinin dose-dependently promote Gasdermin D (GSDMD) post-shear activation and then induce mitochondrial reactive oxygen species (mtROS) production and this effect is markedly inhibited by pretreatment with N-Acetylcysteine amide (NAC). In addition, combination treatment of LPS and bavachinin significantly induced liver injury in mice, but not LPS or bavachinin alone, and transcriptome analysis further validated these results. Thus, PF and bavachinin can induce the activation of inflammasome by promoting GSDMD cleavage and cause hepatotoxicity in mice. Therefore, PF, bavachinin, and PF-related preparations should be avoided in patients with inflammasome activation-associated diseases.},
}
@article {pmid38962807,
year = {2024},
author = {Lv, H and Yang, H and Duan, Y and Yan, C and Li, G and Zhao, G and Sun, F and Feng, Y and Li, Y and Fu, Y and Li, Y and Zhao, Z and Jia, X},
title = {S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine for the treatment of non-small cell lung cancer through regulating NF-κB signalling pathway without neurotoxicity.},
journal = {Journal of drug targeting},
volume = {32},
number = {9},
pages = {1111-1124},
doi = {10.1080/1061186X.2024.2374037},
pmid = {38962807},
issn = {1029-2330},
mesh = {Animals ; Humans ; Mice ; A549 Cells ; Acetylcysteine/pharmacology ; *Antineoplastic Agents/pharmacology/administration &amp; dosage ; Apoptosis/drug effects ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Ditiocarb/pharmacology ; Epithelial-Mesenchymal Transition/drug effects ; *Lung Neoplasms/drug therapy/pathology ; Mice, Inbred BALB C ; Mice, Nude ; NF-kappa B/metabolism ; *Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; },
abstract = {The discovery of novel targeted agents for non-small cell lung cancer (NSCLC) remains an important research landscape due to the limited efficacy, side effects and drug resistance of current treatment options. Among many repurposed drugs, disulphiram (DSF) has shown the potential to target tumours. However, its unpleasant neurotoxicity greatly limits its use. A DSF derivative, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine (DS-NAC), was synthesised against NSCLC. The therapeutic effects, mechanism and toxicities of DS-NAC were evaluated in A549 and H460 cells and the mouse model of in situ lung cancer. The in vitro results exhibited that DS-NAC had potent anti-proliferation, apoptotic, anti-metastasis and epithelial-mesenchymal transition (EMT) inhibition effects. In the orthotopic lung cancer mouse model, therapeutic effects of DS-NAC were better than those of DSF and were similar to docetaxel (DTX). Also, results from western blot and immunohistochemistry showed that DS-NAC in combination with copper exerted therapeutic effects via regulating NF-κB signalling pathway and ROS-related proteins such as HIF-1α, Nrf2 and PKC-δ rather than regulating ROS level directly. Moreover, the safety evaluation study showed that DS-NAC had low haematologic and hepatic toxicities in comparison with DTX as well as low neurological toxicity compared with DSF. DS-NAC could be a promising anti-lung cancer agent with a favourable safety profile.},
}
@article {pmid38958792,
year = {2024},
author = {Yan, Y and Huang, W and Lu, X and Chen, X and Shan, Y and Luo, X and Li, Y and Yang, X and Li, C},
title = {Zinc oxide nanoparticles induces cell death and consequently leading to incomplete neural tube closure through oxidative stress during embryogenesis.},
journal = {Cell biology and toxicology},
volume = {40},
number = {1},
pages = {51},
pmid = {38958792},
issn = {1573-6822},
support = {2021A1515110232//Guangdong Basic and Applied Basic Research Foundation/ ; 202201011394//the Science and Technology Program of Guangzhou/ ; 2022KTSCX025//Guangdong Scientific Research Platform and Projects for the Higher-educational Institution/ ; 20211112//Research Project of Traditional Chinese Medicine Bureau of Guangdong/ ; No.29//2021 Guangdong Province Undergraduate College Teaching Quality and Teaching Reform Engineering Construction Project/ ; },
mesh = {*Zinc Oxide/toxicity ; Animals ; *Oxidative Stress/drug effects ; Chick Embryo ; *Embryonic Development/drug effects ; Mice ; *Neural Tube/drug effects/embryology/metabolism ; Humans ; *Neural Tube Defects/chemically induced/metabolism/embryology/pathology ; *Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Cell Death/drug effects ; Female ; Mitochondria/drug effects/metabolism ; Metal Nanoparticles/toxicity ; Autophagy/drug effects ; Cell Line, Tumor ; Nanoparticles/toxicity ; },
abstract = {The implementation of Zinc oxide nanoparticles (ZnO NPs) raises concerns regarding their potential toxic effects on human health. Although more and more researches have confirmed the toxic effects of ZnO NPs, limited attention has been given to their impact on the early embryonic nervous system. This study aimed to explore the impact of exposure to ZnO NPs on early neurogenesis and explore its underlying mechanisms. We conducted experiments here to confirm the hypothesis that exposure to ZnO NPs causes neural tube defects in early embryonic development. We first used mouse and chicken embryos to confirm that ZnO NPs and the Zn[2+] they release are able to penetrate the placental barrier, influence fetal growth and result in incomplete neural tube closure. Using SH-SY5Y cells, we determined that ZnO NPs-induced incomplete neural tube closure was caused by activation of various cell death modes, including ferroptosis, apoptosis and autophagy. Moreover, dissolved Zn[2+] played a role in triggering widespread cell death. ZnO NPs were accumulated within mitochondria after entering cells, damaging mitochondrial function and resulting in the over production of reactive oxygen species, ultimately inducing cellular oxidative stress. The N-acetylcysteine (NAC) exhibits significant efficacy in mitigating cellular oxidative stress, thereby alleviating the cytotoxicity and neurotoxicity brought about by ZnO NPs. These findings indicated that the exposure of ZnO NPs in early embryonic development can induce cell death through oxidative stress, resulting in a reduced number of cells involved in early neural tube closure and ultimately resulting in incomplete neural tube closure during embryo development. The findings of this study could raise public awareness regarding the potential risks associated with the exposure and use of ZnO NPs in early pregnancy.},
}
@article {pmid38958241,
year = {2024},
author = {Zuo, XS and Wang, QY and Wang, SS and Li, G and Zhan, LY},
title = {The role of N-acetylcysteine on adhesion and biofilm formation of Candida parapsilosis isolated from catheter-related candidemia.},
journal = {Journal of medical microbiology},
volume = {73},
number = {7},
pages = {},
pmid = {38958241},
issn = {1473-5644},
mesh = {*Biofilms/drug effects/growth &amp; development ; *Acetylcysteine/pharmacology ; Humans ; *Candida parapsilosis/drug effects/genetics/physiology ; *Catheter-Related Infections/microbiology ; *Candidemia/microbiology ; Fungal Proteins/genetics/metabolism ; Antifungal Agents/pharmacology ; },
abstract = {Objectives. Anti-fungal agents are increasingly becoming less effective due to the development of resistance. In addition, it is difficult to treat Candida organisms that form biofilms due to a lack of ability of drugs to penetrate the biofilms. We are attempting to assess the effect of a new therapeutic agent, N-acetylcysteine (NAC), on adhesion and biofilm formation in Candida parapsilosis clinical strains. Meanwhile, to detect the transcription level changes of adhesion and biofilm formation-associated genes (CpALS6, CpALS7, CpEFG1 and CpBCR1) when administrated with NAC in C. parapsilosis strains, furthermore, to explore the mechanism of drug interference on biofilms.Hypothesis/Gap statement. N-acetylcysteine (NAC) exhibits certain inhibitory effects on adhesion and biofilm formation in C. parapsilosis clinical strains from CRBSIs through: (1) down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections (CRBSIs), (2) regulating the metabolism and biofilm -forming factors of cell structure.Methods. To determine whether non-antifungal agents can exhibit inhibitory effects on adhesion, amounts of total biofilm formation and metabolic activities of C. parapsilosis isolates from candidemia patients, NAC was added to the yeast suspensions at different concentrations, respectively. Reverse transcription was used to detect the transcriptional levels of adhesion-related genes (CpALS6 and CpALS7) and biofilm formation-related factors (CpEFG1 and CpBCR1) in the BCR1 knockout strain, CP7 and CP5 clinical strains in the presence of NAC. To further explore the mechanism of NAC on the biofilms of C. parapsilosis, RNA sequencing was used to calculate gene expression, comparing the differences among samples. Gene Ontology (GO) enrichment analysis helps to illustrate the difference between two particular samples on functional levels.Results. A high concentration of NAC reduces the total amount of biofilm formation in C. parapsilosis. Following co-incubation with NAC, the expression of CpEFG1 in both CP7 and CP5 clinical strains decreased, while there were no significant changes in the transcriptional levels of CpBCR1 compared with the untreated strain. GO enrichment analysis showed that the metabolism and biofilm-forming factors of cell structure were all regulated after NAC intervention.Conclusions. The non-antifungal agent NAC exhibits certain inhibitory effects on clinical isolate biofilm formation by down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections.},
}
@article {pmid38956487,
year = {2024},
author = {Saad, M and Flament, J},
title = {Paracetamol overdose causing acute kidney injury without hepatotoxicity: a case report.},
journal = {International journal of emergency medicine},
volume = {17},
number = {1},
pages = {81},
pmid = {38956487},
issn = {1865-1372},
abstract = {BACKGROUND: Paracetamol is a widely used analgesic and antipyretic. Paracetamol-induced hepatotoxicity is well known, but nephrotoxicity without hepatotoxicity is rarely seen.<br><br>CASE PRESENTATION: We present a case of acute kidney injury without hepatotoxicity in paracetamol overdose. A 15-year-old girl was admitted 48&#xa0;h after she had taken 10&#xa0;g of paracetamol. She was complaining of abdominal pain and vomiting. Her blood level of creatinine was 1.20&#xa0;mg/dL on admission, with a peak at 3.67&#xa0;mg/dL 3 days later. The liver blood tests and blood paracetamol level were negative. She did not receive N-acetyl cysteine and was treated with intravenous fluid (crystalloid). The ultrasonography of the kidneys was normal. Her renal function returned almost to baseline 7 days after admission. It was concluded that the diagnosis was an acute kidney injury caused by acute tubular necrosis due to paracetamol overdose.<br><br>CONCLUSION: This case shows that nephrotoxicity can occur without hepatotoxicity in paracetamol overdose.},
}
@article {pmid38953310,
year = {2024},
author = {Choi, EJ and Oh, HT and Lee, SH and Zhang, CS and Li, M and Kim, SY and Park, S and Chang, TS and Lee, BH and Lin, SC and Jeon, SM},
title = {Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.},
journal = {Autophagy},
volume = {20},
number = {11},
pages = {2490-2510},
pmid = {38953310},
issn = {1554-8635},
mesh = {Mutation ; Stress, Physiological ; Feedback, Physiological ; *Antioxidants/metabolism ; Cell Line, Tumor ; Mice, Inbred BALB C ; Humans ; Male ; Animals ; Mice ; Xenograft Model Antitumor Assays ; *Sequestosome-1 Protein/metabolism ; *AMP-Activated Protein Kinases/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Carcinoma, Non-Small-Cell Lung/genetics/pathology ; *Lung Neoplasms/genetics/pathology ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; AMP-Activated Protein Kinase Kinases/genetics/metabolism ; Tumor Microenvironment/genetics ; Cell Survival ; Oxidative Stress ; },
abstract = {Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca[2+]. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H[+]-translocating ATPase.},
}
@article {pmid38947789,
year = {2024},
author = {Gad, FA and Abdelghaffar Emam, M and Eldeeb, AA and Abdelhameed, AA and Soliman, MM and Alotaibi, KS and Albattal, SB and Abughrien, B},
title = {Mitigative Effects of l-Arginine and N-Acetyl Cysteine against Cisplatin-Induced Testicular Dysfunction and Toxicity through the Regulation of Antioxidant, Anti-inflammatory, and Antiapoptotic Markers: Role of miR-155 and miR-34c Expression.},
journal = {ACS omega},
volume = {9},
number = {25},
pages = {27680-27691},
pmid = {38947789},
issn = {2470-1343},
abstract = {Testicular dysfunction is a common adverse effect of cisplatin (CIS) administration as a chemotherapeutic drug. The current study has outlined the role of micro-RNAs (miR-155 and 34c) in CIS-induced testicular dysfunction and evaluated the protective effect of N-acetyl cysteine (NAC) and/or l-arginine (LA). Seven groups of Albino rats were used for this study. The control (C) group received physiological saline; the CIS group was injected CIS (7 mg/kg IP, once) on day 21 of the experiment; the NAC group was administered NAC (150 mg/kg intragastric, for 28 days); and the LA group was injected LA (50 mg/kg IP, for 28 days). NAC+CIS, LA+CIS, and NAC+LA+CIS groups received the above regime. CIS significantly reduced serum testosterone, LH, and FSH concentrations with decline of testicular enzyme activities. CIS caused significant elevation in testicular oxidative-stress biomarkers, inflammation-associated cytokines, and apoptosis markers, along with overexpression of miR-155 and low miR-34c expression. Additionally, marked testicular degenerative changes were observed in the examined histological section; a significant decrease in the expression of PCNA with significant increase in expressions of F4/80 and BAX was confirmed. The administration of NAC or LA upregulated testicular functions and improved histopathological and immunohistochemical changes as well as miRNA expression compared with the CIS-administered group. Rats receiving both NAC and LA showed a more significant ameliorative effect compared with groups receiving NAC or LA alone. In conclusion, NAC or LA showed an ameliorative effect against CIS-induced testicular toxicity and dysfunction through the regulation of antioxidant, anti-inflammatory, and antiapoptotic markers and via modulating miR-155 and miR-34c expression.},
}
@article {pmid38946815,
year = {2024},
author = {Aldaghi, N and Kamalabadi-Farahani, M and Alizadeh, M and Alizadeh, A and Salehi, M},
title = {Enhancing pressure ulcer healing and tissue regeneration by using N-acetyl-cysteine loaded carboxymethyl cellulose/gelatin/sodium alginate hydrogel.},
journal = {Biomedical engineering letters},
volume = {14},
number = {4},
pages = {833-845},
pmid = {38946815},
issn = {2093-985X},
abstract = {Prolonged pressure on the skin can result in pressure ulcers, which may lead to serious complications, such as infection and tissue damage. In this study, we evaluated the effect of a carboxymethyl cellulose/gelatin/sodium alginate (CMC/Gel/Alg) hydrogel containing N-acetyl-cysteine (NAC) on the healing of pressure ulcers. Pressure ulcers were induced by applying a magnet to the dorsum of rat skin. The wounds were then treated with sterile gauze, ChitoHeal Gel[®], and CMC/Gel/Alg hydrogel dressings with or without NAC for the other groups. We evaluated the morphology, weight loss, swelling, rheology, blood compatibility, cytocompatibility, antioxidant capacity, and wound scratch of the prepared hydrogel. MTT assay revealed that the optimum concentration of NAC was 5 mg/ml, which induced higher cell proliferation and viability. Results of the histopathological evaluation showed increased wound closure, and complete re-epithelialization in the hydrogel-containing NAC group compared to the other groups. The CMC/Gel/Alg/5 mg/ml NAC hydrogel dressing showed 84% wound closure at 14 days after treatment. Immunohistochemical results showed a decrease in the level of TNF-α on day 14 compared day 7. Results of the qPCR assay revealed that NAC hydrogel increased the expression of Collagen type I and TGF-β1 and decreased MMP2 and MMP9 mRNA on the 14th day. The results suggest that the CMC/Gel/Alg/5 mg/ml NAC hydrogel with antioxidant properties is an appropriate dressing for wound healing.},
}
@article {pmid38946388,
year = {2024},
author = {Sun, J and Zhang, X and Wang, L and Di Stefano, AFD and Zanin, V and Magrone, P and Yuan, Y},
title = {Author Correction: Phase I study of the pharmacokinetics and safety of single and multiple doses of intravenous N-acetylcysteine in healthy Chinese subjects.},
journal = {European review for medical and pharmacological sciences},
volume = {28},
number = {12},
pages = {3806},
doi = {10.26355/eurrev_202406_36449},
pmid = {38946388},
issn = {2284-0729},
abstract = {Eur Rev Med Pharmacol Sci 2023; 27 (24): 12103-12111-DOI: 10.26355/eurrev_202312_34808-PMID: 38164872, published online on December 22, 2023. After publication, the authors found that Table III's legend was the same as that of Table II. Therefore, Table III's legend has been corrected as follows: Table III. Plasma PK parameters following repeat doses of IV NAC 600 mg (n = 24). There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34808.},
}
@article {pmid38944154,
year = {2024},
author = {Higham, CS and Shimano, KA and Kharbanda, S and Chu, J and Cisneros, GS and Winestone, LE and Dara, J and Huang, JN and Hermiston, ML and Long-Boyle, JR and Dvorak, CC},
title = {Cyclophosphamide and Thiotepa Increases Risk of Transplant-Associated Thrombotic Microangiopathy.},
journal = {Transplantation and cellular therapy},
volume = {30},
number = {9},
pages = {931.e1-931.e10},
doi = {10.1016/j.jtct.2024.06.020},
pmid = {38944154},
issn = {2666-6367},
mesh = {Humans ; *Thiotepa/administration &amp; dosage/therapeutic use ; *Thrombotic Microangiopathies/epidemiology/etiology ; *Cyclophosphamide/adverse effects/therapeutic use ; Male ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Female ; Retrospective Studies ; Adolescent ; Child ; Young Adult ; *Transplantation Conditioning/adverse effects ; Child, Preschool ; Adult ; Risk Factors ; Infant ; },
abstract = {Transplant associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic cell transplant (HCT) associated with endothelial injury resulting in severe end organ damage, acute and long-term morbidity, and mortality. Myeloablative conditioning is a known risk factor, though specific causative agents have not been identified. We hypothesized that the combination of cyclophosphamide and thiotepa (CY + TT) is particularly toxic to the endothelium, placing patients at elevated risk for TA-TMA. We conducted a retrospective review of pediatric and young adult patients who received conditioned autologous and allogeneic HCT between 2012 and August 2023 at UCSF Benioff Children's Hospital, San Francisco. We excluded patients undergoing gene therapy or triple tandem transplants for brain tumors. Neuroblastoma tandem transplants were classified a single transplant occurrence. High dose N-acetylcysteine (NAC) prophylaxis was incorporated into the institutional standard of care from December 2016-May 2019 and May 2022-August 2023. Defibrotide was given prophylactically to patients deemed high-risk for sinusoidal obstruction syndrome (SOS) per institutional guidelines or on clinical trial NCT#02851407 for SOS prophylaxis or NCT#03384693 for TA-TMA prophylaxis. Kaplan-Meier analysis was used to estimate the 1-year cumulative incidence of TA-TMA. Univariate analysis was performed for each of the potential risk factors of interest using log-rank tests and bivariate analysis with Cox regression models using backward selection and hazard ratios were built using all covariates with a univariate P-value < .2 for allogeneic HCT. SPSS (v29) was used to estimate all summary statistics, cumulative incidences, and uni- and bi-variate analyses. A total of 558 transplants were performed with 43 patients developing TA-TMA, for a 1-year cumulative incidence of 8.6% (95% CI, 5.9-11.3) and 7.2% (95% CI, 2.9-11.5) in allogeneic and autologous HCTs, respectively (P = .62). In allogeneic recipients (n = 417), the 1-year cumulative incidence of TA-TMA with CY + TT as part of conditioning was 35.7% (95% CI, 15.7-55.7) compared to 11.7% (95% CI, 7.2-16.2) with either CY or TT alone, and 1.2% (95% CI, 0-2.8) if neither agent was included in the conditioning regimen (P < .001). Use of either CY or TT (HR = 10.14; P = .002) or CY + TT (HR = 35.93; P < .001), viral infections (HR = 4.3; P = .017) and fungal infections (HR = 2.98; P = 0.027) were significant factors resulting in increased risk for developing TA-TMA. In subjects undergoing autologous HCT (n = 141), the 1-year cumulative incidence of TA-TMA with CY + TT was 19.6% (95% CI, 8.8-30.6) while TA-TMA did not occur in patients receiving either CY or TT alone or when neither were included (P < .001). TA-TMA occurred only in patients with neuroblastoma receiving CY + TT as part of their conditioning. For autologous patients who received CY + TT, those who were CMV seronegative at the time of HCT had an incidence of TA-TMA of 6.7% (95% CI, 0.1-15.7) compared to 38.1% (95% CI, 35-41.2) for those CMV seropositive (P = .007). These data show that CY or TT alone or in combination as part of pre-transplant conditioning prior to HCT increase the incidence of TA-TMA. Alternative conditioning excluding the combination of CY + TT should be considered whenever possible to limit the development of TA-TMA.},
}
@article {pmid38943148,
year = {2024},
author = {Üstüner, E and Yıldırım, E and Macun, HC and Ekici, H and Şahin, Y and Güncüm, E and Anteplioğlu, T and Elifoğlu, TB and Bozkaya, E},
title = {Ultrasonographic and histopathological investigation of the effect of N-acetylcysteine on doxorubicin-induced ovarian and uterine toxicity in rats.},
journal = {Journal of ovarian research},
volume = {17},
number = {1},
pages = {135},
pmid = {38943148},
issn = {1757-2215},
mesh = {Animals ; Female ; *Doxorubicin/toxicity ; *Acetylcysteine/pharmacology/therapeutic use ; Rats ; *Ovary/drug effects/pathology/diagnostic imaging ; *Ultrasonography ; *Uterus/drug effects/pathology/diagnostic imaging ; Antibiotics, Antineoplastic/toxicity/adverse effects ; },
abstract = {BACKGROUND: This study aimed to investigate the mitigating effect of N-acetylcysteine (NAC) on doxorubicin (DOX)-induced ovarian and uterine toxicity in rats using laboratory tests, ultrasonographic (US) imaging, and histopathology analysis.<br><br>METHODS: Forty-eight rats were divided into six groups (n&#x2009;=&#x2009;8) as follows: Group A (control) (0.5 mL saline administered intraperitoneally [IP]), Group B (a single 10&#xa0;mg/kg dose of DOX administered IP on day 1), Group C (a single 10&#xa0;mg/kg dose of DOX administered IP 24&#xa0;h before sacrifice), Group D (100&#xa0;mg/kg of NAC administered IP for 21 days), Group E (a single 10&#xa0;mg/kg dose of DOX administered IP on day 1 and 100&#xa0;mg/kg of NAC administered IP for 21 days), and Group F (100&#xa0;mg/kg of NAC administered IP for 21 days and a single 10&#xa0;mg/kg dose of DOX administered IP 24&#xa0;h before sacrifice). The ovaries were examined using B-mode US on days 1, 14, and 21, and the histopathological examinations of the ovaries and the uterus were undertaken after sacrifice on day 22.<br><br>RESULTS: Histomorphological analyses showed that ovarian weight decreased after DOX administration in Group B but not in Group E. US revealed a transient increase in ovarian size in Group B and E, reverting to baseline levels over time, as well as a progressive increase in peritoneal fluid in Groups B and E. Group B exhibited a significant decrease in the thickness of the endometrium and myometrium and uterine cornual length, which was not observed in Group E. Histopathological examination showed that DOX caused a decline in follicular count, especially in primordial, secondary, and Graafian follicles, and resulted in follicular atresia, predominantly in Group B. Destructive degeneration/necrosis and vascular changes were most prominently seen in the corpus luteum of Groups C and B. In NAC-treated rats (Groups E and F), although germ cell damage was present, atretic follicles and vascular changes, such as hyperemia and congestion, were reduced. The anti-m&#xfc;llerian hormone (AMH) level was the highest in Group F.<br><br>CONCLUSIONS: NAC, an antioxidant, attenuated DOX-induced gonadotoxicity in rats.},
}
@article {pmid38936520,
year = {2024},
author = {Tang, M and Xia, W and Song, F and Liu, C and Wang, X and Zhou, H and Mai, K and He, G},
title = {Loss of Gcn2 exacerbates gossypol induced oxidative stress, apoptosis and inflammation in zebrafish.},
journal = {Fish &amp; shellfish immunology},
volume = {151},
number = {},
pages = {109727},
doi = {10.1016/j.fsi.2024.109727},
pmid = {38936520},
issn = {1095-9947},
mesh = {Animals ; *Zebrafish ; *Gossypol/toxicity/pharmacology/administration &amp; dosage ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Inflammation/chemically induced ; Animal Feed/analysis ; Zebrafish Proteins/genetics/metabolism ; Diet/veterinary ; Fish Diseases/chemically induced/immunology ; Protein Serine-Threonine Kinases/genetics/metabolism ; },
abstract = {Gossypol, a naturally occurring compound found in cottonseed meal, shows promising therapeutic potential for human diseases. However, within the aquaculture industry, it is considered an antinutritional factor. The incorporation of cottonseed meal into fish feed introduces gossypol, which induces intracellular stresses and hinders overall health of farmed fish. The aim of this study is to determine the role of General control nonderepressible 2 (gcn2), a sensor for intracellular stresses in gossypol-induced stress responses in fish. In the present study, we established two gcn2 knockout zebrafish lines. A feeding trial was conducted to assess the growth-inhibitory effect of gossypol in both wild type and gcn2 knockout zebrafish. The results showed that in the absence of gcn2, zebrafish exhibited increased oxidative stress and apoptosis when exposed to gossypol, resulting in higher mortality rates. In feeding trial, dietary gossypol intensified liver inflammation in gcn2[-/-] zebrafish, diminishing their growth and feed conversion. Remarkably, administering the antioxidant N-acetylcysteine (NAC) was effective in reversing the gossypol induced oxidative stress and apoptosis, thereby increasing the gossypol tolerance of gcn2[-/-] zebrafish. Exposure to gossypol induces more severe mitochondrial stress in gcn2[-/-] zebrafish, thereby inducing metabolic disorders. These results reveal that gcn2 plays a protective role in reducing gossypol-induced oxidative stress and apoptosis, attenuating inflammation responses, and enhancing the survivability of zebrafish in gossypol-challenged conditions. Therefore, maintaining appropriate activation of Gcn2 may be beneficial for fish fed diets containing gossypol.},
}
@article {pmid38929087,
year = {2024},
author = {Dobariya, P and Xie, W and Rao, SP and Xie, J and Seelig, DM and Vince, R and Lee, MK and More, SS},
title = {Deletion of Glyoxalase 1 Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {6},
pages = {},
pmid = {38929087},
issn = {2076-3921},
support = {R01 AG062469/AG/NIA NIH HHS/United States ; R01-AG062469/NH/NIH HHS/United States ; NA//Center for Drug Design, Research Endowment Funds/ ; },
abstract = {Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events, culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC), has a narrow therapeutic window, and early treatment is essential for a satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end products (AGEs) and the consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase 1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in the APAP-mediated activation of RAGE and downstream cell death cascades. Constitutive Glo-1-knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were used as tools. Our findings showed elevated oxidative stress resulting from the activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild-type controls. A unique feature of the hepatic necrosis in GKO mice was the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than the inflammation seen in the wild type. The GSH surrogate and general antioxidant ψ-GSH alleviated APAP toxicity irrespective of the Glo-1 status, suggesting that oxidative stress is the primary driver of APAP toxicity. Overall, the exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against the initial stages of APAP overdose.},
}
@article {pmid38928002,
year = {2024},
author = {Dymanowska-Dyjak, I and Frankowska, K and Abramiuk, M and Polak, G},
title = {Oxidative Imbalance in Endometriosis-Related Infertility-The Therapeutic Role of Antioxidants.},
journal = {International journal of molecular sciences},
volume = {25},
number = {12},
pages = {},
pmid = {38928002},
issn = {1422-0067},
support = {DS121//Medical University of Lublin/ ; },
mesh = {*Endometriosis/metabolism/drug therapy/complications ; Humans ; Female ; *Antioxidants/therapeutic use ; *Oxidative Stress/drug effects ; *Infertility, Female/etiology/metabolism/drug therapy ; Acetylcysteine/therapeutic use/pharmacology ; },
abstract = {Endometriosis in half of affected women is closely related to problems with fertility. Endometriosis-associated infertility is caused by a wide range of abnormalities affecting the female reproductive tract, from oocyte quality impairment to disturbances in the eutopic endometrium or mechanical abnormalities resulting from disease progression. Since supportive antioxidant therapies, in addition to surgical treatment or assisted reproductive techniques (ARTs), have overall been proven to be effective tools in endometriosis management, the objective of our review was to analyze the role of antioxidant substances, including vitamins, micronutrients, N-acetylcysteine (NAC), curcumin, melatonin, and resveratrol, in endometriosis-related infertility. Most of these substances have been proven to alleviate the systemic oxidant predominance, which has been expressed through decreased oxidative stress (OS) markers and enhanced antioxidative defense. In addition, we demonstrated that the predominant effect of the aforementioned substances is the inhibition of the development of endometriotic lesions as well as the suppression of pro-inflammatory molecules. Although we can undoubtedly conclude that antioxidants are beneficial in fertility support, further studies explaining the detailed pathways of their action are needed.},
}
@article {pmid38923010,
year = {2025},
author = {Gong, Z and Yang, S and Ling, S and Wang, H and Xu, X and Lin, Z},
title = {Dermatopathological features and successful treatment with topical antioxidant for ichthyosiform lesions in Mitchell syndrome caused by an ACOX1 variant.},
journal = {The Journal of dermatology},
volume = {52},
number = {3},
pages = {445-451},
doi = {10.1111/1346-8138.17346},
pmid = {38923010},
issn = {1346-8138},
support = {82373459//National Natural Science Foundation of China/ ; 82373500//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Acyl-CoA Oxidase/genetics ; Administration, Topical ; *Antioxidants/administration &amp; dosage/therapeutic use ; Skin/pathology ; Treatment Outcome ; },
abstract = {Peroxisomal acyl-CoA oxidase 1 (ACOX1), is a peroxisomal enzyme that catalyzes β-oxidation of very-long-chain fatty acids (VLCFA). The gain-of-function variant p.Asn237Ser in ACOX1 has been shown to cause Mitchell syndrome (MITCH), a neurodegenerative disorder characterized by episodic demyelination, hearing loss, and polyneuropathy, through the overproduction of hydrogen peroxide. Only eight cases of MITCH have been reported. While all these patients experienced cutaneous abnormalities, detailed skin features and potential treatment have not been documented. Herein, we report two MITCH patients who harbored a de novo heterozygous variant p.Asn237Ser in ACOX1 and experienced progressive ichthyosiform erythroderma. Skin histopathology revealed hyperkeratosis and parakeratosis with focal hypogranulosis as well as dyskeratotic keratinocytes. Lipid accumulation in the epidermis was observed using Oil Red O staining. Both patients exhibited a remarkable response to treatment with the topical antioxidant N-acetylcysteine (NAC), with Patient 1 achieving complete recovery after 3 months of consistent treatment. This study provides the first comprehensive description of the clinicopathological characteristics and effective treatment of skin lesions in MITCH patients. The successful treatment with topical NAC suggests excessive reactive oxygen species might play a significant role in the pathogenesis of skin lesions in MITCH.},
}
@article {pmid38918702,
year = {2024},
author = {Kagemichi, N and Umemura, M and Ishikawa, S and Iida, Y and Takayasu, S and Nagasako, A and Nakakaji, R and Akimoto, T and Ohtake, M and Horinouchi, T and Yamamoto, T and Ishikawa, Y},
title = {Cytotoxic effects of the cigarette smoke extract of heated tobacco products on human oral squamous cell carcinoma: the role of reactive oxygen species and CaMKK2.},
journal = {The journal of physiological sciences : JPS},
volume = {74},
number = {1},
pages = {35},
pmid = {38918702},
issn = {1880-6562},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Mouth Neoplasms/metabolism/pathology ; Cell Line, Tumor ; *Smoke/adverse effects ; *Carcinoma, Squamous Cell/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism ; *Tobacco Products/adverse effects ; Apoptosis/drug effects ; Calcium/metabolism ; Cell Survival/drug effects ; },
abstract = {BACKGROUND: The increasing prevalence of heated tobacco products (HTPs) has heightened concerns regarding their potential health risks. Previous studies have demonstrated the toxicity of cigarette smoke extract (CSE) from traditional tobacco's mainstream smoke, even after the removal of nicotine and tar. Our study aimed to investigate the cytotoxicity of CSE derived from HTPs and traditional tobacco, with a particular focus on the role of reactive oxygen species (ROS) and intracellular Ca[2+].<br><br>METHODS: A human oral squamous cell carcinoma (OSCC) cell line, HSC-3 was utilized. To prepare CSE, aerosols from HTPs (IQOS) and traditional tobacco products (1R6F reference cigarette) were collected into cell culture media. A cell viability assay, apoptosis assay, western blotting, and Fluo-4 assay were conducted. Changes in ROS levels were measured using electron spin resonance spectroscopy and the high-sensitivity 2',7'-dichlorofluorescein diacetate assay. We performed a knockdown of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) by shRNA lentivirus in OSCC cells.<br><br>RESULTS: CSE from both HTPs and traditional tobacco exhibited cytotoxic effects in OSCC cells. Exposure to CSE from both sources led to an increase in intracellular Ca[2+] concentration and induced p38 phosphorylation. Additionally, these extracts prompted cell apoptosis and heightened ROS levels. N-acetylcysteine (NAC) mitigated the cytotoxic effects and p38 phosphorylation. Furthermore, the knockdown of CaMKK2 in HSC-3 cells reduced cytotoxicity, ROS production, and p38 phosphorylation in response to CSE.<br><br>CONCLUSION: Our findings suggest that the CSE from both HTPs and traditional tobacco induce cytotoxicity. This toxicity is mediated by ROS, which are regulated through Ca[2+] signaling and CaMKK2 pathways.},
}
@article {pmid38915482,
year = {2024},
author = {Mudambi, S and Fitzgerald, ME and Washington, DL and Pera, PJ and Huss, WJ and Paragh, G},
title = {Dual targeting of KDM1A and antioxidants is an effective anticancer strategy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38915482},
issn = {2692-8205},
support = {P30 CA016056/CA/NCI NIH HHS/United States ; },
abstract = {Lysine Specific Demethylase 1 (KDM1A / LSD1) regulates mitochondrial respiration and stabilizes HIF-1A (hypoxia-inducible factor 1A). HIF-1A modulates reactive oxygen species (ROS) levels by increasing cellular glucose uptake, glycolysis, and endogenous antioxidants. The role of KDM1A in cellular ROS response has not previously been described. We determined the role of KDM1A in regulating the ROS response and the utility of KDM1A inhibitors in combination with ROS-inducing cancer therapies. Our results show that KDM1A inhibition sensitized cells to oxidative stress and increased total cellular ROS, which was mitigated by treatment with the antioxidant N-acetyl cysteine. KDM1A inhibition decreased basal mitochondrial respiration and impaired induction of HIF-1A after ROS exposure. Overexpression of HIF-1A salvaged cells from KDM1A inhibition enhanced sensitivity to ROS. Thus we found that increased sensitivity of ROS after KDM1A inhibition was mediated by HIF-1A and depletion of endogenous glutathione. We also show that KDM1A-specific inhibitor bizine synergized with antioxidant-depleting therapies, buthionine sulfoximine, and auranofin in rhabdomyosarcoma cell lines (Rh28 and Rh30). In this study, we describe a novel role for KDM1A in regulating HIF-1A functions under oxidative stress and found that dual targeting of KDM1A and antioxidant systems may serve as an effective combination anticancer strategy.},
}
@article {pmid38910554,
year = {2024},
author = {Shao, Y and Zhang, Y and Zou, S and Wang, J and Li, X and Qin, M and Sun, L and Yin, W and Chang, X and Wang, S and Han, X and Wu, T and Chen, F},
title = {(-)-Epigallocatechin 3-gallate protects pancreatic β-cell against excessive autophagy-induced injury through promoting FTO degradation.},
journal = {Autophagy},
volume = {20},
number = {11},
pages = {2460-2477},
pmid = {38910554},
issn = {1554-8635},
mesh = {Animals ; *Catechin/analogs &amp; derivatives/pharmacology ; *Autophagy/drug effects/physiology/genetics ; *Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism/genetics ; *Insulin-Secreting Cells/metabolism/drug effects ; Mice ; Oxidative Stress/drug effects ; Proteolysis/drug effects ; Protective Agents/pharmacology ; Mice, Inbred C57BL ; },
abstract = {Excessive macroautophagy/autophagy leads to pancreatic β-cell failure that contributes to the development of diabetes. Our previous study proved that the occurrence of deleterious hyperactive autophagy attributes to glucolipotoxicity-induced NR3C1 activation. Here, we explored the potential protective effects of (-)-epigallocatechin 3-gallate (EGCG) on β-cell-specific NR3C1 overexpression mice in vivo and NR3C1-enhanced β cells in vitro. We showed that EGCG protects pancreatic β cells against NR3C1 enhancement-induced failure through inhibiting excessive autophagy. RNA demethylase FTO (FTO alpha-ketoglutarate dependent dioxygenase) caused diminished m[6]A modifications on mRNAs of three pro-oxidant genes (Tlr4, Rela, Src) and, hence, oxidative stress occurs; by contrast, EGCG promotes FTO degradation by the ubiquitin-proteasome system in NR3C1-enhanced β cells, which alleviates oxidative stress, and thereby prevents excessive autophagy. Moreover, FTO overexpression abolishes the beneficial effects of EGCG on β cells against NR3C1 enhancement-induced damage. Collectively, our results demonstrate that EGCG protects pancreatic β cells against NR3C1 enhancement-induced excessive autophagy through suppressing FTO-stimulated oxidative stress, which provides novel insights into the mechanisms for the anti-diabetic effect of EGCG.Abbreviation 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ad: adenovirus; ALD: aldosterone; AUC: area under curve; βNR3C1 mice: pancreatic β-cell-specific NR3C1 overexpression mice; Ctrl: control; CHX: cycloheximide; DEX: dexamethasone; DHE: dihydroethidium; EGCG: (-)-epigallocatechin 3-gallate; FTO: FTO alpha-ketoglutarate dependent dioxygenase; GSIS: glucose-stimulated insulin secretion; HFD: high-fat diet; HG: high glucose; i.p.: intraperitoneal; IOD: immunofluorescence optical density; KSIS: potassium-stimulated insulin secretion; m[6]A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NO: nitric oxide; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NAC: N-acetylcysteine; NC: negative control; PBS: phosphate-buffered saline; PI: propidium iodide; OCR: oxygen consumption rate; Palm.: palmitate; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RNA-seq: RNA sequencing; O2[.-]: superoxide anion; SRC: Rous sarcoma oncogene; ROS: reactive oxygen species; T2D: type 2 diabetes; TEM: transmission electron microscopy; TLR4: toll-like receptor 4; TUNEL: terminal dUTP nick-end labeling; UTR: untranslated region; WT: wild-type.},
}
@article {pmid38904252,
year = {2024},
author = {Panja, S and Nahomi, RB and Rankenberg, J and Michel, CR and Nagaraj, RH},
title = {Thiol-Mediated Enhancement of N[ε]-Acetyllysine Formation in Lens Proteins.},
journal = {ACS chemical biology},
volume = {19},
number = {7},
pages = {1495-1505},
pmid = {38904252},
issn = {1554-8937},
support = {R01 EY023286/EY/NEI NIH HHS/United States ; R01 EY028836/EY/NEI NIH HHS/United States ; R01 EY033915/EY/NEI NIH HHS/United States ; S10 OD028538/OD/NIH HHS/United States ; },
mesh = {*Lysine/metabolism/chemistry ; *Sulfhydryl Compounds/chemistry/metabolism ; Acetylation ; Crystallins/metabolism/chemistry ; Lens, Crystalline/metabolism ; Protein Processing, Post-Translational ; Humans ; Acetyl Coenzyme A/metabolism/chemistry ; },
abstract = {Lysine acetylation (AcK) is a prominent post-translational modification in eye lens crystallins. We have observed that AcK formation is preferred in some lysine residues over others in crystallins. In this study, we have investigated the role of thiols in such AcK formation. Upon incubation with acetyl-CoA (AcCoA), αA-Crystallin, which contains two cysteine residues, showed significantly higher levels of AcK than αB-Crystallin, which lacks cysteine residues. Incubation with thiol-rich γS-Crystallin resulted in higher AcK formation in αB-Crystallin from AcCoA. External free thiol (glutathione and N-acetyl cysteine) increased the AcK content in AcCoA-incubated αB-Crystallin. Reductive alkylation of cysteine residues significantly decreased (p < 0.001) the AcCoA-mediated AcK formation in αA-Crystallin. Introduction of cysteine residues within ∼5 Å of lysine residues (K92C, E99C, and V169C) in αB-Crystallin followed by incubation with AcCoA resulted in a 3.5-, 1.3- and 1.3-fold increase in the AcK levels when compared to wild-type αB-Crystallin, respectively. Together, these results suggested that AcK formation in α-Crystallin is promoted by the proximal cysteine residues and protein-free thiols through an S → N acetyl transfer mechanism.},
}
@article {pmid38899269,
year = {2024},
author = {Qadir, NA and Stachler, L and Reddy, AD and Diaz-Garcia, G and Sottile, E},
title = {Polysubstance-Induced Hepatotoxicity and the Role of Supportive Management.},
journal = {Cureus},
volume = {16},
number = {5},
pages = {e60649},
pmid = {38899269},
issn = {2168-8184},
abstract = {With the continued rise of polysubstance use throughout the country, it has been shown to affect a multitude of organ systems. Drug-induced liver injury (DILI) has been widely documented in its association with salicylates or acetaminophen and the utility of using N-acetylcysteine (NAC) for its hepatoprotective effects. However, DILI caused by illicit drug use and guideline-directed management has had little research. We present the case of a 29-year-old female who presented with altered mental status. She was found to have a concomitant liver injury and was treated supportively without the use of NAC, with gradual improvement.},
}
@article {pmid38899149,
year = {2024},
author = {Zou, H and Boboltz, A and Cheema, Y and Song, D and Cahn, D and Duncan, GA},
title = {Synthetic mucus barrier arrays as a nanoparticle formulation screening platform.},
journal = {RSC pharmaceutics},
volume = {1},
number = {2},
pages = {218-226},
pmid = {38899149},
issn = {2976-8713},
support = {R01 HL160540/HL/NHLBI NIH HHS/United States ; },
abstract = {A mucus gel layer lines the luminal surface of tissues throughout the body to protect them from infectious agents and particulates. As a result, nanoparticle drug delivery systems delivered to these sites may become trapped in mucus and subsequently cleared before they can reach target cells. As such, optimizing the properties of nanoparticle delivery vehicles, such as their surface chemistry and size, is essential to improving their penetration through the mucus barrier. In previous work, we developed a mucin-based hydrogel that has viscoelastic properties like that of native mucus which can be further tailored to mimic specific mucosal tissues and disease states. Using this biomimetic hydrogel system, a 3D-printed array containing synthetic mucus barriers was created that is compatible with a 96-well plate enabling its use as a high-throughput screening platform for nanoparticle drug delivery applications. To validate this system, we evaluated several established design parameters to determine their impact on nanoparticle penetration through synthetic mucus barriers. Consistent with the literature, we found nanoparticles of smaller size and coated with a protective PEG layer more efficiently penetrated through synthetic mucus barriers. In addition, we evaluated a mucolytic (tris(2-carboxyethyl) phosphine, TCEP) for use as a permeation enhancer for mucosal drug delivery. In comparison to N-acetyl cysteine (NAC), we found TCEP significantly improved nanoparticle penetration through a disease-like synthetic mucus barrier. Overall, our results establish a new high-throughput screening approach using synthetic mucus barrier arrays to identify promising nanoparticle formulation strategies for drug delivery to mucosal tissues.},
}
@article {pmid38897422,
year = {2024},
author = {Russell-Guzmán, J and Américo-Da Silva, L and Cadagan, C and Maturana, M and Palomero, J and Estrada, M and Barrientos, G and Buvinic, S and Hidalgo, C and Llanos, P},
title = {Activation of the ROS/TXNIP/NLRP3 pathway disrupts insulin-dependent glucose uptake in skeletal muscle of insulin-resistant obese mice.},
journal = {Free radical biology &amp; medicine},
volume = {222},
number = {},
pages = {187-198},
doi = {10.1016/j.freeradbiomed.2024.06.011},
pmid = {38897422},
issn = {1873-4596},
mesh = {Animals ; Male ; Mice ; *Carrier Proteins/metabolism/genetics ; *Diet, High-Fat/adverse effects ; Furans/pharmacology ; *Glucose/metabolism ; Indenes/pharmacology ; Inflammasomes/metabolism ; Insulin/metabolism ; *Insulin Resistance ; Mice, Inbred C57BL ; Mice, Obese ; *Muscle, Skeletal/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Obesity/metabolism/pathology ; *Oxidative Stress ; *Reactive Oxygen Species/metabolism ; *Signal Transduction ; Sulfonamides ; *Thioredoxins/metabolism/genetics ; },
abstract = {Oxidative stress and the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome have been linked to insulin resistance in skeletal muscle. In immune cells, the exacerbated generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome, by facilitating the interaction between thioredoxin interacting protein (TXNIP) and NLRP3. However, the precise role of ROS/TXNIP-dependent NLRP3 inflammasome activation in skeletal muscle during obesity-induced insulin resistance remains undefined. Here, we induced insulin resistance in C57BL/6J mice by feeding them for 8 weeks with a high-fat diet (HFD) and explored whether the ROS/TXNIP/NLRP3 pathway was involved in the induction of insulin resistance in skeletal muscle. Skeletal muscle fibers from insulin-resistant mice exhibited increased oxidative stress, as evidenced by elevated malondialdehyde levels, and altered peroxiredoxin 2 dimerization. Additionally, these fibers displayed augmented activation of the NLRP3 inflammasome, accompanied by heightened ROS-dependent proximity between TXNIP and NLRP3, which was abolished by the antioxidant N-acetylcysteine (NAC). Inhibition of the NLRP3 inflammasome with MCC950 or suppressing the ROS/TXNIP/NLRP3 pathway with NAC restored insulin-dependent glucose uptake in muscle fibers from insulin-resistant mice. These findings provide insights into the mechanistic link between oxidative stress, NLRP3 inflammasome activation, and obesity-induced insulin resistance in skeletal muscle.},
}
@article {pmid38896955,
year = {2024},
author = {Zhao, Q and Liu, G and Ding, Q and Zheng, F and Shi, X and Lin, Z and Liang, Y},
title = {The ROS/TXNIP/NLRP3 pathway mediates LPS-induced microglial inflammatory response.},
journal = {Cytokine},
volume = {181},
number = {},
pages = {156677},
doi = {10.1016/j.cyto.2024.156677},
pmid = {38896955},
issn = {1096-0023},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Microglia/metabolism/drug effects ; *Lipopolysaccharides/pharmacology ; *Carrier Proteins/metabolism ; Animals ; Mice ; *Reactive Oxygen Species/metabolism ; *Caspase 1/metabolism ; *Signal Transduction/drug effects ; *Inflammasomes/metabolism ; *Inflammation/metabolism/pathology ; Cell Line ; Acetylcysteine/pharmacology ; Calcium-Binding Proteins/metabolism ; Interleukin-1beta/metabolism ; Interleukin-18/metabolism ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Microfilament Proteins/metabolism ; Thioredoxins/metabolism ; CARD Signaling Adaptor Proteins/metabolism ; Sepsis-Associated Encephalopathy/metabolism/pathology ; CD68 Molecule ; },
abstract = {BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction activated by microglia. The potential pathological changes of SAE are complex, and the cellular pathophysiological characteristics remains unclear. This study aims to explore the ROS/TXNIP/NLRP3 pathway mediated lipopolysaccharide (LPS)-induced inflammatory response in microglia.<br><br>METHODS: BV-2 cells were pre-incubated with 10&#xa0;&#x3bc;M N-acetyl-L-cysteine (NAC) for 2&#xa0;h, which were then reacted with 1&#xa0;&#x3bc;g/mL LPS for 24&#xa0;h. Western blot assay examined the protein levels of IBA1, CD68, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. The contents of inflammatory factor were detected by ELISA assay. The co-immunoprecipitation assay examined the interaction between TXNIP and NLRP3.<br><br>RESULTS: LPS was confirmed to promote the positive expressions of IBA1 and CD68 in BV-2 cells. The further experiments indicated that LPS enhanced ROS production and NLRP3 inflammasome activation in BV-2 cells. Moreover, we also found that NAC partially reversed the facilitation of LPS on the levels of ROS, IL-1&#x3b2;, IL-18, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. NAC treatment also notably alleviated the interaction between TXNIP and NLRP3 in BV-2 cells.<br><br>CONCLUSION: ROS inhibition mediated NLRP3 signaling inactivation by decreasing TXNIP expression.},
}
@article {pmid38894680,
year = {2024},
author = {Rieckher, M and Gallrein, C and Alquezar-Artieda, N and Bourached-Silva, N and Vaddavalli, PL and Mares, D and Backhaus, M and Blindauer, T and Greger, K and Wiesner, E and Pontel, LB and Schumacher, B},
title = {Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging.},
journal = {Nucleic acids research},
volume = {52},
number = {14},
pages = {8271-8285},
pmid = {38894680},
issn = {1362-4962},
support = {PID2022-136694NB-I00 FEDER//MCIN/AEI/10.13039/501100011033/ ; RYC2021-032395-I//European Union NextGenerationEU/PRTR/ ; 2021 SGR 01309//Generalitat de Catalunya/ ; 61734//John Templeton Foundation/ ; 70114555//Deutsche Krebshilfe/ ; 496650118//Deutsche Forschungsgemeinschaft/ ; DJCLS 04 R/2023//Jos&#xe9; Carreras Leuk&#xe4;mie-Stiftung/ ; },
mesh = {*DNA Repair ; *Caenorhabditis elegans/genetics/drug effects/growth &amp; development ; *Formaldehyde/toxicity ; Animals ; *Reproduction/drug effects/genetics ; *Aging/genetics ; *DNA Damage ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Aldehyde Dehydrogenase/genetics/metabolism ; Mutation ; Humans ; Transcription, Genetic/drug effects ; Acetylcysteine/pharmacology ; Aldehyde Oxidoreductases ; },
abstract = {Formaldehyde (FA) is a recognized environmental and metabolic toxin implicated in cancer development and aging. Inherited mutations in the FA-detoxifying enzymes ADH5 and ALDH2 genes lead to FA overload in the severe multisystem AMeD syndrome. FA accumulation causes genome damage including DNA-protein-, inter- and intra-strand crosslinks and oxidative lesions. However, the influence of distinct DNA repair systems on organismal FA resistance remains elusive. We have here investigated the consequence of a range of DNA repair mutants in a model of endogenous FA overload generated by downregulating the orthologs of human ADH5 and ALDH2 in C. elegans. We have focused on the distinct components of nucleotide excision repair (NER) during developmental growth, reproduction and aging. Our results reveal three distinct modes of repair of FA-induced DNA damage: Transcription-coupled repair (TCR) operating NER-independently during developmental growth or through NER during adulthood, and, in concert with global-genome (GG-) NER, in the germline and early embryonic development. Additionally, we show that the Cockayne syndrome B (CSB) factor is involved in the resolution of FA-induced DNA-protein crosslinks, and that the antioxidant and FA quencher N-acetyl-l-cysteine (NAC) reverses the sensitivity of detoxification and DNA repair defects during development, suggesting a therapeutic intervention to revert FA-pathogenic consequences.},
}
@article {pmid38892556,
year = {2024},
author = {Liu, M and You, Y and Zhu, H and Chen, Y and Hu, Z and Duan, J},
title = {N-Acetylcysteine Alleviates Impaired Muscular Function Resulting from Sphingosine Phosphate Lyase Functional Deficiency-Induced Sphingoid Base and Ceramide Accumulation in Caenorhabditis elegans.},
journal = {Nutrients},
volume = {16},
number = {11},
pages = {},
pmid = {38892556},
issn = {2072-6643},
support = {82171551//National Natural Science Foundation of China/ ; 20232ACB205002//Jiangxi Provincial Natural Science Foundation/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects ; *Acetylcysteine/pharmacology ; *Ceramides/metabolism ; *Aldehyde-Lyases/metabolism ; *Sphingolipids/metabolism ; Reactive Oxygen Species/metabolism ; Antioxidants/pharmacology/metabolism ; Muscles/drug effects/metabolism ; RNA Interference ; Sphingosine/analogs &amp; derivatives/metabolism ; },
abstract = {Sphingosine-1-phosphate lyase (SPL) resides at the endpoint of the sphingolipid metabolic pathway, catalyzing the irreversible breakdown of sphingosine-1-phosphate. Depletion of SPL precipitates compromised muscle morphology and function; nevertheless, the precise mechanistic underpinnings remain elusive. Here, we elucidate a model of SPL functional deficiency in Caenorhabditis elegans using spl-1 RNA interference. Within these SPL-deficient nematodes, we observed diminished motility and perturbed muscle fiber organization, correlated with the accumulation of sphingoid bases, their phosphorylated forms, and ceramides (collectively referred to as the "sphingolipid rheostat"). The disturbance in mitochondrial morphology was also notable, as SPL functional loss resulted in heightened levels of reactive oxygen species. Remarkably, the administration of the antioxidant N-acetylcysteine (NAC) ameliorates locomotor impairment and rectifies muscle fiber disarray, underscoring its therapeutic promise for ceramide-accumulation-related muscle disorders. Our findings emphasize the pivotal role of SPL in preserving muscle integrity and advocate for exploring antioxidant interventions, such as NAC supplementation, as prospective therapeutic strategies for addressing muscle function decline associated with sphingolipid/ceramide metabolism disruption.},
}
@article {pmid38892427,
year = {2024},
author = {Calderón Guzmán, D and Osnaya Brizuela, N and Ortíz Herrera, M and Valenzuela Peraza, A and Labra Ruíz, N and Juárez Olguín, H and Santamaria Del Angel, D and Barragán Mejía, G},
title = {N-Acetylcysteine Attenuates Cisplatin Toxicity in the Cerebrum and Lung of Young Rats with Artificially Induced Protein Deficiency.},
journal = {International journal of molecular sciences},
volume = {25},
number = {11},
pages = {},
pmid = {38892427},
issn = {1422-0067},
mesh = {Animals ; *Cisplatin/adverse effects/toxicity ; *Acetylcysteine/pharmacology ; Rats ; *Rats, Wistar ; *Lung/drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Oxidative Stress/drug effects ; Male ; Cerebrum/drug effects/metabolism ; Glutathione/metabolism ; Neuroprotective Agents/pharmacology ; Antineoplastic Agents/adverse effects ; },
abstract = {Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the main mechanisms involved in brain and lung toxicity. The aim of the present work was to study the influence of the amount of protein on some oxidative parameters in the brain and lungs of rats treated with Cisplatin (CP) and N-Acetylcysteine (NAC) as neuroprotectors. Four groups of Wistar rats, each containing six animals, were fed with a protein diet at 7% for 15 days. Thereafter, the groups were given either a unique dose of CP[®] 5 mg/kg or NAC[®] 5 mg/kg as follows: group 1 (control), NaCl 0.9% vehicle; group 2, CP; group 3, NAC; and group 4, NAC + CP. The animals were sacrificed immediately after the treatments. Blood samples were collected upon sacrifice and used to measure blood triglycerides and glucose. The brain and lungs of each animal were obtained and used to assay lipid peroxidation (TBARS), glutathione (GSH), serotonin metabolite (5-HIAA), catalase, and the activity of Ca[+2], and Mg[+2] ATPase using validated methods. TBARS, H2O2, and GSH were found to be significantly decreased in the cortex and cerebellum/medulla oblongata of the groups treated with CP and NAC. The total ATPase showed a significant increase in the lung and cerebellum/medulla oblongata, while 5-HIAA showed the same tendency in the cortex of the same group of animals. The increase in 5-HIAA and ATPase during NAC and CP administration resulted in brain protection. This effect could be even more powerful when membrane fluidity is increased, thus proving the efficacy of combined NAC and CP drug therapy, which appears to be a promising strategy for future chemotherapy in malnourished patients.},
}
@article {pmid38892239,
year = {2024},
author = {Wrotek, A and Badyda, A and Jackowska, T},
title = {Molecular Mechanisms of N-Acetylcysteine in RSV Infections and Air Pollution-Induced Alterations: A Scoping Review.},
journal = {International journal of molecular sciences},
volume = {25},
number = {11},
pages = {},
pmid = {38892239},
issn = {1422-0067},
support = {501-1-020-19-23.//Centre of Postgraduate Medical Education in Warsaw/ ; },
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Respiratory Syncytial Virus Infections/drug therapy/virology/metabolism ; Animals ; *Air Pollution/adverse effects ; ErbB Receptors/metabolism ; },
abstract = {N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. The respiratory syncytial virus (RSV) is one of the most important etiological factors of lower respiratory tract infections, and exposure to air pollution appears to be additionally associated with higher RSV incidence and disease severity. We aimed to systematically review the existing literature to determine which molecular mechanisms mediate the effects of NAC in an RSV infection and air pollution, and to identify the knowledge gaps in this field. A search for original studies was carried out in three databases and a calibrated extraction grid was used to extract data on the NAC treatment (dose, timing), the air pollutant type, and the most significant mechanisms. We identified only 28 studies conducted in human cellular models (n = 18), animal models (n = 7), and mixed models (n = 3). NAC treatment improves the barrier function of the epithelium damaged by RSV and air pollution, and reduces the epithelial permeability, protecting against viral entry. NAC may also block RSV-activated phosphorylation of the epidermal growth factor receptor (EGFR), which promotes endocytosis and facilitates cell entry. EGFR also enhances the release of a mucin gene, MUC5AC, which increases mucus viscosity and causes goblet cell metaplasia; the effects are abrogated by NAC. NAC blocks virus release from the infected cells, attenuates the cigarette smoke-induced shift from necrosis to apoptosis, and reverses the block in IFN-γ-induced antiviral gene expression caused by the inhibited Stat1 phosphorylation. Increased synthesis of pro-inflammatory cytokines and chemokines is induced by both RSV and air pollutants and is mediated by the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that are activated in response to oxidative stress. MCP-1 (monocyte chemoattractant protein-1) and RANTES (regulated upon activation, expressed and secreted by normal T cells) partially mediate airway hyperresponsiveness (AHR), and therapeutic (but not preventive) NAC administration reduces the inflammatory response and has been shown to reduce ozone-induced AHR. Oxidative stress-induced DNA damage and cellular senescence, observed during RSV infection and exposure to air pollution, can be partially reversed by NAC administration, while data on the emphysema formation are disputed. The review identified potential common molecular mechanisms of interest that are affected by NAC and may alleviate both the RSV infection and the effects of air pollution. Data are limited and gaps in knowledge include the optimal timing or dosage of NAC administration, therefore future studies should clarify these uncertainties and verify its practical use.},
}
@article {pmid38891420,
year = {2024},
author = {Alatta, A and Nassar, M and Gorduysus, M and Alkhatib, W and Sayed, M},
title = {In Vitro Investigation of the Effects of Various Reducing Agents on Dentin Treated with Hydrogen Peroxide.},
journal = {Polymers},
volume = {16},
number = {11},
pages = {},
pmid = {38891420},
issn = {2073-4360},
support = {Research Project (G20) ID (89).//This research was supported by the Office of Vice Chancellor for Research and Graduate Studies, University of Sharjah, Sharjah, United Arab Emirates./ ; },
abstract = {We assessed the effect of non-protein thiols (NPSH), reduced glutathione (GSH) and n-acetylcysteine (NAC), on resin shear bond strength (SBS) to hydrogen peroxide (H2O2)-treated dentin, and their effects on the characteristics of dentin in comparison to ascorbic acid (AA) and sodium thiosulfate (STS). H2O2-treated dentin was conditioned with 5% AA, GSH, NAC, or STS applied for 1 or 5 min. The positive control group received H2O2 without antioxidant application, and the first negative control group received distilled water (DW). The specimens received resin bonding immediately after treatment except for the second negative control group (delayed bonding). Microhardness, roughness, and topography were studied. The SBS values of all antioxidants were statistically greater than the positive control group (p < 0.05); however, NAC and AA applied for 1 min demonstrated the highest values, which were comparable to delayed bonding. All treatments removed the smear layer except DW, H2O2, and STS. The negative effect of H2O2 on resin-dentin bonding was mitigated by the application of the antioxidants; however, their efficiencies were dependent on the antioxidant type and time of application. NAC was more effective in optimizing resin bonding to bleached dentin compared to GSH at 1 min application and STS at both application times but was comparable to AA. Negligible negative effects on the substrate's roughness and microhardness were detected. The antioxidant properties of the agent and its capacity to remove the smear layer are the processes underpinning the ability of a certain antioxidant to reverse the effect of H2O2 on bonding.},
}
@article {pmid38885551,
year = {2024},
author = {Bresson, SE and Ruzzin, J},
title = {Persistent organic pollutants disrupt the oxidant/antioxidant balance of INS-1E pancreatic β-cells causing their physiological dysfunctions.},
journal = {Environment international},
volume = {190},
number = {},
pages = {108821},
doi = {10.1016/j.envint.2024.108821},
pmid = {38885551},
issn = {1873-6750},
mesh = {*Insulin-Secreting Cells/drug effects/metabolism ; *Antioxidants/metabolism ; *Polychlorinated Biphenyls/toxicity ; *Reactive Oxygen Species/metabolism ; *Receptors, Aryl Hydrocarbon/metabolism/genetics ; *Polychlorinated Dibenzodioxins/toxicity ; *Persistent Organic Pollutants ; *Cell Survival/drug effects ; Receptors, Cytoplasmic and Nuclear/metabolism/genetics ; Constitutive Androstane Receptor ; Insulin/metabolism ; Dichlorodiphenyl Dichloroethylene/toxicity ; Oxidative Stress/drug effects ; Oxidants/toxicity ; Cell Line ; Humans ; Acetylcysteine/pharmacology ; Animals ; Rats ; Pregnane X Receptor/metabolism/genetics ; },
abstract = {BACKGROUND: Persistent organic pollutants (POPs) have emerged as potent diabetogenic agents, but their mechanisms of action remain poorly identified.<br><br>OBJECTIVES: In this study, we aim to determine the mechanisms regulating the damaging effects of POPs in pancreatic &#x3b2;-cells, which have a central role in the development of diabetes.<br><br>METHODS: We treated INS-1E pancreatic &#x3b2;-cells with PCB-153, p,p'-DDE, PCB-126, or TCDD at doses ranging from 1&#xa0;&#xd7;&#xa0;10[-15]to 5&#xa0;&#xd7;&#xa0;10[-6]M. We measured insulin content and secretion, cell viability and assessed the mRNA expression of the xenobiotic nuclear receptors Nr1i2 and Nr1i3, and the aryl hydrocarbon receptor (Ahr). In addition, we evaluated the antioxidant defense and production of reactive oxygen species (ROS). Finally, we studied the ability of the antioxidant N-acetyl-L-cysteine (NAC) to counteract the effects of POPs in INS-1E cells.<br><br>RESULTS: When exposed to environmental POP levels, INS-1E cells had impaired production and secretion of insulin. These defects were observed for all tested POPs and were paralleled by reduced Ins1 and Ins2 mRNA expression. While POP treatment for 3&#xa0;days did not affect INS-1E cell viability, longer treatment progressively killed the cells. Furthermore, we found that the xenobiotic detoxification machinery is poorly expressed in the INS-1E cells, as characterized by the absence of Nr1i2 and Nr1i3 and their respective downstream targets Cyp3a1/Cyp3a2 and Cyp2b1/Cyp2b3, and the weak functionality of the Ahr/Cyp1a1 signaling. Interestingly, POPs dysregulated key antioxidant enzymes such as glutathione peroxidases, peroxiredoxins, thioredoxins, and catalases. In parallel, the production of intracellular ROS, including superoxide anion (O2[&#x2022;-]) and hydrogen peroxide (H2O2), was increased by POP exposure. Improving the oxidant scavenging capacity of INS-1E cells by NAC treatment restored the production and secretion of insulin.<br><br>CONCLUSION: By promoting oxidative stress and impairing the ability of INS-1E cells to produce and secrete insulin, this study reveals how POPs can mechanistically act as diabetogenic agents, and provides new scientific evidence supporting the concept that POPs are fueling the diabetes epidemics.},
}
@article {pmid38885202,
year = {2024},
author = {Guo, X and Zhang, M and Li, Y and Ding, Z and Liu, M and Li, W and Peng, Y and Zheng, J},
title = {CYP3A4-Mediated Metabolic Activation and Cytotoxicity of Chlortoluron.},
journal = {Chemical research in toxicology},
volume = {37},
number = {7},
pages = {1104-1112},
doi = {10.1021/acs.chemrestox.3c00351},
pmid = {38885202},
issn = {1520-5010},
mesh = {Animals ; Rats ; *Cytochrome P-450 CYP3A/metabolism ; Humans ; *Hepatocytes/drug effects/metabolism ; Male ; *Microsomes, Liver/metabolism ; Rats, Sprague-Dawley ; Activation, Metabolic ; Cell Survival/drug effects ; Cells, Cultured ; Molecular Structure ; Herbicides/toxicity/metabolism ; Dose-Response Relationship, Drug ; },
abstract = {Chlortoluron (CTU) is an herbicide extensively used in agricultural settings for crop cultivation. Its presence in water has been identified as a pollutant detrimental to aquatic species. The objective of the present study was to explore the metabolic activation and hepatotoxicity of CTU. Through human and rat liver microsomal incubations supplemented with CTU, nicotinamide adenine dinucleotide phosphate (NADPH), and either glutathione or N-acetyl cysteine, a benzylic alcohol metabolite (M1) was discerned, alongside a phenol metabolite (M2), a glutathione conjugate (M3), and an N-acetyl cysteine conjugate (M4). In rats exposed to CTU, biliary M3 and urinary M4 were detected in their bile and urine, respectively. The generation of M1 was detected in the presence of NADPH. The observation of M3 and M4 suggests the formation of an iminoquinone methide intermediate arising from the oxidation of M1. CYP3A4 was found to be the principal enzyme catalyzing the metabolic activation of CTU. Furthermore, CTU exhibited cytotoxic properties in cultured rat primary hepatocytes in a concentration-dependent pattern. Concomitant treatment of hepatocytes with ketoconazole mitigated their susceptibility to the cytotoxic effects of CTU.},
}
@article {pmid38884516,
year = {2024},
author = {Tang, W and Zhu, D and Wu, F and Xu, JF and Yang, JP and Deng, ZP and Chen, XB and Papi, A and Qu, JM},
title = {Author Correction: Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion.},
journal = {European review for medical and pharmacological sciences},
volume = {28},
number = {11},
pages = {3697},
doi = {10.26355/eurrev_202406_36388},
pmid = {38884516},
issn = {2284-0729},
abstract = {Eur Rev Med Pharmacol Sci 2023; 27 (11): 5119-5127-DOI: 10.26355/eurrev_202306_32628-PMID: 37318485, published online on June 13, 2023. After publication, the authors have found some mistakes. This erratum corrects the following: In Figure 1, "4 withdrawal" has been corrected into "7 withdrawal" and "95 completed study" has been corrected into "97 corrected study" In the "Efficacy" paragraph at page 5123, "1.0 in the placebo group" has been corrected into "-1.0 in the placebo group". The legend of Table V has been corrected as follows: Table V. Published clinical studies of the mucolytic and expectorant efficacy of IV NAC in respiratory diseases. In Table V, the data regarding the Treatment groups (duration) by Grassi et al5 have been corrected as follows: NAC oral 200 mg TID NAC IM 300 mg BID NAC IV 500 mg OD (6 days) In Table V, the data regarding the Treatment groups (duration) by Henneghien et al8 have been corrected as follows: NAC oral 200 mg TID NAC IV 300 mg TID (3-10 days) NAC IV 500 mg BID (12 days) There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/32628.},
}
@article {pmid38880547,
year = {2024},
author = {Yakovlev, AV and Detterer, AS and Yakovleva, OV and Hermann, A and Sitdikova, GF},
title = {H2S prevents the disruption of the blood-brain barrier in rats with prenatal hyperhomocysteinemia.},
journal = {Journal of pharmacological sciences},
volume = {155},
number = {4},
pages = {131-139},
doi = {10.1016/j.jphs.2024.05.001},
pmid = {38880547},
issn = {1347-8648},
mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; Pregnancy ; *Hyperhomocysteinemia/metabolism ; Female ; *Hydrogen Sulfide/metabolism ; *Neuroprotective Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Cytokines/metabolism ; Homocysteine/blood/metabolism/analogs &amp; derivatives ; Rats, Wistar ; Sulfides/pharmacology/administration &amp; dosage ; Rats ; Male ; Pregnancy Complications ; Brain/metabolism ; L-Lactate Dehydrogenase/metabolism/blood ; Permeability ; Nitrites/metabolism/blood ; },
abstract = {Elevation of the homocysteine concentration in the plasma called hyperhomocysteinemia (hHCY) during pregnancy causes a number of pre- and postnatal developmental disorders. The aim of our study was to analyze the effects of H2S donors -NaHS and N-acetylcysteine (NAC) on blood-brain barrier (BBB) permeability in rats with prenatal hHCY. In rats with mild hHCY BBB permeability assessed by Evans Blue extravasation in brain increased markedly throughout life. Administration of NaHS or NAC during pregnancy attenuated hHCY-associated damage and increased endogenous concentrations of sulfides in brain tissues. Acute application of dl-homocysteine thiolactone induced BBB leakage, which was prevented by the NMDA receptor antagonist MK-801 or H2S donors. Rats with hHCY demonstrated high levels of NO metabolite - nitrites and proinflammatory cytokines (IL-1β, TNF-α, IL-6) in brain. Lactate dehydrogenase (LDH) activity in the serum was higher in rats with hHCY. Mitochondrial complex-I activity was lower in brain of hHCY rats. NaHS treatment during pregnancy restored levels of proinflammatory cytokines, nitrites and activity of the respiratory chain complex in brain as well as the LDH activity in serum. Our data suggest that H2S has neuroprotective effects against prenatal hHCY-associated BBB disturbance providing a potential strategy for the prevention of developmental impairments in newborns.},
}
@article {pmid38879122,
year = {2025},
author = {Cai, J and Huang, J and Li, D and Zhang, X and Shi, B and Liu, Q and Fang, C and Xu, S and Zhang, Z},
title = {Hippo-YAP/TAZ-ROS signaling axis regulates metaflammation induced by SelenoM deficiency in high-fat diet-derived obesity.},
journal = {Journal of advanced research},
volume = {71},
number = {},
pages = {603-620},
pmid = {38879122},
issn = {2090-1224},
mesh = {Animals ; Diet, High-Fat/adverse effects ; *Obesity/metabolism/etiology/pathology ; Mice ; Signal Transduction ; *Inflammation/metabolism/pathology/etiology ; *Reactive Oxygen Species/metabolism ; YAP-Signaling Proteins ; Adipose Tissue/metabolism/pathology ; Protein Serine-Threonine Kinases/metabolism ; Hippo Signaling Pathway ; Macrophages/metabolism ; Male ; *Transcription Factors/metabolism ; Mice, Inbred C57BL ; *Adaptor Proteins, Signal Transducing/metabolism ; Mice, Knockout ; },
abstract = {INTRODUCTION: Metabolic inflammation (metaflammation) in obesity is primarily initiated by proinflammatory macrophage infiltration into adipose tissue. SelenoM contributes to the modulation of antioxidative stress and inflammation in multiple pathological processes; however, its roles in metaflammation and the proinflammatory macrophage (M1)-like state in adipose tissue have not been determined.<br><br>OBJECTIVES: We hypothesize that SelenoM could effectively regulate metaflammation via the Hippo-YAP/TAZ-ROS signaling axis in obesity derived from a high-fat diet.<br><br>METHODS: Morphological changes in adipose tissue were examined by hematoxylin-eosin (H&amp;E) staining and fluorescence microscopy. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to evaluate the impact of SelenoM deficiency on blood glucose levels. RNA-Seq analysis, LC-MS analysis, Mass spectrometry analysis and western blotting were performed to detect the levels of genes and proteins related to glycolipid metabolism in adipose tissue.<br><br>RESULTS: Herein, we evaluated the inflammatory features and metabolic microenvironment of mice with SelenoM-deficient adipose tissues by multi-omics analyses. The deletion of SelenoM resulted in glycolipid metabolic disturbances and insulin resistance, thereby accelerating weight gain, adiposity, and hyperglycemia. Mice lacking SelenoM in white adipocytes developed severe adipocyte hypertrophy via impaired lipolysis. SelenoM deficiency aggravated the generation of ROS by reducing equivalents (NADPH and glutathione) in adipocytes, thereby promoting inflammatory cytokine production and the M1-proinflammatory reaction, which was related to a change in nuclear factor kappa-B (NF-&#x3ba;B) levels in macrophages. Mechanistically, SelenoM deficiency promoted metaflammation via Hippo-YAP/TAZ-ROS-mediated transcriptional regulation by targeting large tumor suppressor 2 (LATS2). Moreover, supplementation with N-acetyl cysteine (NAC) to reduce excessive oxidative stress partially rescued adipocyte inflammatory responses and macrophage M1 activation.<br><br>CONCLUSION: Our data indicate that SelenoM ameliorates metaflammation mainly via the Hippo-YAP/TAZ-ROS signaling axis in obesity. The identification of SelenoM as a key regulator of metaflammation presents opportunities for the development of novel therapeutic interventions targeting adipose tissue dysfunction in obesity.},
}
@article {pmid38876744,
year = {2024},
author = {Goedert, M and Griesinger, C and Outeiro, TF and Riek, R and Schröder, GF and Spillantini, MG},
title = {Abandon the NAC in α-synuclein.},
journal = {The Lancet. Neurology},
volume = {23},
number = {7},
pages = {669},
doi = {10.1016/S1474-4422(24)00176-5},
pmid = {38876744},
issn = {1474-4465},
mesh = {Humans ; *alpha-Synuclein/metabolism ; Parkinson Disease/drug therapy ; Acetylcysteine/therapeutic use ; Animals ; },
}
@article {pmid38875923,
year = {2024},
author = {Bagri, KM and de Andrade Abraham, C and Santos, AT and da Silva, WS and Costa, ML and Mermelstein, C},
title = {Rotenone inhibits embryonic chick myogenesis in a ROS-dependent mechanism.},
journal = {Tissue &amp; cell},
volume = {89},
number = {},
pages = {102423},
doi = {10.1016/j.tice.2024.102423},
pmid = {38875923},
issn = {1532-3072},
mesh = {Animals ; *Reactive Oxygen Species/metabolism ; *Muscle Development/drug effects ; Chick Embryo ; *Rotenone/pharmacology ; *Muscle Fibers, Skeletal/metabolism/drug effects/cytology ; *Myoblasts/metabolism/drug effects/cytology ; Fibroblasts/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; },
abstract = {Skeletal muscle function is highly dependent on the energy supply provided by mitochondria. Besides ATP production, mitochondria have several other roles, such as calcium storage, heat production, cell death signaling, autophagy regulation and redox state modulation. Mitochondrial function is crucial for skeletal muscle fiber formation. Disorders that affect mitochondria have a major impact in muscle development and function. Here we studied the role of mitochondria during chick skeletal myogenesis. We analyzed the intracellular distribution of mitochondria in myoblasts, fibroblasts and myotubes using Mitotracker labeling. Mitochondrial respiration was investigated in chick muscle cells. Our results show that (i) myoblasts and myotubes have more mitochondria than muscle fibroblasts; (ii) mitochondria are organized in long lines within the whole cytoplasm and around the nuclei of myotubes, while in myoblasts they are dispersed in the cytoplasm; (iii) the area of mitochondria in myotubes increases during myogenesis, while in myoblasts and fibroblasts there is a slight decrease; (iv) mitochondrial length increases in the three cell types (myoblasts, fibroblasts and myotubes) during myogenesis; (v) the distance of mitochondria to the nucleus increases in myoblasts and myotubes during myogenesis; (vi) Rotenone inhibits muscle fiber formation, while FCCP increases the size of myotubes; (vii) N-acetyl cysteine (NAC), an inhibitor of ROS formation, rescues the effects of Rotenone on muscle fiber size; and (viii) Rotenone induces the production of ROS in chick myogenic cells. The collection of our results suggests a role of ROS signaling in mitochondrial function during chick myogenesis.},
}
@article {pmid38873925,
year = {2024},
author = {Yin, Z and Zhang, J and Zhao, M and Liu, J and Xu, Y and Peng, S and Pan, W and Wei, C and Zheng, Z and Liu, S and Qin, JJ and Wan, J and Wang, M},
title = {EDIL3/Del-1 prevents aortic dissection through enhancing internalization and degradation of apoptotic vascular smooth muscle cells.},
journal = {Autophagy},
volume = {20},
number = {11},
pages = {2405-2425},
pmid = {38873925},
issn = {1554-8635},
mesh = {Animals ; Mice ; *Aortic Dissection/pathology/metabolism ; *Apoptosis/drug effects ; *Muscle, Smooth, Vascular/metabolism/pathology ; *Mice, Knockout ; *Phagocytosis/drug effects/physiology ; Macrophages/metabolism ; Mice, Inbred C57BL ; RAW 264.7 Cells ; Myocytes, Smooth Muscle/metabolism/drug effects ; Reactive Oxygen Species/metabolism ; Calcium-Binding Proteins/metabolism ; Male ; Autophagy/physiology/drug effects ; },
abstract = {Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein involved in macrophage efferocytosis in acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of apoptotic VSMCs during TAD. The levels of EDIL3 were decreased in the serum and aortic tissue from TAD mice. Global edil3 knockout (edil3[-/-]) mice and edil3[-/-] bone marrow chimeric mice exhibited a considerable exacerbation in β-aminopropionitrile monofumarate (BAPN)-induced TAD, accompanied with increased apoptotic VSMCs accumulating in the damaged aortic tissue. Two types of phagocytes, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used for in vitro efferocytosis assay. edil3-deficient phagocytes exhibited inefficient internalization and degradation of apoptotic VSMCs. Instead, EDIL3 promoted the internalization phase through interacting with phosphatidylserine (PtdSer) on apoptotic VSMCs and binding to the macrophage ITGAV/αv-ITGB3/β3 integrin. In addition, EDIL3 accelerated the degradation phase through activating LC3-associated phagocytosis (LAP). Mechanically, following the engulfment, EDIL3 enhanced the activity of SMPD1/acid sphingomyelinase in the phagosome through blocking ITGAV-ITGB3 integrin, which facilitates phagosomal reactive oxygen species (ROS) production by NAPDH oxidase CYBB/NOX2. Furthermore, exogenous EDIL3 supplementation alleviated BAPN-induced TAD and promoted apoptotic cell clearance. EDIL3 may be a novel factor for the prevention and treatment of TAD.Abbreviations: BAPN: β-aminopropionitrile monofumarate; BMDM: bone marrow-derived macrophage; C12FDG: 5-dodecanoylaminofluorescein-di-β-D-galactopyranoside; CTRL: control; CYBB/NOX2: cytochrome b-245, beta polypeptide; DCFH-DA: 2',7'-dichlorofluorescin diacetate; EDIL3/Del-1: EGF-like repeats and discoidin I-like domains 3; EdU: 5-ethynyl-2'-deoxyuridine; EVG: elastic van Gieson; H&amp;E: hematoxylin and eosin; IL: interleukin; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAC: N-acetylcysteine; PtdSer: phosphatidylserine; rEDIL3: recombinant EDIL3; ROS: reactive oxygen species; SMPD1: sphingomyelin phosphodiesterase 1; TAD: thoracic aortic dissection; TEM: transmission electron microscopy; VSMC: vascular smooth muscle cell; WT: wild-type.},
}
@article {pmid38870779,
year = {2024},
author = {Liu, J and Bai, Y and Feng, Y and Liu, X and Pang, B and Zhang, S and Jiang, M and Chen, A and Huang, H and Chen, Y and Ling, J and Mei, L},
title = {ABCC1 deficiency potentiated noise-induced hearing loss in mice by impairing cochlear antioxidant capacity.},
journal = {Redox biology},
volume = {74},
number = {},
pages = {103218},
pmid = {38870779},
issn = {2213-2317},
mesh = {Animals ; Mice ; *ATP-Binding Cassette, Sub-Family C Proteins/metabolism/genetics ; *Cochlea/metabolism/pathology ; *Hearing Loss, Noise-Induced/metabolism/genetics ; *Mice, Knockout ; *Antioxidants/metabolism ; *Oxidative Stress ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; Endothelial Cells/metabolism ; },
abstract = {The ABCC1 gene belongs to the ATP-binding cassette membrane transporter superfamily, which plays a crucial role in the efflux of various endogenous and exogenous substances. Mutations in ABCC1 can result in autosomal dominant hearing loss. However, the specific roles of ABCC1 in auditory function are not fully understood. Through immunofluorescence, we found that ABCC1 was expressed in microvascular endothelial cells (ECs) of the stria vascularis (StV) in the murine cochlea. Then, an Abcc1 knockout mouse model was established by using CRISPR/Cas9 technology to elucidate the role of ABCC1 in the inner ear. The ABR threshold did not significantly differ between WT and Abcc1[-/-] mice at any age studied. After noise exposure, the ABR thresholds of the WT and Abcc1[-/-] mice were significantly elevated. Interestingly, after 14 days of noise exposure, ABR thresholds largely returned to pre-exposure levels in WT mice but not in Abcc1[-/-] mice. Our subsequent experiments showed that microvascular integrity in the StV was compromised and that the number of outer hair cells and the number of ribbons were significantly decreased in the cochleae of Abcc1[-/-] mice post-exposure. Besides, the production of ROS and the accumulation of 4-HNE significantly increased. Furthermore, StV microvascular ECs were cultured to elucidate the role of ABCC1 in these cells under glucose oxidase challenge. Notably, 30 U/L glucose oxidase (GO) induced severe oxidative stress damage in Abcc1[-/-] cells. Compared with WT cells, the ROS and 4-HNE levels and the apoptotic rate were significantly elevated in Abcc1[-/-] cells. In addition, the reduced GSH/GSSG ratio was significantly decreased in Abcc1[-/-] cells after GO treatment. Taken together, Abcc1[-/-] mice are more susceptible to noise-induced hearing loss, possibly because ABCC1 knockdown compromises the GSH antioxidant system of StV ECs. The exogenous antioxidant N-acetylcysteine (NAC) may protect against oxidative damage in Abcc1[-/-] murine cochleae and ECs.},
}
@article {pmid38867461,
year = {2024},
author = {Maxwell, MN and Marullo, AL and Valverde-Pérez, E and Slyne, AD and Murphy, BT and O'Halloran, KD},
title = {Chronic N-acetyl cysteine treatment does not improve respiratory system performance in the mdx mouse model of Duchenne muscular dystrophy.},
journal = {Experimental physiology},
volume = {109},
number = {8},
pages = {1370-1384},
pmid = {38867461},
issn = {1469-445X},
support = {FFP/19/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; },
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Mice, Inbred mdx ; *Muscular Dystrophy, Duchenne/drug therapy/physiopathology ; Male ; Mice ; *Disease Models, Animal ; *Diaphragm/drug effects/physiopathology ; Mice, Inbred C57BL ; Respiratory Muscles/drug effects/physiopathology ; Respiration/drug effects ; Antioxidants/pharmacology ; Respiratory System/drug effects/physiopathology/metabolism ; },
abstract = {Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin-deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N-acetylcysteine (NAC) has been shown to exert anti-inflammatory and anti-fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short-term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One-month-old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force-generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure-generating capacity. NAC treatment did not affect force-generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD.},
}
@article {pmid38866114,
year = {2024},
author = {Khan, AQ and Al-Tamimi, M and Anver, R and Agha, MV and Anamangadan, G and Raza, SS and Ahmad, F and Ahmad, A and Alam, M and Buddenkotte, J and Steinhoff, M and Uddin, S},
title = {Targeting of S-phase kinase associated protein 2 stabilized tumor suppressors leading to apoptotic cell death in squamous skin cancer cells.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1870},
number = {7},
pages = {167286},
doi = {10.1016/j.bbadis.2024.167286},
pmid = {38866114},
issn = {1879-260X},
mesh = {Humans ; *S-Phase Kinase-Associated Proteins/metabolism/genetics ; *Apoptosis/drug effects ; *Skin Neoplasms/pathology/metabolism/genetics/drug therapy ; *Carcinoma, Squamous Cell/pathology/metabolism/genetics/drug therapy ; Cell Line, Tumor ; *Kruppel-Like Factor 4/metabolism ; Cell Proliferation/drug effects ; Curcumin/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; },
abstract = {S-phase kinase-associated protein 2 (Skp2) is an F-box protein overexpressed in human cancers and linked with poor prognosis. It triggers cancer pathogenesis, including stemness and drug resistance. In this study, we have explored the potential role of Skp2 targeting in restoring the expression of tumor suppressors in human cutaneous squamous cell carcinoma (cSCC) cells. Our results showed that genetic and pharmacological Skp2 targeting markedly suppressed cSCC cell proliferation, colony growth, spheroid formation, and enhanced sensitization to chemotherapeutic drugs. Further, western blot results demonstrated restoration of tumor suppressor (KLF4) and CDKI (p21) and suppression of vimentin and survivin in Skp2-knocked-down cSCC cells. Importantly, we also explored that Skp2 targeting potentiates apoptosis of cSCC cells through MAPK signaling. Moreover, co-targeting of Skp2 and PI3K/AKT resulted in increased cancer cell death. Interestingly, curcumin, a well-known naturally derived anticancer agent, also inhibits Skp2 expression with concomitant CDKI upregulation. In line, curcumin suppressed cSCC cell growth through ROS-mediated apoptosis, while the use of N-acetyl cysteine (NAC) reversed curcumin-induced cell death. Curcumin treatment also sensitized cSCC cells to conventional anticancer drugs, such as cisplatin and doxorubicin. Altogether, these data suggest that Skp2 targeting restores the functioning of tumor suppressors, inhibits the expression of genes associated with cell proliferation and stemness, and sensitizes cancer cells to anticancer drugs. Thus, genetic, and pharmacological ablation of Skp2 can be an important strategy for attenuating cancer pathogenesis and associated complications in skin squamous cell carcinoma.},
}
@article {pmid38862667,
year = {2024},
author = {Kang, F and Wu, J and Hong, L and Zhang, P and Song, J},
title = {Iodine-125 seed inhibits proliferation and promotes apoptosis of cholangiocarcinoma cells by inducing the ROS/p53 axis.},
journal = {Functional &amp; integrative genomics},
volume = {24},
number = {3},
pages = {114},
pmid = {38862667},
issn = {1438-7948},
mesh = {*Cholangiocarcinoma/metabolism/radiotherapy/pathology/genetics/drug therapy ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Iodine Radioisotopes ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; Humans ; Cell Line, Tumor ; Bile Duct Neoplasms/metabolism/pathology/genetics/radiotherapy ; Acetylcysteine/pharmacology ; Benzothiazoles/pharmacology ; Signal Transduction/drug effects ; },
abstract = {With advances in radioactive particle implantation in clinical practice, Iodine-125 ([125]I) seed brachytherapy has emerged as a promising treatment for cholangiocarcinoma (CCA), showing good prognosis; however, the underlying molecular mechanism of the therapeutic effect of [125]I seed is unclear. To study the effects of [125]I seed on the proliferation and apoptosis of CCA cells. CCA cell lines, RBE and HCCC-9810, were treated with reactive oxygen species (ROS) scavenger acetylcysteine (NAC) or the p53 functional inhibitor, pifithrin-α hydrobromide (PFTα). Cell counting kit-8 (CCK-8) assay, 5-bromo-2-deoxy-uridine (BrdU) staining, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry assay were performed to test the radiation-sensitivity of [125]I seed toward CCA cells at different radiation doses (0.4 mCi and 0.8 mCi). 2,7-dichlorofluorescein diacetate (DCF-DA) assay, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot analysis were performed to assess the effect of [125]I seed on the ROS/p53 axis. A dose-dependent inhibitory effect of [125]I seeds on the proliferation of CCA cells was observed. The [125]I seed promoted apoptosis of CCA cells and induced the activation of the ROS/p53 pathway in a dose-dependent manner. NAC or PFTα treatment effectively reversed the stimulatory effect of [125]I seed on the proliferation of CCA cells. NAC or PFTα suppressed apoptosis and p53 protein expression induced by the [125]I seed. [125]I seed can inhibit cell growth mainly through the apoptotic pathway. The mechanism may involve the activation of p53 and its downstream apoptotic pathway by up-regulating the level of ROS in cells.},
}
@article {pmid38858642,
year = {2024},
author = {Hao, J and Zhang, X and Hu, R and Lu, X and Wang, H and Li, Y and Cheng, K and Li, Q},
title = {Metabolomics combined with network pharmacology reveals a role for astragaloside IV in inhibiting enterovirus 71 replication via PI3K-AKT signaling.},
journal = {Journal of translational medicine},
volume = {22},
number = {1},
pages = {555},
pmid = {38858642},
issn = {1479-5876},
support = {81301426//the National Natural Science Foundation of China/ ; 201901D111329//the Provincial Natural Science Foundation of Shanxi/ ; 202102130501005//Key Research and Development Plan of Shanxi Province/ ; 2020SHFZ38//the Mega Research and Development Projects of L&#xfc;liang/ ; 2020ZDSYS17//the Key Laboratory Platform Construction Projects of L&#xfc;liang/ ; 2023SHFZ50//the Luliang City Social Development Key Research and Development Project/ ; 2022C25//the Shanxi Medical University Fenyang College Project/ ; },
mesh = {*Virus Replication/drug effects ; *Saponins/pharmacology ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects ; *Triterpenes/pharmacology ; Humans ; *Phosphatidylinositol 3-Kinases/metabolism ; *Network Pharmacology ; *Metabolomics ; *Enterovirus A, Human/drug effects ; },
abstract = {BACKGROUND: Astragaloside IV (AST-IV), as an effective active ingredient of Astragalus membranaceus (Fisch.) Bunge. It has been found that AST-IV inhibits the replication of dengue virus, hepatitis B virus, adenovirus, and coxsackievirus B3. Enterovirus 71 (EV71) serves as the main pathogen in severe hand-foot-mouth disease (HFMD), but there are no specific drugs available. In this study, we focus on investigating whether AST-IV can inhibit EV71 replication and explore the potential underlying mechanisms.<br><br>METHODS: The GES-1 or RD cells were infected with EV71, treated with AST-IV, or co-treated with both EV71 and AST-IV. The EV71 structural protein VP1 levels, the viral titers in the supernatant were measured using western blot and 50% tissue culture infective dose (TCID50), respectively. Network pharmacology was used to predict possible pathways and targets for AST-IV to inhibit EV71 replication. Additionally, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was used to investigate the potential targeted metabolites of AST-IV. Associations between metabolites and apparent indicators were performed via Spearman's algorithm.<br><br>RESULTS: This study illustrated that AST-IV effectively inhibited EV71 replication. Network pharmacology suggested that AST-IV inhibits EV71 replication by targeting PI3K-AKT. Metabolomics results showed that AST-IV achieved these effects by elevating the levels of hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-hydroxy-1&#xa0;H-indole-3- acetamide, oxypurinol, while reducing the levels of PC (14:0/15:0). Furthermore, AST-IV also mitigated EV71-induced oxidative stress by reducing the levels of MDA, ROS, while increasing the activity of T-AOC, CAT, GSH-Px. The inhibition of EV71 replication was also observed when using the ROS inhibitor N-Acetylcysteine (NAC). Additionally, AST-IV exhibited the ability to activate the PI3K-AKT signaling pathway and suppress EV71-induced apoptosis.<br><br>CONCLUSION: This study suggests that AST-IV may activate the cAMP and the antioxidant stress response by targeting eight key metabolites, including hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-Hydroxy-1&#xa0;H-indole-3-acetamide, oxypurinol and PC (14:0/15:0). This activation can further stimulate the PI3K-AKT signaling to inhibit EV71-induced apoptosis and EV71 replication.},
}
@article {pmid38857427,
year = {2024},
author = {Zhang, R and Guan, S and Meng, Z and Deng, X and Lu, J},
title = {3-MCPD Induces Renal Cell Pyroptosis and Inflammation by Inhibiting ESCRT-III-Mediated Cell Repair and Mitophagy.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.4c01994},
pmid = {38857427},
issn = {1520-5118},
abstract = {3-Monochloropropane-1,2-diol (3-MCPD) is a chloropropyl alcohol contaminant mainly from the thermal processing of food and could affect kidneys. Pyroptosis is programmed cell death mediated by inflammasomes and gasdermins, and excessive cellular pyroptosis and inflammation can lead to tissue injury. In the present study, we found that 3-MCPD increased lactate dehydrogenase (LDH) levels in vitro and in vivo, increased the protein expression of NOD-like receptor family pyrin domain containing 3 (NLRP3), N-terminal domain of GSDMD (GSDMD-N), and cleaved caspase-1 and promoted the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18), which induced renal cell pyroptosis and inflammation. Mechanistic studies indicated that the addition of N-acetylcysteine (NAC), a ROS scavenger, inhibited NLRP3 activation and attenuated pyroptosis. Furthermore, we revealed that 3-MCPD induced ROS accumulation by inhibiting ESCRT-III-mediated mitophagy. These results were further validated by the overexpression of charged multivesicular body protein 4B (CHMP4B), a key subunit of ESCRT-III, and the addition of the mitophagy activator carbonyl cyanide m-chlorophenylhydrazone (CCCP) and rapamycin (Rapa). Thus, our results showed that 3-MCPD could induce mitochondrial damage and produce ROS. 3-MCPD suppressed mitophagy, leading to the accumulation of damaged mitochondria and ROS, thereby activating NLRP3 and pyroptosis. Meanwhile, 3-MCPD-mediated suppression of ESCRT-III hindered the repair of GSDMD-induced cell membrane rupture, which further caused the occurrence of pyroptosis. Our findings provide new perspectives for studying the mechanisms underlying 3-MCPD-induced renal injury.},
}
@article {pmid38854233,
year = {2024},
author = {Shah, N and Campbell, H and Patel, V and Moormeier, J},
title = {A Clinical Course of Repeated Supratherapeutic Ingestion of Acetaminophen.},
journal = {Cureus},
volume = {16},
number = {5},
pages = {e59883},
pmid = {38854233},
issn = {2168-8184},
abstract = {Acute liver failure (ALF) exemplifies a rapid decline in liver function among individuals with previously healthy livers, often manifesting through symptoms such as jaundice, confusion, and potentially life-threatening complications. Timely medical intervention, and, in severe instances, liver transplantation, are essential for enhancing outcomes and averting further deterioration. While the causes of ALF are multifaceted, in developed nations, it predominantly arises from drug-induced liver injury. Treatment primarily revolves around supportive measures, with severe cases necessitating liver transplantation. In instances where acute overdose with acetaminophen serves as the instigating factor, N-acetylcysteine (NAC) emerges as a pivotal component of management, as indicated by the Rumack-Matthew nomogram. The Rumack-Matthew nomogram guides treatment for acetaminophen overdose by correlating serum levels with the risk of liver damage. If levels exceed a set threshold, NAC is administered to prevent toxicity by replenishing glutathione. The decision to administer NAC is typically guided by this clinical tool, which aids healthcare providers in determining the appropriate course of action. NAC assumes a critical role in ameliorating the detrimental effects of acetaminophen overdose, particularly in averting liver damage, thus holding significant importance in patient care and recovery. While chronic acetaminophen overdose cases leading to ALF may also benefit from NAC, the supporting evidence remains weak. In this context, we present a case of ALF stemming from chronic acetaminophen ingestion, managed with NAC when liver transplantation was not a viable option.},
}
@article {pmid38847101,
year = {2024},
author = {Li, G and Li, M and Deng, Q and Yan, C and Lv, H and Zhao, G and Li, Y and Feng, Y and Sun, F and Fu, Y and Li, Y and Zhao, Z},
title = {Design, Synthesis and Preliminary Bioactivity Evaluation of N-Acetylcysteine Derivatives as Antioxidative and Anti-Inflammatory Agents.},
journal = {ChemMedChem},
volume = {19},
number = {18},
pages = {e202400110},
doi = {10.1002/cmdc.202400110},
pmid = {38847101},
issn = {1860-7187},
support = {2018CXGC1411//Key R&amp;D Programs of Shandong Province/ ; 2021CXGC010514//Key R&amp;D Programs of Shandong Province/ ; },
mesh = {*Acetylcysteine/pharmacology/chemistry/chemical synthesis ; Animals ; *Drug Design ; Structure-Activity Relationship ; *Antioxidants/pharmacology/chemical synthesis/chemistry ; Mice ; Molecular Structure ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/chemical synthesis/chemistry ; Dose-Response Relationship, Drug ; Pulmonary Fibrosis/drug therapy/chemically induced/pathology ; Male ; Humans ; Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; },
abstract = {N-acetylcysteine (NAC) is a commonly used mucolytic agent and antidote for acetaminophen overdose. For pulmonary diseases, NAC exhibits antioxidative properties, regulates cytokine production, reduces apoptosis of lung epithelial cells, and facilitates the resolution of inflammation. However, the efficacy of NAC in clinical trials targeting different pathological conditions is constrained by its short half-life and low bioavailability. In the present study, a series of NAC derivatives were designed and synthesized to further enhance its pharmacological activity. Structure-activity relationship (SAR) studies were conducted to optimize the activating groups. In vitro evaluations revealed that compounds 4 r, 4 t, 4 w, and 4 x exhibited superior antioxidative and anti-inflammatory activities compared to the positive controls of NAC and fudosteine. The ADME prediction analysis indicated that these compounds exhibited a favorable pharmacological profile. In-vivo experiments with compound 4 r demonstrated that the high-dose group (80 mg/kg) exhibited improved therapeutic effects in reversing the HPY level in mice with pulmonary fibrosis compared to the NAC group (500 mg/kg), further proving its superior oral bioavailability and therapeutic effect compared to NAC.},
}
@article {pmid38845374,
year = {2024},
author = {Bhowmik, A and Chakraborty, S and Rohit, A and Chauhan, A},
title = {Transcriptomic responses of extensively drug resistant Klebsiella pneumoniae to N-acetyl cysteine reveals suppression of major biogenesis pathways leading to bacterial killing and biofilm eradication.},
journal = {Journal of applied microbiology},
volume = {135},
number = {6},
pages = {},
doi = {10.1093/jambio/lxae136},
pmid = {38845374},
issn = {1365-2672},
support = {//UGC/ ; F.30-487/2019//BSR/ ; //DST/ ; OMI/20/2020-ECD-1//ICMR/ ; CRG/2021/001974//SERB/ ; //Department of Biotechnology/ ; },
mesh = {*Biofilms/drug effects ; *Klebsiella pneumoniae/drug effects/genetics ; *Anti-Bacterial Agents/pharmacology ; *Acetylcysteine/pharmacology ; Humans ; *Drug Resistance, Multiple, Bacterial/genetics ; *Transcriptome ; Klebsiella Infections/microbiology ; Microbial Sensitivity Tests ; India ; Bacterial Proteins/genetics/metabolism ; },
abstract = {AIMS: Carbapenemase-producing Klebsiella pneumoniae is categorized as a "critical global priority-one" pathogen by WHO and new and efficient treatment options are warranted. This study aims to assess the antibacterial and antibiofilm potential of N-acetyl cysteine (NAC), against clinical isolates of extensively drug resistant (XDR) K. pneumoniae and elucidate the mechanism of killing.<br><br>METHODS AND RESULTS: XDR-K. pneumoniae were isolated from patients admitted to Madras Medical Mission Hospital, India. Antibiofilm activity of NAC was checked using in vitro continuous flow model and RNA sequencing was done using Illumina Novoseq. Data quality was checked using FastQC and MultiQC software. Our findings revealed that NAC at a concentration of 100&#x2009;mg/ml was safe, and could inhibit the growth and completely eradicate mature biofilms of all XDR-K. pneumoniae isolates. Transcriptomic responses in XDR-K. pneumoniae to NAC showed significant downregulation of the genes associated with crucial biogenesis pathways, including electron transport chain and oxidoreductase activity besides a specific cluster of genes linked to ribosomal proteins.<br><br>CONCLUSIONS: Our results indicate that NAC kills the XDR- K. pneumoniae clinical isolates by shutting the overall metabolism and, hence, successfully eradicate in vitro biofilms formed on catheters.},
}
@article {pmid38843996,
year = {2024},
author = {Adiyeke, E and Bakan, N and Uvez, A and Arslan, DO and Kilic, S and Koc, B and Ozer, S and Saatci, O and Armutak, E&#x130;},
title = {The effect of N-acetylcysteine on the neurotoxicity of sevoflurane in developing hippocampus cells.},
journal = {Neurotoxicology},
volume = {103},
number = {},
pages = {96-104},
doi = {10.1016/j.neuro.2024.05.006},
pmid = {38843996},
issn = {1872-9711},
mesh = {*Sevoflurane/toxicity ; Animals ; *Acetylcysteine/pharmacology ; *Hippocampus/drug effects/metabolism/pathology ; *Anesthetics, Inhalation/toxicity ; Rats ; *Apoptosis/drug effects ; *Neuroprotective Agents/pharmacology ; Autophagy/drug effects ; Rats, Sprague-Dawley ; Male ; Neurons/drug effects/pathology/metabolism ; },
abstract = {Sevoflurane, a common pediatric anesthetic, has been linked to neurodegeneration, raising safety concerns. This study explored N-acetylcysteine's protective potential against sevoflurane-induced neurotoxicity in rat hippocampi. Four groups were examined: Control: Received 6 hours of 3 l/min gas (air and 30 % O2) and intraperitoneal saline. NAC: Received 6 hours of 3 l/min gas and 150 mg/kg NAC intraperitoneally. Sev: Exposed to 6 hours of 3 l/min gas and 3 % sevoflurane. Sev+NAC: Received 6 hours of 3 l/min gas, 3 % sevoflurane, and 150 mg/kg NAC. Protein levels of NRF-2, NLRP3, IL-1β, caspase-1, Beclin 1, p62, LC3A, and apoptosis markers were assessed. Sevoflurane and NAC alone reduced autophagy, while Sev+NAC group maintained autophagy levels. Sev group had elevated NRF-2, NLRP3, pNRF2, Caspase-1, and IL-1β, which were reduced in Sev+NAC. Apoptosis was higher in Sev, but Sev+NAC showed reduced apoptosis compared to the control. In summary, sevoflurane induced neurotoxicity in developing hippocampus, which was mitigated by N-acetylcysteine administration.},
}
@article {pmid38842239,
year = {2025},
author = {Hassan, AA and Ismail, NR and Rezk, AE and Elfeky, HM and Mady, AM and Allam, AG and Abbas, KS},
title = {Efficacy of N-acetylcysteine in reducing the risk of postoperative atrial fibrillation in cardiothoracic surgery: a systematic review and meta-analysis of randomized controlled trials.},
journal = {Minerva cardiology and angiology},
volume = {73},
number = {3},
pages = {387-396},
doi = {10.23736/S2724-5683.24.06482-2},
pmid = {38842239},
issn = {2724-5772},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Atrial Fibrillation/prevention &amp; control/etiology/epidemiology ; Randomized Controlled Trials as Topic ; *Cardiac Surgical Procedures/adverse effects ; *Postoperative Complications/prevention &amp; control/epidemiology ; Incidence ; },
abstract = {INTRODUCTION: New-onset postoperative atrial fibrillation (POAF) is a common complication following cardiac surgeries. N-acetylcysteine (NAC) showed a significant reduction in the incidence of POAF. This review aimed to systematically summarize and Meta-analyze data from previously published Randomized Controlled Trials (RCTs).<br><br>EVIDENCE ACQUISITION: Electronic databases: PubMed, Cochrane, Embase, Scopus, and Web of Science were searched. Data was extracted and the quality of the included studies was assessed. A random-effects DerSimonian Laird model was employed for meta-analysis.<br><br>EVIDENCE SYNTHESIS: Fifteen RCTs were included in this study (NAC, N.=940; control, N.=935). In the NAC group, 16.38% developed POAF compared with 23.53% in the control group. NAC supplementation was associated with a decreased incidence of POAF in patients undergoing cardiothoracic surgery (RR 0.69; 95% CI 0.52, 0.91; P=0.008). Meta-regression of randomized trial data showed that the incidence of POAF was not related to the NAC dose (P=0.439). A subgroup analysis in terms of the time of NAC administration revealed that preoperative and postoperative NAC administration was the only subgroup that demonstrated a statistically significant difference (RR 0.48, 95% CI 0.32, 0.71; P=0.0003) compared with placebo and showed no heterogeneity.<br><br>CONCLUSIONS: Atrial fibrillation is a significant postoperative complication, particularly in cardiothoracic surgery. This study highlights the need for further research on optimal NAC dosing and timing, with evidence suggesting that preoperative and postoperative NAC administration may significantly decrease postoperative atrial fibrillation in cardiothoracic surgery patients, although limitations and variability in study designs need to be considered.},
}
@article {pmid38841121,
year = {2024},
author = {Jenkins, DD and Garner, SS and Brennan, A and Morris, J and Bonham, K and Adams, L and Hunt, S and Moss, H and Badran, BW and George, MS and Wiest, DB},
title = {Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds.},
journal = {Frontiers in human neuroscience},
volume = {18},
number = {},
pages = {1373543},
pmid = {38841121},
issn = {1662-5161},
support = {P20 GM109040/GM/NIGMS NIH HHS/United States ; P2C HD086844/HD/NICHD NIH HHS/United States ; },
abstract = {OBJECTIVE: This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds.<br><br>METHODS: We treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100&#x2009;mg/kg/dose) was given by nasogastric (NG) administration every 6&#x2009;h for 4&#x2009;days, then combined with taVNS paired with 2 daily feeds for another 14&#x2009;days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone.<br><br>RESULTS: NAC 100&#x2009;mg/kg/dose every 6&#x2009;h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13&#x2009;&#xb1;&#x2009;0.08&#x2009;mM (p&#x2009;=&#x2009;0.01, compared to baseline). Mean daily feeding volumes increased over 14&#x2009;days of NAC&#x2009;+&#x2009;taVNS compared to the 14&#x2009;days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake.<br><br>CONCLUSION: In IDM failing oral feeds, NAC 100&#x2009;mg/kg/dose every 6&#x2009;h NG for 4&#x2009;days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.},
}
@article {pmid38836732,
year = {2024},
author = {Chen, J and Zhu, Y and Zheng, C and Zhao, W and Liu, Q},
title = {Influence Factors of the Therapeutic Effect of Budesonide Combined with N-Acetylcysteine in Children with Mycoplasma Pneumoniae Infection Analyzed by Lasso-Logistic and Construction of a Nomogram Prediction Model.},
journal = {Alternative therapies in health and medicine},
volume = {30},
number = {9},
pages = {112-117},
pmid = {38836732},
issn = {1078-6791},
mesh = {Humans ; *Nomograms ; *Acetylcysteine/therapeutic use ; Female ; Male ; Child ; *Pneumonia, Mycoplasma/drug therapy ; Retrospective Studies ; *Budesonide/therapeutic use/administration &amp; dosage ; Child, Preschool ; Drug Therapy, Combination ; Logistic Models ; Mycoplasma pneumoniae/drug effects ; Treatment Outcome ; Adolescent ; },
abstract = {OBJECTIVE: This study aims to analyze the factors influencing the efficacy of budesonide (BUD) combined with N-acetylcysteine (NAC) treatment in children with Mycoplasma pneumoniae (MP) infection through Lasso-Logistic analysis, construct a Nomogram predictive model, and provide personalized treatment plans for clinicians. Additionally, it aims to fill the knowledge gap regarding the treatment of MP-infected children with BUD combined with NAC.<br><br>METHODS: We retrospectively analyzed clinical data from 96 children treated with BUD and NAC for MP infection at our hospital from January 2022 to May 2023. Treatment outcomes were categorized as good or poor. Logistic regression and Lasso-Logistic analysis were used to identify independent factors influencing outcomes and construct a predictive Nomogram model, which was validated through ROC curve analysis.<br><br>RESULTS: Logistic regression identified prolonged fever (&#x2265;7 days), high fever, and elevated levels of TNF-&#x3b1;, IL-6, and CRP as independent risk factors for poor outcomes. The Nomogram model, based on these factors, demonstrated excellent predictive accuracy with a C-index of 0.992 and AUC values of 0.987 and 0.948 in the modeling and validation cohorts, respectively.<br><br>CONCLUSION: The developed Nomogram model provides clinicians with a reliable tool to predict poor treatment outcomes in children with MP infection treated with BUD and NAC, supporting more personalized and effective treatment plans.},
}
@article {pmid38828636,
year = {2024},
author = {Lu, J and Zhao, P and Ding, X and Liu, Y and Li, H},
title = {N-Acetylcysteine assists muscle development in offspring of mice subjected to maternal heat stress during pregnancy.},
journal = {Journal of the science of food and agriculture},
volume = {104},
number = {13},
pages = {7895-7906},
doi = {10.1002/jsfa.13620},
pmid = {38828636},
issn = {1097-0010},
support = {No.32172725//National Natural Science Foundation of China/ ; 2023AAC02013//Ningxia Natural Science Foundation of China/ ; 2021YFC2101403//National Key Research and Development Program of China/ ; },
mesh = {Animals ; *Acetylcysteine/administration &amp; dosage/pharmacology ; Female ; Mice ; Pregnancy ; *Muscle Development/drug effects ; Male ; *Heat-Shock Response/drug effects ; *Muscle, Skeletal/metabolism/drug effects/growth &amp; development ; Antioxidants/metabolism ; Prenatal Exposure Delayed Effects ; Humans ; Dietary Supplements/analysis ; },
abstract = {BACKGROUND: Heat stress (HS) has been shown to affect reproductive performance and muscle development negatively in animals. N-Acetylcysteine (NAC) plays a pivotal role in enhancing the antioxidant performance in animals as a recognized antioxidant. The present study assesses the potential of NAC to modulate the reproductive performance and antioxidant function in pregnant mice exposed to HS. The role of NAC in muscle development of offspring mice was also explored.<br><br>RESULTS: The results showed that NAC supplementation from day 12 to day 18 of gestation increased the number of litters and enhanced the antioxidant function in pregnant mice under HS exposure. It improved the weight and body condition significantly in the offspring mice (P&#x2009;<&#x2009;0.05). The alleviation of HS-induced muscle impairment with NAC was consistent with the alleviation of apoptosis, the enrichment of the proliferation and differentiation in the offspring mice muscle. N-Acetylcysteine also reversed HS-induced reduction in the cross-sectional area of the leg muscle and increased the proportion of myosin heavy chain IIx (MYHCIIx) in the muscle fiber.<br><br>CONCLUSION: The results of the present study support the use of NAC at a dose of 100&#x2009;mg&#x2009;kg[-1] body weight as supplement for protecting the offspring derived from pregnant mice exposed to HS from muscle impairment by accelerating proliferation and differentiation. &#xa9; 2024 Society of Chemical Industry.},
}
@article {pmid38825302,
year = {2024},
author = {Zhang, Y and Qu, Y and Cai, R and Gao, J and Xu, Q and Zhang, L and Kang, M and Jia, H and Chen, Q and Liu, Y and Ren, F and Zhou, MS},
title = {Atorvastatin ameliorates diabetic nephropathy through inhibiting oxidative stress and ferroptosis signaling.},
journal = {European journal of pharmacology},
volume = {976},
number = {},
pages = {176699},
doi = {10.1016/j.ejphar.2024.176699},
pmid = {38825302},
issn = {1879-0712},
mesh = {*Ferroptosis/drug effects ; Animals ; *Diabetic Nephropathies/drug therapy/metabolism/pathology/prevention &amp; control ; *Oxidative Stress/drug effects ; *Atorvastatin/pharmacology/therapeutic use ; Male ; *Signal Transduction/drug effects ; Mice ; *Reactive Oxygen Species/metabolism ; Diabetes Mellitus, Experimental/drug therapy/metabolism/complications ; Mice, Inbred C57BL ; Humans ; Kidney/drug effects/metabolism/pathology ; Cell Line ; Phenylenediamines/pharmacology/therapeutic use ; },
abstract = {Clinically, statins have long been used for the prevention and treatment of chronic renal diseases, however, the underlying mechanisms are not fully elucidated. The present study investigated the effects of atorvastatin on diabetes renal injury and ferroptosis signaling. A mouse model of diabetes was established by the intraperitoneal injection of streptozotocin (50 mg/kg/day) plus a high fat diet with or without atorvastatin treatment. Diabetes mice manifested increased plasma glucose and lipid profile, proteinuria, renal injury and fibrosis, atorvastatin significantly lowered plasma lipid profile, proteinuria, renal injury in diabetes mice. Atorvastatin reduced renal reactive oxygen species (ROS), iron accumulation and renal expression of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), transferrin receptor 1 (TFR1), and increased renal expression of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2) and ferritin heavy chain (FTH) in diabetes mice. Consistent with the findings in vivo, atorvastatin prevented high glucose-induced ROS formation and Fe[2+] accumulation, an increase in the expression of 4-HNE, MDA and TFR1, and a decrease in cell viability and the expression of NRF2, GPX4 and FTH in HK2 cells. Atorvastatin also reversed ferroptosis inducer erastin-induced ROS production, intracellular Fe[2+] accumulation and the changes in the expression of above-mentioned ferroptosis signaling molecules in HK2 cells. In addition, atorvastatin alleviated high glucose- or erastin-induced mitochondria injury. Ferroptosis inhibitor ferrostatin-1 and antioxidant N-acetylcysteine (NAC) equally reversed the expression of high glucose-induced ferroptosis signaling molecules. Our data support the notion that statins can inhibit diabetes-induced renal oxidative stress and ferroptosis, which may contribute to statins protection of diabetic nephropathy.},
}
@article {pmid38821668,
year = {2024},
author = {Naser, H and Munn, K and Lawrence, R and Wright, R and Grewal, E and Williams, L and Doak, S and Jenkins, G},
title = {Human plasma can modulate micronucleus frequency in TK6 and OE33 cells in vitro.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {896},
number = {},
pages = {503766},
doi = {10.1016/j.mrgentox.2024.503766},
pmid = {38821668},
issn = {1879-3592},
mesh = {Humans ; *Micronucleus Tests ; *DNA Damage ; *Barrett Esophagus/pathology/genetics ; *Adenocarcinoma/pathology/genetics ; *Esophageal Neoplasms/genetics/pathology ; Plasma/metabolism ; Interleukin-8/metabolism/genetics ; Cell Line, Tumor ; Cell Cycle/drug effects ; Male ; Middle Aged ; Adult ; Cell Survival/drug effects ; Female ; Micronuclei, Chromosome-Defective ; Interferon-beta ; Aged ; },
abstract = {In this paper, we studied the potential genotoxic effects of human plasma from healthy volunteers, as well as patients with gastro-oesophageal reflux disease, Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) using the oesophageal adenocarcinoma cell line (OE33) and the lymphoblastoid cell line (TK6). Both TK6 and OE33 cells were treated with plasma (10 % volume, replacing foetal bovine serum (FBS) or horse serum (HS)) at different time points of 4 h (for the micronucleus (Mn) assay and the invasion assay) and 24 h (for the cell cycle studies). Plasma-induced effects on DNA damage levels, cell viability and the cell cycle were studied by the micronucleus assay, cytokinesis block proliferation index (CBPI) and flow cytometry respectively. The expression of IL-8 in supernatants of TK6 cells and IFN-β in OE33 cells was also analysed by enzyme-linked immunosorbent assay (ELISA). Finally, we carried out an assessment of cellular invasion of OE33 cells following plasma treatment. The results of the micronucleus assay confirmed the genotoxicity of direct plasma treatment from some participants through the increase in DNA damage in TK6 cells. Conversely, some individual patient plasma samples reduced background levels of TK6 cell Mn frequency, in an anti-genotoxic fashion. In TK6 cells, (on average) plasma samples from patients with Barrett's oesophagus induced higher micronucleus levels than healthy volunteers (p= 0.0019). There was little difference in Mn induction when using plasma versus serum to treat the cells in vitro. Cell cycle results showed that direct plasma treatment had a marked impact on OE33 cells at 24 h (p=0.0182 for BO and p=0.0320 for OAC) by decreasing the proportion of cells in the S phase, while plasma exposure was less impactful on the cell cycle of TK6 cells. Invasion of OE33 cells was also seen to be non-significantly affected by plasma treatment of OE33 cells. The addition of N-acetyl cysteine NAC in a dose-dependent matter did not alter the formation of Mn in TK6 cells, suggesting that reactive oxygen species (ROS) are not the root cause of plasma's genotoxicity. The concentration of IL-8 in TK6 cells and IFN-β in OE33 cells was significantly higher in cells treated with OAC-derived plasma than in the untreated negative control. Collectively, our results demonstrate that plasma-specific effects are detectable which helps us better understand some important aspects of the biology of blood-based biomarkers under development.},
}
@article {pmid38821596,
year = {2024},
author = {Wang, YJ and Hao, YY and Lee, DH and Guo, XY and Sun, HN and Kwon, T},
title = {Hispidin Increases Cell Apoptosis and Ferroptosis in Prostate Cancer Cells Through Phosphatidylinositol-3-Kinase and Mitogen-activated Protein Kinase Signaling Pathway.},
journal = {Anticancer research},
volume = {44},
number = {6},
pages = {2533-2544},
doi = {10.21873/anticanres.17059},
pmid = {38821596},
issn = {1791-7530},
mesh = {Humans ; Male ; *Ferroptosis/drug effects ; *Prostatic Neoplasms/pathology/metabolism/drug therapy ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; MAP Kinase Signaling System/drug effects ; Cell Movement/drug effects ; Signal Transduction/drug effects ; Mitochondria/drug effects/metabolism ; Pyridones/pharmacology ; Phosphatidylinositol 3-Kinase/metabolism ; Pyrones ; },
abstract = {BACKGROUND/AIM: Chemotherapy is mainly used in the clinical treatment of prostate cancer. Different anticancer mechanisms can induce cell death in various cancers. Reactive oxygen species (ROS) play crucial roles in cell proliferation, differentiation, apoptosis, and signal transduction. It is widely accepted that ROS accumulation is closely related to chemical drug-induced cancer cell death.<br><br>MATERIALS AND METHODS: We utilized the MTT assay to detect changes in cell proliferation. Additionally, colony formation and wound healing assay were conducted to investigate the effect of hispidin on cell colony formation and migration ability. Fluorescence microscopy was used to detect intracellular and mitochondrial ROS levels, while western blot was used for detection of cell apoptosis.<br><br>RESULTS: Hispidin treatment significantly decreased viability of PC3 and DU145 cancer cells but exhibited no cytotoxicity in WPMY-1 cells. Furthermore, hispidin treatment inhibited cell migration and colony formation and triggered cellular and mitochondrial ROS accumulation, leading to mitochondrial dysfunction and mitochondrion-dependent apoptosis. Moreover, hispidin treatment induced ferroptosis in PC3 cells. Scavenging of ROS with N-acetyl cysteine significantly inhibited hispidin-induced apoptosis by altering the expression of apoptosis-related proteins, such as cleaved caspase-3, 9, Bax, and Bcl2. Furthermore, hispidin treatment dramatically up-regulated MAPK (involving p38, ERK, and JNK proteins) and NF-kB signaling pathways while down-regulating AKT phosphorylation. Hispidin treatment also inhibited ferroptosis signaling pathways (involving P53, Nrf-2, and HO-1 proteins) in PC3 cells. In addition, inhibiting these signaling pathways via treatment with specific inhibitors significantly reversed hispidin-induced apoptosis, cellular ROS levels, mitochondrial dysfunction, and ferroptosis.<br><br>CONCLUSION: Hispidin may represent a potential candidate for treating prostate cancer.},
}
@article {pmid38818810,
year = {2025},
author = {Li, X and Li, Y and Yu, H and Men, LL and Deng, G and Liu, Z and Du, JL},
title = {Oxidized Low-Density Lipoprotein Decreases the Survival of Bone Marrow Stem Cells via Inhibition of Bcl-2 Expression.},
journal = {Tissue engineering. Part A},
volume = {31},
number = {7-8},
pages = {325-333},
doi = {10.1089/ten.TEA.2024.0025},
pmid = {38818810},
issn = {1937-335X},
mesh = {*Lipoproteins, LDL/pharmacology ; Animals ; *Proto-Oncogene Proteins c-bcl-2/metabolism ; Cell Survival/drug effects ; Mice, Inbred C57BL ; Mice ; *Mesenchymal Stem Cells/cytology/metabolism/drug effects ; *Bone Marrow Cells/cytology/metabolism/drug effects ; Male ; L-Lactate Dehydrogenase/metabolism ; },
abstract = {Therapy with mesenchymal stem cells (MSCs) is considered an attractive strategy for the repair or regeneration of damaged tissues. However, low survival of MSCs limits their applications clinically. Oxidized low-density lipoprotein (ox-LDL) is significantly increased in patients with hyperlipidemia and decreases the survival of MSCs. Bcl-2 is critically involved in important cell functions, including cell membrane integrity and cell survival. The present study was designed to test the hypothesis that ox-LDL attenuates the survival of MSCs through suppression of Bcl-2 expression. Bone marrow MSCs from C57BL/6 mice were cultured with ox-LDL at different concentrations (0-140 μg/mL) for 24 h with native LDL as control. Ox-LDL treatment substantially decreased the survival of MSCs dose-dependently and enhanced the release of intracellular lactate dehydrogenase (LDH) in association with a significant decrease in Bcl-2 protein level without change in BAX protein expression in MSCs. Bcl-2 overexpression effectively protected MSCs against ox-LDL-induced damages with preserved cell numbers without significant increase in LDH release. Treatment with N-acetylcysteine (NAC) (1 mM) effectively preserved Bcl-2 protein expression in MSCs and significantly attenuated ox-LDL-induced decrease of cell number and increase in the release of intracellular LDH. These data indicated that ox-LDL treatment resulted in a significant damage of cell membrane and dramatically decreased the survival of MSCs dose-dependently through inhibition of Bcl-2 expression. NAC treatment significantly protected MSCs against the damage of cell membrane by ox-LDL and promoted the survival of MSCs in association with preserved Bcl-2 expression.},
}
@article {pmid38815788,
year = {2024},
author = {Ge, L and Liu, P and Tian, L and Li, Y and Chen, L},
title = {Se-methylselenocysteine inhibits the progression of non-small cell lung cancer via ROS-mediated NF-κB signaling pathway.},
journal = {Experimental cell research},
volume = {440},
number = {1},
pages = {114101},
doi = {10.1016/j.yexcr.2024.114101},
pmid = {38815788},
issn = {1090-2422},
mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/metabolism/pathology/drug therapy ; Animals ; *Lung Neoplasms/pathology/metabolism/drug therapy ; *Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; *NF-kappa B/metabolism ; *Selenocysteine/analogs &amp; derivatives/pharmacology ; *Cell Proliferation/drug effects ; Mice ; *Apoptosis/drug effects ; Cell Movement/drug effects ; Mice, Nude ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; A549 Cells ; Organoselenium Compounds/pharmacology ; Mice, Inbred BALB C ; },
abstract = {Se-methylselenocysteine (MSC) is recognized for its potential in cancer prevention, yet the specific effects and underlying processes it initiates within non-small cell lung cancer (NSCLC) remain to be fully delineated. Employing a comprehensive array of assays, including CCK-8, colony formation, flow cytometry, MitoSOX Red staining, wound healing, transwell, and TUNEL staining, we evaluated MSC's effects on A549 and 95D cell lines. Our investigation extended to the ROS-mediated NF-κB signaling pathway, utilizing Western blot analysis, P65 overexpression, and the application of IκB-α inhibitor (BAY11-7082) or N-acetyl-cysteine (NAC) to elucidate MSC's mechanism of action. In vivo studies involving subcutaneous xenografts in mice further confirmed MSC's inhibitory effect on tumor growth. Our findings indicated that MSC inhibited the proliferation of A549 and 95D cells, arresting cell cycle G0/G1 phase and reducing migration and invasion, while also inducing apoptosis and increasing intracellular ROS levels. This was accompanied by modulation of key proteins, including the upregulation of p21, p53, E-cadherin, Bax, cleaved caspase-3, cleaved-PARP, and downregulation of CDK4, SOD2, GPX-1. MSC was found to inhibit the NF-κB pathway, as evidenced by decreased levels of P-P65 and P-IκBα. Notably, overexpression of P65 and modulation of ROS levels with NAC could attenuate MSC's effects on cellular proliferation and metastasis. Moreover, MSC significantly curtailed tumor growth in vivo and disrupted the NF-κB signaling pathway. In conclusion, our research demonstrates that MSC exhibits anticancer effects against NSCLC by modulating the ROS/NF-κB signaling pathway, suggesting its potential as a therapeutic agent in NSCLC treatment.},
}
@article {pmid38814824,
year = {2024},
author = {Zheng, F and Ye, C and Lei, JZ and Ge, R and Li, N and Bo, JH and Chen, AD and Zhang, F and Zhou, H and Wang, JJ and Chen, Q and Li, YH and Zhu, GQ and Han, Y},
title = {Intervention of Asprosin Attenuates Oxidative Stress and Neointima Formation in Vascular Injury.},
journal = {Antioxidants &amp; redox signaling},
volume = {41},
number = {7-9},
pages = {488-504},
doi = {10.1089/ars.2023.0383},
pmid = {38814824},
issn = {1557-7716},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Neointima/metabolism/pathology ; Mice ; *Fibrillin-1/metabolism/genetics ; *Cell Proliferation/drug effects ; *Muscle, Smooth, Vascular/metabolism/cytology ; *Cell Movement/drug effects ; *Vascular System Injuries/metabolism/pathology ; Myocytes, Smooth Muscle/metabolism ; NF-E2-Related Factor 2/metabolism ; Male ; Toll-Like Receptor 4/metabolism ; Disease Models, Animal ; },
abstract = {Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury. Antioxid. Redox Signal. 41, 488-504.},
}
@article {pmid38812790,
year = {2024},
author = {Chung, J and Jernigan, J and Menees, KB and Lee, JK},
title = {RGS10 mitigates high glucose-induced microglial inflammation via the reactive oxidative stress pathway and enhances synuclein clearance in microglia.},
journal = {Frontiers in cellular neuroscience},
volume = {18},
number = {},
pages = {1374298},
pmid = {38812790},
issn = {1662-5102},
support = {R01 NS119610/NS/NINDS NIH HHS/United States ; R21 NS118224/NS/NINDS NIH HHS/United States ; },
abstract = {Microglia play a critical role in maintaining brain homeostasis but become dysregulated in neurodegenerative diseases. Regulator of G-protein Signaling 10 (RGS10), one of the most abundant homeostasis proteins in microglia, decreases with aging and functions as a negative regulator of microglia activation. RGS10-deficient mice exhibit impaired glucose tolerance, and high-fat diet induces insulin resistance in these mice. In this study, we investigated whether RGS10 modulates microglia activation in response to hyperglycemic conditions, complementing our previous findings of its role in inflammatory stimuli. In RGS10 knockdown (KD) BV2 cells, TNF production increased significantly in response to high glucose, particularly under proinflammatory conditions. Additionally, glucose uptake and GLUT1 mRNA levels were significantly elevated in RGS10 KD BV2 cells. These cells produced higher ROS and displayed reduced sensitivity to the antioxidant N-Acetyl Cysteine (NAC) when exposed to high glucose. Notably, both BV2 cells and primary microglia that lack RGS10 exhibited impaired uptake of alpha-synuclein aggregates. These findings suggest that RGS10 acts as a negative regulator of microglia activation not only in response to inflammation but also under hyperglycemic conditions.},
}
@article {pmid38812125,
year = {2024},
author = {Chu, CS and Chen, YT and Liang, WZ},
title = {Investigation of the mechanisms behind ochratoxin A-induced cytotoxicity in human astrocytes and the protective effects of N-acetylcysteine.},
journal = {Journal of applied toxicology : JAT},
volume = {44},
number = {9},
pages = {1454-1465},
doi = {10.1002/jat.4652},
pmid = {38812125},
issn = {1099-1263},
support = {//Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University/ ; },
mesh = {*Ochratoxins/toxicity ; Humans ; *Astrocytes/drug effects ; *Acetylcysteine/pharmacology ; *Reactive Oxygen Species/metabolism ; Cell Line ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; *Glutathione/metabolism ; Cell Survival/drug effects ; Antioxidants/pharmacology ; NF-E2-Related Factor 2/metabolism ; Caspase 3/metabolism ; Heme Oxygenase-1/metabolism ; bcl-2-Associated X Protein/metabolism ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; },
abstract = {Ochratoxin A (OTA) is a type of mycotoxin commonly found in raw and processed foods. It is essential to be aware of this toxin, as it can harm your health if consumed in high quantities. OTA can induce toxic effects in various cell models. However, a more comprehensive understanding of the harmful effects of OTA on human astrocytes is required. This study evaluated OTA's neurotoxic effects on the Gibco® Human Astrocyte (GHA) cell line, its underlying mechanisms, and the antioxidant N-acetylcysteine (NAC) ability to prevent them. OTA exposure within 5-30 μM has induced concentration-dependent cytotoxicity. In the OTA-treated cells, the levels of reactive oxygen species (ROS) were found to be significantly increased, while the glutathione (GSH) contents were found to decrease considerably. The western blotting of OTA-treated cells has revealed increased Bax, cleaved caspase-9/caspase-3 protein levels, and increased Bax/Bcl-2 ratio. In addition, exposure to OTA has resulted in the induction of antioxidant responses associated with the protein expressions of Nrf2, HO-1, and NQO1. On the other hand, the pretreatment with NAC has partially alleviated the significant toxic effects of OTA. In conclusion, our findings suggest that oxidative stress and apoptosis are involved in the OTA-induced cytotoxicity in GHA cells. NAC could act as a protective agent against OTA-induced oxidative damage.},
}
@article {pmid38810310,
year = {2024},
author = {Shen, P and Xue, M and Hu, Z and Han, L and Deng, X},
title = {Direct targeting of S100A9 with Icariin counteracted acetaminophen‑induced hepatotoxicity.},
journal = {International immunopharmacology},
volume = {136},
number = {},
pages = {112296},
doi = {10.1016/j.intimp.2024.112296},
pmid = {38810310},
issn = {1878-1705},
mesh = {Animals ; *Flavonoids/pharmacology/therapeutic use ; *Acetaminophen ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/pathology ; *Mice, Inbred C57BL ; Male ; Mice ; *Calgranulin B/metabolism/genetics ; Apoptosis/drug effects ; NF-E2-Related Factor 2/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Liver/drug effects/pathology/metabolism ; Humans ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/metabolism/genetics ; },
abstract = {Acetaminophen (APAP) is a widely used antipyretic and analgesic medication, but its overdose can induce acute liver failure with lack of effective therapies. Icariin is a bioactive compound derived from the herb Epimedium that displays hepatoprotective activities. Here, we explored the protective effects and mechanism of icariin on APAP-induced hepatotoxicity. Icariin (25/50 mg/kg) or N-Acetylcysteine (NAC, 300 mg/kg) were orally administered in wild-type C57BL/6 mice for 7 consecutive days before the APAP administration. Icariin attenuated APAP-induced acute liver injury in mice, as measured by alleviated serum enzymes activities and hepatic apoptosis. In vitro, icariin pretreatment significantly inhibited hepatocellular damage and apoptosis by reducing the BAX/Bcl-2 ratio as well as the expression of cleaved-caspase 3 and cleaved-PARP depended on the p53 pathway. Moreover, icariin attenuated APAP-mediated inflammatory response and oxidative stress via the Nrf2 and NF-κB pathways. Importantly, icariin reduced the expression of S100A9, icariin interacts with S100A9 as a direct cellular target, which was supported by molecular dynamics simulation and surface plasmon resonance assay (equilibrium dissociation constant, KD = 1.14 μM). In addition, the genetic deletion and inhibition of S100A9 not only alleviated APAP-induced injury but also reduced the icariin's protective activity in APAP-mediated liver injury. These data indicated that icariin targeted S100A9 to alleviate APAP-induced liver damage via the following signaling pathways NF-κB, p53, and Nrf2.},
}
@article {pmid38810283,
year = {2024},
author = {Zhu, Y and Zhang, S and Shao, Y and Tang, L and Zhang, C and Tang, S and Lu, H},
title = {Regulatory role of oxidative stress in retrorsine - Induced apoptosis and autophagy in primary rat hepatocytes.},
journal = {Ecotoxicology and environmental safety},
volume = {279},
number = {},
pages = {116515},
doi = {10.1016/j.ecoenv.2024.116515},
pmid = {38810283},
issn = {1090-2414},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Hepatocytes/drug effects ; *Apoptosis/drug effects ; *Autophagy/drug effects ; *Pyrrolizidine Alkaloids/toxicity ; Rats ; Male ; Reactive Oxygen Species/metabolism ; Rats, Sprague-Dawley ; Cells, Cultured ; Aspartate Aminotransferases ; Alanine Transaminase ; },
abstract = {Pyrrolizidine alkaloids (PAs) are a group of naturally occurring alkaloids widely present in plants. PAs are highly hepatotoxic and have been documented to cause many incidents of human and animal poisoning. Retrorsine (RTS) is a pyrrolizidine alkaloid (PA) derived from the Compositae Senecio, which has been shown to cause hepatotoxicity. Human liver poisoning occurs through the consumption of RTS-contaminated food, and animals can also be poisoned by ingesting RTS-containing toxic plants. The mechanism of RTS-induced liver toxicity is not fully understood. In this study, we demonstrated that RTS-induced oxidative stress plays a pivotal role in RTS-induced liver toxicity involving apoptosis and autophagy. The results showed that RTS treatment in the cultured Primary rat hepatocytes caused cytotoxicity and release of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in a time- and dose-dependent manner. Our study showed that treatment of RTS induced ROS and MDA (malondialdehyde, a lipid peroxidation marker) in the hepatocytes, and reduced antioxidant capacity (GSH content, SOD activity), suggesting RTS treatment caused oxidative stress response in the hepatocytes. Furthermore, we found that RTS induced apoptosis and autophagy in the hepatocytes, and RTS-induced apoptosis and autophagy could be alleviated by ROS scavenger N-acetylcysteine (NAC) and the MAPK pathway inhibitors suggesting ROS/MAPK signaling pathway plays a role in RTS induced apoptosis and autophagy. Collectively, this study reveals the regulatory mechanism of oxidative stress in RTS-induced apoptosis and autophagy in the hepatocytes, providing important insights of molecular mechanisms of hepatotoxicity induced by RTS and related pyrrolizidine alkaloids in liver. This mechanism provides a basis for the prevention and treatment of PA poisoning in humans and animals.},
}
@article {pmid38804152,
year = {2024},
author = {Wang, Y and Long, L and Luo, Q and Huang, X and Zhang, Y and Meng, X and Chen, D},
title = {Aflatoxin B1 induces ROS-dependent mitophagy by modulating the PINK1/Parkin pathway in HepG2 cells.},
journal = {Basic &amp; clinical pharmacology &amp; toxicology},
volume = {135},
number = {2},
pages = {195-209},
doi = {10.1111/bcpt.14034},
pmid = {38804152},
issn = {1742-7843},
mesh = {Humans ; *Mitophagy/drug effects ; Hep G2 Cells ; *Reactive Oxygen Species/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Membrane Potential, Mitochondrial/drug effects ; *Protein Kinases/metabolism ; *Aflatoxin B1/toxicity ; *Adenosine Triphosphate/metabolism ; *NF-E2-Related Factor 2/metabolism/genetics ; Signal Transduction/drug effects ; Phosphoprotein Phosphatases/metabolism/genetics ; Mitochondria/drug effects/metabolism ; Acetylcysteine/pharmacology ; Mitochondrial Proteins/metabolism/genetics ; PTEN-Induced Putative Kinase ; },
abstract = {Aflatoxin B1 (AFB1) is extremely harmful to both humans and animals. Mitophagy is a selective process of self-elimination and has an important role in controlling mitochondrial quality. The present study aimed to investigate the effect of reactive oxygen species (ROS) accumulation on AFB1-induced mitophagy in HepG2 cells to provide a new perspective from which to design novel therapeutic strategies to treat AFB1 poisoning. ROS release was induced in HepG2 cells with AFB1 (10 μmol/L). Cell autophagy activity, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) levels, Parkin translocation and both the transcription and expression of mitophagy-related proteins were measured when N-acetyl-L-cysteine (NAC) partially decreased the ROS level, while the knockdown of nuclear factor erythroid 2-related factor 2 (Nrf2) resulted in a large accumulation of ROS. The results reveal that NAC pretreatment ameliorated the decline in both the MMP and the ATP levels while also activating phosphoglycerate mutase 5 (PGAM5)-PTEN-induced kinase 1 (PINK1)/Parkin, while the Nrf2 knockdown group exhibited the opposite trend. These results suggest that AFB1-induced mitophagy in HepG2 cells depends on ROS, and proper ROS activates mitophagy to play a protective role.},
}
@article {pmid38800031,
year = {2024},
author = {Raeeszadeh, M and Arvand, S and Shojaee Moghadam, D and Akradi, L},
title = {Evaluation of the influence of N-acetylcysteine and broccoli extract on systemic paraquat poisoning: Implications for biochemical, physiological, and histopathological parameters in rats.},
journal = {Iranian journal of basic medical sciences},
volume = {27},
number = {7},
pages = {895-903},
pmid = {38800031},
issn = {2008-3866},
abstract = {OBJECTIVES: Paraquat (PQ), a potent environmental herbicide, is recognized for inducing irreparable toxic damage to biological systems. This study aimed to evaluate the effectiveness of N-acetylcysteine (NAC) and broccoli extract, individually and in combination, in alleviating PQ poisoning in rats, leveraging the exceptional anti-oxidant, anti-inflammatory, and anti-apoptotic properties of broccoli.<br><br>MATERIALS AND METHODS: Seventy Wistar rats were categorized into seven groups: C (control, vehicle), PQ (paraquat at 40 mg/kg), BC (broccoli extract at 300 mg/kg), NC (N-acetylcysteine at the same dose of 300 mg/kg), and combined groups PQ+BC, PQ+NC, and NC+PQ+BC, all administered equivalent doses. After 42 days, blood samples were collected to evaluate liver and kidney parameters, proinflammatory biomarkers, caspase-3, and caspase-9. Lung tissues were excised, with one part preserved for hydroxyproline and oxidative stress parameter measurement and another sectioned and stained for histopathological analysis.<br><br>RESULTS: The PQ group exhibited the highest lung-to-body weight (LW/BW) ratio, while the PQ+BC+NC group demonstrated the lowest ratio. Results indicated an elevated lung hydroxyproline concentration and a significant reduction in anti-oxidant enzymes (catalase, glutathione peroxidase, superoxide dismutase, and total anti-oxidant capacity) (P<0.001). The PQ+BC group showed modified malondialdehyde levels, reaching a peak in the PQ group. Additionally, a significant decrease in tumor necrosis factor, interleukin-1, caspase-3, and caspase-9 was observed in the PQ+BC+NC group (P<0.01). Pulmonary edema, hyperemia, and severe hemorrhage observed in the PQ group were notably reduced in the PQ+BC+NC group.<br><br>CONCLUSION: The combination of active compounds from broccoli and NAC demonstrated significant systemic and pulmonary effects in mitigating PQ-induced toxicity.},
}
@article {pmid38800015,
year = {2024},
author = {Fan, H and Le, JW and Sun, M and Zhu, JH},
title = {N-acetylcysteine protects septic acute kidney injury by inhibiting SIRT3-mediated mitochondrial dysfunction and apoptosis.},
journal = {Iranian journal of basic medical sciences},
volume = {27},
number = {7},
pages = {850-856},
pmid = {38800015},
issn = {2008-3866},
abstract = {OBJECTIVES: To investigate the protective effect of N-acetylcysteine (NAC) on septic acute kidney injury (SAKI) via regulating Sirtuin3 (SIRT3)-mediated mitochondrial dysfunction and apoptosis.<br><br>MATERIALS AND METHODS: By constructing SIRT3 knockout mice and culturing kidney tubular epithelial cells (KTECs), we assessed the changes of renal function and detected the protein expression of adenine nucleotide translocator (ANT), cyclophilin (CypD) and voltage-dependent anion channel (VDAC) using western-blotting, and simultaneously detected toll-like receptor 4 (TLR4), inhibitor of kappa B kinase (IKK&#x3b2;), inhibitor of Kappa B&#x3b1; (I&#x3ba;B&#x3b1;), and p65 protein expression. We observed mitochondrial damage of KTECs using a transmission electron microscope and assessed apoptosis by TdT-mediated dUTP Nick-End Labeling and flow cytometry.<br><br>RESULTS: SIRT3 deficiency led to the deterioration of renal function, and caused a significant increase in inducible nitric oxide synthase production, a decrease in mitochondrial volume, up-regulation of TLR4, I&#x3ba;B&#x3b1;, IKK&#x3b2;, and p65 proteins, and up-regulation of ANT, CypD and VDAC proteins. However, NAC significantly improved renal function and down-regulated the expression of TLR4, I&#x3ba;B&#x3b1;, IKK&#x3b2;, and p65 proteins. Furthermore, SIRT3 deficiency led to a significant increase in KTEC apoptosis, while NAC up-regulated the expression of SIRT3 and inhibited apoptosis.<br><br>CONCLUSION: NAC has a significant protective effect on SAKI by inhibiting SIRT3-mediated mitochondrial dysfunction and apoptosis of KTECs.},
}
@article {pmid38799536,
year = {2024},
author = {Jamalvi, SA and Rauf, SA and Sherali, A and Ali, SK and Shah, HH and Jamalvi, F and Yogeeta, F and Dave, T},
title = {COVID-19 presenting as severe acute hepatitis in a pediatric patient with thalassemia minor: A case report.},
journal = {Clinical case reports},
volume = {12},
number = {6},
pages = {e8955},
pmid = {38799536},
issn = {2050-0904},
abstract = {KEY CLINICAL MESSAGE: This case emphasizes the significance of COVID-19 in pediatric patients presenting with unusual hepatic manifestations, urging clinicians to broaden their diagnostic lens. The unexpected elevation of SARS-CoV-2 antibodies and the effective use of N-acetyl cysteine highlight the importance of adaptability in treatment strategies.<br><br>ABSTRACT: This case report presents a unique manifestation of severe hepatic involvement in a 4-year-old girl with thalassemia minor and COVID-19. Despite the absence of prominent respiratory symptoms, the patient exhibited jaundice, elevated liver enzymes, and coagulopathy. Initial suspicion of viral hepatitis was replaced by the discovery of significantly elevated SARS-CoV-2 antibodies. A multidisciplinary approach, including gastroenterology consultation and an extensive workup, was pivotal in ruling out alternative etiologies. Unconventional use of N-acetyl cysteine contributed to clinical improvement, highlighting the need for adaptable treatment strategies. This case underscores the importance of heightened awareness in recognizing atypical presentations of COVID-19 in pediatric patients, especially those with underlying health conditions. Further exploration into nuanced manifestations and treatment approaches is warranted for comprehensive clinical management.},
}
@article {pmid38798604,
year = {2024},
author = {Winterlind, EL and Malone, SG and Setzer, MR and Murphy, MA and Saunders, D and Gray, JC},
title = {N-acetylcysteine as a treatment for substance use cravings: A meta-analysis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {38798604},
support = {R01 AA030041/AA/NIAAA NIH HHS/United States ; },
abstract = {N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of the this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with a SUD and (2) explore subgroup differences, risk of bias, and publication bias across trials. Database searches of PubMed, Cochrane Library, and ClinicalTrials.gov were conducted in June and July of 2023 to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analyzed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses, and leave-one-out analyses were conducted to examine treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests, and funnel plot tests were conducted to examine risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015 - 0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. Overall, our findings are contrary to those of prior meta-analyses, suggesting limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.},
}
@article {pmid38797057,
year = {2024},
author = {Li, Y and Guo, M and Wang, Q and Zhou, H and Wu, W and Lin, H and Fan, H},
title = {Glaesserella parasuis serotype 5 induces pyroptosis via the RIG-I/MAVS/NLRP3 pathway in swine tracheal epithelial cells.},
journal = {Veterinary microbiology},
volume = {294},
number = {},
pages = {110127},
doi = {10.1016/j.vetmic.2024.110127},
pmid = {38797057},
issn = {1873-2542},
mesh = {Animals ; *Pyroptosis ; *Epithelial Cells/microbiology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; Swine ; *Signal Transduction ; Haemophilus parasuis/pathogenicity/genetics ; Trachea/microbiology/cytology ; Swine Diseases/microbiology ; Serogroup ; Adaptor Proteins, Signal Transducing/metabolism/genetics ; Inflammasomes/metabolism/genetics ; DEAD Box Protein 58/genetics/metabolism ; Haemophilus Infections/veterinary/microbiology ; },
abstract = {Glaesserella parasuis (G. parasuis) is a common Gram-negative commensal bacterium in the upper respiratory tract of swine that can cause Glässer's disease under stress conditions. Pyroptosis is an important immune defence mechanism of the body that plays a crucial role in clearing pathogen infections and endogenous danger signals. This study aimed to investigate the mechanism of G. parasuis serotype 5 SQ (GPS5-SQ)-induced pyroptosis in swine tracheal epithelial cells (STECs). The results of the present study demonstrated that GPS5-SQ infection induces pyroptosis in STECs by enhancing the protein level of the N-terminal domain of gasdermin D (GSDMD-N) and activating the NOD-like receptor protein 3 (NLRP3) inflammasome. Furthermore, the levels of pyroptosis-related proteins, including GSDMD-N and cleaved caspase-1 were considerably decreased in STECs after the knockdown of retinoic acid inducible gene-I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). These results indicated that GPS5-SQ might trigger pyroptosis through the activation of the RIG-I/MAVS/NLRP3 signaling pathway. More importantly, the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) repressed the activation of the RIG-I/MAVS/NLRP3 signaling and rescued the decrease in Occludin and zonula occludens-1 (ZO-1) after GPS5-SQ infection. Overall, our findings show that GPS5-SQ can activate RIG-I/MAVS/NLRP3 signaling and destroy the integrity of the epithelial barrier by inducing ROS generation in STECs, shedding new light on G. parasuis pathogenesis.},
}
@article {pmid38791242,
year = {2024},
author = {Pascal, W and Smoliński, A and Gotowiec, M and Wojtkiewicz, M and Stachura, A and Pełka, K and Kopka, M and Quinn, KP and Woessner, AE and Grzelecki, D and Włodarski, P},
title = {Pre-Incisional and Multiple Intradermal Injection of N-Acetylcysteine Slightly Improves Incisional Wound Healing in an Animal Model.},
journal = {International journal of molecular sciences},
volume = {25},
number = {10},
pages = {},
pmid = {38791242},
issn = {1422-0067},
support = {1M15/NM1/17//Medical University of Warsaw/ ; MNiSW/2019/106/DIR/NN3//Polish Ministry of Science and Higher Education/ ; },
mesh = {Animals ; *Wound Healing/drug effects ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Rats ; *Rats, Sprague-Dawley ; Injections, Intradermal ; Disease Models, Animal ; Skin/drug effects/pathology/injuries ; Male ; Surgical Wound/drug therapy/pathology ; Collagen/metabolism ; Cicatrix/pathology/drug therapy ; },
abstract = {The objective of this study was to investigate if delivering multiple doses of N-acetylcysteine (NAC) post-surgery in addition to pre-incisional administration significantly impacts the wound healing process in a rat model. Full-thickness skin incisions were carried out on the dorsum of 24 Sprague-Dawley rats in six locations. Fifteen minutes prior to the incision, half of the sites were treated with a control solution, with the wounds on the contralateral side treated with solutions containing 0.015%, 0.03% and 0.045% of NAC. In the case of the NAC treated group, further injections were given every 8 h for three days. On days 3, 7, 14 and 60 post-op, rats were sacrificed to gather material for the histological analysis, which included histomorphometry, collagen fiber organization analysis, immunohistochemistry and Abramov scale scoring. It was determined that scars treated with 0.015% NAC had significantly lower reepithelization than the control at day 60 post-op (p = 0.0018). Scars treated with 0.045% NAC had a significantly lower collagen fiber variance compared to 0.015% NAC at day 14 post-op (p = 0.02 and p = 0.04) and a lower mean scar width than the control at day 60 post-op (p = 0.0354 and p = 0.0224). No significant differences in the recruitment of immune cells and histological parameters were found. The results point to a limited efficacy of multiple NAC injections post-surgery in wound healing.},
}
@article {pmid38788361,
year = {2024},
author = {Cao, W and Zeng, Y and Su, Y and Gong, H and He, J and Liu, Y and Li, C},
title = {The involvement of oxidative stress and the TLR4/NF-κB/NLRP3 pathway in acute lung injury induced by high-altitude hypoxia.},
journal = {Immunobiology},
volume = {229},
number = {3},
pages = {152809},
doi = {10.1016/j.imbio.2024.152809},
pmid = {38788361},
issn = {1878-3279},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Toll-Like Receptor 4/metabolism ; *Acute Lung Injury/etiology/metabolism ; Rats ; *Oxidative Stress ; *NF-kappa B/metabolism ; *Signal Transduction ; Male ; *Disease Models, Animal ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Cytokines/metabolism ; Hypoxia/metabolism ; Inflammasomes/metabolism ; Lung/metabolism/pathology ; Altitude ; Sulfonamides/pharmacology ; },
abstract = {OBJECTIVE: This study investigated the effect of oxidative stress and the TLR4/NF-κB/NLRP3 pathway on the pathogenesis of acute lung injury (ALI) induced by high-altitude hypoxia.<br><br>METHODS: Rats were placed in an animal hyperbaric oxygen chamber to establish a rat model of ALI induced by high-altitude hypoxia after treatment with N-acetylcysteine (NAC; a reactive oxygen species [ROS] inhibitor) or/and MCC950 (an NLPR3 inflammasome inhibitor). After modeling, the wet-to-dry weight ratio (W/D) of rat lung tissues was calculated. In lung tissues, ROS levels were detected with immunofluorescence, the enzyme activity was tested with the kit, and the expression of TLR4/NF-&#x3ba;B/NLRP3 pathway-related genes and proteins was measured with western blotting and qRT-PCR. The levels of inflammatory factors in the serum were quantified with ELISA.<br><br>RESULTS: After modeling, rats showed significantly increased W/D, ROS levels, and Malondialdehyde (MDA) concentrations and markedly diminished Superoxide dismutase (SOD) and Glutathione (GSH) concentrations in lung tissues (all P&#xa0;<&#xa0;0.01), accompanied by substantially enhanced serum levels of TNF-&#x3b1;, IL-6, and IL-1&#x3b2;, significantly reduced serum levels of IL-10, and remarkably augmented TLR4, NLRP3, p-NF-&#x3ba;B p65, NF-&#x3ba;B p65 mRNA, and Caspase-1 expression in lung tissues (all P&#xa0;<&#xa0;0.01). Furthermore, treatment with NAC or MCC950 alone or in combination prominently lowered the W/D of lung tissues (P&#xa0;<&#xa0;0.01), serum levels of TNF-&#x3b1; (P&#xa0;<&#xa0;0.05), IL-6 (P&#xa0;<&#xa0;0.05), and IL-1&#x3b2; (P&#xa0;<&#xa0;0.01), and NF-&#x3ba;B p65 expression and phosphorylation (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01) while significantly increasing SOD and GSH concentrations (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01) and serum levels of IL-10 (P&#xa0;<&#xa0;0.01) in modeled rats. Meanwhile, treatment of NAC alone or combined with MCC950 significantly reduced MDA concentration and ROS levels (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01) in modeled rats, and treatment of MCC950 alone or combined with NAC considerably declined TLR4, NLRP3, and Caspase-1 expression in modeled rats (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01).<br><br>CONCLUSION: Inhibition of oxidative stress and the TLR4/NF-&#x3ba;B/NLRP3 pathway can ameliorate ALI in rats exposed to high-altitude hypoxia.},
}
@article {pmid38785564,
year = {2024},
author = {Kobroob, A and Kumfu, S and Chattipakorn, N and Wongmekiat, O},
title = {Modulation of Sirtuin 3 by N-Acetylcysteine Preserves Mitochondrial Oxidative Phosphorylation and Restores Bisphenol A-Induced Kidney Damage in High-Fat-Diet-Fed Rats.},
journal = {Current issues in molecular biology},
volume = {46},
number = {5},
pages = {4935-4950},
pmid = {38785564},
issn = {1467-3045},
support = {075/2564//The Faculty of Medicine Endowment Fund for Medical Research, Chiang Mai University, Chiang Mai, Thailand/ ; },
abstract = {Bisphenol A (BPA) and high-fat diets (HFD) are known to adversely affect the kidneys. However, the combined effects of both cases on kidney health and the potential benefits of N-acetylcysteine (NAC) in mitigating these effects have not been investigated. To explore these aspects, male Wistar rats were fed with HFD and allocated to receive a vehicle or BPA. At week twelve, the BPA-exposed rats were subdivided to receive a vehicle or NAC along with BPA until week sixteen. Rats fed HFD and exposed to BPA showed renal dysfunction and structural abnormalities, oxidative stress, inflammation, and mitochondrial dysfunction, with alterations in key proteins related to mitochondrial oxidative phosphorylation (OXPHOS), bioenergetics, oxidative balance, dynamics, apoptosis, and inflammation. Treatment with NAC for 4 weeks significantly improved these conditions. The findings suggest that NAC is beneficial in protecting renal deterioration brought on by prolonged exposure to BPA in combination with HFD, and modulation of sirtuin 3 (SIRT3) signaling by NAC appears to play a key role in the preservation of homeostasis and integrity within the mitochondria by enhancing OXPHOS activity, maintaining redox balance, and reducing inflammation. This study provides valuable insights into potential therapeutic strategies for preserving kidney health in the face of environmental and dietary challenges.},
}
@article {pmid38781725,
year = {2024},
author = {Nagano, S and Unuma, K and Aki, T and Uemura, K},
title = {N-acetylcysteine alleviates arsenic trioxide-induced reductions in hepatic catalase gene expression both in vitro and in vivo.},
journal = {Legal medicine (Tokyo, Japan)},
volume = {69},
number = {},
pages = {102458},
doi = {10.1016/j.legalmed.2024.102458},
pmid = {38781725},
issn = {1873-4162},
mesh = {*Arsenic Trioxide/pharmacology ; *Acetylcysteine/pharmacology ; Animals ; *Catalase/metabolism/genetics ; Rats ; *Liver/metabolism/drug effects ; *Oxides ; Male ; Arsenicals ; Humans ; Gene Expression/drug effects ; Antioxidants/pharmacology/metabolism ; },
abstract = {Arsenic trioxide (ATO), one of the oldest and most frequently used poisons, is well-known in forensic science for inducing hepatotoxicity. The regulation of peroxisomal antioxidative enzyme catalase (CAT) involves intricate mechanisms at both transcriptional and post-transcriptional levels. However, the molecular mechanisms underlying the regulation of CAT gene expression in hepatic cells remain elusive. Furthermore, the regulation of CAT gene expression evident in animals administered with ATO in vivo is not well-explored, although several studies have revealed ATO-induced reductions in CAT enzymatic activity in rat livers. In this study, we revealed ATO-dependent reductions in CAT gene expression in both rat liver and Huh-7 human hepatoma cells. Our results indicate that the decline in CAT enzymatic activity can be attributed, at least in part, to the downregulation of its gene expression. The ATO-induced reduction in CAT expression was concurrent with the reduction in peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator (PGC)-1α and inactivation of PPARγ, both considered as positive regulators of CAT gene expression. Moreover, antioxidant N-acetylcysteine (NAC) demonstrated the capability to alleviate the downregulation of CAT gene expression both in vivo and in vitro. Additionally, NAC played a role in alleviating ATO-induced hepatotoxicity, potentially by mitigating the transcriptional downregulation of the CAT gene. Altogether, these results indicate that ATO exerts toxicity by inhibiting the antioxidant defense mechanism, which may be useful for forensic diagnosis of arsenic poisoning and clinical treatment of mitigating ATO-induced hepatotoxicity.},
}
@article {pmid38775255,
year = {2024},
author = {Bolarinwa, AB and Oduwole, O and Okebe, J and Ogbenna, AA and Otokiti, OE and Olatinwo, AT},
title = {Antioxidant supplementation for sickle cell disease.},
journal = {The Cochrane database of systematic reviews},
volume = {5},
number = {5},
pages = {CD013590},
pmid = {38775255},
issn = {1469-493X},
mesh = {Humans ; *Anemia, Sickle Cell/drug therapy/blood ; *Antioxidants/therapeutic use ; Ascorbic Acid/therapeutic use ; Bias ; *Dietary Supplements ; Oxidative Stress/drug effects ; Placebos/therapeutic use ; Quality of Life ; *Randomized Controlled Trials as Topic ; },
abstract = {BACKGROUND: Sickle cell disease (SCD) refers to a group of genetic disorders characterized by the presence of an abnormal haemoglobin molecule called haemoglobin S (HbS). When subjected to oxidative stress from low oxygen concentrations, HbS molecules form rigid polymers, giving the red cell the typical sickle shape. Antioxidants have been shown to reduce oxidative stress and improve outcomes in other diseases associated with oxidative stress. Therefore, it is important to review and synthesize the available evidence on the effect of antioxidants on the clinical outcomes of people with SCD.<br><br>OBJECTIVES: To assess the effectiveness and safety of antioxidant supplementation for improving health outcomes in people with SCD.<br><br>SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 15 August 2023.<br><br>SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials comparing antioxidant supplementation to placebo, other antioxidants, or different doses of antioxidants, in people with SCD.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed the risk of bias and certainty of the evidence, and reported according to Cochrane methodological procedures.<br><br>MAIN RESULTS: The review included 1609 participants in 26 studies, with 17 comparisons. We rated 13 studies as having a high risk of bias overall, and 13 studies as having an unclear risk of bias overall due to study limitations. We used GRADE to rate the certainty of evidence. Only eight studies reported on our important outcomes at six months. Vitamin C (1400 mg) plus vitamin E (800 mg) versus placebo Based on evidence from one study in 83 participants, vitamin C (1400 mg) plus vitamin E (800 mg) may not be better than placebo at reducing the frequency of crisis (risk ratio (RR) 1.18, 95% confidence interval (CI) 0.64 to 2.18), the severity of pain (RR 1.33, 95% CI 0.40 to 4.37), or adverse effects (AE), of which the most common were headache, nausea, fatigue, diarrhoea, and epigastric pain (RR 0.56, 95% CI 0.31 to 1.00). Vitamin C plus vitamin E may increase the risk of SCD-related complications (acute chest syndrome: RR 2.66, 95% CI 0.77 to 9.13; 1 study, 83 participants), and increase haemoglobin level (median (interquartile range) 90 (81 to 96) g/L versus 93.5 (84 to 105) g/L) (1 study, 83 participants) compared to placebo. However, the evidence for all the above effects is very uncertain. The study did not report on quality of life (QoL) of participants and their caregivers, nor on frequency of hospitalization. Zinc versus placebo Zinc may not be better than placebo at reducing the frequency of crisis at six months (rate ratio 0.62, 95% CI 0.17 to 2.29; 1 study, 36 participants; low-certainty evidence). We are uncertain whether zinc is better than placebo at improving sickle cell-related complications (complete healing of leg ulcers at six months: RR 2.00, 95% CI 0.60 to 6.72; 1 study, 34 participants; very low-certainty evidence). Zinc may be better than placebo at increasing haemoglobin level (g/dL) (MD 1.26, 95% CI 0.44 to 1.26; 1 study, 36 participants; low-certainty evidence). The study did not report on severity of pain, QoL, AE, and frequency of hospitalization. N-acetylcysteine versus placebo N-acetylcysteine (NAC) 1200 mg may not be better than placebo at reducing the frequency of crisis in SCD, reported as pain days (rate ratio 0.99 days, 95% CI 0.53 to 1.84; 1 study, 96 participants; low-certainty evidence). Low-certainty evidence from one study (96 participants) suggests NAC (1200 mg) may not be better than placebo at reducing the severity of pain (MD 0.17, 95% CI -0.53 to 0.87). Compared to placebo, NAC (1200 mg) may not be better at improving physical QoL (MD -1.80, 95% CI -5.01 to 1.41) and mental QoL (MD 2.00, 95% CI -1.45 to 5.45; very low-certainty evidence), reducing the risk of adverse effects (gastrointestinal complaints, pruritus, or rash) (RR 0.92, 95% CI 0.75 to 1.14; low-certainty evidence), reducing the frequency of hospitalizations (rate ratio 0.98, 95% CI 0.41 to 2.38; low-certainty evidence), and sickle cell-related complications (RR 5.00, 95% CI 0.25 to 101.48; very low-certainty evidence), or increasing haemoglobin level (MD -0.18 g/dL, 95% CI -0.40 to 0.04; low-certainty evidence). L-arginine versus placebo L-arginine may not be better than placebo at reducing the frequency of crisis (monthly pain) (RR 0.71, 95% CI 0.26 to 1.95; 1 study, 50 participants; low-certainty evidence). However, L-arginine may be better than placebo at reducing the severity of pain (MD -1.41, 95% CI -1.65 to -1.18; 2 studies, 125 participants; low-certainty evidence). One participant allocated to L-arginine developed hives during infusion of L-arginine, another experienced acute clinical deterioration, and a participant in the placebo group had clinically relevant increases in liver function enzymes. The evidence is very uncertain whether L-arginine is better at reducing the mean number of days in hospital compared to placebo (MD -0.85 days, 95% CI -1.87 to 0.17; 2 studies, 125 participants; very low-certainty evidence). Also, L-arginine may not be better than placebo at increasing haemoglobin level (MD 0.4 g/dL, 95% CI -0.50 to 1.3; 2 studies, 106 participants; low-certainty evidence). No study in this comparison reported on QoL and sickle cell-related complications. Omega-3 versus placebo Very low-certainty evidence shows no evidence of a difference in the risk of adverse effects of omega-3 compared to placebo (RR 1.05, 95% CI 0.74 to 1.48; 1 study, 67 participants). Very low-certainty evidence suggests that omega-3 may not be better than placebo at increasing haemoglobin level (MD 0.36 g/L, 95% CI -0.21 to 0.93; 1 study, 67 participants). The study did not report on frequency of crisis, severity of pain, QoL, frequency of hospitalization, and sickle cell-related complications.<br><br>AUTHORS' CONCLUSIONS: There was inconsistent evidence on all outcomes to draw conclusions on the beneficial and harmful effects of antioxidants. However, L-arginine may be better than placebo at reducing the severity of pain at six months, and zinc may be better than placebo at increasing haemoglobin level. We are uncertain whether other antioxidants are beneficial for SCD. Larger studies conducted on each comparison would reduce the current uncertainties.},
}
@article {pmid38774197,
year = {2023},
author = {Sztolsztener, K and Dzięcioł, J and Chabowski, A},
title = {N-acetylcysteine acts as a potent anti-inflammatory agent altering the eicosanoid profile in the development of simple steatosis and its progression to hepatitis.},
journal = {Clinical and experimental hepatology},
volume = {9},
number = {4},
pages = {386-395},
pmid = {38774197},
issn = {2392-1099},
abstract = {AIM OF THE STUDY: We aimed to examine the influence of N-acetylcysteine (NAC) on the development of metabolic dysfunction-associated steatotic liver disease (MASLD) in rats with a specific focus on the eicosanoid pathway.<br><br>MATERIAL AND METHODS: The experiment was conducted on male Wistar rats fed a standard diet or a high-fat diet (HFD) for eight weeks. In the entire experiment, half of rats from both groups received intragastrically NAC solution prepared in normal saline. H + E staining was used for the histological assessment of liver tissue. The gas-liquid chromatography (GLC) technique was used for the assessment of the activity of n-3 and n-6 polyunsaturated fatty acid (PUFA) pathways and arachidonic acid concentration. ELISA and multiplex immunoassay kits were applied for the measurement of eicosanoid, cytokine, and chemokine levels. The Western blot technique was applied to determine the expression of proteins involved in the inflammation pathway.<br><br>RESULTS: NAC decreased hepatic n-6 PUFA activity in all examined lipid pools and decreased the hepatic content of arachidonic acid as a pro-inflammatory precursor in each lipid pool, especially in the phospholipid fraction in rats with fatty lipid disease. NAC administration abolished 5-LOX expression, leading to a decrease in the content of pro-inflammatory leukotriene B4 and leukotriene C4. In rats with steatosis, NAC weakened NF-&#x3ba;B expression and raised Nrf-2 expression, inhibiting the synthesis of pro-inflammatory cytokines and chemokines.<br><br>CONCLUSIONS: NAC treatment significantly rate-limited the progression of simple hepatic steatosis to hepatitis in a rat model of MASLD.},
}
@article {pmid38770316,
year = {2024},
author = {Huang, HL and Cheng, N and Zhou, CX and Liang, J},
title = {Megalin-targeted acetylcysteine polymeric prodrug ameliorates ischemia-reperfusion-induced acute kidney injury.},
journal = {Heliyon},
volume = {10},
number = {10},
pages = {e30947},
pmid = {38770316},
issn = {2405-8440},
abstract = {Acute kidney injury (AKI), a condition associated with reactive oxygen species (ROS), causes high mortality in clinics annually. Active targeted antioxidative therapy is emerging as a novel strategy for AKI treatment. In this study, we developed a polymeric prodrug that targets the highly expressed Megalin receptor on proximal tubule cells, enabling direct delivery of N-Acetylcysteine (NAC) for the treatment of ischemia reperfusion injury (IRI)-induced AKI. We conjugated NAC with low molecular weight chitosan (LMWC), a biocompatible and biodegradable polymer consisting of glucosamine and N-acetylglucosamine, to enhance its internalization by tubular epithelial cells. Moreover, we further conjugated triphenylphosphonium (TPP), a lipophilic cation with a delocalized positive charge, to low molecular weight chitosan-NAC in order to enhance the distribution of NAC in mitochondria. Our study confirmed that triphenylphosphonium-low molecular weight chitosan-NAC (TLN) exhibits remarkable therapeutic effects on IRI-AKI mice. This was evidenced by improvements in renal function, reduction in oxidative stress, mitigation of pathological progress, and decreased levels of kidney injury molecule-1. These findings suggested that the polymeric prodrug TLN holds promising potential for IRI-AKI treatment.},
}
@article {pmid38769217,
year = {2024},
author = {Takahashi, K and Tanaka, T and Ishihara, A and Ohta, T},
title = {Strobilurin X acts as an anticancer drug by inhibiting protein synthesis and suppressing mitochondrial respiratory chain activity.},
journal = {Discover oncology},
volume = {15},
number = {1},
pages = {177},
pmid = {38769217},
issn = {2730-6011},
abstract = {PURPOSE: Strobilurins act as antifungal agents by inhibiting the mitochondrial respiratory chain. The cytotoxic activity of strobilurins, focusing on its anticancer activities, has been reported. However, the mechanisms involved in these activities remain unclear.<br><br>METHODS: The cytotoxic effects of strobilurin X isolated from the mycelium of Mucidula. venosolamellata were examined in human cancer cell lines (A549 and HeLa) and normal fibroblasts (WI-38).<br><br>RESULTS: Strobilurin X significantly decreased the viability of A549 and HeLa cells compared to that in the WI-38 cells after 48&#xa0;h of exposure. The EC50 values for cytotoxicity in the A549, HeLa, and WI-38 cells were 3.4, 5.4, and 16.8&#xa0;&#x3bc;g/mL, respectively. Strobilurin X inhibited the mitochondrial respiratory chain and enhanced the release of lactate in the A549 cells. The IC50 value of strobilurin X against the mitochondrial respiratory chain complex III activity was 139.8&#xa0;ng/mL. The cytotoxicity induced by strobilurin X was not completely rescued after adding uridine, methyl pyruvate, or N-acetyl cysteine. Furthermore, pharmacological approaches demonstrated that strobilurin X failed to modulate the mitogen-activated protein kinase family and phosphoinositide 3-kinase-Akt pathways; alternatively, it suppressed protein synthesis independent of uridine.<br><br>CONCLUSION: Strobilurin X induced cytotoxicity by blocking the mitochondrial respiratory chain and suppressing protein synthesis. These findings may aid in the development of novel anticancer drugs using strobilurins.},
}
@article {pmid38762757,
year = {2024},
author = {Qi, Z and Yang, W and Xue, B and Chen, T and Lu, X and Zhang, R and Li, Z and Zhao, X and Zhang, Y and Han, F and Kong, X and Liu, R and Yao, X and Jia, R and Feng, S},
title = {ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.},
journal = {Autophagy},
volume = {20},
number = {9},
pages = {2000-2016},
pmid = {38762757},
issn = {1554-8635},
mesh = {*Bleomycin/pharmacology ; *Cellular Senescence/drug effects ; *Reactive Oxygen Species/metabolism ; *Lysosomes/metabolism/drug effects ; *Autophagy/drug effects/physiology ; Animals ; Humans ; Mice ; Intracellular Membranes/metabolism/drug effects ; Permeability/drug effects ; Mice, Inbred C57BL ; },
abstract = {Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.},
}
@article {pmid38761382,
year = {2024},
author = {Li, X and Xin, L and Yang, L and Yang, Y and Li, W and Zhang, M and Liao, Y and Sun, C and Li, W and Peng, Y and Zheng, J},
title = {Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo.},
journal = {Chemical research in toxicology},
volume = {37},
number = {6},
pages = {935-943},
doi = {10.1021/acs.chemrestox.4c00008},
pmid = {38761382},
issn = {1520-5010},
mesh = {Animals ; *Amitriptyline/metabolism ; Rats ; *Cytochrome P-450 CYP3A/metabolism ; *Microsomes, Liver/metabolism ; *Hepatocytes/drug effects/metabolism ; Male ; *Rats, Sprague-Dawley ; *Epoxy Compounds/metabolism/toxicity/chemistry ; Glutathione/metabolism ; Cells, Cultured ; },
abstract = {Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.},
}
@article {pmid38759847,
year = {2024},
author = {Shin, BJ and Kim, BJ and Paeng, EJ and Rifkin, JT and Moon, SH and Shin, SH and Ryu, BY},
title = {N-Acetyl-L-cysteine attenuates titanium dioxide nanoparticle (TiO2 NP)-induced autophagy in male germ cells.},
journal = {Environmental toxicology and pharmacology},
volume = {108},
number = {},
pages = {104466},
doi = {10.1016/j.etap.2024.104466},
pmid = {38759847},
issn = {1872-7077},
mesh = {*Titanium/toxicity ; Male ; *Autophagy/drug effects ; Animals ; *Acetylcysteine/pharmacology ; Mice ; *Reactive Oxygen Species/metabolism ; Cell Line ; *Cell Proliferation/drug effects ; *Metal Nanoparticles/toxicity ; Spermatogonia/drug effects ; Nanoparticles/toxicity ; },
abstract = {Titanium dioxide nanoparticles (TiO2 NPs) are widely used in consumer products, raising concerns about their impact on human health. This study investigates the effects of TiO2 NPs on male germ cells while focusing on cell proliferation inhibition and underlying mechanisms. This was done by utilizing mouse GC-1 spermatogonia cells, an immortalized spermatogonia cell line. TiO2 NPs induced a concentration-dependent proliferation inhibition with increased reactive oxygen species (ROS) generation. Notably, TiO2 NPs induced autophagy and decreased ERK phosphorylation. Treatment with the ROS inhibitor N-Acetyl-l-cysteine (NAC) alleviated TiO2 NPs-induced autophagy, restored ERK phosphorylation, and promoted cell proliferation. These findings call attention to the reproductive risks posed by TiO2 NPs while also highlighting NAC as a possible protective agent against reproductive toxins.},
}
@article {pmid38754743,
year = {2024},
author = {Nguyen, UTT and Youn, E and Le, TAN and Ha, NM and Tran, SH and Lee, S and Cha, JW and Park, JS and Kwon, HC and Kang, K},
title = {Photodynamic treatment increases the lifespan and oxidative stress resistance of Caenorhabditis elegans.},
journal = {Free radical biology &amp; medicine},
volume = {221},
number = {},
pages = {98-110},
doi = {10.1016/j.freeradbiomed.2024.05.023},
pmid = {38754743},
issn = {1873-4596},
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism/genetics ; *Oxidative Stress/drug effects ; *Longevity/drug effects ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Photochemotherapy/methods ; *Photosensitizing Agents/pharmacology ; *Reactive Oxygen Species/metabolism ; *Transcription Factors/metabolism/genetics ; *Perylene/analogs &amp; derivatives/pharmacology ; Anthracenes/pharmacology ; Forkhead Transcription Factors/metabolism/genetics ; DNA-Binding Proteins/metabolism/genetics ; Superoxide Dismutase/metabolism/genetics ; NF-E2-Related Factor 2/metabolism/genetics ; Gene Expression Regulation/drug effects ; Light ; Acetylcysteine/pharmacology ; },
abstract = {Photodynamic therapy is a noninvasive treatment in which specific photosensitizers and light are used to produce high amounts of reactive oxygen species (ROS), which can be employed for targeted tissue destruction in cancer treatment or antimicrobial therapy. However, it remains unknown whether lower amounts of ROS produced by mild photodynamic therapy increase lifespan and stress resistance at the organism level. Here, we introduce a novel photodynamic treatment (PDTr) that uses 20 μM hypericin, a photosensitizer that originates from Hypericum perforatum, and orange light (590 nm, 5.4 W/m[2], 1 min) to induce intracellular ROS formation (ROS), thereby resulting in lifespan extension and improved stress resistance in C. elegans. The PDTr-induced increase in longevity was abrogated by N-acetyl cysteine, suggesting the hormetic response was driven by prooxidative mechanisms. PDTr activated the translocation of SKN-1/NRF-2 and DAF-16/FOXO, leading to elevated expression of downstream oxidative stress-responsive genes, including ctl-1, gst-4, and sod-3. In summary, our findings suggest a novel PDTr method that extends the lifespan of C. elegans under both normal and oxidative stress conditions through the activation of SKN-1 and DAF-16 via the involvement of many antioxidant genes.},
}
@article {pmid38751162,
year = {2024},
author = {Roydeva, A and Beleva, G and Gadzhakov, D and Milanova, A},
title = {Pharmacokinetics of N-acetyl-l-cysteine in chickens.},
journal = {Journal of veterinary pharmacology and therapeutics},
volume = {47},
number = {5},
pages = {403-415},
doi = {10.1111/jvp.13452},
pmid = {38751162},
issn = {1365-2885},
support = {BG-RRP-2.004-0006-C02//Bulgarian Ministry of Education and Science (MES)/ ; },
mesh = {Animals ; *Chickens/metabolism ; *Acetylcysteine/pharmacokinetics/administration &amp; dosage ; Administration, Oral ; Male ; Half-Life ; Area Under Curve ; Injections, Intravenous/veterinary ; Biological Availability ; Female ; },
abstract = {N-acetyl-l-cysteine (NAC) has been suggested as an antioxidant that can alleviate the negative effects of stress conditions in broilers. However, knowledge of its pharmacokinetics (PK) in this avian species is very limited. Therefore, the study aimed to shed more light on the PK properties of NAC in chickens. Broilers were subjected to single intravenous (i.v.) or oral (p.o.) treatment or multiple NAC administrations via the feed. Drug concentrations were determined by LC-MS/MS, and the data were subjected to non-compartmental analysis and modeled by non-linear mixed effect approach. NAC was eliminated in a short time after i.v. treatment, with a t 1/2el of 0.93 (0.59-2.09) h. It showed limited distribution with population mean of volumes of distribution in the central and peripheral compartments V 1 of 0.148 L/kg and V 2 of 0.199 L/kg, respectively, and V darea of 0.39 (0.258-0.635) L/kg. The value of MRT was 1.76 h (range of 0.96-2.69, p < .05) after single p.o. treatment, indicating a twofold increase if compared to i.v. administration (0.87 h, 0.55-1.78). Both methods of Pk analysis revealed very limited bioavailability, <10%. Feeding behavior led to a later achievement of lower maximum plasma concentrations (5.74, range of 3.44-9.32 μg/mL, p < .05), which were maintained during the 5 days of treatment.},
}
@article {pmid38750444,
year = {2024},
author = {Li, YS and Xia, J and Chen, CY and Ren, SH and He, MR},
title = {Upregulated dual oxidase 1-induced oxidative stress and caspase-1-dependent pyroptosis reflect the etiologies of heart failure.},
journal = {BMC molecular and cell biology},
volume = {25},
number = {1},
pages = {16},
pmid = {38750444},
issn = {2661-8850},
support = {ZK2019A07//Songjiang District New round of Medical key discipline Construction Project (Cardiology Department)/ ; },
mesh = {Humans ; Caspase 1/metabolism ; Cell Line ; Doxorubicin/pharmacology ; *Dual Oxidases/metabolism/genetics ; *Heart Failure/chemically induced/genetics/metabolism ; Interleukin-18/metabolism ; Interleukin-1beta/metabolism ; *Oxidative Stress ; *Pyroptosis ; *Reactive Oxygen Species/metabolism ; Up-Regulation ; },
abstract = {BACKGROUND: Oxidative stress is implicated in the pathogenesis of heart failure. Dual oxidase 1 (DUOX1) might be important in heart failure development through its mediating role in oxidative stress. This study was designed to evaluate the potential role of DUOX1 in heart failure.<br><br>MATERIALS AND METHODS: AC16 cells were treated with 2 &#xb5;mol/L of doxorubicin (DOX) for 12, 24, and 48&#xa0;h to construct a heart failure model. DUOX1 overexpression and silencing in AC16 cell were established. DUOX1 expression was detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Pyroptosis and reactive oxygen species (ROS) production were measured by flow cytometry.<br><br>RESULTS: Increased DUOX1 expression levels were observed after DOX treatment for 24&#xa0;h in AC16 cells. DUOX1 silencing inhibited DOX-induced pyroptosis and ROS production. The release of IL-1&#x3b2;, IL-18, and lactate dehydrogenase (LDH), and expression levels of pyroptosis-related proteins were also decreased. DUOX1 overexpression increased pyroptosis, ROS production, IL-1&#x3b2;, IL-18, and LDH release, and pyroptosis-related protein expression. N-acetyl-cysteine (NAC) significantly reversed DUOX1-induced pyroptosis, ROS, and related factors.<br><br>CONCLUSION: These results suggest that DUOX1-derived genotoxicity could promote heart failure development. In the process, oxidative stress and pyroptosis may be involved in the regulation of DUOX1 in heart failure.},
}
@article {pmid38749218,
year = {2024},
author = {Han, YK and Lim, HJ and Jang, G and Jang, SY and Park, KM},
title = {Kidney ischemia/reperfusion injury causes cholangiocytes primary cilia disruption and abnormal bile secretion.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1870},
number = {6},
pages = {167225},
doi = {10.1016/j.bbadis.2024.167225},
pmid = {38749218},
issn = {1879-260X},
mesh = {Animals ; *Reperfusion Injury/metabolism/pathology ; *Cilia/metabolism/pathology ; Mice ; *Bile/metabolism ; Male ; Acute Kidney Injury/metabolism/pathology ; Mice, Inbred C57BL ; Glutathione/metabolism ; Mice, Knockout ; Liver/pathology/metabolism ; Hepatocytes/metabolism/pathology ; Cystathionine gamma-Lyase/metabolism/genetics ; Kidney/metabolism/pathology ; Hydrogen Sulfide/metabolism/pharmacology ; Bile Ducts/pathology/metabolism ; Epithelial Cells/metabolism/pathology ; },
abstract = {BACKGROUND: Acute kidney injury (AKI) causes distant liver injury, to date, which causes poor outcomes of patients with AKI. Many studies have been performed to overcome AKI-associated liver injury. However, those studies have mainly focused on hepatocytes, and AKI-induced liver injury still remains a clinical problem. Here, we investigated the implication of cholangiocytes and their primary cilia which are critical in final bile secretion. Cholangiocyte, a lining cell of bile ducts, are the only liver epithelial cell containing primary cilium (a microtubule-based cell surface signal-sensing organelle).<br><br>METHODS: Cystathione &#x3b3;-lyase (CSE, a transsulfuration enzyme) deficient and wild-type mice were subjected to kidney ischemia followed by reperfusion (KIR). Some mice were administered with N-acetyl-cysteine (NAC).<br><br>RESULTS: KIR damaged hepatocytes and cholagiocytes, disrupted cholangiocytes primary cilia, released the disrupted ciliary fragments into the bile, and caused abnormal bile secretion. Glutathione (GSH) and H2S levels in the livers were significantly reduced by KIR, resulting in increased the ratio oxidized GSH to total GSH, and oxidation of tissue and bile. CSE and cystathione &#x3b2;-synthase (CBS) expression were lowered in the liver after KIR. NAC administration increased total GSH and H2S levels in the liver and attenuated KIR-induced liver injuries. In contrast, Cse deletion caused the reduction of total GSH levels and worsened KIR-induced liver injuries, including primary cilia damage and abnormal bile secretion.<br><br>CONCLUSIONS: These results indicate that KIR causes cholangiocyte damage, cholangiocytes primary cilia disruption, and abnormal bile secretion through reduced antioxidative ability of the liver.},
}
@article {pmid38740632,
year = {2024},
author = {Boppana, TK and Mittal, S and Madan, K and Tiwari, P and Mohan, A and Hadda, V},
title = {Antioxidant therapies for obstructive sleep apnea: A systematic review and meta-analysis.},
journal = {Sleep &amp; breathing = Schlaf &amp; Atmung},
volume = {28},
number = {4},
pages = {1513-1522},
pmid = {38740632},
issn = {1522-1709},
mesh = {Humans ; *Antioxidants/pharmacology/therapeutic use ; *Oxidative Stress/drug effects/physiology ; *Sleep Apnea, Obstructive/drug therapy/physiopathology ; },
abstract = {PURPOSE: Obstructive sleep apnea (OSA) is a common clinical problem that is associated with adverse cardiovascular outcomes attributed to the oxidative stress due to sympathetic overstimulation. Treatment approaches targeting oxidative stress have been tried by multiple investigators. This systematic review and meta-analysis evaluated the efficacy and safety of such approaches.<br><br>METHODS: Pubmed and Embase databases were searched for human studies evaluating the utility of antioxidant therapies in patients with OSA.<br><br>RESULTS: A total of six studies (five randomized trials and one case-control study) were included, including 160 patients with OSA using N-acetyl cysteine, vitamin C, carbocysteine, superoxide dismutase, vitamin E, allopurinol, and their combinations. There was a significant improvement in flow-mediated dilatation (FMD) following antioxidants, with the pooled effect being 2.16 % (95% CI 1.65-2.67) using the random-effects model (I2 = 0% and p<0.001). It was also associated with a significant reduction in malondialdehyde levels and an increase in reduced glutathione (GSH) levels. There was also a significant improvement in the Epworth sleepiness scale, oxygen desaturation index, and minimum oxygen saturation during sleep without any significant adverse effects.<br><br>CONCLUSION: Antioxidant therapy in patients with OSA is associated with improved endothelial function, reduced oxidative stress, and improved sleep parameters. These results call for future multicentre studies with longer follow-ups to assess the utility of antioxidant therapy in patients with OSA.},
}
@article {pmid38735462,
year = {2024},
author = {Li, M and Tang, S and Velkov, T and Shen, J and Dai, C},
title = {Copper exposure induces mitochondrial dysfunction and hepatotoxicity via the induction of oxidative stress and PERK/ATF4 -mediated endoplasmic reticulum stress.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {352},
number = {},
pages = {124145},
doi = {10.1016/j.envpol.2024.124145},
pmid = {38735462},
issn = {1873-6424},
mesh = {*Endoplasmic Reticulum Stress/drug effects ; Animals ; *Oxidative Stress/drug effects ; Humans ; Mice ; *Activating Transcription Factor 4/metabolism/genetics ; *Mitochondria/drug effects/metabolism ; Hep G2 Cells ; *eIF-2 Kinase/metabolism/genetics ; *Endoplasmic Reticulum Chaperone BiP ; *Mice, Inbred C57BL ; Copper/toxicity ; Chemical and Drug Induced Liver Injury/metabolism ; Copper Sulfate/toxicity ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Male ; Liver/drug effects/metabolism ; Cell Survival/drug effects ; },
abstract = {Copper is an essential trace element, and excessive exposure could result in hepatoxicity, however, the underlying molecular mechanisms remain incompletely understood. The present study is aimed to investigate the molecular mechanisms of copper sulfate (CuSO4) exposure-induced hepatoxicity both in vivo and in vitro. In vitro, HepG2 and L02 cells were exposed to various doses of CuSO4 for 24 h. Cell viability, ROS production, oxidative stress biomarkers, mitochondrial functions, ultrastructure, intracellular calcium (Ca[2+)] concentration, and the expression of proteins related to mitochondrial apoptosis and endoplasmic reticulum (ER) stress were assessed. In vivo, C57BL/6 mice were treated with CuSO4 at doses of 10 and 30 mg/kg BW/day and co-treated with 4-PBA at 100 mg/kg BW/day for 35 days. Subsequently, liver function, histopathological features, and protein expression were evaluated. Results found that exposure to CuSO4 at concentrations of 100-400 μM for 24 h significantly decreased the viabilities of HepG2 and L02 cells and it was in a dose-dependent manner. Additionally, CuSO4 exposure induced significant oxidative stress and mitochondrial dysfunction in HepG2 cells, which were partially ameliorated by the antioxidant N-acetylcysteine (NAC). Furthermore, CuSO4 exposure prominently triggered ER stress, as evidenced by the upregulation of GRP94, GRP78, phosphorylated forms of PERK and eIF2α, and CHOP proteins in livers of mice and HepG2 cells. NAC treatment significantly inhibited CuSO4 exposure -induced ER stress in HepG2 cells. Pharmacological inhibition of ER stress through co-treatment with 4-PBA and the PERK inhibitor GSK2606414, as well as genetic knockdown of ATF4, partially mitigated CuSO4-induced cytotoxicity in HepG2 cells by reducing mitochondrial dysfunction and inhibiting the mitochondrial apoptotic pathway. Moreover, 4-PBA treatment significantly attenuated CuSO4-induced caspase activation and hepatoxicity in mice. In conclusion, these results reveal that CuSO4-induced hepatotoxicity involves mitochondrial dysfunction and ER stress by activating oxidative stress induction and PERK/ATF4 pathway.},
}
@article {pmid38735082,
year = {2024},
author = {Yu, N and Wu, X and Zhang, C and Qin, Q and Gu, Y and Ke, W and Liu, X and Zhang, Q and Liu, Z and Chen, M and Wang, K},
title = {NADPH and NAC synergistically inhibits chronic ocular hypertension-induced neurodegeneration and neuroinflammation through regulating p38/MAPK pathway and peroxidation.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {175},
number = {},
pages = {116711},
doi = {10.1016/j.biopha.2024.116711},
pmid = {38735082},
issn = {1950-6007},
mesh = {Animals ; *NADP/metabolism ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Ocular Hypertension/metabolism/drug therapy/pathology ; *Acetylcysteine/pharmacology ; Rats ; Male ; *Retinal Ganglion Cells/drug effects/metabolism/pathology ; *Rats, Sprague-Dawley ; Glaucoma/metabolism/pathology/drug therapy ; Neuroinflammatory Diseases/drug therapy/metabolism ; Humans ; Ependymoglial Cells/drug effects/metabolism/pathology ; Disease Models, Animal ; MAP Kinase Signaling System/drug effects ; Apoptosis/drug effects ; Chronic Disease ; Neuroprotective Agents/pharmacology ; Cells, Cultured ; Lipid Peroxidation/drug effects ; },
abstract = {Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by neurodegeneration and neuroinflammation with retinal NAD/NADP and GSH decline. Nicotinamide adenine dinucleotide (NAD)/NAD phosphate (NADP) and glutathione (GSH) are two redox reducers in neuronal and glial metabolism. However, therapeutic strategies targeting NAD/NADP or GSH do not exert ideal effects, and the underlying mechanisms are still poorly understood. We assessed morphological changes in retinal ganglion cells (RGCs), the affected neurons in glaucoma, and Müller cells, the major glial cells in the retina, as well as the levels of phosphorylated p38 (p-p38) and Caspase-3 in glaucoma patients. We constructed a modified chronic ocular hypertensive rat model and an oxygen-glucose deprivation (OGD) cell model. After applying NADPH and N-acetylcysteine (NAC), a precursor to cysteine, the rate-limiting substrate in GSH biosynthesis, to cells, apoptosis, axonal damage and peroxidation were reduced in the RGCs of the NAC group and p-p38 levels were decreased in the RGCs of the NADPH group, while in stimulated Müller cells cultured individually or cocultured with RGCs, gliosis and p38/MAPK, rather than JNK/MAPK, activation were inhibited. The results were more synergistic in the rat model, where either NADPH or NAC showed crossover effects on inhibiting peroxidation and p38/MAPK pathway activation. Moreover, the combination of NADPH and NAC ameliorated RGC electrophysiological function and prevented Müller cell gliosis to the greatest extent. These data illustrated conjoined mechanisms in glaucomatous RGC injury and Müller cell gliosis and suggested that NADPH and NAC collaborate as a neuroprotective and anti-inflammatory combination treatment for glaucoma and other underlying human neurodegenerative diseases.},
}
@article {pmid38733769,
year = {2024},
author = {Wang, R and Zhong, L and Wang, T and Sun, T and Yang, J and Liu, X and Wu, Y and Guo, Q and Gao, Y and Zhao, K},
title = {Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production.},
journal = {Neoplasia (New York, N.Y.)},
volume = {53},
number = {},
pages = {101004},
pmid = {38733769},
issn = {1476-5586},
mesh = {Humans ; Cell Line, Tumor ; A549 Cells ; HEK293 Cells ; Animals ; Mice ; Mice, Nude ; *Thioredoxin Reductase 1/antagonists &amp; inhibitors ; Male ; Female ; Middle Aged ; Aged ; *Antineoplastic Agents/chemistry/pharmacology ; Apoptosis/drug effects ; Heterografts ; *Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred BALB C ; *Lung Neoplasms/drug therapy ; Auranofin/pharmacology ; },
abstract = {Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system, such as Auranofin, are effective in eradicating cancer cells. However, the clinical significance of thioredoxin reductase 1 (TrxR1) in lung cancer, as well as the potential for its antagonist as a treatment option, necessitated further experimental validation. In this study, we observed significant upregulation of TrxR1 specifically in non-small cell lung cancer (NSCLC), rather than small cell lung cancer. Moreover, TrxR1 expression exhibited associations with survival rate, tumor volume, and histological classification. We developed a novel TrxR1 inhibitor named LW-216 and assessed its antitumor efficacy in NSCLC. Our results revealed that LW-216 is effectively bound with intracellular TrxR1 at sites R371 and G442, facilitating TrxR1 ubiquitination and suppressing TrxR1 expression, while not affecting TrxR2 expression. Treatment of LW-216-induced DNA damage and cell apoptosis in NSCLC cells through the generation of reactive oxygen species (ROS). Importantly, supplementation with N-acetylcysteine (NAC) or ectopic TrxR1 expression reversed LW-216-induced apoptosis. Furthermore, LW-216 displayed potent tumor growth inhibition in NSCLC cell-implanted mice, reducing TrxR1 expression in xenografts. Remarkably, LW-216 exhibited superior antitumor activity compared to Auranofin in vivo. Collectively, our research provides compelling evidence supporting the potential of targeting TrxR1 by LW-216 as a promising therapeutic strategy for NSCLC.},
}
@article {pmid38732054,
year = {2024},
author = {Padalhin, A and Abueva, C and Ryu, HS and Yoo, SH and Seo, HH and Park, SY and Chung, PS and Woo, SH},
title = {Impact of Thermo-Responsive N-Acetylcysteine Hydrogel on Dermal Wound Healing and Oral Ulcer Regeneration.},
journal = {International journal of molecular sciences},
volume = {25},
number = {9},
pages = {},
pmid = {38732054},
issn = {1422-0067},
support = {RS-2020-KD000027//Ministry of Science and ICT/ ; RS-2023-00247651//National Research Foundation of Korea/ ; NRF-2020R1A6A1A03043283//National Research Foundation of Korea/ ; },
mesh = {*Wound Healing/drug effects ; *Acetylcysteine/pharmacology ; Animals ; Rats ; Humans ; *Hydrogels/chemistry/pharmacology ; *Rats, Sprague-Dawley ; *Oral Ulcer/drug therapy/pathology ; Regeneration/drug effects ; Fibroblasts/drug effects ; Male ; Temperature ; Cell Survival/drug effects ; },
abstract = {This study investigates the efficacy of a thermo-responsive N-acetylcysteine (NAC) hydrogel on wound healing and oral ulcer recovery. Formulated by combining NAC with methylcellulose, the hydrogel's properties were assessed for temperature-induced gelation and cell viability using human fibroblast cells. In vivo experiments on Sprague Dawley rats compared the hydrogel's effects against saline, NAC solution, and a commercial NAC product. Results show that a 5% NAC and 1% methylcellulose solution exhibited optimal outcomes. While modest improvements in wound healing were observed, significant enhancements were noted in oral ulcer recovery, with histological analyses indicating fully regenerated mucosal tissue. The study concludes that modifying viscosity enhances NAC retention, facilitating tissue regeneration. These findings support previous research on the beneficial effects of antioxidant application on damaged tissues, suggesting the potential of NAC hydrogels in improving wound care and oral ulcer treatment.},
}
@article {pmid38731862,
year = {2024},
author = {Yi, LX and Tan, EK and Zhou, ZD},
title = {Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {25},
number = {9},
pages = {},
pmid = {38731862},
issn = {1422-0067},
support = {CS-IRG, OF-IRG, HLCA2022, STaR, OF-LCG 000207//National Medical Research Council/ ; Collaboration pilot grant//Duke-NUS Medical School/ ; },
mesh = {Animals ; Humans ; Dopamine/metabolism ; *Dopamine Agonists/therapeutic use/pharmacology ; Dopaminergic Neurons/drug effects/metabolism ; Drug Therapy, Combination ; Enzyme Inhibitors/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy/metabolism ; *Tyrosine 3-Monooxygenase/antagonists &amp; inhibitors/metabolism ; },
abstract = {There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.},
}
@article {pmid38730615,
year = {2024},
author = {Forbes, M and Kempa, R and Mastrobuoni, G and Rayman, L and Pietzke, M and Bayram, S and Arlt, B and Spruessel, A and Deubzer, HE and Kempa, S},
title = {L-Glyceraldehyde Inhibits Neuroblastoma Cell Growth via a Multi-Modal Mechanism on Metabolism and Signaling.},
journal = {Cancers},
volume = {16},
number = {9},
pages = {},
pmid = {38730615},
issn = {2072-6694},
abstract = {Glyceraldehyde (GA) is a three-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits neuroblastoma cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and [13]C-labeling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in neuroblastoma cells. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. Analysis of nucleotide pools in L-GA-treated cells depicted a previously unreported observation, in which nucleotide biosynthesis is significantly inhibited. The inhibitory action of L-GA was partially relieved with the co-application of the antioxidant N-acetyl-cysteine. We present novel evidence for a simple sugar that inhibits cancer cell proliferation via dysregulating its fragile homeostatic environment.},
}
@article {pmid38729599,
year = {2024},
author = {Wang, Z and Hu, Q and Tian, C and Wang, R and Jiao, Q and Chen, F and Wu, T and Wang, J and Zhu, Y and Liu, A and Zhang, W and Li, J and Shen, H},
title = {Prophylactic Effects of n-Acethylcysteine on Inflammation-induced Depression-like Behaviors in Mice.},
journal = {Neuroscience},
volume = {549},
number = {},
pages = {42-54},
doi = {10.1016/j.neuroscience.2024.05.005},
pmid = {38729599},
issn = {1873-7544},
mesh = {Animals ; Male ; *Depression/drug therapy/etiology/metabolism/prevention &amp; control ; *Acetylcysteine/pharmacology ; *Mice, Inbred C57BL ; Mice ; *Brain-Derived Neurotrophic Factor/metabolism ; *Inflammation/drug therapy/metabolism ; *Lipopolysaccharides/pharmacology ; *Neuronal Plasticity/drug effects ; Receptors, AMPA/metabolism ; Excitatory Postsynaptic Potentials/drug effects/physiology ; Synaptic Transmission/drug effects ; Behavior, Animal/drug effects ; Disease Models, Animal ; Neurons/drug effects/metabolism ; },
abstract = {Depression, affecting individuals worldwide, is a prevalent mental disease, with an increasing incidence. Numerous studies have been conducted on depression, yet its pathogenesis remains elusive. Recent advancements in research indicate that disturbances in synaptic transmission, synaptic plasticity, and reduced neurotrophic factor expression significantly contribute to depression's pathogenesis. In our study, we utilized adult male C57BL/6J mice. Lipopolysaccharide (LPS) can induce both chronic and acute depression-like symptoms in mice, a widely used model for studying depression associated with inflammation. N-acetylcysteine (NAC) exhibits anti-inflammatory and ameliorative effects on depressive symptoms. This study sought to determine whether NAC use could mitigate inflammatory depressive behavior through the enhancement of synaptic transmission, synaptic plasticity, and increasing levels of brain-derived neurotrophic factor (BDNF). In this study, we discovered that in mice modeled with depression-like symptoms, the expression levels of dendrites, BDNF, and miniature excitatory postsynaptic potential (mEPSC) in glutamatergic neurons, as well as the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPARs) GluA1 and GluA2 subunits, were significantly decreased. These findings suggest an impairment in the synaptic transmission of glutamatergic neurons. Following treatment with NAC, the previously mentioned levels improved, indicating an enhancement in both synaptic transmission and synaptic plasticity. Our results suggest that NAC exerts a protective effect on mouse models of inflammatory depression, potentially through the enhancement of synaptic transmission and plasticity, as well as the restoration of neurotrophic factor expression. These findings offer vital animal experimental evidence supporting NAC's role in mitigating inflammatory depressive behaviors.},
}
@article {pmid38726279,
year = {2024},
author = {Zhao, MM and Wang, B and Huang, WX and Zhang, L and Peng, R and Wang, C},
title = {Verteporfin suppressed mitophagy via PINK1/parkin pathway in endometrial cancer.},
journal = {American journal of cancer research},
volume = {14},
number = {4},
pages = {1935-1946},
pmid = {38726279},
issn = {2156-6976},
abstract = {Endometrial cancer (EC) is a malignancy that poses a threat to woman's health worldwide. Building upon prior work, we explored the inhibitory effect of verteporfin on EC. We showed that verteporfin can damage the mitochondria of EC cells, leading to a decrease of mitochondrial membrane potential and an increase in ROS (reactive oxygen species). In addition, verteporfin treatment was shown to inhibit the proliferation and migration of EC cells, promote apoptosis, and reduce the expression of mitophagy-related proteins PINK1/parkin and TOM20. The ROS inhibitor N-Acetyl Cysteine was able to rescue the expression of PINK1/parkin proteins. This suggests that verteporfin may inhibit mitophagy by elevating ROS levels, thereby inhibiting EC cell viability. The effect of verteporfin on mitophagy supports further investigation as a potential therapeutic option for EC.},
}
@article {pmid38718763,
year = {2024},
author = {Behtaj, D and Ghorbani, A and Eslamian, G and Malekpour Alamdari, N and Abbasi, M and Zand, H and Shakery, A and Shimi, G and Sohouli, MH and Fazeli Taherian, S},
title = {Ex vivo Anti-Senescence Activity of N-Acetylcysteine in Visceral Adipose Tissue of Obese Volunteers.},
journal = {Obesity facts},
volume = {17},
number = {4},
pages = {355-363},
pmid = {38718763},
issn = {1662-4033},
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Intra-Abdominal Fat/metabolism/drug effects ; *Cellular Senescence/drug effects ; Adult ; Male ; *beta-Galactosidase/metabolism ; *Interleukin-6/metabolism ; *Tumor Necrosis Factor-alpha/metabolism ; Female ; *Obesity/metabolism/drug therapy ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Middle Aged ; Tumor Suppressor Protein p53/metabolism ; Antioxidants/pharmacology/metabolism ; Oxidative Stress/drug effects ; Inflammation/metabolism ; },
abstract = {INTRODUCTION: Excessive visceral adiposity is known to drive the onset of metabolic derangements, mostly involving oxidative stress, prolonged inflammation, and cellular senescence. N-acetylcysteine (NAC) is a synthetic form of <sc>l</sc>-cysteine with potential antioxidant, anti-inflammatory, and anti-senescence properties. This ex-vivo study aimed to determine the effect of NAC on some markers of senescence including β-galactosidase activity and p16, p53, p21, IL-6, and TNF-α gene expressions in visceral adipose tissue in obese adults.<br><br>METHODS: This ex-vivo experimental study involved 10 obese participants who were candidates for bariatric surgery. Duplicate biopsies from the abdominal visceral adipose tissue were obtained from the omentum. The biopsies were treated with or without NAC (5 and 10 m<sc>m</sc>). To evaluate adipose tissue senescence, beta-galactosidase (&#x3b2;-gal) activity and the expression of P16, P21, P53, IL-6, and TNF-&#x3b1; were determined. ANOVA test was employed to analyze the varying markers of cellular senescence and inflammation between treatment groups.<br><br>RESULTS: The NAC at concentrations of 5 m<sc>m</sc> and 10 m<sc>m</sc> resulted in a noteworthy reduction &#x3b2;-gal activity compared to the control group (p < 0.001). Additionally, the expression of P16, P21, and IL-6 was significantly reduced following treatment with NAC (5 m<sc>m</sc>) and NAC (10 m<sc>m</sc>) compared to the control group (All p < 0.001).<br><br>DISCUSSION/CONCLUSION: Taken together, these data suggest the senotherapeutic effect of NAC, as it effectively reduces the activity of SA-&#x3b2;-gal and the expression of IL-6, P16, and P21 genes in the visceral adipose tissue of obese individuals.},
}
@article {pmid38718420,
year = {2024},
author = {Gökalp, G and Nalbant, T and Bıcılıoğlu, Y},
title = {The Insidious Enemy of the Liver: The Situation in Childhood Acetaminophen Poisoning and Early N-AC Treatment.},
journal = {Pediatric emergency care},
volume = {40},
number = {7},
pages = {e89-e93},
doi = {10.1097/PEC.0000000000003176},
pmid = {38718420},
issn = {1535-1815},
mesh = {Humans ; *Acetaminophen/poisoning ; Retrospective Studies ; Female ; Male ; Cross-Sectional Studies ; Child ; Child, Preschool ; *Chemical and Drug Induced Liver Injury/etiology/epidemiology ; *Acetylcysteine/therapeutic use ; Infant ; Analgesics, Non-Narcotic/poisoning ; Drug Overdose ; Antidotes/therapeutic use ; Liver Transplantation ; Adolescent ; Liver ; },
abstract = {METHODS: This study was designed as a cross-sectional, observational, retrospective study. The variables of the study were paracetamol overdose, demographic information, poisoning mechanisms, clinical, laboratory findings, and clinical progression of the cases. The cases compared in whom treatment was initiated within the first 8 hours after poisoning and those in whom it was not. χ 2 , t test, and logistic regression analyses were conducted at appropriate facilities.<br><br>RESULTS: Three hundred forty-eight cases were included in the study. N-AC treatment was initiated within the first 8 hours after poisoning in 322 cases (92.5%), and 26 cases received N-AC treatment after 8 hours after poisoning. Liver toxicity developed in 6 cases (1.7%), and indications for liver transplantation were met in 36 cases (10.3%). Among the 26 cases for which treatment was not initiated within the first 8 hours, 18 cases (69.2%) had indications for liver transplantation (P < 0.01). It was found that N-AC within the first 8 hours reduced the risk by 43 times (P = 0.02) and being older than 6 years, being admitted to the intensive care unit, and having alanine aminotransferase values above 1000 U/L increased the risk significantly (P = 0.009, P = 0.005, P < 0.001). When a receiver operating characteristic curve was plotted for the 4th-hour blood acetaminophen level to predict liver transplantation, a value of 684.5 &#x3bc;g/mL emerged with 89% sensitivity and 93% specificity (area under the curve, 0.951).<br><br>CONCLUSIONS: As a result, this study demonstrates the protective effect of early-initiated N-AC therapy on liver toxicity in pediatric acetaminophen poisoning cases. It also highlights a significant impact of gastrointestinal decontamination methods.},
}
@article {pmid38715671,
year = {2024},
author = {Zhao, W and Wang, K and Yu, L and Guo, Y and Li, Z},
title = {Dasatinib-induced pleural effusions, pericardial effusion and pulmonary arterial hypertension: a case report.},
journal = {Translational pediatrics},
volume = {13},
number = {4},
pages = {673-681},
pmid = {38715671},
issn = {2224-4344},
abstract = {BACKGROUND: Pleural effusion, pericardial effusion, and pulmonary arterial hypertension have been shown to have potential associations with the use of dasatinib in adults. However, due to the limited data regarding the efficacy and safety of tyrosine kinase inhibitors (TKIs) in pediatric patients necessities reliance on clinical experience gained from treating adults.<br><br>CASE DESCRIPTION: We present a case of a 12-year-old female patient with chronic myelogenous leukemia (CML) who developed significant right-sided pleural effusion, moderate pericardial effusion, and pulmonary arterial hypertension during dasatinib therapy. Dasatinib was promptly discontinued upon identification of these adverse events. This was followed by the use of bosentan for pulmonary hypertension, furosemide and spironolactone diuretics, prednisone anti-inflammatory, and especially a bold attempt to improve pulmonary endothelial permeability with acetyl cysteine aerosolization. At the same time, according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data reported by the patient and combined with the actual situation, the appropriate TKI was selected for the patient to continue the CML treatment.<br><br>CONCLUSIONS: FAERS data gathered on OpenVigil indicates that the signal associated with pericardial effusion is stronger among individuals under the age of 18 when imatinib is used instead of dasatinib (exactly the reverse of the results in the adult group). However, this does not imply that dasatinib is safer for the smaller group. In our situation, dasatinib-induced adverse effects include pericardial effusion. As a result, while administering TKIs to pediatric patients, we still need to increase monitoring-particularly for pulmonary and cardiovascular toxicity-and take swift action in the event that a major adverse reaction occurs. In addition, it is important to report these adverse effects as much as possible in order to give pediatric patients utilizing TKIs more helpful information.},
}
@article {pmid38713059,
year = {2024},
author = {Vargas-Barona, A and Bernáldez-Sarabia, J and Castro-Ceseña, AB},
title = {Lipid-polymer hybrid nanoparticles loaded with N-acetylcysteine for the modulation of neuroinflammatory biomarkers in human iPSC-derived PSEN2 (N141I) astrocytes as a model of Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {12},
number = {21},
pages = {5085-5097},
doi = {10.1039/d4tb00521j},
pmid = {38713059},
issn = {2050-7518},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Nanoparticles/chemistry ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; *Acetylcysteine/chemistry/pharmacology ; *Astrocytes/drug effects/metabolism ; Polymers/chemistry/pharmacology ; Lipids/chemistry ; Biomarkers/metabolism ; Particle Size ; Neuroinflammatory Diseases/drug therapy ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment associated with the accumulation of beta-amyloid protein (Aβ). Aβ activates glial cells in the brain, increasing the secretion of proinflammatory cytokines, which leads to neuroinflammation and neuronal death. Currently, there are no effective treatments that cure or stop its progression; therefore, AD is considered a global health priority. The main limitations are the low drug bioavailability and impermeability of the blood-brain barrier (BBB). Fortunately, nanomedicine has emerged as a promising field for the development of new nanosystems for the controlled and targeted delivery of drugs to the brain. Therefore, in this work, lipid-polymer hybrid nanoparticles (LPHNPs) conjugated with transferrin (Tf) to facilitate crossing the BBB and loaded with N-acetylcysteine (NAC) for its anti-inflammatory effect were synthesized, and their physicochemical characterization was carried out. Subsequently, an in vitro model involving human astrocytes derived from induced pluripotent stem cells (iPSC) from an AD-diagnosed patient was developed, which was brought to a reactive state by stimulation with lipopolysaccharides (LPSs). The cell culture was treated with either Tf-conjugated LPHNPs loaded with NAC (NAC-Tf-LPHNPs) at 0.25 mg mL[-1], or free NAC at 5 mM. The results showed that NAC-Tf-LPHNPs favorably modulated the expression of proinflammatory genes such as interleukin-1β (IL-1β), amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP). In addition, they reduced the secretion of the proinflammatory cytokines interleukin 6 (IL-6), IL-1β and interferon-gamma (INF-γ). Results for both cases were compared to the group of cells that did not receive any treatment. In contrast, free NAC only had this effect on the expression of IL-1β and the secretion of the cytokines IL-6 and INF-γ. These results indicate the potential of NAC-Tf-LPHNPs for AD treatment.},
}
@article {pmid38704503,
year = {2024},
author = {Wajih, N and Erali, RA and Forsythe, SD and Schaaf, CR and Shen, P and Levine, EA and Soker, S and Morris, DL and Votanopoulos, KI},
title = {Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer.},
journal = {Annals of surgical oncology},
volume = {31},
number = {8},
pages = {5377-5389},
pmid = {38704503},
issn = {1534-4681},
support = {R01 CA249087/CA/NCI NIH HHS/United States ; T32 OD010957/OD/NIH HHS/United States ; CA258692//Foundation for the National Institutes of Health/ ; CA249087//Foundation for the National Institutes of Health/ ; R01 CA258692/CA/NCI NIH HHS/United States ; },
mesh = {*Bromelains/pharmacology ; Humans ; *Appendiceal Neoplasms/pathology/therapy/drug therapy ; *Hyperthermic Intraperitoneal Chemotherapy ; *Cisplatin/pharmacology/administration &amp; dosage ; Male ; Female ; Middle Aged ; Apoptosis/drug effects ; Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use ; Tumor Cells, Cultured ; Mitomycin/pharmacology/administration &amp; dosage ; Aged ; Cell Proliferation/drug effects ; Cytoreduction Surgical Procedures ; Adenocarcinoma, Mucinous/pathology/therapy/drug therapy/metabolism ; Prognosis ; Follow-Up Studies ; },
abstract = {INTRODUCTION: Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line.<br><br>PATIENTS AND METHODS: PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37&#xa0;&#xb0;C and 42&#xa0;&#xb0;C with and without bromelain pretreatment.<br><br>RESULTS: From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p&#x2009;=&#x2009;0.0009) or NAC alone (47% versus 12.8%, p&#x2009;=&#x2009;0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p&#x2009;<&#x2009;0.001) and > 66% in 48 h (p&#x2009;<&#x2009;0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p&#x2009;=&#x2009;0.0001) and 35.5% (p&#x2009;=&#x2009;0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p&#x2009;=&#x2009;0.009) and Bcl-xL (p&#x2009;=&#x2009;0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p&#x2009;<&#x2009;0.03) and II (p&#x2009;<&#x2009;0.031) were increased; while ATG7 (p&#x2009;<&#x2009;0.01), ATG 12 (p&#x2009;<&#x2009;0.04), and Becline 1(p&#x2009;<&#x2009;0.03), expression decreased in bromelain-treated PTOs.<br><br>CONCLUSIONS: Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.},
}
@article {pmid38703034,
year = {2024},
author = {Mato, S and Municio, S and Alonso, JL and Alonso, ER and León, I},
title = {Impact of the Acetyl Group on Cysteine: A Study of N-Acetyl-Cysteine through Rotational Spectroscopy.},
journal = {Chemphyschem : a European journal of chemical physics and physical chemistry},
volume = {25},
number = {15},
pages = {e202400191},
doi = {10.1002/cphc.202400191},
pmid = {38703034},
issn = {1439-7641},
support = {PID2019-111396GB-I00//Ministerio de Ciencia e Innovaci&#xf3;n/ ; VA244P20//Junta de Castilla y Le&#xf3;n/ ; 23CO1/002570//Ministerio de Ciencia e Innovaci&#xf3;n for a postgraduate fellowship/ ; },
mesh = {*Acetylcysteine/chemistry ; Cysteine/chemistry ; Rotation ; Spectrum Analysis/methods ; Molecular Conformation ; Microwaves ; },
abstract = {Herein, we report a spectroscopic study of N-acetyl-L-cysteine, an important antioxidant drug, using Fourier-transform microwave techniques and in isolated conditions. Two conformers are observed, where most stable structure adopts a cis disposition, and the second conformer has a lower abundance and adopts a trans disposition. The rotational constants and the barriers to methyl internal rotation are determined for each conformer, allowing a precise conformation identification. The results show that the cis form adopts an identical structure in the crystal, solution, and gas phases. Additionally, the structures are contrasted against those of cysteine.},
}
@article {pmid38702594,
year = {2024},
author = {Sohouli, MH and Eslamian, G and Ardehali, SH and Raeissadat, SA and Shimi, G and Pourvali, K and Zand, H},
title = {Effects of N-acetylcysteine on the expressions of UCP1 and factors related to thyroid function in visceral adipose tissue of obese adults: a randomized, double-blind clinical trial.},
journal = {Genes &amp; nutrition},
volume = {19},
number = {1},
pages = {8},
pmid = {38702594},
issn = {1555-8932},
abstract = {BACKGROUND: Evidences have shown that obesity is influenced by various factors, including various hormones such as thyroid hormones and the body's metabolism rate. It seems that practical solutions such as weight loss diets and common drugs can affect these potential disorders. In this study, we investigate one of these common drugs, N-Acetylcysteine (NAC), on expressions of UCP1 and factors related to thyroid function in adults with obesity.<br><br>METHODS AND ANALYSIS: The current investigation was carried out as a randomized clinical trial (RCT) including 43 adults with obesity who were potential candidates for bariatric surgery. These individuals were randomly divided into two groups: 600&#xa0;mg of NAC (n&#x2009;=&#x2009;22) or placebo (n&#x2009;=&#x2009;21) for a duration of 8 weeks. Visceral adipose tissue was utilized in the context of bariatric surgery to investigate the gene expression of UCP1 and thyroid function. Polymerase chain reaction (PCR) was performed in duplicate for UCP1, DIO2, DIO3, THR&#x3b1; and &#x3b2;, and 18s RNA (as an internal control) using the provided instructions to investigate the expression of the respective genes.<br><br>RESULTS: Our findings revealed that after 8 weeks compared to placebo, NAC caused a significant decrease in the expression of the DIO3 gene as one of the genes related to thyroid function and metabolism. However, regarding other related genes, no statistically significant was found (despite the increase in UCP1, DIO2, and THR&#x3b1; expression and decrease in THR&#x3b2; expression). In addition, after adjustment of possible confounders, no significant effect was observed on anthropometric factors and serum levels of thyroid hormones.<br><br>CONCLUSION: The results of this study indicate that, following an 8-week period, NAC effectively decreases the expression of the DIO3 gene in the visceral fat tissue, in comparison to the placebo.},
}
@article {pmid38702220,
year = {2024},
author = {Hodgson, S and Abouchedid, R and Cleary, K and Tile, N and Wong, A},
title = {Acute arsenic exposure secondary to deliberate self-poisoning with sheep dip.},
journal = {The American journal of emergency medicine},
volume = {80},
number = {},
pages = {226.e1-226.e3},
doi = {10.1016/j.ajem.2024.04.050},
pmid = {38702220},
issn = {1532-8171},
mesh = {Male ; Humans ; Middle Aged ; *Suicide, Attempted ; *Arsenic Poisoning ; *Acetylcysteine/therapeutic use ; *Arsenicals ; Arsenic Trioxide/poisoning ; Oxides/poisoning ; Antidotes/therapeutic use ; Unithiol/therapeutic use ; },
abstract = {A 53-year-old male patient presented to a regional hospital Emergency Department approximately 2 h post an intentional ingestion of Coopers Instant Wetting Powder Sheep Dip (66% arsenic trioxide, 23% sulphur and 0.42% rotenone), mixed in 600 mL water, as a suicide attempt. On arrival to the Emergency Department, the patient had nausea, vomiting and diarrhoea. Seven hours post ingestion, hypotension developed (BP 90/60 mmHg) and intravenous fluids were commenced. He later developed QTc prolongation. He was treated with 2,3-Dimercapto-1-propanesulfonic acid (DMPS) and N-acetylcysteine and improved without development of neurology. Further investigation of NAC efficacy in humans in the setting of acute arsenic poisoning is required and the optimal duration of treatment and dosing needs to be established. This case highlights an uncommon poisoning which presented to the Emergency Department, the acute symptoms of arsenic toxicity and considerations for management.},
}
@article {pmid38700012,
year = {2024},
author = {Abouelgreed, TA and Amer, MA and Mamdouh, H and El-Sherbiny, AF and Aboelwafa, H and Fahmy, SF and Omar, OA and Abdelshakour, M and Elesawy, M and Sonbol, M and Maawad, AN and Elsayed, OK},
title = {The influence of oral antioxidants on men with infertility: a systemic review.},
journal = {Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica},
volume = {96},
number = {2},
pages = {12323},
doi = {10.4081/aiua.2024.12323},
pmid = {38700012},
issn = {2282-4197},
mesh = {Humans ; Male ; *Antioxidants/administration &amp; dosage/therapeutic use ; *Infertility, Male/drug therapy/etiology ; Administration, Oral ; Randomized Controlled Trials as Topic ; Semen Analysis ; Dietary Supplements ; },
abstract = {OBJECTIVE: This study aims to investigate the current evidence regarding the impact of oral antioxidant supplementation on semen parameters of infertile men.<br><br>MATERIALS AND METHODS: We conducted a systematic search of PubMed, and Cochrane electronic databases, adhering to modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The focus was on studies exploring the effects of antioxidant therapy on infertile men, with an examination of antioxidants in terms of types, doses, rationale for use, and their impact on semen parameters measures.<br><br>RESULTS: A total of 18 studies that met the inclusion criteria were included in this study. Out of these, 14 studies reported a significantly positive influence of antioxidant therapy on basic semen parameters and advanced sperm function. These comprised 11 randomized clinical trials and 7 prospective studies. Commonly utilized antioxidants included Vitamin E, Vitamin C, carnitines, co-enzyme Q10, N-acetyl cysteine, zinc, selenium, folic acid, and lycopene.<br><br>CONCLUSIONS: Overall, antioxidants generally demonstrate a favorable effect on semen parameters of infertile men. However, further research is necessary to pinpoint the optimal antioxidant regimen that can be applied safely and effectively in clinical practice.},
}
@article {pmid38693878,
year = {2024},
author = {Pandey, R and Pinon, V and Garren, M and Maffe, P and Mondal, A and Brisbois, EJ and Handa, H},
title = {N-Acetyl Cysteine-Decorated Nitric Oxide-Releasing Interface for Biomedical Applications.},
journal = {ACS applied materials &amp; interfaces},
volume = {16},
number = {19},
pages = {24248-24260},
pmid = {38693878},
issn = {1944-8252},
support = {R01 HL134899/HL/NHLBI NIH HHS/United States ; R01 HL157587/HL/NHLBI NIH HHS/United States ; },
mesh = {*Acetylcysteine/chemistry/pharmacology ; *Nitric Oxide/chemistry/metabolism/pharmacology ; *Staphylococcus aureus/drug effects ; *Escherichia coli/drug effects ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Biofilms/drug effects ; Polyethyleneimine/chemistry/pharmacology ; Biocompatible Materials/chemistry/pharmacology ; Microbial Sensitivity Tests ; Polyvinyl Chloride/chemistry ; Nitric Oxide Donors/chemistry/pharmacology ; },
abstract = {Biomedical devices are vulnerable to infections and biofilm formation, leading to extended hospital stays, high expenditure, and increased mortality. Infections are clinically treated via the administration of systemic antibiotics, leading to the development of antibiotic resistance. A multimechanistic strategy is needed to design an effective biomaterial with broad-spectrum antibacterial potential. Recent approaches have investigated the fabrication of innately antimicrobial biomedical device surfaces in the hope of making the antibiotic treatment obsolete. Herein, we report a novel fabrication strategy combining antibacterial nitric oxide (NO) with an antibiofilm agent N-acetyl cysteine (NAC) on a polyvinyl chloride surface using polycationic polyethylenimine (PEI) as a linker. The designed biomaterial could release NO for at least 7 days with minimal NO donor leaching under physiological conditions. The proposed surface technology significantly reduced the viability of Gram-negative Escherichia coli (>97%) and Gram-positive Staphylococcus aureus (>99%) bacteria in both adhered and planktonic forms in a 24 h antibacterial assay. The composites also exhibited a significant reduction in biomass and extra polymeric substance accumulation in a dynamic environment over 72 h. Overall, these results indicate that the proposed combination of the NO donor with mucolytic NAC on a polymer surface efficiently resists microbial adhesion and can be used to prevent device-associated biofilm formation.},
}
@article {pmid38693516,
year = {2024},
author = {Ozawa, K and Packwood, W and Muller, MA and Qi, Y and Xie, A and Varlamov, O and McCarty, OJ and Chung, D and López, JA and Lindner, JR},
title = {Removal of endothelial surface-associated von villebrand factor suppresses accelerate datherosclerosis after myocardial infarction.},
journal = {Journal of translational medicine},
volume = {22},
number = {1},
pages = {412},
pmid = {38693516},
issn = {1479-5876},
support = {R35 HL145262/HL/NHLBI NIH HHS/United States ; NIH R01-HL078610/NH/NIH HHS/United States ; NIH R01-HL165422/NH/NIH HHS/United States ; R35-HL145262/NH/NIH HHS/United States ; R01 HL130046/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; *von Willebrand Factor/metabolism ; *Myocardial Infarction/pathology/complications ; *ADAMTS13 Protein/metabolism ; Vascular Cell Adhesion Molecule-1/metabolism ; Mice ; Plaque, Atherosclerotic/pathology ; P-Selectin/metabolism ; Endothelial Cells/metabolism/drug effects ; Male ; Molecular Imaging ; Aorta/pathology/drug effects ; Acetylcysteine/pharmacology/therapeutic use ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI).<br><br>METHODS: Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIb&#x3b1;, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21.<br><br>RESULTS: Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIb&#x3b1; were all increased several-fold (p&#x2009;<&#x2009;0.01) in post-MI mice versus sham-treated animals at day 3 and 21. Treatment with NAC and ADAMTS13 significantly attenuated the post-MI increase for all four molecular targets by >&#x2009;50% (p&#x2009;<&#x2009;0.05 vs. non-treated at day 3 and 21). On aortic root histology, mice undergoing MI versus controls had 2-4 fold greater plaque size and macrophage content (p&#x2009;<&#x2009;0.05), approximately 20-fold greater platelet adhesion (p&#x2009;<&#x2009;0.05), and increased staining for markers of platelet transforming growth factor-&#x3b2;1 signaling. Accelerated plaque growth and inflammatory activation was almost entirely prevented by ADAMTS13 and NAC. Inhibition of FXI had no significant effect on molecular imaging signal or plaque morphology.<br><br>CONCLUSIONS: Plaque inflammatory activation in remote arteries after MI is strongly influenced by VWF-mediated platelet adhesion to the endothelium. These findings support investigation into new secondary preventive therapies for reducing non-culprit artery events after MI.},
}
@article {pmid38691522,
year = {2024},
author = {Gao, X and Hu, Z and Wang, Y and Zhao, G and Shen, Y and Zhou, H and Liao, Y and Li, W and Peng, Y and Zheng, J},
title = {Metabolic Activation and Cytotoxicity of Gramine Mediated by CYP3A in Rats.},
journal = {Journal of agricultural and food chemistry},
volume = {72},
number = {19},
pages = {10897-10908},
doi = {10.1021/acs.jafc.4c00400},
pmid = {38691522},
issn = {1520-5118},
mesh = {Animals ; Rats ; Male ; *Hepatocytes/metabolism/drug effects ; *Cytochrome P-450 CYP3A/metabolism/genetics ; *Rats, Sprague-Dawley ; *Activation, Metabolic ; Microsomes, Liver/metabolism ; Glutathione/metabolism ; Insecticides/toxicity/metabolism ; Alkaloids/metabolism ; },
abstract = {Gramine (GRM), which occurs in Gramineae plants, has been developed to be a biological insecticide. Exposure to GRM was reported to induce elevations of serum ALT and AST in rats, but the mechanisms of the observed hepatotoxicity have not been elucidated. The present study aimed to identify reactive metabolites that potentially participate in the toxicity. In rat liver microsomal incubations fortified with glutathione or N-acetylcysteine, one oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetylcysteine conjugate (M3) were detected after exposure to GRM. The corresponding conjugates were detected in the bile and urine of rats after GRM administration. CYP3A was the main enzyme mediating the metabolic activation of GRM. The detected GSH and NAC conjugates suggest that GRM was metabolized to a quinone imine intermediate. Both GRM and M1 showed significant toxicity to rat primary hepatocytes.},
}
@article {pmid38688172,
year = {2024},
author = {Chen, Y and Xu, M and Liu, XM and Wang, JX and Sun, MF and Song, JX and Guan, P and Ji, ES and Wang, N},
title = {Mechanistic study of Huangqi Guizhi Wuwu decoction amelioration of doxorubicin-induced cardiotoxicity by reducing oxidative stress and inhibiting cellular pyroptosis.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {175},
number = {},
pages = {116653},
doi = {10.1016/j.biopha.2024.116653},
pmid = {38688172},
issn = {1950-6007},
mesh = {Animals ; *Doxorubicin/toxicity ; *Pyroptosis/drug effects ; *Drugs, Chinese Herbal/pharmacology ; *Oxidative Stress/drug effects ; *Cardiotoxicity/drug therapy/metabolism/prevention &amp; control ; Rats ; Male ; *Rats, Sprague-Dawley ; Myocytes, Cardiac/drug effects/metabolism/pathology ; Cell Line ; Network Pharmacology ; },
abstract = {Huangqi Guizhi Wuwu Decoction (HQGZWWD) has shown promising potential in treating various cardiovascular diseases. This study aimed to elucidate the molecular basis and therapeutic role of HQGZWWD in the treatment of doxorubicin (DOX)-induced myocardial injury. The HPLC fingerprint of HQGZWWD was used to analyze the active components. A DOX-induced myocardial damage rat model was developed, and the therapeutic effects of HQGZWWD were evaluated using echocardiography, myocardial enzyme levels, and hematoxylin and eosin staining. Network pharmacology was used to screen treatment targets, and western blotting and immunohistochemistry were performed to assess cellular pyroptosis levels. Oxidative stress levels were measured using assay kits, and mitochondrial damage was examined using transmission electron microscopy. An in vitro model of DOX-induced cell damage was established, and treatment was administered using serum containing HQGZWWD and N-acetylcysteine (NAC). Oxidative stress levels were detected using assay kits and DCFH-DA, whereas cellular pyroptosis levels were assessed through WB, immunofluorescence, and ELISA assays. HQGZWWD ameliorated DOX-induced myocardial injury. Network pharmacology identified IL-1β and IL-18 as crucial targets. HQGZWWD downregulated the protein levels of the inflammatory factors IL-1β and IL-18, inhibited the expression of GSDMD-NT, and simultaneously suppressed the synthesis of Caspase-1, ASC, NLRP3, and Caspase-11. Additionally, HQGZWWD inhibited oxidative stress, and the use of NAC as an oxidative stress inhibitor resulted in significant inhibition of the GSDMD-NT protein in H9C2 cells. These findings highlight the myocardial protective effects of HQGZWWD by inhibiting oxidative stress and suppressing both canonical and non-canonical pyroptotic pathways.},
}
@article {pmid38687644,
year = {2025},
author = {Manhas, A and Arnold, CG and Bush, AM},
title = {Underreporting Supplements: A Case of Drug-induced Liver Injury Due to a Testosterone Booster.},
journal = {Military medicine},
volume = {190},
number = {1-2},
pages = {e453-e455},
doi = {10.1093/milmed/usae136},
pmid = {38687644},
issn = {1930-613X},
mesh = {Humans ; Male ; *Chemical and Drug Induced Liver Injury/etiology/diagnosis ; Adult ; *Testosterone/adverse effects/therapeutic use ; *Dietary Supplements/adverse effects ; },
abstract = {Acute liver injuries (ALIs) are caused by a wide range of etiologies, and determining the cause can often be challenging. Detailed history taking is essential in patients with liver injuries to promptly determine the underlying source of injury and for timely treatment and prognosis. A 27-year-old active duty man presented to the emergency department (ED) with jaundice. On medication reconciliation, he only reported taking acetaminophen for a recent upper respiratory infection. The patient had an ALI and was treated with N-acetyl cysteine for presumed acetaminophen toxicity. Initially, his liver-associated enzymes (LAEs) improved, but 2 weeks after discharge, he returned to the ED upon referral from ship medical for jaundice and worsening liver injury. Repeated query into the patient's history revealed that he was using a testosterone booster supplement for 6 months preceding initial hospitalization. After evaluation of other etiologies for liver injury returned negative, drug-induced liver injury from the testosterone booster was determined to be the underlying etiology. With discontinuation of the supplement, his liver injury improved. Hepatotoxicity is a major concern in supplement use; however, it is largely underreported. Supplements are often not recognized or reported as medications by patients, leading to failure to identify them as potential toxicants. This case highlights the importance of including supplement education and questioning in the evaluation of ALI and maintaining a high index of suspicion when other common etiologies of liver disease are negative.},
}
@article {pmid38687431,
year = {2024},
author = {Giri, S and Anirvan, P and Vaidya, A and Praharaj, DL},
title = {Dengue-related acute liver failure-A scoping review.},
journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology},
volume = {43},
number = {2},
pages = {407-424},
pmid = {38687431},
issn = {0975-0711},
mesh = {Humans ; *Liver Failure, Acute/etiology/epidemiology/therapy ; *Dengue/complications/epidemiology ; Risk Factors ; Liver Transplantation ; Female ; Male ; Child ; India/epidemiology ; Adult ; Incidence ; },
abstract = {Infection by dengue virus is common in tropical countries. Hepatic involvement in dengue can range from asymptomatic elevation of transaminases to life-threatening acute liver failure (ALF). Dengue-related ALF (DALF) is responsible for significant morbidity and mortality, especially in Southeast Asia. However, there is a scarcity of literature on DALF, necessitating a thorough examination of its clinical determinants and management strategies. All relevant studies related to DALF were reviewed until December 2023. Case reports, case series and studies reporting ALF in dengue infection were included. Demographics, clinical profiles, management and outcomes of DALF cases were analyzed, which revealed a predominance of DALF incidence in pediatric patients (1.1% to 15.8%) and an upward trend over the years, particularly in India. The proportion of ALF cases attributable to dengue was also higher among pediatric ALF patients (6.7% to 34.3%). Age ≤ 40 years, persistent nausea, vomiting and elevated serum bilirubin and alkaline phosphatase (ALP) with aspartate aminotransferase (AST) > 1000 IU/mL within the first five days of illness, more than 10% of atypical lymphocytes in peripheral blood, platelet count of < 50,000/cu·mm, severe hepatitis at presentation and baseline model for end-stage liver disease (MELD) > 15 were the risk factors for the development of DALF. Histopathological features of DALF included multi-lobular hepatic necrosis, steatosis and occasional cholestasis. Mortality in DALF ranged from 0% to 80%; admission pH and lactate strongly predicted mortality, while mortality was found to be significantly higher in patients with cirrhosis. N-Acetyl cysteine (NAC) has been used as a treatment modality with varying results. There is limited evidence regarding the use of extra-corporeal support systems, while candidate selection for liver transplantation (LT) in DALF remains poorly defined.},
}
@article {pmid38686842,
year = {2024},
author = {Hamsho, M and Ranneh, Y and Fadel, A},
title = {Comments on "A Meta-Analysis of the Efficacy of L-Carnitine/L-Acetyl-Carnitine or N-Acetyl-Cysteine in Men with Idiopathic Asthenozoospermia".},
journal = {American journal of men's health},
volume = {18},
number = {2},
pages = {15579883241249109},
pmid = {38686842},
issn = {1557-9891},
mesh = {Humans ; Male ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Asthenozoospermia/drug therapy ; *Carnitine/therapeutic use ; Meta-Analysis as Topic ; Acetylcarnitine/therapeutic use ; Treatment Outcome ; },
}
@article {pmid38686557,
year = {2024},
author = {Yang, L and Wang, X and Ma, Z and Sui, Y and Liu, X},
title = {Fangchinoline inhibits growth and biofilm of Candida albicans by inducing ROS overproduction.},
journal = {Journal of cellular and molecular medicine},
volume = {28},
number = {9},
pages = {e18354},
pmid = {38686557},
issn = {1582-4934},
support = {20220505041ZP//the Science and Technology Development Plan Project of Jilin Province/ ; 20200201595JC//Natural Science Foundation of Jilin Province/ ; JJKH20231220KJ//the Education Department of Jilin Province/ ; },
mesh = {*Biofilms/drug effects/growth &amp; development ; *Candida albicans/drug effects/growth &amp; development ; *Antifungal Agents/pharmacology ; *Reactive Oxygen Species/metabolism ; *Benzylisoquinolines/pharmacology ; *Microbial Sensitivity Tests ; Hyphae/drug effects/growth &amp; development ; },
abstract = {Infections caused by Candida species, especially Candida albicans, threaten the public health and create economic burden. Shortage of antifungals and emergence of drug resistance call for new antifungal therapies while natural products were attractive sources for developing new drugs. In our study, fangchinoline, a bis-benzylisoquinoline alkaloid from Chinese herb Stephania tetrandra S. Moore, exerted antifungal effects on planktonic growth of several Candida species including C. albicans, with MIC no more than 50 μg/mL. In addition, results from microscopic, MTT and XTT reduction assays showed that fangchinoline had inhibitory activities against the multiple virulence factors of C. albicans, such as adhesion, hyphal growth and biofilm formation. Furthermore, this compound could also suppress the metabolic activity of preformed C. albicans biofilms. PI staining, followed by confocal laser scanning microscope (CLSM) analysis showed that fangchinoline can elevate permeability of cell membrane. DCFH-DA staining suggested its anti-Candida mechanism also involved overproduction of intracellular ROS, which was further confirmed by N-acetyl-cysteine rescue tests. Moreover, fangchinoline showed synergy with three antifungal drugs (amphotericin B, fluconazole and caspofungin), further indicating its potential use in treating C. albicans infections. Therefore, these results indicated that fangchinoline could be a potential candidate for developing anti-Candida therapies.},
}
@article {pmid38682430,
year = {2024},
author = {Chen, HX and Wang, XY and Yu, B and Feng, CL and Cheng, GF and Zhang, L and Wang, JJ and Wang, Y and Guo, RW and Ji, XM and Xie, WJ and Chen, WL and Song, C and Zhang, X},
title = {Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field.},
journal = {Zoological research},
volume = {45},
number = {3},
pages = {478-491},
pmid = {38682430},
issn = {2095-8137},
mesh = {*Acetaminophen/toxicity ; Animals ; Mice ; *Chemical and Drug Induced Liver Injury ; *Drug Overdose ; *Analgesics, Non-Narcotic/toxicity ; Oxidative Stress/drug effects ; Male ; Magnetic Fields ; Acetylcysteine/therapeutic use/pharmacology ; },
abstract = {Acetaminophen (APAP), the most frequently used mild analgesic and antipyretic drug worldwide, is implicated in causing 46% of all acute liver failures in the USA and between 40% and 70% in Europe. The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine (NAC); however, its efficacy is limited in cases of advanced liver injury or when administered at a late stage. In the current study, we discovered that treatment with a moderate intensity static magnetic field (SMF) notably reduced the mortality rate in mice subjected to high-dose APAP from 40% to 0%, proving effective at both the initial liver injury stage and the subsequent recovery stage. During the early phase of liver injury, SMF markedly reduced APAP-induced oxidative stress, free radicals, and liver damage, resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione (GSH). During the later stage of liver recovery, application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery, even 24 h post overdose, when the effectiveness of NAC alone substantially declines. Overall, this study provides a non-invasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose. Of note, this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP, and potentially other toxic overdoses.},
}
@article {pmid38678953,
year = {2024},
author = {Dou, M and Zhu, D and Cui, G and Li, H and Di, L and Wang, L},
title = {Euphorbia helioscopia L. exhibits promising therapeutic effects on hemangioendothelioma and melanoma through angiogenesis inhibition.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {129},
number = {},
pages = {155666},
doi = {10.1016/j.phymed.2024.155666},
pmid = {38678953},
issn = {1618-095X},
mesh = {Animals ; *Euphorbia/chemistry ; *Hemangioendothelioma/drug therapy ; *Reactive Oxygen Species/metabolism ; *Angiogenesis Inhibitors/pharmacology ; Humans ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; Mice ; *Plant Extracts/pharmacology ; *Antineoplastic Agents, Phytogenic/pharmacology ; Cell Line, Tumor ; Melanoma/drug therapy ; Plant Leaves/chemistry ; Melanoma, Experimental/drug therapy ; Neovascularization, Pathologic/drug therapy ; Mice, Inbred C57BL ; Male ; Angiogenesis ; },
abstract = {BACKGROUND: Euphorbia helioscopia L (EHL), a widely used medicinal plant in traditional Chinese medicine, has shown promising effects on certain cancers. However, previous studies on EHL did not elucidate the underlying molecular mechanisms. Herein, for the first time, we present the strong therapeutic potential of EHL extracts on malignant hemangioendothelioma, a rare type of vascular tumor.<br><br>PURPOSE: To investigate the potential anti-tumor mechanism of extracts of EHL on hemangioendothelioma and melanoma.<br><br>METHODS: The dried stems and leaves of EHL were extracted with Ethyl Acetate and n-Butyl alcohol, yielding two crude extracts Ethyl Acetate fraction (EA) and n-Butyl alcohol fraction (Bu). EA and Bu were prepared to assess the potential mechanism by assays for cell proliferation, cell cycle, apoptosis, colony formation, tube formation, cellular metabolic activity, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, RNA expression and western blot. To further confirm the anti-tumor effect of EHL in vivo, we established hemangioendothelioma and melanoma tumor-bearing mouse model using node mice and administered with EA and Bu, tracked alterations in tumor volume and survival rate. Furthermore, tissue samples were obtained for histological, protein, and genetic investigations.<br><br>RESULTS: We demonstrate that the injection of EA and Bu, significantly inhibits tumor growth and prolongs the lifespan of tumor-bearing mice. Bu treatment exhibited a remarkable 33 % healing effect on the primary hemangioendothelioma tumor, bringing the survival rate to a level comparable to that of healthy mice. Mechanically, both EA and Bu impair respiratory chain complexes, leading to mitochondrial dysfunction and accumulation of reactive oxygen species (ROS), resulting in DNA damage, cell apoptosis, and finally blocked angiogenesis. While EA demonstrates robust inhibitory effects on cancer cell growth and a broader impact on metabolism in vitro, the in vivo effect of Bu surpasses that of EA in terms of strength. EA and Bu also exhibit potent anti-tumor effects on a primary melanoma model by inhibiting angiogenesis. Importantly, when compared to other compounds used in the treatment of hemangioendothelioma, EA and Bu demonstrate more profound anti-tumor effects.<br><br>CONCLUSION: For the first time, our findings reveal that EHL extracts, especially the high polarity compounds, exhibit potent anti-tumor effects by targeting cellular metabolism, specifically through the inhibition of mitochondria-related metabolic activities. This leads to the accumulation of ROS and effectively suppresses abnormal angiogenesis.},
}
@article {pmid38675591,
year = {2024},
author = {Zigová, M and Miškufová, V and Budovská, M and Michalková, R and Mojžiš, J},
title = {Exploring the Antiproliferative and Modulatory Effects of 1-Methoxyisobrassinin on Ovarian Cancer Cells: Insights into Cell Cycle Regulation, Apoptosis, Autophagy, and Its Interactions with NAC.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {8},
pages = {},
pmid = {38675591},
issn = {1420-3049},
support = {APVV-16-0446//Slovak Research and Development Agency/ ; VEGA 1/0653/19//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Repub-lic/ ; VEGA 1/0498/23//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Republic/ ; VEGA 1/0446/22//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Republic/ ; ITMS2014+: 313011V455//ERDF/ ; },
mesh = {Female ; Humans ; *Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology/chemistry ; *Apoptosis/drug effects ; *Autophagy/drug effects ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor/drug effects ; *Cell Proliferation/drug effects ; Cisplatin/pharmacology ; DNA Damage/drug effects ; Drug Resistance, Neoplasm/drug effects ; *Ovarian Neoplasms/drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; *Phytoalexins/pharmacology ; *Indoles/pharmacology ; Thiocarbamates/pharmacology ; },
abstract = {Ovarian cancer, a highly lethal malignancy among reproductive organ cancers, poses a significant challenge with its high mortality rate, particularly in advanced-stage cases resistant to platinum-based chemotherapy. This study explores the potential therapeutic efficacy of 1-methoxyisobrassinin (MB-591), a derivative of indole phytoalexins found in Cruciferae family plants, on both cisplatin-sensitive (A2780) and cisplatin-resistant ovarian cancer cells (A2780 cis). The findings reveal that MB-591 exhibits an antiproliferative effect on both cell lines, with significantly increased potency against cisplatin-sensitive cells. The substance induces alterations in the distribution of the cell cycle, particularly in the S and G2/M phases, accompanied by changes in key regulatory proteins. Moreover, MB-591 triggers apoptosis in both cell lines, involving caspase-9 cleavage, PARP cleavage induction, and DNA damage, accompanied by the generation of reactive oxygen species (ROS) and mitochondrial dysfunction. Notably, the substance selectively induces autophagy in cisplatin-resistant cells, suggesting potential targeted therapeutic applications. The study further explores the interplay between MB-591 and antioxidant N-acetylcysteine (NAC), in modulating cellular processes. NAC demonstrates a protective effect against MB-591-induced cytotoxicity, affecting cell cycle distribution and apoptosis-related proteins. Additionally, NAC exhibits inhibitory effects on autophagy initiation in cisplatin-resistant cells, suggesting its potential role in overcoming resistance mechanisms.},
}
@article {pmid38672493,
year = {2024},
author = {Kamenshchyk, A and Belenichev, I and Oksenych, V and Kamyshnyi, O},
title = {Combined Pharmacological Modulation of Translational and Transcriptional Activity Signaling Pathways as a Promising Therapeutic Approach in Children with Myocardial Changes.},
journal = {Biomolecules},
volume = {14},
number = {4},
pages = {},
pmid = {38672493},
issn = {2218-273X},
mesh = {Humans ; *Signal Transduction/drug effects ; Child ; Animals ; Myocardium/metabolism/pathology ; Transcription, Genetic/drug effects ; Protein Biosynthesis/drug effects ; Cardiomegaly/drug therapy/metabolism/genetics ; },
abstract = {Myocardial hypertrophy is the most common condition that accompanies heart development in children. Transcriptional gene expression regulating pathways play a critical role both in cardiac embryogenesis and in the pathogenesis of congenital hypertrophic cardiomyopathy, neonatal posthypoxic myocardial hypertrophy, and congenital heart diseases. This paper describes the state of cardiac gene expression and potential pharmacological modulators at different transcriptional levels. An experimental model of perinatal cardiac hypoxia showed the downregulated expression of genes responsible for cardiac muscle integrity and overexpressed genes associated with energy metabolism and apoptosis, which may provide a basis for a therapeutic approach. Current evidence suggests that RNA drugs, theaflavin, neuraminidase, proton pumps, and histone deacetylase inhibitors are promising pharmacological agents in progressive cardiac hypertrophy. The different points of application of the above drugs make combined use possible, potentiating the effects of inhibition in specific signaling pathways. The special role of N-acetyl cysteine in both the inhibition of several signaling pathways and the reduction of oxidative stress was emphasized.},
}
@article {pmid38672280,
year = {2024},
author = {Altay, O and Yang, H and Yildirim, S and Bayram, C and Bolat, I and Oner, S and Tozlu, OO and Arslan, ME and Hacimuftuoglu, A and Shoaie, S and Zhang, C and Borén, J and Uhlén, M and Turkez, H and Mardinoglu, A},
title = {Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases.},
journal = {Biomedicines},
volume = {12},
number = {4},
pages = {},
pmid = {38672280},
issn = {2227-9059},
support = {72110//Knut and Alice Wallenberg Foundation/ ; },
abstract = {BACKGROUND: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate.<br><br>METHODS: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations.<br><br>FINDINGS: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals.<br><br>INTERPRETATION: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.},
}
@article {pmid38672256,
year = {2024},
author = {Chen, R and Zheng, Y and Zhou, C and Dai, H and Wang, Y and Chu, Y and Luo, J},
title = {N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress.},
journal = {Biomedicines},
volume = {12},
number = {4},
pages = {},
pmid = {38672256},
issn = {2227-9059},
abstract = {(1) Background: Sepsis-induced muscle atrophy is characterized by a loss of muscle mass and function which leads to decreased quality of life and worsens the long-term prognosis of patients. N-acetylcysteine (NAC) has powerful antioxidant and anti-inflammatory properties, and it relieves muscle wasting caused by several diseases, whereas its effect on sepsis-induced muscle atrophy has not been reported. The present study investigated the effect of NAC on sepsis-induced muscle atrophy and its possible mechanisms. (2) Methods: The effect of NAC on sepsis-induced muscle atrophy was assessed in vivo and in vitro using cecal ligation and puncture-operated (CLP) C57BL/6 mice and LPS-treated C2C12 myotubes. We used immunofluorescence staining to analyze changes in the cross-sectional area (CSA) of myofibers in mice and the myotube diameter of C2C12. Protein expressions were analyzed by Western blotting. (3) Results: In the septic mice, the atrophic response manifested as a reduction in skeletal muscle weight and myofiber cross-sectional area, which is mediated by muscle-specific ubiquitin ligases-muscle atrophy F-box (MAFbx)/Atrogin-1 and muscle ring finger 1 (MuRF1). NAC alleviated sepsis-induced skeletal muscle wasting and LPS-induced C2C12 myotube atrophy. Meanwhile, NAC inhibited the sepsis-induced activation of the endoplasmic reticulum (ER) stress signaling pathway. Furthermore, using 4-Phenylbutyric acid (4-PBA) to inhibit ER stress in LPS-treated C2C12 myotubes could partly abrogate the anti-muscle-atrophy effect of NAC. Finally, NAC alleviated myotube atrophy induced by the ER stress agonist Thapsigargin (Thap). (4) Conclusions: NAC can attenuate sepsis-induced muscle atrophy, which may be related to downregulating ER stress.},
}
@article {pmid38671944,
year = {2024},
author = {Kim, RJ and Park, HB},
title = {Protective and Regenerative Effects of Reconstituted HDL on Human Rotator Cuff Fibroblasts under Hypoxia: An In Vitro Study.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {4},
pages = {},
pmid = {38671944},
issn = {2076-3921},
support = {2021R1A2C1008931//National Research Foundation of Korea/ ; },
abstract = {Hypoxia and hypo-high-density lipoproteinemia (hypo-HDLemia) are proposed risk factors for rotator cuff tear. HDL is recognized for its potential benefits in ischemia-driven angiogenesis and wound healing. Nevertheless, research on the potential benefits of reconstituted HDL (rHDL) on human rotator cuff fibroblasts (RCFs) under hypoxia is limited. This study investigates the cytoprotective and regenerative effects of rHDL, as well as N-acetylcysteine (NAC), vitamin C (Vit C), and HDL on human RCFs under hypoxic conditions. Sixth-passage human RCFs were divided into normoxia, hypoxia, and hypoxia groups pretreated with antioxidants (NAC, Vit C, rHDL, HDL). Hypoxia was induced by 1000 µM CoCl2. In the hypoxia group compared to the normoxia group, there were significant increases in hypoxia-inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1), and Bcl-2/E1B-19kDa interacting protein 3 (BNIP3) expressions, along with reduced cell viability, elevated reactive oxygen species (ROS) production, apoptosis rate, expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase-1 (PARP-1), vascular endothelial growth factors (VEGF), and matrix metalloproteinase-2 (MMP-2), as well as decreased collagen I and III production, and markedly lower cell proliferative activity (p ≤ 0.039). These responses were significantly mitigated by pretreatment with rHDL (p ≤ 0.046). This study suggests that rHDL can enhance cell proliferation and collagen I and III production while reducing apoptosis in human RCFs under hypoxic conditions.},
}
@article {pmid38671832,
year = {2024},
author = {Cai, J and Li, Y and Zhao, B and Bao, Z and Li, J and Sun, S and Chen, Y and Wu, X},
title = {N-Acetylcysteine Alleviates D-Galactose-Induced Injury of Ovarian Granulosa Cells in Female Rabbits by Regulating the PI3K/Akt/mTOR Signaling Pathway.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {4},
pages = {},
pmid = {38671832},
issn = {2076-3921},
abstract = {The ovary plays a crucial role in the reproductive system of female animals. Ovarian problems such as ovarian insufficiency, premature aging, polycystic ovary syndrome, and ovarian cysts may lead to ovulation disorders, abnormal hormone secretion, or luteal dysfunction, thereby increasing the risk of infertility and abortion. Only when the ovarian function and other organs in the reproductive system remain healthy and work normally can female animals be ensured to carry out reproductive activities regularly, improve the pregnancy rate and litter size, promote the healthy development of the fetus, and then improve their economic value. The follicle, as the functional unit of the ovary, is composed of theca cells, granulosa cells (GCs), and oocytes. GCs are the largest cell population and main functional unit in follicles and provide the necessary nutrients for the growth and development of follicles. N-acetylcysteine (NAC) is a prevalent and cell-permeable antioxidant molecule that effectively prevents apoptosis and promotes cellular survival. Over the past few years, its function in boosting reproductive performance in animals at the cellular level has been widely acknowledged. However, its specific role and mechanism in influencing GCs is yet to be fully understood. The objective of this study was to examine the effects of NAC on ovarian damage in female rabbits. For this purpose, D-galactose (D-gal) was first used to establish a model of damaged GCs, with exposure to 1.5 mg/mL of D-gal leading to substantial damage. Subsequently, varying concentrations of NAC were introduced to determine the precise mechanism through which it influences cell damage. Based on the results of the Cell Counting Kit-8 assay, flow cytometry, and Western blotting, it was found that 0.5 mg/mL of NAC could significantly suppress cell apoptosis and promote proliferation. In particular, it decreased the expression levels of Bax, p53, and Caspase-9 genes, while concurrently upregulating the expression of the BCL-2 gene. Moreover, NAC was found to alleviate intracellular oxidative stress, suppress the discharge of mitochondrial Cytochrome c, and boost the enzymatic activities of CAT (Catalase), GSH (Glutathione), and SOD (Superoxide dismutase). RNA sequencing analysis subsequently underscored the critical role of the PI3K/Akt/mTOR pathway in governing proliferation and apoptosis within GCs. These findings demonstrated that NAC could significantly influence gene expression within this pathway, thereby clarifying the exact relationship between the PI3K/Akt/mTOR signaling cascade and the underlying cellular processes controlling proliferation and apoptosis. In conclusion, NAC can reduce the expression of Bax, p53, and Caspase-9 genes, inhibit the apoptosis of GCs, improve cell viability, and resist D-gal-induced oxidative stress by increasing the activity of CAT, GSH, and SOD. The molecular mechanism of NAC in alleviating D-gal-induced ovarian GC injury in female rabbits by regulating the PI3K/Akt/mTOR signaling pathway provides experimental evidence for the effect of NAC on animal reproductive function at the cellular level.},
}
@article {pmid38670497,
year = {2024},
author = {Liang, WZ and Chia, YY and Sun, HJ and Sun, GC},
title = {Exploration of beauvericin's toxic effects and mechanisms in human astrocytes and N-acetylcysteine's protective role.},
journal = {Toxicon : official journal of the International Society on Toxinology},
volume = {243},
number = {},
pages = {107734},
doi = {10.1016/j.toxicon.2024.107734},
pmid = {38670497},
issn = {1879-3150},
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Astrocytes/drug effects ; *Oxidative Stress/drug effects ; *Depsipeptides/toxicity ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; Cell Line ; Antioxidants/pharmacology ; },
abstract = {Beauvericin (BEA) is a newly identified mycotoxin produced by various Fusarium species, and its contamination in food and animal feed is widespread globally. This mycotoxin demonstrates cytotoxic effects by inducing oxidative stress in multiple models. Furthermore, evidence indicates that BEA possesses diverse toxic activities, making it a promising candidate for toxicological research. Recent studies have highlighted the ability of BEA to traverse the blood-brain barrier, suggesting its potential neurotoxicity. However, limited information is available regarding the neurotoxic effects of BEA on human astrocytes. Therefore, this study aimed to assess the neurotoxic effects of BEA on the Gibco® Human Astrocyte (GHA) cell line and elucidate the underlying mechanisms. Additionally, the study aimed to investigate the protective effects of the antioxidant N-acetylcysteine (NAC) against BEA-induced toxicity. The data show that exposure to BEA within the 2.5-15 μM concentration range resulted in concentration-dependent cytotoxicity. BEA-treated cells exhibited significantly increased levels of reactive oxygen species (ROS), while intracellular glutathione (GSH) content was significantly reduced. Western blot analysis of cells treated with BEA revealed altered protein levels of Bax, cleaved caspase-9, and caspase-3, along with an increased Bax/Bcl-2 ratio, indicating the induction of apoptosis. Additionally, BEA exposure triggered antioxidant responses, as evidenced by increased protein expression of Nrf2, HO-1, and NQO1. Significantly, pretreatment with NAC partially attenuated the significant toxic effects of BEA. In conclusion, our findings suggest that BEA-induced cytotoxicity in GHA cells involves oxidative stress-associated apoptosis. Furthermore, NAC demonstrates potential as a protective agent against BEA-induced oxidative damage.},
}
@article {pmid38670245,
year = {2024},
author = {Lu, W and Cheng, S and Xu, J and Xiao, Z and Yu, Y and Xie, Q and Fang, Y and Chen, R and Shen, B and Xie, Y and Ding, X},
title = {Roles of AhR/CYP1s signaling pathway mediated ROS production in uremic cardiomyopathy.},
journal = {Toxicology letters},
volume = {396},
number = {},
pages = {81-93},
doi = {10.1016/j.toxlet.2024.04.005},
pmid = {38670245},
issn = {1879-3169},
mesh = {Animals ; *Receptors, Aryl Hydrocarbon/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; *Uremia/metabolism ; *Myocytes, Cardiac/metabolism/drug effects/pathology ; *Signal Transduction ; *Indican/toxicity ; Humans ; *Cardiomyopathies/metabolism/pathology ; Rats ; Male ; *Rats, Sprague-Dawley ; Cell Line ; Basic Helix-Loop-Helix Proteins/metabolism/genetics ; Oxidative Stress ; Disease Models, Animal ; Renal Insufficiency, Chronic/metabolism/pathology ; },
abstract = {PURPOSE: Uremic cardiomyopathy (UCM) is the leading cause of chronic kidney disease (CKD) related mortality. Uremic toxins including indoxyl sulfate (IS) play important role during the progression of UCM. This study was to explore the underlying mechanism of IS related myocardial injury.<br><br>METHODS: UCM rat model was established through five-sixths nephrectomy to evaluate its effects on blood pressure, cardiac impairment, and histological changes using echocardiography and histological analysis. Additionally, IS was administered to neonatal rat cardiomyocytes (NRCMs) and the human cardiomyocyte cell line AC16. DHE staining and peroxide-sensitive dye 2',7'-dichlorofluorescein diacetate (H2DCFDA) was conducted to assess the reactive oxygen species (ROS) production. Cardiomyocyte hypertrophy was estimated using wheat germ agglutinin (WGA) staining and immunofluorescence. Aryl hydrocarbon receptor (AhR) translocation was observed by immunofluorescence. The activation of AhR was evaluated by immunoblotting of cytochrome P450 1&#x202f;s (CYP1s) and quantitative real-time PCR (RT-PCR) analysis of AHRR and PTGS2. Additionally, the pro-oxidative and pro-hypertrophic effects were evaluated using the AhR inhibitor CH-223191, the CYP1s inhibitor Alizarin and the ROS scavenger N-Acetylcysteine (NAC).<br><br>RESULTS: UCM rat model was successfully established, and cardiac hypertrophy, accompanied by increased blood pressure, and myocardial fibrosis. Further research confirmed the activation of the AhR pathway in UCM rats including AhR translocation and downstream protein CYP1s expression, accompanied with increasing ROS production detected by DHE staining. In vitro experiment demonstrated a translocation of AhR triggered by IS, leading to significant increase of downstream gene expression. Subsequently study indicated a close relationship between the production of ROS and the activation of AhR/CYP1s, which was effectively blocked by applying AhR inhibitor, CYP1s inhibitor and siRNA against AhR. Moreover, the inhibition of AhR/CYP1s/ROS pathway collectively blocked the pro-hypertrophic effect of IS-mediated cardiomyopathy.<br><br>CONCLUSION: This study provides evidence that the AhR/CYP1s pathway is activated in UCM rats, and this activation is correlated with the uremic toxin IS. In vitro studies indicate that IS can stimulate the AhR translocation in cardiomyocyte, triggering to the production of intracellular ROS via CYP1s. This process leads to prolonged oxidative stress stimulation and thus contributes to the progression of uremic toxin-mediated cardiomyopathy.},
}
@article {pmid38669982,
year = {2024},
author = {An, K and Fan, J and Lin, B and Han, Y},
title = {A lysosome-targeted fluorescent probe for fluorescence imaging of hypochlorous acid in living cells and in vivo.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {316},
number = {},
pages = {124316},
doi = {10.1016/j.saa.2024.124316},
pmid = {38669982},
issn = {1873-3557},
mesh = {*Hypochlorous Acid/analysis/metabolism ; *Lysosomes/metabolism/chemistry ; *Fluorescent Dyes/chemistry/chemical synthesis ; Animals ; *Zebrafish ; *Optical Imaging ; Humans ; RAW 264.7 Cells ; Mice ; Boron Compounds/chemistry ; Spectrometry, Fluorescence ; Pyridines/chemistry ; Limit of Detection ; },
abstract = {Lysosomes, as crucial acidic organelles in cells, play a significant role in cellular functions. The levels and distribution of hypochlorous acid (HOCl) within lysosomes can profoundly impact their biological functionality. Hence, real-time monitoring of the concentration of HOCl in lysosomes holds paramount importance for further understanding various physiological and pathological processes associated with lysosomes. In this study, we developed a bodipy-based fluorescent probe derived from pyridine and phenyl selenide for the specific detection of HOCl in aqueous solutions. Leveraging the probe's sensitive photoinduced electron transfer effect from phenyl selenide to the fluorophore, the probe exhibited satisfactory high sensitivity (with a limit of detection of 5.2 nM and a response time of 15 s) to hypochlorous acid. Further biological experiments confirmed that the introduction of the pyridine moiety enabled the probe molecule to selectively target lysosomes. Moreover, the probe successfully facilitated real-time monitoring of HOCl in cell models stimulated by N-acetylcysteine (NAC) and lipopolysaccharide (LPS), as well as in a normal zebrafish model. This provides a universal method for dynamically sensing HOCl in lysosomes.},
}
@article {pmid38665380,
year = {2024},
author = {Gangadharan Nambiar, G and Gonzalez Szachowicz, S and Zirbes, CF and Hill, JJ and Powers, LS and Meyerholz, DK and Thornell, IM and Stoltz, DA and Fischer, AJ},
title = {Pancreatic enzymes digest obstructive meconium from cystic fibrosis pig intestines.},
journal = {Frontiers in pediatrics},
volume = {12},
number = {},
pages = {1387171},
pmid = {38665380},
issn = {2296-2360},
support = {P30 DK054759/DK/NIDDK NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; },
abstract = {INTRODUCTION: Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often fail, requiring surgical intervention. MI typically occurs in newborns with pancreatic insufficiency from CF. Meconium contains mucin glycoprotein, a potential substrate for pancreatic enzymes or mucolytics. Our study aim was to determine whether pancreatic enzymes in combination with mucolytic treatments dissolve obstructive meconium using the CF pig model.<br><br>METHODS: We collected meconium from CF pigs at birth and submerged it in solutions with and without pancreatic enzymes, including normal saline, 7% hypertonic saline, and the reducing agents N-acetylcysteine (NAC) and dithiothreitol (DTT). We digested meconium at 37 &#xb0;C with agitation, and measured meconium pigment release by spectrophotometry and residual meconium solids by filtration.<br><br>RESULTS AND DISCUSSION: In CF pigs, meconium appeared as a solid pigmented mass obstructing the ileum. Meconium microscopically contained mucus glycoprotein, cellular debris, and bile pigments. Meconium fragments released pigments with maximal absorption at 405&#x2005;nm after submersion in saline over approximately 8&#x2005;h. Pancreatic enzymes significantly increased pigment release and decreased residual meconium solids. DTT did not improve meconium digestion and the acidic reducing agent NAC worsened digestion. Pancreatic enzymes digested CF meconium best at neutral pH in isotonic saline. We conclude that pancreatic enzymes digest obstructive meconium from CF pigs, while hydrating or reducing agents alone were less effective. This work suggests a potential role for pancreatic enzymes in relieving obstruction due to MI in newborns with CF.},
}
@article {pmid38657455,
year = {2024},
author = {Zhang, L and Xu, F and Yang, Y and Yang, L and Wu, Q and Sun, H and An, Z and Li, J and Wu, H and Song, J and Wu, W},
title = {PM2.5 exposure upregulates pro-inflammatory protein expression in human microglial cells via oxidant stress and TLR4/NF-κB pathway.},
journal = {Ecotoxicology and environmental safety},
volume = {277},
number = {},
pages = {116386},
doi = {10.1016/j.ecoenv.2024.116386},
pmid = {38657455},
issn = {1090-2414},
mesh = {Humans ; Air Pollutants/toxicity ; *Brain-Derived Neurotrophic Factor/metabolism ; Cell Line ; *Cyclooxygenase 2/metabolism ; *Interleukin-6/metabolism ; *Microglia/drug effects/metabolism ; NF-kappa B/metabolism ; *Oxidative Stress/drug effects ; *Particulate Matter/toxicity ; *Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 4/metabolism ; Up-Regulation/drug effects ; },
abstract = {Exposure to ambient PM2.5 is associated with neurodegenerative disorders, in which microglia activation plays a critical role. Thus far, the underlying mechanisms for PM2.5-induced microglia activation have not been well elucidated. In this study, a human microglial cell line (HMC3) was used as the in vitro model to examine the inflammatory effect (hall marker of microglia activation) of PM2.5 and regulatory pathways. The expression of inflammatory mediators including interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) as well as the brain derived neurotrophic factor (BDNF) were determined by ELISA and/or real-time PCR, respectively. Flow cytometry was used to measure the production of intracellular reactive oxygen species (ROS). Western blot was used to measure protein levels of Toll-like receptor 4 (TLR4), NF-κB inhibitor α (IκBα) and COX-2. It was shown that PM2.5 stimulation increased IL-6 and COX-2 expression but decreased BDNF expression in a dose-dependent manner. Further studies showed that PM2.5 triggered the formation of ROS and pre-treatment with the ROS scavenger acetylcysteine (NAC) significantly suppressed PM2.5-induced IL-6 and COX-2 expression. Moreover, the nuclear factor kappa B (NF-κB) inhibitor BAY11-7085 or the TLR4 neutralizing antibody markedly blocked PM2.5-induced IL-6 and COX-2 expression. However, NAC or BAY11-7085 exhibited minimal effect on PM2.5-induced BDNF down-regulation. In addition, pre-treatment with BAY11-7085 or TLR4 neutralizing antibody reduced ROS production induced by PM2.5, and NAC pre-treatment inhibited TLR4 expression and NF-κB activation induced by PM2.5. Collectively, PM2.5 treatment induced IL-6 and COX-2 but suppressed BDNF expression. PM2.5-induced IL-6 and COX-2 expression was mediated by interactive oxidative stress and TLR4/NF-κB pathway.},
}
@article {pmid38647950,
year = {2024},
author = {Zhou, D and Yang, Y and Chen, J and Zhou, J and He, J and Liu, D and Zhang, A and Yuan, B and Jiang, Y and Xia, W and Han, R and Xia, Z},
title = {N-acetylcysteine Protects Against Myocardial Ischemia-Reperfusion Injury Through Anti-ferroptosis in Type 1 Diabetic Mice.},
journal = {Cardiovascular toxicology},
volume = {24},
number = {5},
pages = {481-498},
pmid = {38647950},
issn = {1559-0259},
support = {81970247//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Myocardial Reperfusion Injury/prevention &amp; control/pathology/metabolism/physiopathology ; *Acetylcysteine/pharmacology ; *Diabetes Mellitus, Experimental/drug therapy/complications ; Male ; *Diabetes Mellitus, Type 1/complications/drug therapy/metabolism ; *Antioxidants/pharmacology ; *Ferroptosis/drug effects ; *Mice, Inbred C57BL ; Myocardial Infarction/prevention &amp; control/pathology/metabolism/physiopathology/drug therapy ; Time Factors ; Myocardium/pathology/metabolism ; Mice ; Oxidative Stress/drug effects ; },
abstract = {The hearts of subjects with diabetes are vulnerable to ischemia-reperfusion injury (IRI). In contrast, experimentally rodent hearts have been shown to be more resistant to IRI at the very early stages of diabetes induction than the heart of the non-diabetic control mice, and the mechanism is largely unclear. Ferroptosis has recently been shown to play an important role in myocardial IRI including that in diabetes, while the specific mechanisms are still unclear. Non-diabetic control (NC) and streptozotocin-induced diabetic (DM) mice were treated with the antioxidant N-acetylcysteine (NAC) in drinking water for 4 week starting at 1 week after diabetes induction. Mice were subjected to myocardial IRI induced by occluding the coronary artery for 30 min followed by 2 h of reperfusion, subsequently at 1, 2, and 5 week of diabetes induction. The post-ischemic myocardial infarct size in the DM mice was smaller than that in NC mice at 1 week of diabetes but greater than that in the NC mice at 2 and 5 week of diabetes, which were associated with a significant increase of ferroptosis at 2 and 5 week but a significant reduction of ferroptosis at 1 week of diabetes. NAC significantly attenuated post-ischemic ferroptosis as well as oxidative stress and reduced infarct size at 2 and 5 week of diabetes. Application of erastin, a ferroptosis inducer, reversed the cardioprotective effects of NAC. It is concluded that increased oxidative stress and ferroptosis are the major factors attributable to the increased vulnerability to myocardial IRI in diabetes and that attenuation of ferroptosis represents a major mechanism whereby NAC confers cardioprotection against myocardial IRI in diabetes.},
}
@article {pmid38647195,
year = {2024},
author = {Picchi, SC and Rebelatto, D and Martins, PMM and Blumer, S and Mesquita, GL and Hippler, FWR and Mattos, D and Boaretto, RM and Machado, MA and Takita, MA and Coletta-Filho, HD and de Souza, AA},
title = {N-acetylcysteine absorption and its potential dual effect improve fitness and fruit yield in Xylella fastidiosa infected plants.},
journal = {Pest management science},
volume = {80},
number = {9},
pages = {4333-4343},
doi = {10.1002/ps.8137},
pmid = {38647195},
issn = {1526-4998},
support = {//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; //Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; },
mesh = {*Xylella/drug effects/physiology ; *Acetylcysteine/pharmacology ; *Plant Diseases/microbiology/prevention &amp; control ; Citrus/microbiology ; Fruit/microbiology ; },
abstract = {BACKGROUND: Xylella fastidiosa is a multi-host bacterium that can be detected in hundreds of plant species including several crops. Diseases caused by X. fastidiosa are considered a threat to global food production. The primary method for managing diseases caused by X. fastidiosa involves using insecticides to control the vector. Hence, it is necessary to adopt new and sustainable disease management technologies to control not only the insect but also the bacteria and plant health. We demonstrated that N-acetylcysteine (NAC), a low-cost cysteine analogue, is a sustainable molecule that can be used in agriculture to decrease the damage caused by X. fastidiosa and improve plant health.<br><br>RESULTS: Using [15]N-NAC we proved that this analogue was absorbed by the roots and transported to different parts of the plant. Inside the plant, NAC reduced the bacterial population by 60-fold and the number of xylem vessels blocked by bacterial biofilms. This reflected in a recovery of 0.28-fold of the daily sap flow compared to health plants. In addition, NAC-treated citrus variegated chlorosis (CVC) plants decreased the oxidative stress by improving the activity of detoxifying enzymes. Moreover, the use of NAC in field conditions positively contributed to the increase in fruit yield of CVC-diseased plants.<br><br>CONCLUSION: Our research not only advances the understanding of NAC absorption in plants, but also indicates its dual effect as an antimicrobial and antioxidant molecule. This, in turn, negatively affects bacterial survival while improving plant health by decreasing oxidative stress. Overall, the positive field-based evidence supports the viability of NAC as a sustainable agricultural application. &#xa9; 2024 Society of Chemical Industry.},
}
@article {pmid38643270,
year = {2024},
author = {Bates, JN and Baby, SM and Getsy, PM and Coffee, GA and Hsieh, YH and Knauss, ZT and Dahan, A and Bubier, JA and MacFarlane, PM and Mueller, D and Lewis, SJ},
title = {L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {9091},
pmid = {38643270},
issn = {2045-2322},
support = {R01 DA048890/DA/NIDA NIH HHS/United States ; R01 DA059060/DA/NIDA NIH HHS/United States ; U01 DA051373/DA/NIDA NIH HHS/United States ; U01DA051373/DA/NIDA NIH HHS/United States ; },
mesh = {Rats ; Male ; Animals ; Fentanyl/pharmacology ; Acetylcysteine/*analogs &amp; derivatives ; Rats, Sprague-Dawley ; *Substance Withdrawal Syndrome ; Naloxone/pharmacology ; Narcotic Antagonists/pharmacology ; *Morphine Dependence ; Lysine/*analogs &amp; derivatives ; },
abstract = {N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 μmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 μmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 μg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.},
}
@article {pmid38641841,
year = {2024},
author = {Sajedi, F and Abdi, A and Mehrpooya, M and Faramarzi, V and Mohammadi, Y and Sheida, F},
title = {Comparison of therapeutic effects of N-Acetylcysteine with pregabalin in improving the clinical symptoms of painful diabetic neuropathy: a randomized, double-blind clinical trial.},
journal = {Clinical diabetes and endocrinology},
volume = {10},
number = {1},
pages = {15},
pmid = {38641841},
issn = {2055-8260},
support = {IR.UMSHA.REC.1397.137//Hamadan University of Medical Sciences/ ; },
abstract = {OBJECTIVES: Painful diabetic neuropathy (PDN) is highly prevalent and annoyingly in patients with diabetes. The aim of this study was to investigate the effects of oral N-acetylcysteine (NAC) compared to pregabalin in PDN.<br><br>METHODS: One hundred two eligible patients with type 2 diabetes and PDN were randomly recievied pregabalin (150 mg/day) or N-Acetylcysteine (NAC) (600 mg/ twice a day) for 8 weeks. Mean pain score, Sleep interference score (SIS), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and also, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.<br><br>RESULTS: NAC was well tolerated in all patients. The decrease in mean pain scores and increase in SIS was similar between two groups. More improvement in PGIC and CGIC from the baseline was reported in NAC group. NAC, significantly, decreased serum levels of MDA, and NO, but increased TAC, TTG, and CAT. Pregabalin, significantly, decreased serum levels of MDA, and NO and increased TAC.<br><br>DISCUSSION: NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects.<br><br>TRIAL REGISTRATION: The research protocol received approval from the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.137). The trial registry URL and number in Iranian Registry of Clinical Trials (IRCT): https://www.irct.ir/trial/33313 , IRCT20180814040795N2 (Registration date: 2019-01-21, Retrospectively registered).},
}
@article {pmid38641701,
year = {2024},
author = {Hassan, YF and Shabaan, DA},
title = {Effect of N-acetylcysteine on hair follicle changes in mouse model of cyclophosphamide-induced alopecia: histological and biochemical study.},
journal = {Histochemistry and cell biology},
volume = {161},
number = {6},
pages = {477-491},
pmid = {38641701},
issn = {1432-119X},
mesh = {Animals ; *Cyclophosphamide ; *Alopecia/chemically induced/drug therapy/pathology/metabolism ; Mice ; *Hair Follicle/metabolism/drug effects/pathology ; Female ; *Acetylcysteine/pharmacology ; *Mice, Inbred C57BL ; *Disease Models, Animal ; Antineoplastic Agents, Alkylating ; },
abstract = {Chemotherapy-induced alopecia (CIA) represents one of the most severe side effects of chemotherapy, which forces some patients to reject cancer treatment. The exact pathophysiological mechanisms of CIA are not clearly understood, which makes it difficult to discover efficient preventive or therapeutic procedures for this adverse effect. N-acetylcysteine (NAC) has a strong antioxidant activity as it stimulates glutathione synthesis and acts as an oxygen radical scavenger. The current study tried to investigate the efficacy of NAC in preserving biochemical parameters and hair follicle structure against cyclophosphamide (CYP) administration. In total, 40 adult female C57BL/6 mice were induced to enter anagen by depilation (day 0) and divided into four groups: group I (control), group II (CYP) received a single dose of CYP [150 mg/kg body weight (B.W.)/intraperitoneal injection (IP)] at day 9, group III (CYP &amp; NAC) received a single dose of CYP at day 9 as well as NAC (500 mg/kg B.W./day/IP) from day 6-16, and group IV (NAC) received NAC from day 6-16. CYP administration in group II induced an increase in malondialdehyde (MDA), decrease in superoxide dismutase (SOD), histological hair follicle dystrophy, disruption of follicular melanogenesis, overexpression of p53, and loss of ki67 immunoreactivity. NAC coadministration in group III reversed CYP-induced alterations in the biochemical parameters and preserved hair follicle structure, typical follicular melanin distribution as well as normal pattern of p53 and ki67 expression. These findings indicated that NAC could be used as an efficient and safe therapeutic option for hair loss induced by chemotherapy.},
}
@article {pmid38639871,
year = {2024},
author = {Nakai, A and Fukushima, Y and Yamamoto, A and Amatsu, Y and Chen, X and Nishigori, M and Yoshioka, Y and Kaneko, M and Koshiba, T and Watanabe, T},
title = {Increased ROS levels in mitochondrial outer membrane protein Mul1-deficient oocytes result in abnormal preimplantation embryogenesis.},
journal = {FEBS letters},
volume = {598},
number = {14},
pages = {1740-1752},
doi = {10.1002/1873-3468.14876},
pmid = {38639871},
issn = {1873-3468},
support = {26291032//Japan Society for the Promotion of Science/ ; 17H03667//Japan Society for the Promotion of Science/ ; 23H02096//Japan Society for the Promotion of Science/ ; //Nara Women's University Intramural Grant for Project Research/ ; },
mesh = {Animals ; Female ; Mice ; Acetylcysteine/pharmacology ; Blastocyst/metabolism ; DNA Damage ; *Embryonic Development/genetics ; Mice, Knockout ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Mitochondrial Proteins/metabolism/genetics/deficiency ; *Oocytes/metabolism ; *Reactive Oxygen Species/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics/deficiency ; },
abstract = {Reactive oxygen species (ROS) are associated with oocyte maturation inhibition, and N-acetyl-l-cysteine (NAC) partially reduces their harmful effects. Mitochondrial E3 ubiquitin ligase 1 (Mul1) localizes to the mitochondrial outer membrane. We found that female Mul1-deficient mice are infertile, and their oocytes contain high ROS concentrations. After fertilization, Mul1-deficient embryos showed a DNA damage response (DDR) and abnormal preimplantation embryogenesis, which was rescued by NAC addition and ROS depletion. These observations clearly demonstrate that loss of Mul1 in oocytes increases ROS concentrations and triggers DDR, resulting in abnormal preimplantation embryogenesis. We conclude that manipulating the mitochondrial ROS levels in oocytes may be a potential therapeutic approach to target infertility.},
}
@article {pmid38636660,
year = {2024},
author = {Boeglin, WE and Stec, DF and Noguchi, S and Calcutt, MW and Brash, AR},
title = {The Michael addition of thiols to 13-oxo-octadecadienoate (13-oxo-ODE) with implications for LC-MS analysis of glutathione conjugation.},
journal = {The Journal of biological chemistry},
volume = {300},
number = {5},
pages = {107293},
pmid = {38636660},
issn = {1083-351X},
support = {R01 GM134548/GM/NIGMS NIH HHS/United States ; },
mesh = {*Glutathione/chemistry/metabolism ; *Sulfhydryl Compounds/chemistry ; Mass Spectrometry/methods ; Chromatography, High Pressure Liquid/methods ; Chromatography, Liquid/methods ; Mercaptoethanol/chemistry ; Liquid Chromatography-Mass Spectrometry ; },
abstract = {Unsaturated fatty acid ketones with αβ,γδ conjugation are susceptible to Michael addition of thiols, with unresolved issues on the site of adduction and precise structures of the conjugates. Herein we reacted 13-keto-octadecadienoic acid (13-oxo-ODE or 13-KODE) with glutathione (GSH), N-acetyl-cysteine, and β-mercaptoethanol and identified the adducts. HPLC-UV analyses indicated none of the products exhibit a conjugated enone UV chromophore, a result that conflicts with the literature and is relevant to the mass spectral interpretation of 1,4 versus 1,6 thiol adduction. Aided by the development of an HPLC solvent system that separates the GSH diastereomers and thus avoids overlap of signals in proton NMR experiments, we established the two major conjugates are formed by 1,6 addition of GSH at the 9-carbon of 13-oxo-ODE with the remaining double bond α to the thiol in the 10,11 position. N-acetyl cysteine reacts similarly, while β-mercaptoethanol gives equal amounts of 1,4 and 1,6 addition products. Equine glutathione transferase catalyzed 1,6 addition of GSH to the two major diastereomers in 44:56 proportions. LC-MS in positive ion mode gives a product ion interpreted before as evidence of 1,4-thiol adduction, whereas here we find this ion using the authentic 1,6 adduct. LC-MS with negative ion APCI gave a fragment selective for 1,4 adduction. These results clarify the structures of thiol conjugates of a prototypical unsaturated keto-fatty acid and have relevance to the application of LC-MS for the structural analysis of keto-fatty acid glutathione conjugation.},
}
@article {pmid38634668,
year = {2024},
author = {Hakimi, F and Karimi Torshizi, MA and Hezavehei, M and Sharafi, M},
title = {Protective Effect of N-Acetylcysteine on Rooster Semen Cryopreservation.},
journal = {Biopreservation and biobanking},
volume = {22},
number = {6},
pages = {609-615},
pmid = {38634668},
issn = {1947-5543},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Male ; *Cryopreservation/methods ; *Semen Preservation/methods/veterinary ; *Chickens ; *Membrane Potential, Mitochondrial/drug effects ; *Sperm Motility/drug effects ; *Lipid Peroxidation/drug effects ; Spermatozoa/drug effects ; Semen/drug effects/metabolism ; Antioxidants/pharmacology ; Cryoprotective Agents/pharmacology ; Semen Analysis ; Cell Survival/drug effects ; Reactive Oxygen Species/metabolism ; },
abstract = {Cryopreservation of avian semen is a useful reproductive technique in the poultry industry. However, during cooling, elevated reactive oxygen species (ROS) levels have destructive effects on both quality and function of thawed sperm. The aim of the current study is to investigate the antioxidant effects of N-acetylcysteine (NAC) during rooster semen cryopreservation. Semen samples were collected from ten Ross 308 broiler breeder roosters (32 weeks) and mixed. The mixed samples were divided into five equal parts and cryopreserved in Lake Buffer extender that contained different concentrations (0, 0.01, 0.1, 1, and 10 mM) of NAC. The optimum concentration of NAC was determined based on quality parameters of mobility, viability, membrane integrity, acrosome integrity, lipid peroxidation, and mitochondrial membrane potential after the freeze-thaw process. There was a higher percentage (p < 0.05) of total motility (TM) (60.9 ± 2.4%) and progressive motility (PM) (35.6 ± 1.9%) observed with the NAC-0.1 group compared to the other groups. Significantly higher percentages of viability (74.4 ± 2.3% and 71 ± 2.3%), membrane integrity (76.4 ± 1.5% and 74.7 ± 1.5%) and mitochondrial membrane potential (67.1 ± 1.6% and 66.3 ± 1.6%) were observed in the NAC-0.1 and NAC-1 groups compared to the other frozen groups (p < 0.05). The lowest percentage of lipid peroxidation and nonviable sperm was found in the NAC-0.1 and NAC-1 groups compared to the other groups (p < 0.05). The average path velocity (VAP), straight line velocity (VSL), curvilinear velocity (VCL), and acrosome integrity, were not affected by different concentrations of NAC in the thawed sperm (p > 0.05). Both NAC-0.1 and NAC-1 appear to be beneficial for maintaining the quality of rooster sperm after thawing.},
}
@article {pmid38633147,
year = {2024},
author = {Shams, G and Allah, SA and Ezzat, R and Said, MA},
title = {Ameliorative effects of berberine and selenium against paracetamol-induced hepatic toxicity in rats.},
journal = {Open veterinary journal},
volume = {14},
number = {1},
pages = {292-303},
pmid = {38633147},
issn = {2218-6050},
mesh = {Humans ; Rats ; Male ; Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Acetaminophen/pharmacology ; *Selenium/pharmacology ; *Berberine/pharmacology/therapeutic use ; Oxidative Stress ; Rats, Wistar ; },
abstract = {BACKGROUND: Paracetamol (PCM) overdosing induces hepatotoxicity, which can result in death if the dose is high enough and the patients are not given N-acetyl cysteine. Berberine (BBR) has a variety of biological proprieties including anti-inflammatory and antioxidant activities.<br><br>AIM: Assessment of the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity in rats.<br><br>METHODS: This research involved 40 clinically healthy mature adult male albino rats, their weights ranged from 150 to 200 g and housed in standard conditions. Our study involved evaluating the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity via estimation of the liver function tests, determination of the antioxidant enzyme activities, lipid peroxidation markers, immune-modulatory effects, liver histopathological, and immunohistochemical studies.<br><br>RESULTS: Co-treatment of BBR (150 mg/kg BW) with selenium (5 mg/kg BW) showed significant improvement in the liver function parameters, the antioxidant enzyme activities, reduction in the nitric oxide (NO), lysozyme, malondialdehyde (MDA), TNF-&#x3b1;, and TGF-&#x3b2;1 levels, and marked elevation in the IgM levels.<br><br>CONCLUSION: Altogether, BBR, selenium, or both augment antioxidant activity and alleviate PCM-induced hepatic toxicity.},
}
@article {pmid38629620,
year = {2024},
author = {Kim, SH and Kang, DW and Kwon, D and Jung, YS},
title = {Critical role of endoplasmic reticulum stress on bisphenol A-induced cytotoxicity in human keratinocyte HaCaT cells.},
journal = {Environmental toxicology},
volume = {39},
number = {8},
pages = {4091-4104},
doi = {10.1002/tox.24290},
pmid = {38629620},
issn = {1522-7278},
support = {2022R1I1A1A01070024//National Research Foundation of Korea/ ; //Korean Government (MSIT)/ ; 20014436//Technology Innovation Program/ ; //Ministry of Trade, Industry &amp; Energy (MOTIE, Korea)/ ; },
mesh = {*Benzhydryl Compounds/toxicity ; *Phenols/toxicity ; Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Keratinocytes/drug effects ; *Reactive Oxygen Species/metabolism ; *Cell Survival/drug effects ; Oxidative Stress/drug effects ; Taurochenodeoxycholic Acid/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; HaCaT Cells ; Acetylcysteine/pharmacology ; Cell Line ; Bisphenol A Compounds ; },
abstract = {Bisphenol A (BPA) is widely used in plastic and paper products, and its exposure can occur through skin contact or oral ingestion. The hazardous effects of BPA absorbed through the skin may be more severe; however, few studies have investigated the skin toxicity of BPA. This study investigated the effects of BPA on human epidermal keratinocyte cell lines, which is relevant for skin exposure. BPA treatment reduced cell viability in a time- and concentration-dependent manner and elevated oxidative and endoplasmic reticulum (ER) stress. N-acetylcysteine (NAC), an oxidative stress inhibitor, reduced BPA-induced reactive oxygen species (ROS) levels. However, only 10% of the decreased cell viability was restored at the highest NAC concentration. Treatment with tauroursodeoxycholic acid (TUDCA), which is an ER stress inhibitor, effectively countered the increase in ER stress-related proteins induced by BPA. Moreover, TUDCA treatment led to a reduction in oxidative stress, as demonstrated by the decrease in ROS levels, maintenance of mitochondrial membrane potential, and modulation of stress signaling proteins. Consequently, TUDCA significantly improved BPA-induced cytotoxicity in a concentration-dependent manner. Notably, combined treatment using TUDCA and NAC further reduced the BPA-induced ROS levels; however, no significant difference in cell viability was observed compared with that for TUDCA treatment alone. These findings indicated that the oxidative stress observed following BPA exposure was exacerbated by ER stress. Moreover, the principal factor driving BPA-induced cytotoxicity was indeed ER stress, which has potential implications for developing therapeutic strategies for diseases associated with similar stress responses.},
}
@article {pmid38622261,
year = {2024},
author = {Liu, C and Zha, J and Sun, T and Kong, L and Zhang, X and Wang, D and Ni, G},
title = {Cold atmospheric plasma attenuates skin cancer via ROS induced apoptosis.},
journal = {Molecular biology reports},
volume = {51},
number = {1},
pages = {518},
pmid = {38622261},
issn = {1573-4978},
mesh = {Animals ; *Skin Neoplasms/drug therapy/pathology ; *Carcinoma, Squamous Cell/drug therapy/pathology ; Reactive Oxygen Species/pharmacology ; Matrix Metalloproteinase 2/genetics ; Matrix Metalloproteinase 9/genetics ; *Plasma Gases/pharmacology ; Proliferating Cell Nuclear Antigen/genetics ; bcl-2-Associated X Protein ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; },
abstract = {BACKGROUND: Cold atmospheric plasma (CAP) has been widely used in biomedical research, especially in vitro cancer therapy. Cutaneous squamous cell carcinoma (CSCC) is a malignant tumor originating from epidermal keratinocytes. However, the mechanism of CAP therapy on CSCC remains unclear.<br><br>METHODS AND RESULTS: The animal models of CSCC induced by 7,12-dimethylbenz(a) anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) were constructed. For the CAP treatment group, after each TPA application, CAP was administered for 3&#xa0;min twice weekly after drying. HE staining were used to detect the pathological status of tumor tissue in each group. The levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 were evaluated by western blot and qPCR. TUNEL staining were used to detect apoptosis in tumor tissues. In vivo, serum samples were used for ELISA of total ROS. MTT assay was used to detect the viability of A431 cells. Western blot and qPCR were used to detect the levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 in A431 cells. A431 cell proliferation was examined by colony formation assay. The proportions of apoptosis of A431 cells were detected by flow cytometry. Transwell assessed the ability of A431 cells migration and proliferation. We found that CAP could induce skin cancer cells apoptosis and inhibit the progress of skin cancer. Through experiments in vitro, reactive oxygen species (ROS) generated by N-acetylcysteine (NAC) and CAP inhibited the proliferation and migration of A431 skin cancer cells while promoting apoptosis.<br><br>CONCLUSIONS: These evidences suggest the protective effect of CAP in CSCC, and CAP has the potential clinical application of CSCC.},
}
@article {pmid38618504,
year = {2024},
author = {Ameri, A and Rahmati, A and Soroushfar, S and Lalehzari, M and Dehghani, T and Haghi-Aminjan, H and Shamseddin, J and Omidi, M},
title = {The Protective Effect of N-acetylcysteine against Deltamethrin-Induced Hepatotoxicity in Mice.},
journal = {Avicenna journal of medical biotechnology},
volume = {16},
number = {2},
pages = {88-94},
pmid = {38618504},
issn = {2008-2835},
abstract = {BACKGROUND: Exposure to pesticides is of concern to public health officials worldwide. Deltamethrin is a synthetic pyrethroid pesticide which is widely used in agriculture and veterinary medicine. Deltamethrin poisoning is always one of the concerns in medical centers due to the deltamethrin induced hepatotoxicity. This study evaluated the hepato-protective effects of N-acetylcysteine (NAC) against deltamethrin induced hepatotoxicity in mice.<br><br>METHODS: A total of 40 BALB/c male mice were randomly divided into four groups; the first group was used as a control (0.5 ml normal saline); Groups 2-4 were treated with NAC [160 mg/kg Body Weight (BW)], deltamethrin (50 mg/kg BW), and NAC plus deltamethrin. At 1 and 24 hr after treatment, the animals were sacrificed and blood and liver samples were obtained for analysis and the liver/body ration, hepatic enzymes as Aspartate aminotransferase (AST), Alanine Transaminase (ALT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH), Glutathione (GSH) content and Reactive Oxygen Species (ROS) level were measured. For comparison between more than two experimental groups, one-way ANOVA following Tukey test was used by SPSS software.<br><br>RESULTS: The deltamethrin significantly increased AST, ALT, ALP, and the level of ROS level at the end of 1 and 24 hr after treatment; while the LDH level and GSH content were decreased. Mice in the deltamethrin treated group had a higher liver/body weight ratio than in other treated groups after 24 hr. On the other hand, NAC in combination with deltamethrin significantly reduced the activities of AST, ALT, ALP, and increased GSH levels.<br><br>CONCLUSION: This study demonstrated that NAC has a hepatoprotective role against deltamethrin-induced toxicity.},
}
@article {pmid38611747,
year = {2024},
author = {Abdelkader, I and Guisán, JM and Sayari, A and Fernández-Lorente, G},
title = {Various Strategies for the Immobilization of a Phospholipase C from Bacillus cereus for the Modulation of Its Biochemical Properties.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {7},
pages = {},
pmid = {38611747},
issn = {1420-3049},
mesh = {*Bacillus cereus ; Sepharose ; *Acetylcysteine ; Enzymes, Immobilized ; Type C Phospholipases ; *Glyoxylates ; },
abstract = {In this study, the effect of various immobilization methods on the biochemical properties of phospholipase C (PLC) from Bacillus cereus obtained from the oily soil located in Sfax, Tunisia, was described. Different supports were checked: octyl sepharose, glyoxyl agarose in the presence of N-acetyl cysteine, and Q-sepharose. In the immobilization by hydrophobic adsorption, a hyperactivation of the PLCBc was obtained with a fold of around 2 times. The recovery activity after immobilization on Q-sepharose and glyoxyl agarose in the presence of N-acetyl cysteine was 80% and 58%, respectively. Furthermore, the biochemical characterization showed an important improvement in the three immobilized enzymes. The performance of the various immobilized PLCBc was compared with the soluble enzyme. The derivatives acquired using Q-sepharose, octyl sepharose, and glyoxyl agarose were stable at 50 °C, 60 °C, and 70 °C. Nevertheless, the three derivatives were more stable in a large range of pH than the soluble enzyme. The three derivatives and the free enzyme were stable in 50% (v/v) ethanol, hexane, methanol, and acetone. The glyoxyl agarose derivative showed high long-term storage at 4 °C, with an activity of 60% after 19 days. These results suggest the sustainable biotechnological application of the developed immobilized enzyme.},
}
@article {pmid38608750,
year = {2024},
author = {Salas, G and Litta, AA and Medeot, AC and Schuck, VS and Andermatten, RB and Miszczuk, GS and Ciriaci, N and Razori, MV and Barosso, IR and Sánchez Pozzi, EJ and Roma, MG and Basiglio, CL and Crocenzi, FA},
title = {NADPH oxidase-generated reactive oxygen species are involved in estradiol 17ß-d-glucuronide-induced cholestasis.},
journal = {Biochimie},
volume = {223},
number = {},
pages = {41-53},
doi = {10.1016/j.biochi.2024.04.002},
pmid = {38608750},
issn = {1638-6183},
mesh = {Animals ; *NADPH Oxidases/metabolism ; *Reactive Oxygen Species/metabolism ; Rats ; *Hepatocytes/metabolism/drug effects ; *Estradiol/pharmacology/metabolism/analogs &amp; derivatives ; Female ; Cholestasis/chemically induced/metabolism/pathology ; Rats, Wistar ; Acetophenones/pharmacology ; Oxidative Stress/drug effects ; Acetylcysteine/pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; ATP-Binding Cassette, Sub-Family C Proteins/metabolism ; MAP Kinase Signaling System/drug effects ; Cells, Cultured ; Antioxidants/pharmacology/metabolism ; Cholestasis, Intrahepatic ; Pregnancy Complications ; ATP-Binding Cassette Transporters ; Pregnancy ; },
abstract = {The endogenous metabolite of estradiol, estradiol 17β-D-glucuronide (E17G), is considered the main responsible of the intrahepatic cholestasis of pregnancy. E17G alters the activity of canalicular transporters through a signaling pathway-dependent cellular internalization, phenomenon that was attributed to oxidative stress in different cholestatic conditions. However, there are no reports involving oxidative stress in E17G-induced cholestasis, representing this the aim of our work. Using polarized hepatocyte cultures, we showed that antioxidant compounds prevented E17G-induced Mrp2 activity alteration, being this alteration equally prevented by the NADPH oxidase (NOX) inhibitor apocynin. The model antioxidant N-acetyl-cysteine prevented, in isolated and perfused rat livers, E17G-induced impairment of bile flow and Mrp2 activity, thus confirming the participation of reactive oxygen species (ROS) in this cholestasis. In primary cultured hepatocytes, pretreatment with specific inhibitors of ERK1/2 and p38MAPK impeded E17G-induced ROS production; contrarily, NOX inhibition did not affect ERK1/2 and p38MAPK phosphorylation. Both, knockdown of p47phox by siRNA and preincubation with apocynin in sandwich-cultured rat hepatocytes significantly prevented E17G-induced internalization of Mrp2, suggesting a crucial role for NOX in this phenomenon. Concluding, E17G-induced cholestasis is partially mediated by NOX-generated ROS through internalization of canalicular transporters like Mrp2, being ERK1/2 and p38MAPK necessary for NOX activation.},
}
@article {pmid38608558,
year = {2024},
author = {Madhu, M and Santhoshkumar, S and Tseng, WB and Kumar, ASK and Tseng, WL},
title = {Synthesis of rhenium disulfide nanodots exhibiting pH-dependent fluorescence and phosphorescence for anticounterfeiting and hazardous gas detection.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {315},
number = {},
pages = {124240},
doi = {10.1016/j.saa.2024.124240},
pmid = {38608558},
issn = {1873-3557},
abstract = {The synthesis and characterization of ReS2 nanodots (NDs) are detailed, by highlighting their structure, morphological, and optical properties. ReS2 NDs were synthesized using NH4ReO4 as a rhenium source, thiourea as a sulfur source, and N-acetyl cysteine as a capping agent. The synthesis involved the hydrothermal reaction of these precursors, leading to the nucleation and growth of ReS2 NDs. Characterization techniques including transmission electron microscopy, energy dispersive X-ray spectroscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy confirmed the formation of ReS2 NDs with a spherical morphology, crystalline structure, and rich sulfur sites. The fluorescence behavior of ReS2 NDs was found to be influenced by the solution pH, with fluorescence intensity increasing with rising pH values. This pH-dependent fluorescence response was attributed to the dissociation of functional groups and the subsequent impact on the excited-state proton transfer process. The fluorescence intensity of ReS2 NDs showed a correlation with solution pH, enabling pH detection from 3.0 to 12.5 with an interval of 0.5 pH unit. Additionally, the incorporation of ReS2 NDs into a polyvinyl alcohol (PVA) matrix resulted in pH-sensitive phosphorescence, offering a new avenue for pH sensing. The strong interaction between PVA and ReS2 NDs was proposed to enhance phosphorescence intensity and trigger a blue shift in the phosphorescent peak at high pH. The ReS2 NDs/PVA-deposited filter paper exhibited pH-sensitive fluorescence and phosphorescence, which could be utilized as unique identifiers or authentication markers. Moreover, the ReS2 NDs/PVA-deposited filter paper showed potential for discriminating between hydrogen chloride and ammonia, based on their distinct fluorescence and phosphorescence responses.},
}
@article {pmid38591866,
year = {2024},
author = {Monou, PK and Andriotis, E and Tzetzis, D and Tzimtzimis, E and Panteris, E and Andreadis, D and Demiri, E and Vizirianakis, IS and Fatouros, DG},
title = {Evaluation of 3D-Printed Solid Microneedles Coated with Electrosprayed Polymeric Nanoparticles for Simultaneous Delivery of Rivastigmine and N-Acetyl Cysteine.},
journal = {ACS applied bio materials},
volume = {7},
number = {5},
pages = {2710-2724},
doi = {10.1021/acsabm.3c00750},
pmid = {38591866},
issn = {2576-6422},
mesh = {*Acetylcysteine/chemistry/pharmacology ; *Rivastigmine/chemistry/pharmacology/administration &amp; dosage ; Humans ; *Printing, Three-Dimensional ; *Needles ; *Nanoparticles/chemistry ; *Biocompatible Materials/chemistry/pharmacology ; *Materials Testing ; *Particle Size ; Drug Delivery Systems ; Skin/metabolism ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Cell Survival/drug effects ; },
abstract = {In the current study, coated microneedle arrays were fabricated by means of digital light processing (DLP) printing. Three different shapes were designed, printed, and coated with PLGA particles containing two different actives. Rivastigmine (RIV) and N-acetyl-cysteine (NAC) were coformulated via electrohydrodynamic atomization (EHDA), and they were incorporated into the PLGA particles. The two actives are administered as a combined therapy for Alzheimer's disease. The printed arrays were evaluated regarding their ability to penetrate skin and their mechanical properties. Optical microscopy and scanning electron microscopy (SEM) were employed to further characterize the microneedle structure. Confocal laser microscopy studies were conducted to construct 3D imaging of the coating and to simulate the diffusion of the particles through artificial skin samples. Permeation studies were performed to investigate the transport of the drugs across human skin ex vivo. Subsequently, a series of tape strippings were performed in an attempt to examine the deposition of the APIs on and within the skin. Light microscopy and histological studies revealed no drastic effects on the membrane integrity of the stratum corneum. Finally, the cytocompatibility of the microneedles and their precursors was evaluated by measuring cell viability (MTT assay and live/dead staining) and membrane damages followed by LDH release.},
}
@article {pmid38583854,
year = {2024},
author = {Kim, NY and Shivanne Gowda, SG and Lee, SG and Sethi, G and Ahn, KS},
title = {Cannabidiol induces ERK activation and ROS production to promote autophagy and ferroptosis in glioblastoma cells.},
journal = {Chemico-biological interactions},
volume = {394},
number = {},
pages = {110995},
doi = {10.1016/j.cbi.2024.110995},
pmid = {38583854},
issn = {1872-7786},
mesh = {Humans ; *Autophagy/drug effects ; Beclin-1/metabolism ; *Cannabidiol/pharmacology ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/drug effects ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/drug effects/metabolism ; *Ferroptosis/drug effects ; *Glioblastoma/metabolism/pathology/drug therapy ; MAP Kinase Signaling System/drug effects ; *Reactive Oxygen Species/metabolism ; },
abstract = {Small molecule-driven ERK activation is known to induce autophagy and ferroptosis in cancer cells. Herein the effect of cannabidiol (CBD), a phytochemical derived from Cannabis sativa, on ERK-driven autophagy and ferroptosis has been demonstrated in glioblastoma (GBM) cells (U87 and U373 cells). CBD imparted significant cytotoxicity in GBM cells, induced activation of ERK (not JNK and p38), and increased intracellular reactive oxygen species (ROS) levels. It increased the autophagy-related proteins such as LC3 II, Atg7, and Beclin-1 and modulated the expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4), SLC7A11, and TFRC. CBD significantly elevated the endoplasmic reticulum stress, ROS, and iron load, and decreased GSH levels. Inhibitors of autophagy (3-MA) and ferroptosis (Fer-1) had a marginal effect on CBD-induced autophagy/ferroptosis. Treatment with N-acetyl-cysteine (antioxidant) or PD98059 (ERK inhibitor) partly reverted the CBD-induced autophagy/ferroptosis by decreasing the activation of ERK and the production of ROS. Overall, CBD induced autophagy and ferroptosis through the activation of ERK and generation of ROS in GBM cells.},
}
@article {pmid38583502,
year = {2024},
author = {Kim, SG and Jeon, JH and Shin, SH and Varias, DC and Moon, SH and Ryu, BY},
title = {Inhibition of reactive oxygen species generation by N-Acetyl Cysteine can mitigate male germ cell toxicity induced by bisphenol analogs.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {188},
number = {},
pages = {114652},
doi = {10.1016/j.fct.2024.114652},
pmid = {38583502},
issn = {1873-6351},
mesh = {*Reactive Oxygen Species/metabolism ; Male ; *Phenols/toxicity ; Animals ; *Benzhydryl Compounds/toxicity ; *Acetylcysteine/pharmacology ; Mice ; *Cell Proliferation/drug effects ; *Apoptosis/drug effects ; Sesquiterpenes/pharmacology ; Cell Line ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Spermatogonia/drug effects/metabolism ; TOR Serine-Threonine Kinases/metabolism ; NF-kappa B/metabolism ; Bisphenol A Compounds ; Bisphenol F Compounds ; },
abstract = {The estrogen-like effect of bisphenol A (BPA) disrupting the maintenance of functional male germ cells is associated with male sub-fertility. This study investigated toxicity of male germ cells induced by four bisphenol analogs: BPA, BPAF, BPF, and BPS. The investigation of bisphenol analogs' impact on male germ cells included assessing proliferation, apoptosis induction, and the capacity to generate reactive oxygen species (ROS) in GC-1 spermatogonia (spg) cells, specifically type B spermatogonia. Additionally, the therapeutic potential and protective effects of N-Acetyl Cysteine (NAC) and NF-κB inhibitor parthenolide was evaluated. In comparison to BPA, BPF and BPS, BPAF exhibited the most pronounced adverse effect in GC-1 spg cell proliferation. This effect was characterized by pronounced inhibition of phosphorylation of PI3K, AKT, and mTOR, along with increased release of cytochrome c and subsequent cleavages of caspase 3, caspase 7, and poly (ADP-ribose) polymerase. Both NAC and parthenolide were effective reducing cellular ROS induced by BPAF. However, only NAC demonstrated a substantial recovery in proliferation, accompanied by a significant reduction in cytochrome c release and cleaved PARP. These results suggest that NAC supplementation may play an effective therapeutic role in countering germ cell toxicity induced by environmental pollutants with robust oxidative stress-generating capacity.},
}
@article {pmid38576186,
year = {2024},
author = {Lopes, AR and Costa Silva, DG and Rodrigues, NR and Kemmerich Martins, I and Paganotto Leandro, L and Nunes, MEM and Posser, T and Franco, J},
title = {Investigating the impact of Psidium guajava leaf hydroalcoholic extract in improving glutamatergic toxicity-induced oxidative stress in Danio rerio larvae.},
journal = {Journal of toxicology and environmental health. Part A},
volume = {87},
number = {11},
pages = {457-470},
doi = {10.1080/15287394.2024.2337366},
pmid = {38576186},
issn = {2381-3504},
mesh = {Animals ; Glutamates/toxicity ; Oxidative Stress ; Plant Extracts/pharmacology/therapeutic use ; Plant Leaves ; *Psidium ; *Zebrafish ; },
abstract = {Glutamate is one of the predominant excitatory neurotransmitters released from the central nervous system; however, at high concentrations, this substance may induce excitotoxicity. This phenomenon is involved in numerous neuropathologies. At present, clinically available pharmacotherapeutic agents to counteract glutamatergic excitotoxicity are not completely effective; therefore, research to develop novel compounds is necessary. In this study, the main objective was to determine the pharmacotherapeutic potential of the hydroalcoholic extract of Psidium guajava (PG) in a model of oxidative stress-induced by exposure to glutamate utilizing Danio rerio larvae (zebrafish) as a model. Data showed that treatment with glutamate produced a significant increase in oxidative stress, chromatin damage, apoptosis, and locomotor dysfunction. All these effects were attenuated by pre-treatment with the classical antioxidant N-acetylcysteine (NAC). Treatment with PG inhibited oxidative stress responsible for cellular damage induced by glutamate. However, exposure to PG failed to prevent glutamate-initiated locomotor damage. Our findings suggest that under conditions of oxidative stress, PG can be considered as a promising candidate for treatment of glutamatergic excitotoxicity and consequent neurodegenerative diseases.},
}
@article {pmid38565435,
year = {2024},
author = {Liu, JJ and Zhang, X and Cai, BL and Qi, MM and Chi, YB and Peng, B and Zhang, DH},
title = {Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells.},
journal = {Journal of integrative medicine},
volume = {22},
number = {3},
pages = {286-294},
doi = {10.1016/j.joim.2024.03.007},
pmid = {38565435},
issn = {2095-4964},
mesh = {Humans ; Hep G2 Cells ; *Pentacyclic Triterpenes/pharmacology ; *Insulin Resistance ; *Ferroptosis/drug effects ; Triterpenes/pharmacology ; Cyclohexylamines/pharmacology ; Acetylcysteine/pharmacology ; Phenylenediamines/pharmacology ; Molecular Docking Simulation ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics/metabolism ; },
abstract = {OBJECTIVE: Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity.<br><br>METHODS: In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48&#xa0;h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis.<br><br>RESULTS: Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol's toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells.<br><br>CONCLUSION: One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects. Please cite this article as: Liu JJ, Zhang X, Qi MM, Chi YB, Cai BL, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. J Integr Med. 2024; 22(3): 286-294.},
}
@article {pmid38556154,
year = {2024},
author = {Teixeira-Fonseca, JL and Souza, DS and Conceição, MRL and Marques, LP and Durço, AO and Silva, PLD and Joviano-Santos, JV and Santos-Miranda, A and Roman-Campos, D},
title = {In vivo tebuconazole administration impairs heart electrical function and facilitates the occurrence of dobutamine-induced arrhythmias: involvement of reactive oxygen species.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {187},
number = {},
pages = {114596},
doi = {10.1016/j.fct.2024.114596},
pmid = {38556154},
issn = {1873-6351},
mesh = {Humans ; Rats ; Animals ; Male ; Reactive Oxygen Species ; Rats, Wistar ; *Dobutamine ; *Arrhythmias, Cardiac/chemically induced ; Acetylcysteine ; Myocytes, Cardiac ; *Triazoles ; },
abstract = {Tebuconazole (TEB), a widely used pesticide in agriculture to combat fungal infections, is commonly detected in global food, potable water, groundwater, and human urine samples. Despite its known in vivo toxicity, its impact on heart function remains unclear. In a 28-day study on male Wistar rats (approximately 100 g), administering 10 mg/kg/day TEB or a vehicle (control) revealed no effect on body weight gain or heart weight, but an increase in the infarct area in TEB-treated animals. Notably, TEB induced time-dependent changes in in vivo electrocardiograms, particularly prolonging the QT interval after 28 days of administration. Isolated left ventricular cardiomyocytes exposed to TEB exhibited lengthened action potentials and reduced transient outward potassium current. TEB also increased reactive oxygen species (ROS) production in these cardiomyocytes, a phenomenon reversed by N-acetylcysteine (NAC). Furthermore, TEB-treated animals, when subjected to an in vivo dobutamine (Dob) and caffeine (Caf) challenge, displayed heightened susceptibility to severe arrhythmias, a phenotype prevented by NAC. In conclusion, TEB at the no observed adverse effect level (NOAEL) dose adversely affects heart electrical function, increases arrhythmic susceptibility, partially through ROS overproduction, and this phenotype is reversible by scavenging ROS with NAC.},
}
@article {pmid38555190,
year = {2024},
author = {Papi, A and Alfano, F and Bigoni, T and Mancini, L and Mawass, A and Baraldi, F and Aljama, C and Contoli, M and Miravitlles, M},
title = {N-acetylcysteine Treatment in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis/Pre-COPD: Distinct Meta-analyses.},
journal = {Archivos de bronconeumologia},
volume = {60},
number = {5},
pages = {269-278},
doi = {10.1016/j.arbres.2024.03.010},
pmid = {38555190},
issn = {1579-2129},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Bronchitis, Chronic/drug therapy ; Disease Progression ; Expectorants/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; *Quality of Life ; Randomized Controlled Trials as Topic ; Treatment Outcome ; },
abstract = {INTRODUCTION: N-acetylcysteine (NAC) is a mucolytic agent with antioxidant properties. Oxidative stress is a key pathogenic mechanism in chronic respiratory conditions such as COPD and chronic bronchitis (CB). In these meta-analyses we investigated the efficacy of NAC in subjects with COPD or CB, the latter being a potential pre-COPD condition (CB/pre-COPD).<br><br>METHODS: The meta-analyses were conducted according to PRISMA guidelines. Exacerbations were assessed using total number of exacerbations. Improvement in patients' respiratory symptoms and/or patients quality of life (QoL) were measured by validated tools or assessed at the end of the study.<br><br>RESULTS: Twenty studies were included, of which seven evaluated NAC in patients with symptoms of CB/pre-COPD as entry criterion. NAC treated patients showed a significant reduction of the incidence of exacerbations as compared to placebo both in COPD (IRR=0.76; 95% confidence interval (CI) 0.59-0.99) and CB/pre-COPD (IRR=0.81; 95% CI 0.69-0.95). Sensitivity analyses in studies with duration higher than 5 months, confirmed the overall results. CB/pre-COPD patients treated with NAC were significantly more likely to experience an improvement in symptoms and/or QoL compared to placebo (odds ratio (OR)=3.47; 95% CI 1.92-6.26). A similar trend was observed in the few COPD studies evaluable. Sensitivity analyses showed a significant association of NAC with improvement in symptoms and/or QoL both in CB/pre-COPD and COPD patients.<br><br>CONCLUSIONS: These findings provide novel data of NAC on the improvement in symptoms and QoL in addition to prevention of exacerbations in COPD and CB/pre-COPD. PROSPERO registry no. CRD42023468154.},
}
@article {pmid38554666,
year = {2024},
author = {Sriwastava, S and Elkhooly, M and Amatya, S and Shrestha, K and Kagzi, Y and Bhatia, D and Gupta, R and Jaiswal, S and Lisak, RP},
title = {Recent advances in the treatment of primary and secondary progressive Multiple Sclerosis.},
journal = {Journal of neuroimmunology},
volume = {390},
number = {},
pages = {578315},
doi = {10.1016/j.jneuroim.2024.578315},
pmid = {38554666},
issn = {1872-8421},
mesh = {Animals ; Humans ; *Multiple Sclerosis, Chronic Progressive/drug therapy ; *Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; },
abstract = {BACKGROUND: The article highlights upcoming potential treatments, which target different phases of inflammation and offer remyelinating strategies as well as direct and indirect neuroprotective and oligodendrocyte protective effects, providing a hopeful outlook for patients with primary and secondary progressive multiple sclerosis (PPMS and SPMS).<br><br>OBJECTIVES: The review aims to identify potential treatments and ongoing clinical trials for PPMS and SPMS, and compare their mechanisms of action, efficacy, and side effects with current treatments.<br><br>METHODS: We reviewed ongoing clinical trials for PPMS and SPMS on the NIH website, as well as articles from PubMed, Embase, and clinicaltrails.gov since 2010.<br><br>RESULTS: BTKIs like, tolebrutinib, and fenebrutinib are being explored as potential PMS treatments. Vidofludimus calcium, an orally available treatment, has shown a reduction of active and new MRI lesions. Other treatments like simvastatin, N-acetylcysteine (NAC), and alpha-lipoic acid are being explored for their antioxidant properties. AHSCT and mesenchymal stem cell therapy are experimental options for younger patients with high inflammatory activity.<br><br>CONCLUSIONS: SPMS and PPMS are being studied for new treatments and future trials should consider combination therapies targeting inflammation, demyelination, and neuronal death, as the pathogenesis of PMS involves complex factors.},
}
@article {pmid38551724,
year = {2024},
author = {Adelusi, OB and Akakpo, JY and Eichenbaum, G and Sadaff, E and Ramachandran, A and Jaeschke, H},
title = {The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.},
journal = {Archives of toxicology},
volume = {98},
number = {6},
pages = {1843-1858},
pmid = {38551724},
issn = {1432-0738},
support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; R21 AG073892/AG/NIA NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; DK102142/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Male ; Mice ; *Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Cell Proliferation/drug effects ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/drug therapy ; Hepatocytes/drug effects ; *Liver/drug effects/metabolism/pathology ; *Liver Regeneration/drug effects ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Pyrazoles/pharmacology ; Receptors, Thrombopoietin/metabolism ; *Thrombopoietin/pharmacology ; Intercellular Signaling Peptides and Proteins ; },
abstract = {Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42-48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.},
}
@article {pmid38547615,
year = {2024},
author = {Li, Z and Bao, Z and Tan, J and Chen, G and Ye, B and Zhao, J and Zhang, L and Xu, H},
title = {Neobractatin induces pyroptosis of esophageal cancer cells by TOM20/BAX signaling pathway.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {128},
number = {},
pages = {155547},
doi = {10.1016/j.phymed.2024.155547},
pmid = {38547615},
issn = {1618-095X},
mesh = {Animals ; Humans ; Male ; Mice ; *bcl-2-Associated X Protein/metabolism ; Caspase 3/metabolism ; Cell Line, Tumor ; *Esophageal Neoplasms/drug therapy/metabolism ; *Gasdermins ; Mice, Nude ; Mitochondria/drug effects/metabolism ; *Mitochondrial Precursor Protein Import Complex Proteins ; Phosphate-Binding Proteins/metabolism ; *Pyroptosis/drug effects ; *Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; Up-Regulation/drug effects ; },
abstract = {BACKGROUND: Emerging evidence suggests that pyroptosis, a form of programmed cell death, has been implicated in cancer progression. The involvement of specific proteins in pyroptosis is an area of growing interest. TOM20, an outer mitochondrial membrane protein, has recently garnered attention for its potential role in pyroptosis. Our previous study found that NBT could induce pyroptosis by ROS/JNK pathway in esophageal cancer cells.<br><br>PURPOSE: This study aims to investigate whether NBT induces pyroptosis and verify whether such effects are involved in up-regulation of TOM20 in esophageal cancer cells.<br><br>METHODS: The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) was used to analyze the clinical significance of GSDME in esophageal cancer. MTT assay, morphological observation and Western blot were performed to verify the roles of TOM20 and BAX in NBT-induced pyroptosis after CRISPR-Cas9-mediated knockout. Immunofluorescence was used to determine the subcellular locations of BAX and cytochrome c. MitoSOX Red was employed to assess the mitochondrial reactive oxygen species (ROS) level. KYSE450 and TOM20 knockout KYSE450-/- xenograft models were established to elucidate the mechanisms involved in NBT-induced cell death.<br><br>RESULTS: In this study, NBT effectively upregulated the expression of TOM20 and facilitated the translocation of BAX to mitochondria, which promoted the release of cytochrome c from mitochondria to the cytoplasm, leading to the activation of caspase-9 and caspase-3, and finally induced pyroptosis. Knocking out TOM20 by CRISPR-Cas9 significantly inhibited the expression of BAX and the downstream BAX/caspase-3/GSDME pathway, which attenuated NBT-induced pyroptosis. The elevated mitochondrial ROS level was observed after NBT treatment. Remarkably, the inhibition of ROS by N-acetylcysteine (NAC) effectively suppressed the activation of TOM20/BAX pathway. Moreover, in vivo experiments demonstrated that NBT exhibited potent antitumor effects in both KYSE450 and TOM20 knockout KYSE450-/- xenograft models. Notably, the attenuated antitumor effects and reduced cleavage of GSDME were observed in the TOM20 knockout model.<br><br>CONCLUSION: These findings reveal that NBT induces pyroptosis through ROS/TOM20/BAX/GSDME pathway, which highlight the therapeutic potential of targeting TOM20 and GSDME, providing promising prospects for the development of innovative and effective treatment approaches for esophageal cancer.},
}
@article {pmid38547333,
year = {2024},
author = {Smith, JE and Rockey, DC},
title = {Update on ischemic hepatitis.},
journal = {Current opinion in gastroenterology},
volume = {40},
number = {3},
pages = {143-147},
pmid = {38547333},
issn = {1531-7056},
mesh = {Humans ; *Hepatitis/complications ; Acetylcysteine/therapeutic use ; },
abstract = {PURPOSE OF REVIEW: Ischemic hepatitis (IH) refers to diffuse liver injury secondary to hypoperfusion. The condition is usually seen in the critical care setting and is associated with significant mortality. IH typically occurs in the setting of systemic hypotension superimposed on some form of underlying cardiac dysfunction. This review aims to report what is known and what is new about the etiology, pathophysiology, and clinical features associated with IH.<br><br>RECENT FINDINGS: In recent years, studies on IH have largely confirmed earlier reports regarding etiologies, comorbid conditions, and associated mortality. Recent study has also shed light on the potential treatment of IH with N -acetyl-cysteine (NAC).<br><br>SUMMARY: IH is typically associated with underlying cardiac disease, and patients with IH have a very high mortality rate. Treatment remains largely supportive, although the utility of agents such as NAC are being explored.},
}
@article {pmid38541080,
year = {2024},
author = {Russo, C and Rusciano, D and Santangelo, R and Malaguarnera, L},
title = {Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {60},
number = {3},
pages = {},
pmid = {38541080},
issn = {1648-9144},
mesh = {Humans ; Edaravone/pharmacology ; Antioxidants/pharmacology ; Oxidative Stress ; *Eye Diseases ; *Retinal Diseases/drug therapy ; Ophthalmic Solutions ; },
abstract = {Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.},
}
@article {pmid38539819,
year = {2024},
author = {Islam, A and Chang, YC and Tsao, NW and Wang, SY and Chueh, PJ},
title = {Calocedrus formosana Essential Oils Induce ROS-Mediated Autophagy and Apoptosis by Targeting SIRT1 in Colon Cancer Cells.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {3},
pages = {},
pmid = {38539819},
issn = {2076-3921},
abstract = {Colorectal cancer is the most common cancer that affects both sexes and has a poor prognosis due to aggressiveness and chemoresistance. Essential oils isolated from Calocedrus formosana (CF-EOs) have been shown to demonstrate anti-termite, antifungal, anti-mosquito, and anti-microbial activities. However, the anticancer effects of CF-EOs are not yet fully understood. Therefore, the present study aimed to explore the molecular mechanism underlying CF-EOs-mediated anti-proliferative activity in colon cancer cells. Here, cell impedance measurements showed that CF-EOs inhibit proliferation in colon cancer cells with wild-type or mutant p53. Flow cytometry revealed that CF-EOs at 20, 50 µg/mL significantly induced ROS generation and autophagy in both HCT116 p53-wt and HCT116 p53-null cell lines, whereas pretreatment with the ROS scavenger N-acetyl cysteine (NAC) markedly attenuated these changes. CF-EOs also induced apoptosis at 50 µg/mL in both lines, as determined by flow cytometry. Protein analysis showed that CF-EOs markedly induced apoptosis markers, including Trail, cleaved caspase-3, cleaved caspase-9, and cleaved PARP, as well as autophagy markers, such as the levels of ULK1, Atg5, Atg6, Atg7, and the conversion of LC3-I to LC3-II. CF-EOs were further found to inhibit the activity and expression of the NAD[+]-dependent deacetylase SIRT1 to increase the levels of acetylated p53 (Ac-p53) in p53-wt cells and acetylated c-Myc (Ac-c-Myc) in p53-null cells, ultimately inducing apoptosis in both lines. Interestingly, suppression of SIRT1 by CF-EOs enhanced the acetylation of ULK1, which in turn prompted ROS-dependent autophagy in colon cancer cells. The induction of apoptosis and autophagy by CF-EOs suggests that they may have potential as a promising new approach for treating cancer. Collectively, our results suggest that essential oils isolated from Calocedrus formosana act as a promising anticancer agent against colon cancer cells by targeting SIRT1 to induce ROS-mediated autophagy and apoptosis.},
}
@article {pmid38537439,
year = {2024},
author = {Chen, X and Zhu, N and Wu, Y and Zhang, Y and Zhang, Y and Jin, K and Zhou, Z and Chen, G and Wang, J},
title = {Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {128},
number = {},
pages = {155317},
doi = {10.1016/j.phymed.2023.155317},
pmid = {38537439},
issn = {1618-095X},
mesh = {*Withanolides/pharmacology ; *Endoplasmic Reticulum Stress/drug effects ; Humans ; *Carcinoma, Hepatocellular/drug therapy ; *Reactive Oxygen Species/metabolism ; *Liver Neoplasms/drug therapy ; Animals ; *DNA Damage/drug effects ; *Drug Synergism ; *Sorafenib/pharmacology ; Cell Line, Tumor ; *Apoptosis/drug effects ; *Mice, Nude ; Thioredoxin Reductase 1/metabolism ; Mice, Inbred BALB C ; Cell Proliferation/drug effects ; Mice ; Xenograft Model Antitumor Assays ; Activating Transcription Factor 4/metabolism ; },
abstract = {BACKGROUND: Sorafenib (Sora), a multi-target tyrosine kinase inhibitor, is widely recognized as a standard chemotherapy treatment for advanced hepatocellular carcinoma (HCC). However, drug resistance mechanisms hinder its anticancer efficacy. Derived from Withania somnifera, Withaferin A (WA) exhibits remarkable anti-tumor properties as a natural bioactive compound. This study aimed to examine the mechanisms that underlie the impacts of Sora and WA co-treatment on HCC.<br><br>METHODS: Cell proliferation was evaluated through colony formation and MTT assays. Flow cytometry was employed to determine cellular apoptosis and reactive oxygen species (ROS) levels. The evaluation of apoptosis-related protein levels, DNA damage, and endoplasmic reticulum stress was conducte utilizing IHC staining and western blotting. Moreover, the caspase inhibitor Z-VAD-FMK, ATF4 siRNA, ROS scavenger N-acetyl cysteine (NAC), and TrxR1 shRNA were used to elucidate the underlying signaling pathways. To validate the antitumor effects of Sora/WA co-treatment, in vivo experiments were ultimately executed using Huh7 xenografts.<br><br>RESULTS: Sora/WA co-treatment demonstrated significant synergistic antitumor impacts both in vivo and in vitro. Mechanistically, the enhanced antitumor impact of Sora by WA was achieved through the inhibition of TrxR1 activity, resulting in ROS accumulation. Moreover, ROS generation induced the activation of DNA damage and endoplasmic reticulum (ER) stress pathways, eventually triggering cellular apoptosis. Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment. Additionally, the inhibition of ATF4 by small interfering RNA (siRNA) attenuated Sora/WA co-treatment-induced apoptosis. In vivo, Sora/WA co-treatment significantly suppressed tumor growth in HCC xenograft models and decreased TrxR1 activity in tumor tissues.<br><br>CONCLUSION: Our study suggests that WA synergistically enhances the antitumor effect of Sora, offering promising implications for evolving treatment approaches for HCC.},
}
@article {pmid38536095,
year = {2024},
author = {Aragona, SE and Fabbri, C and Cammarota, G and Ciprandi, G and , },
title = {Probiotic mixture in patients after Helicobacter pylori eradication: a real-life experience.},
journal = {Minerva gastroenterology},
volume = {70},
number = {2},
pages = {197-207},
doi = {10.23736/S2724-5985.24.03634-9},
pmid = {38536095},
issn = {2724-5365},
mesh = {Humans ; *Probiotics/therapeutic use ; *Helicobacter Infections/drug therapy ; Male ; Female ; *Helicobacter pylori ; Middle Aged ; Adult ; Lacticaseibacillus rhamnosus ; Acetylcysteine/therapeutic use ; Treatment Outcome ; Aged ; Dysbiosis ; Dietary Supplements ; },
abstract = {BACKGROUND: Eradication for Helicobacter pylori usually induces digestive dysbiosis that, in turn, elicits symptoms. Consequently, probiotic supplementation may counterbalance the disturbed microbiota after this procedure. So, probiotics may restore microbiota homeostasis quickly relieve complaints.<br><br>METHODS: The current study evaluated the efficacy and safety of Abivisor[&#xae;], a food supplement containing Lacticaseibacillus rhamnosus LR06 (3 billion living cells), Lactiplantibacillus pentosus LPS01(100 million living cells), Lactiplantibacillus plantarum LP01 (1 billion living cells), and N-acetyl cysteine (60 mg). Patients were randomized into two groups (2:1). Group A took one stick/daily for 60 days after eradication. Group B was considered as control. Patients were evaluated at baseline (T0) and after 15 (T1), 30 (T2), and 60 (T3) days. The severity of digestive symptoms was measured by patients using a Visual Analog Scale. The percentage of patients with each symptom was also evaluated.<br><br>RESULTS: Abivisor[&#xae;] has significantly and progressively diminished intestinal symptoms' presence and severity at T1, T2, and even more at T3. Accordingly, the percentage of symptomatic patients diminished more rapidly and significantly in group A than in B. All patients well tolerated the food supplement.<br><br>CONCLUSIONS: The present study suggests that Abivisor[&#xae;] may be an effective and safe therapeutic option for managing patients undergoing H. pylori eradication.},
}
@article {pmid38535516,
year = {2024},
author = {Tamur, S and Alyahya, B and Alsani, F and Bahauddin, AA and Aljaid, M and Al-Malki, S and Alzahrani, A and Khayat, A and Shams, A and Chalut, DS},
title = {Two versus Three Infusion Regimens of N-Acetylcysteine for Acetaminophen Overdose.},
journal = {Pediatric reports},
volume = {16},
number = {1},
pages = {232-242},
pmid = {38535516},
issn = {2036-749X},
abstract = {BACKGROUND: Acetaminophen overdose is a common clinical condition, often leading to liver toxicity. Current treatments involve the three-infusion N-Acetylcysteine (NAC) regimen (FDA-labeled), which may be complex, time-consuming, and need to be changed. An alternative uses two infusions instead, which offers possible advantages regarding simplicity and administration errors. This study sought to compare the respective efficacies and safety outcomes when treating acute acetaminophen overdose among children and adolescents.<br><br>METHODS: At Montreal Children's Hospital, a retrospective study was conducted comparing pre-2003 FDA-labelled three-infusion NAC therapy with a two-infusion regimen. Information was collected regarding patient demographics, NAC administration details, errors, rates of hepatotoxicity, and adverse reactions, and the statistical test Chi-square test was employed to obtain the results.<br><br>RESULTS: A total of 126 patients met the inclusion criteria. Of these patients, 65 received a two-infusion regimen, and 61 patients received the FDA-labeled regimen. The two-infusion group experienced significantly fewer administration errors (4 errors vs. 23 errors; p < 0.001), while the rates of hepatotoxicity between them were similar. There were no instances of liver transplantation or mortality due to either regimen. Adverse reactions occurred equally frequently between both regimens with no discernible difference-the meantime to administer NAC was 9 h for the two-infusion regimen and 8.5 h for FDA-labeled regimen groups, respectively. Three cases of hepatitis were successfully treated with timely NAC therapy, and no liver transplantation or mortality occurred. Adverse reactions, including anaphylactoid reactions, were observed in both groups but were resolved when temporarily stopped and restarted at a slower infusion rate.<br><br>CONCLUSIONS: The two-infusion NAC regimen proved similar efficacy at protecting liver damage and improving patient outcomes compared to its FDA-labeled three-stage counterpart, with significantly fewer administration errors for this version of NAC treatment, suggesting potential advantages in terms of safety and simplicity. Future research should investigate larger cohorts and more variables to validate these results further and optimize the management of acetaminophen overdose cases; further investigation should focus on dosing strategies, personalized approaches, and long-term patient care in this context.},
}
@article {pmid38534586,
year = {2024},
author = {Domínguez-Martínez, J and López-Sánchez, J and García-Galván, F and Serrano, A and Barranco, V and Galván, JC and Rodríguez de la Fuente, &#xd3; and Carmona, N},
title = {Eco-Friendly Sol-Gel Coatings with Organic Corrosion Inhibitors for Lightweight AZ61 Alloy.},
journal = {Gels (Basel, Switzerland)},
volume = {10},
number = {3},
pages = {},
pmid = {38534586},
issn = {2310-2861},
support = {PID2019-104717RB-I00//Spanish Ministry of Economics Affairs and Digital Transformation/ ; PID2021-122980OB-C51//Spanish Ministry of Economic Affairs and Digital Transformation (MINECO)/ ; RYC2022-035912-I and RYC2021-031236-I//MCIN "Ram&#xf3;n y Cajal" Program/ ; },
abstract = {The latest advances in technology and materials science have catalyzed a transformative shift towards the adoption of environmentally conscious and lightweight materials across key sectors such as aeronautics, biomedical, and automotive industries. Noteworthy among these innovations are the magnesium-aluminum (Mg-Al) alloys employed in aeronautical applications, contributing to the overall reduction in aircraft weight and subsequently diminishing fuel consumption and mitigating atmospheric emissions. The present work delves into a study of the anti-corrosive properties inherent in various sol-gel coatings, leveraging a range of environmentally friendly corrosion inhibitors, specifically tailored for samples of the AZ61 alloy. Methodologically, the work involves the synthesis and application of sol-gel coatings on AZ61 alloy containing eco-friendly inhibitors: L-cysteine, N-acetyl-cysteine, curcumin and methylene blue. Subsequently, an accelerated corrosion test in a simulated saline environment is performed. Through microstructural and compositional analyses, the best inhibitors responses are achieved with inhibitors containing S, N heteroatoms and conjugated double bonds in their structure, probably due to the creation of a continuous MgCl2 layer. This research contributes to the ongoing discourse on protective eco-coatings, aligning with the broader paradigm shift towards sustainable and lightweight materials in key industries.},
}
@article {pmid38525131,
year = {2024},
author = {Dong, G and Li, Q and Yu, C and Wang, Q and Zuo, D and Li, X},
title = {n-Acetylcysteine protects against diazinon-induced histopathological damage and apoptosis in renal tissue of rats.},
journal = {Toxicological research},
volume = {40},
number = {2},
pages = {285-295},
pmid = {38525131},
issn = {1976-8257},
abstract = {Diazinon (DZN) is a member of organophosphorus insecticides that has cytotoxic effects on different organs. n-Acetyl cysteine (NAC) is a widely used antioxidant in clinical, in vivo and in vitro studies. We evaluated the protective role of NAC against DZN-induced toxicity in kidney tissue of Wistar rats. 30 male Wistar rats were divided into 5 groups of control, single dose of DZN, continuous dose of DZN, single doses of DZN + NAC and continuous doses of DZN + NAC. Kidney function test (blood urea nitrogen, creatinine and uric acid) was provided. Levels of malondialdehyde (MDA), total antioxidant capacity (TAC) and total sulfhydryl (T-SH) were determined in renal tissues. Renal cells apoptosis was detected using TUNEL assay. The mRNA expressions of apoptosis, oxidative stress and inflammatory mediators, including B-cell lymphoma-2 (Bcl2), Bcl-2-associated X protein (Bax), superoxide dismutase (SOD), catalase (CAT), Interleukin 10 (IL-10), Tumor necrosis factor-α (TNF-α), Caspase-3 and Caspase-8 were analyzed in kidney tissues using Real Time PCR method. Chronic exposure to DZN was associated with severe morphological changes in the kidney, as well as impairment of its function and decreased kidney weights. Continues treatment with DZN significantly decreased the percentage of renal apoptotic cells as compared to rats treated with continuous dose of DZN alone (17.69 ± 3.67% vs. 39.46% ± 2.44%; p < 0.001). Continuous exposure to DZN significantly decreased TAC and T-SH contents, as well as SOD and CAT expression, but increased MDA contents in the kidney tissues (p < 0.001). A significant increase was observed in mRNA expression of Bax, Caspase-3, Caspase-8, as well as TNF-α following exposure to DZN, but the expression of IL-10 and Bcl2 was significantly decreased. NAC can protect kidney tissue against DZN-induced toxicity by elevating antioxidants capacity, mitigating oxidative stress, inflammation and apoptosis.},
}
@article {pmid38524728,
year = {2024},
author = {Khasnavis, S and Belliveau, T and Arnsten, A and Fesharaki-Zadeh, A},
title = {Combined Use of Guanfacine and N-Acetylcysteine for the Treatment of Cognitive Deficits After Traumatic Brain Injury.},
journal = {Neurotrauma reports},
volume = {5},
number = {1},
pages = {226-231},
pmid = {38524728},
issn = {2689-288X},
abstract = {Traumatic Brain Injury (TBI) is a significant contributor to disability across the world. TBIs vary in severity, and most cases are designated mild TBI (mTBI), involving only brief loss of consciousness and no intracranial findings on imaging. Despite this categorization, many persons continue to report persistent cognitive changes in the months to years after injury, with particular impairment in the cognitive and executive functions of the pre-frontal cortex. For these persons, there are no currently approved medications, and treatment is limited to symptom management and cognitive or behavioral therapy. The current case studies explored the use of the alpha-2A adrenoreceptor agonist, guanfacine, combined with the antioxidant, N-acetylcysteine (NAC), in the treatment of post-TBI cognitive symptoms, based on guanfacine's ability to strengthen pre-frontal cortical function, and the open-label use of NAC in treating TBI. Two persons from our TBI clinic were treated with this combined regimen, with neuropsychological testing performed pre- and post-treatment. Guanfacine + NAC improved attention, processing speed, memory, and executive functioning with minimal side effects in both persons. These results encourage future placebo-controlled trials to more firmly establish the efficacy of guanfacine and NAC for the treatment of cognitive deficits caused by TBI.},
}
@article {pmid38522494,
year = {2024},
author = {Mabrouk, NEL and Mastouri, M and Lizard, G and Aouni, M and Harizi, H},
title = {In vitro immunotoxicity effects of carbendazim were inhibited by n-acetylcysteine in microglial BV-2 cells.},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {97},
number = {},
pages = {105812},
doi = {10.1016/j.tiv.2024.105812},
pmid = {38522494},
issn = {1879-3177},
mesh = {*Acetylcysteine/pharmacology ; *Microglia ; Lipopolysaccharides/toxicity ; Benzimidazoles/toxicity ; Nitric Oxide ; *Carbamates ; },
abstract = {Carbendazim (CBZ) is a benzimidazole fungicide widely used worldwide in industrial, agricultural, and veterinary practices. Although, CBZ was found in all brain tissues causing serious neurotoxicity, its impact on brain immune cells remain scarcely understood. Our study investigated the in vitro effects of CBZ on activated microglial BV-2 cells. Lipopolysaccharide (LPS)-stimulated BV-2 cells were exposed to increasing concentrations of CBZ and cytokine release was measured by ELISA, and Cytometric Bead Array (CBA) assays. Mitochondrial superoxide anion (O2[·-]) generation was evaluated by Dihydroethidium (DHE) and nitric oxide (NO) was assessed by Griess reagent. Lipid peroxidation was evaluated by measuring the malonaldehyde (MDA) levels. The transmembrane mitochondrial potential (ΔΨm) was detected by cytometry analysis with dihexyloxacarbocyanine iodide (DiOC6(3)) assay. CBZ concentration-dependently increased IL-1β, IL-6, TNF-α and MCP-1 by LPS-activated BV-2 cells. CBZ significantly promoted oxidative stress by increasing NO, O2[·-] generation, and MDA levels. In contrast, CBZ significantly decreased ΔΨm. Pre-treatment of BV-2 cells with N-acetylcysteine (NAC) reversed all the above mentioned immunotoxic parameters, suggesting a potential protective role of NAC against CBZ-induced immunotoxicity via its antioxidant and anti-inflammatory effects on activated BV-2 cells. Therefore, microglial proinflammatory over-activation by CBZ may be a potential mechanism by which CBZ could induce neurotoxicity and neurodegenerative disorders.},
}
@article {pmid38520518,
year = {2024},
author = {Cao, W and Zhang, J and Yu, S and Gan, X and An, R},
title = {N-acetylcysteine regulates oxalate induced injury of renal tubular epithelial cells through CDKN2B/TGF-β/SMAD axis.},
journal = {Urolithiasis},
volume = {52},
number = {1},
pages = {46},
pmid = {38520518},
issn = {2194-7236},
support = {No.81370803//National Natural Science Foundation of China/ ; No.81370803//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Male ; Rats ; Acetylcysteine/pharmacology ; Calcium Oxalate/metabolism ; Epithelial Cells/metabolism ; *Hyperoxaluria/chemically induced/metabolism ; *Oxalates/metabolism ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Transforming Growth Factor beta1/metabolism ; },
abstract = {This study was aimed to investigate the preventive effects of N-acetyl-L-cysteine (NAC) against renal tubular cell injury induced by oxalate and stone formation and further explore the related mechanism. Transcriptome sequencing combined with bioinformatics analysis were performed to identify differentially expressed gene (DEG) and related pathways. HK-2 cells were pretreated with or without antioxidant NAC/with or silencing DEG before exposed to sodium oxalate. Then, the cell viability, oxidative biomarkers of superoxidase dismutase (SOD) and malondialdehyde (MDA), apoptosis and cell cycle were measured through CCK8, ELISA and flow cytometry assay, respectively. Male SD rats were separated into control group, hyperoxaluria (HOx) group, NAC intervention group, and TGF-β/SMAD pathway inhibitor group. After treatment, the structure changes and oxidative stress and CaOx crystals deposition were evaluated in renal tissues by H&amp;E staining, immunohistochemical and Pizzolato method. The expression of TGF-β/SMAD pathway related proteins (TGF-β1, SMAD3 and SMAD7) were determined by Western blot in vivo and in vitro. CDKN2B is a DEG screened by transcriptome sequencing combined with bioinformatics analysis, and verified by qRT-PCR. Sodium oxalate induced declined HK-2 cell viability, in parallel with inhibited cellular oxidative stress and apoptosis. The changes induced by oxalate in HK-2 cells were significantly reversed by NAC treatment or the silencing of CDKN2B. The cell structure damage and CaOx crystals deposition were observed in kidney tissues of HOx group. Meanwhile, the expression levels of SOD and 8-OHdG were detected in kidney tissues of HOx group. The changes induced by oxalate in kidney tissues were significantly reversed by NAC treatment. Besides, expression of SMAD7 was significantly down-regulated, while TGF-β1 and SMAD3 were accumulated induced by oxalate in vitro and in vivo. The expression levels of TGF-β/SMAD pathway related proteins induced by oxalate were reversed by NAC. In conclusion, we found that NAC could play an anti-calculus role by mediating CDKN2B/TGF-β/SMAD axis.},
}
@article {pmid38518686,
year = {2024},
author = {Kumar, S and Dhiman, M},
title = {Helicobacter pylori secretary Proteins-Induced oxidative stress and its role in NLRP3 inflammasome activation.},
journal = {Cellular immunology},
volume = {399-400},
number = {},
pages = {104811},
doi = {10.1016/j.cellimm.2024.104811},
pmid = {38518686},
issn = {1090-2163},
mesh = {Humans ; *Helicobacter pylori/immunology ; *Oxidative Stress ; *Reactive Oxygen Species/metabolism ; *Helicobacter Infections/immunology/metabolism ; *Inflammasomes/metabolism/immunology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Macrophages/metabolism/immunology ; Bacterial Proteins/metabolism ; Reactive Nitrogen Species/metabolism ; THP-1 Cells ; NADPH Oxidases/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Cell Differentiation/immunology ; },
abstract = {Helicobacter pylori-associated stomach infection is a leading cause of gastric ulcer and related cancer. H. pylori modulates the functions of infiltrated immune cells to survive the killing by reactive oxygen and nitrogen species (ROS and RNS) produced by these cells. Uncontrolled immune responses further produce excess ROS and RNS which lead to mucosal damage. The persistent oxidative stress is a major cause of gastric cancer. H. pylori regulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), nitric oxide synthase 2 (NOS2), and polyamines to control ROS and RNS release through lesser-known mechanisms. ROS and RNS produced by these pathways differentiate macrophages and T cells from protective to inflammatory phenotype. Pathogens-associated molecular patterns (PAMPs) induced ROS activates nuclear oligomerization domain (NOD), leucine rich repeats (LRR) and pyrin domain-containing protein 3 (NLRP3) inflammasome for the release of pro-inflammatory cytokines. This study evaluates the role of H. pylori secreted concentrated proteins (HPSCP) related oxidative stress role in NLRP3 inflammasome activation and macrophage differentiation. To perceive the role of ROS/RNS, THP-1 and AGS cells were treated with 10 μM diphenyleneiodonium (DPI), 50 μM salicyl hydroxamic acid (SHX), 5 μM Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), which are specific inhibitors of NADPH oxidase (NOX), Myeloperoxidase (MPO), and mitochondrial oxidative phosphorylation respectively. Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively. The expression of gp91[phox] (NOX2), NOS2, NLRP3, CD86 and CD163 was analyzed through fluorescent microscopy. THP-1 macrophages growth was unaffected whereas the gastric epithelial AGS cells proliferated in response to higher concentration of HPSCP. ROS and myeloperoxidase (MPO) level increased in THP-1 cells and nitric oxide (NO) and lipid peroxidation significantly decreased in AGS cells. gp91[phox] expression was unchanged, whereas NOS2 and NLRP3 downregulated in response to HPSCP, but increased after inhibition of NO, ROS and MPO in THP-1 cells. HPSCP upregulated the expression of M1 and M2 macrophage markers, CD86 and CD163 respectively, which was decreased after the inhibition of ROS. This study concludes that there are multiple pathways which are generating ROS during H. pylori infection which further regulates other cellular processes. NO is closely associated with MPO and inhibition of NLRP3 inflammasome. The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.},
}
@article {pmid38518383,
year = {2024},
author = {Sun, X and Qin, X and Liang, G and Chang, X and Zhu, H and Zhang, J and Zhang, D and Sun, Y and Feng, S},
title = {Manganese dioxide nanoparticles provoke inflammatory damage in BV2 microglial cells via increasing reactive oxygen species to activate the p38 MAPK pathway.},
journal = {Toxicology and industrial health},
volume = {40},
number = {5},
pages = {244-253},
doi = {10.1177/07482337241242508},
pmid = {38518383},
issn = {1477-0393},
mesh = {*Microglia ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Cell Line ; *Oxides ; *Manganese Compounds ; },
abstract = {With the widespread use of manganese dioxide nanoparticles (nano MnO2), health hazards have also emerged. The inflammatory damage of brain tissues could result from nano MnO2, in which the underlying mechanism is still unclear. During this study, we aimed to investigate the role of ROS-mediated p38 MAPK pathway in nano MnO2-induced inflammatory response in BV2 microglial cells. The inflammatory injury model was established by treating BV2 cells with 2.5, 5.0, and 10.0 μg/mL nano MnO2 suspensions for 12 h. Then, the reactive oxygen species (ROS) scavenger (20 nM N-acetylcysteine, NAC) and the p38 MAPK pathway inhibitor (10 μM SB203580) were used to clarify the role of ROS and the p38 MAPK pathway in nano MnO2-induced inflammatory lesions in BV2 cells. The results indicated that nano MnO2 enhanced the expression of pro-inflammatory cytokines IL-1β and TNF-α, elevated intracellular ROS levels and activated the p38 MAPK pathway in BV2 cells. Controlling intracellular ROS levels with NAC inhibited p38 MAPK pathway activation and attenuated the inflammatory response induced by nano MnO2. Furthermore, inhibition of the p38 MAPK pathway with SB203580 led to a decrease in the production of inflammatory factors (IL-1β and TNF-α) in BV2 cells. In summary, nano MnO2 can induce inflammatory damage by increasing intracellular ROS levels and further activating the p38 MAPK pathway in BV2 microglial cells.},
}
@article {pmid38513962,
year = {2024},
author = {Liang, Z and Sun, G and Zhang, J and Zhang, Q and Li, X and Qin, S and Lv, S and Ding, J and Zhang, Q and Xia, Y and Lu, D},
title = {Protein phosphatase 4 mediates palmitic acid-induced endothelial dysfunction by decreasing eNOS phosphorylation at serine 633 in HUVECs.},
journal = {Experimental cell research},
volume = {437},
number = {1},
pages = {113998},
doi = {10.1016/j.yexcr.2024.113998},
pmid = {38513962},
issn = {1090-2422},
mesh = {Humans ; Phosphorylation ; *Nitric Oxide Synthase Type III/metabolism ; Palmitic Acid/pharmacology ; Serine/metabolism ; Reactive Oxygen Species ; Cells, Cultured ; Protein Phosphatase 2/metabolism ; *Vascular Diseases ; Nitric Oxide/metabolism ; *Phosphoprotein Phosphatases ; },
abstract = {Plasma saturated free fatty acid (FFA)-induced endothelial dysfunction (ED) contributes to the pathogenesis of atherosclerosis and cardiovascular diseases. However, the mechanism underlying saturated FFA-induced ED remains unclear. This study demonstrated that palmitic acid (PA) induced ED by activating the NADPH oxidase (NOX)/ROS signaling pathway to activate protein phosphatase 4 (PP4) and protein phosphatase 2A (PP2A), thereby reducing endothelial nitric oxide synthase (eNOS) phosphorylation at Ser633 and Ser1177, respectively. Okadaic acid (OA) and fostriecin (FST), which are inhibitors of PP2A, inhibited the PA-induced decreases in eNOS phosphorylation at Ser633 and Ser1177. The antioxidants N-acetylcysteine (NAC) and apocynin (APO) or knockdown of gp91phox or p67phox (NOX subunits) restored PA-mediated downregulation of PP4R2 protein expression and eNOS Ser633 phosphorylation. Knockdown of the PP4 catalytic subunit (PP4c) specifically increased eNOS Ser633 phosphorylation, while silencing the PP2A catalytic subunit (PP2Ac) restored only eNOS Ser1177 phosphorylation. Furthermore, PA dramatically decreased the protein expression of the PP4 regulatory subunit R2 (PP4R2) but not the other regulatory subunits. PP4R2 overexpression increased eNOS Ser633 phosphorylation, nitric oxide (NO) production, cell migration and tube formation but did not change eNOS Ser1177 phosphorylation levels. Coimmunoprecipitation (Co-IP) suggested that PP4R2 and PP4c interacted with the PP4R3α and eNOS proteins. In summary, PA decreases PP4R2 protein expression through the Nox/ROS pathway to activate PP4, which contributes to ED by dephosphorylating eNOS at Ser633. The results of this study suggest that PP4 is a novel therapeutic target for ED and ED-associated vascular diseases.},
}
@article {pmid38513858,
year = {2024},
author = {Li, S and Gu, X and Zhang, M and Jiang, Q and Xu, T},
title = {Di (2-ethylhexyl) phthalate and polystyrene microplastics co-exposure caused oxidative stress to activate NF-κB/NLRP3 pathway aggravated pyroptosis and inflammation in mouse kidney.},
journal = {The Science of the total environment},
volume = {926},
number = {},
pages = {171817},
doi = {10.1016/j.scitotenv.2024.171817},
pmid = {38513858},
issn = {1879-1026},
mesh = {Animals ; Mice ; Antioxidants/metabolism ; *Diethylhexyl Phthalate/toxicity/metabolism ; Inflammation/chemically induced ; Kidney/metabolism ; *Microplastics/metabolism/toxicity ; NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Oxidative Stress ; *Phthalic Acids ; Plasticizers/toxicity/metabolism ; Plastics/metabolism/toxicity ; Polystyrenes/toxicity/metabolism ; *Pyroptosis ; },
abstract = {Polystyrene microplastic (PS-MPs) contamination has become a worldwide hotspot of concern, and its entry into organisms can cause oxidative stress resulting in multi-organ damage. The plasticizer di (2-ethylhexyl) phthalate (DEHP) is a common endocrine disruptor, these two environmental toxins often occur together, but their combined toxicity to the kidney and its mechanism of toxicity are unknown. Therefore, in this study, we established PS-MPS and/or DEHP-exposed mouse models. The results showed that alone exposure to both PS-MPs and DEHP caused inflammatory cell infiltration, cell membrane rupture, and content spillage in kidney tissues. There were also down-regulation of antioxidant enzyme levels, increased ROS content, activated of the NF-κB pathway, stimulated the levels of heat shock proteins (HSPs), pyroptosis, and inflammatory associated factors. Notably, the co-exposure group showed greater toxicity to kidney tissues, the cellular assay further validated these results. The introduction of the antioxidant n-acetylcysteine (NAC) and the NLRP3 inhibitor (MCC950) could mitigate the changes in the above measures. In summary, co-exposure of PS-MPs and DEHP induced oxidative stress that activated the NF-κB/NLRP3 pathway and aggravated kidney pyroptosis and inflammation, as well as that HSPs are also involved in this pathologic injury process. This study not only enriched the nephrotoxicity of plasticizers and microplastics, but also provided new insights into the toxicity mechanisms of multicomponent co-pollution in environmental.},
}
@article {pmid38513841,
year = {2024},
author = {Malaviya, R and Meshanni, JA and Sunil, VR and Venosa, A and Guo, C and Abramova, EV and Vayas, KN and Jiang, C and Cervelli, JA and Gow, AJ and Laskin, JD and Laskin, DL},
title = {Role of macrophage bioenergetics in N-acetylcysteine-mediated mitigation of lung injury and oxidative stress induced by nitrogen mustard.},
journal = {Toxicology and applied pharmacology},
volume = {485},
number = {},
pages = {116908},
pmid = {38513841},
issn = {1096-0333},
support = {P30 ES005022/ES/NIEHS NIH HHS/United States ; T32 ES007148/ES/NIEHS NIH HHS/United States ; U54 AR055073/AR/NIAMS NIH HHS/United States ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *Acetylcysteine/pharmacology ; *Mechlorethamine/toxicity ; Male ; *Energy Metabolism/drug effects ; Rats ; *Lung Injury/chemically induced/metabolism/pathology ; Rats, Sprague-Dawley ; Lung/drug effects/metabolism/pathology ; Macrophages/drug effects/metabolism ; Acute Lung Injury/chemically induced/metabolism/pathology ; Macrophages, Alveolar/drug effects/metabolism ; Chemical Warfare Agents/toxicity ; },
abstract = {Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.},
}
@article {pmid38508437,
year = {2024},
author = {Liu, H and Wang, X and He, K and Chen, Z and Li, X and Ren, J and Zhao, X and Liu, S and Zhou, T and Chen, H},
title = {Oxidized DJ-1 activates the p-IKK/NF-κB/Beclin1 pathway by binding PTEN to induce autophagy and exacerbate myocardial ischemia-reperfusion injury.},
journal = {European journal of pharmacology},
volume = {971},
number = {},
pages = {176496},
doi = {10.1016/j.ejphar.2024.176496},
pmid = {38508437},
issn = {1879-0712},
mesh = {Animals ; Humans ; Rats ; Autophagy ; Beclin-1 ; Cysteine/pharmacology ; *Myocardial Reperfusion Injury/metabolism ; *NF-kappa B/metabolism ; PTEN Phosphohydrolase ; Rats, Sprague-Dawley ; Protein Deglycase DJ-1 ; },
abstract = {Patients with myocardial infarction have a much worse prognosis when they have myocardial ischemia-reperfusion (I/R) injury. Further research into the molecular basis of myocardial I/R injury is therefore urgently needed, as well as the identification of novel therapeutic targets and linkages to interventions. Three cysteine residues are present in DJ-1 at amino acids 46, 53, and 106 sites, with the cysteine at position 106 being the most oxidation-prone. This study sought to understand how oxidized DJ-1(C106) contributes to myocardial I/R damage. Rats' left anterior descending branches were tied off to establish a myocardial I/R model in vivo. A myocardial I/R model in vitro was established via anoxia/reoxygenation (A/R) of H9c2 cells. The results showed that autophagy increased after I/R, accompanied by the increased expression of oxidized DJ-1 (ox-DJ-1). In contrast, after pretreatment with NAC (N-acetylcysteine, a ROS scavenger) or Comp-23 (Compound-23, a specific antioxidant binding to the C106 site of DJ-1), the levels of ox-DJ-1, autophagy and LDH release decreased, and cell survival rate increased. Furthermore, the inhibition of interaction between ox-DJ-1 and PTEN could increase PTEN phosphatase activity, inhibit the p-IKK/NF-κB/Beclin1 pathway, reduce injurious autophagy, and alleviate A/R injury. However, BA (Betulinic acid, a NF-κB agonist) was able to reverse the protective effects produced by Comp-23 pretreatment. In conclusion, ox-DJ-1 could activate detrimental autophagy through the PTEN/p-IKK/NF-κB/Beclin1 pathway and exacerbate myocardial I/R injury.},
}
@article {pmid38507470,
year = {2024},
author = {Yin, J and Ge, X and Ding, F and He, L and Song, K and Shi, Z and Ge, Z and Zhang, J and Ji, J and Wang, X and Zhao, N and Shu, C and Lin, F and Wang, Q and Zhou, Q and Cao, Y and Liu, W and Ye, D and Rich, JN and Wang, X and You, Y and Qian, X},
title = {Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly.},
journal = {Science translational medicine},
volume = {16},
number = {739},
pages = {eadg5553},
doi = {10.1126/scitranslmed.adg5553},
pmid = {38507470},
issn = {1946-6242},
mesh = {Humans ; *Glioblastoma/drug therapy ; Iron/metabolism ; *Glioma/drug therapy ; *Brain Neoplasms/drug therapy ; Neoplastic Stem Cells/pathology ; Sulfur/metabolism/therapeutic use ; Fumarates ; Cell Line, Tumor ; PTEN Phosphohydrolase/metabolism ; },
abstract = {Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug N-acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.},
}
@article {pmid38505087,
year = {2024},
author = {Liang, Z and Chen, Q and Pan, L and She, X and Chen, T},
title = {Mebendazole induces apoptosis and inhibits migration via the reactive oxygen species-mediated STAT3 signaling downregulation in non-small cell lung cancer.},
journal = {Journal of thoracic disease},
volume = {16},
number = {2},
pages = {1412-1423},
pmid = {38505087},
issn = {2072-1439},
abstract = {BACKGROUND: The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer and activator of the transcription 3 (STAT3) protein critically participate in the tumorigenesis of NSCLC. Mebendazole (MBZ) has exerts a larger number of pharmacological activities and has anticancer effects in lung cancer, but its mechanism of action remains unclear. This study thus aimed to clarify the impacts of MBZ on NSCLC cell.<br><br>METHODS: Cell proliferation, migration, and apoptosis were investigated via cell counting kit 8 (CCK-8) assay, Transwell assay, colony formation assay, wound-healing assay, and flow cytometry. Reactive oxygen species (ROS) were detected with a multifunctional microplate reader. Markers of cell migration and apoptosis were detected with Western blotting. The transcriptional activity of STAT3 was detected via luciferase assay. ROS scavenger N-acetylcysteine (NAC) was used to determine the effect of MBZ on NSCLC via ROS-regulated STAT3 inactivation and apoptosis. A xenograft model was constructed in vivo to investigate the role of MBZ in NSCLC tumor growth.<br><br>RESULTS: The findings demonstrated that MBZ inhibited NSCLC cell proliferation and migration while promoting apoptosis through triggering ROS generation. In addition, the Janus kinase 2 (JAK2)-STAT3 signaling pathway was abrogated with the treatment of MBZ. NAC could distinctly weaken MBZ-induced apoptosis and STAT3 inactivation. Moreover, MBZ inhibited the tumor growth of NSCLC in vivo.<br><br>CONCLUSIONS: In summary, MBZ inhibited NSCLC cell viability and migration by inducing cell apoptosis via the ROS-JAK2-STAT3 signaling pathway. These data provide a theoretical basis for the use of MBZ in treating NSCLC.},
}
@article {pmid38503729,
year = {2024},
author = {Rodrigues, ACBDC and Silva, SLR and Dias, IRSB and Costa, RGA and Oliveira, MS and Soares, MBP and Dias, RB and Valverde, LF and Rocha, CAG and Johnson, EM and Pina, C and Bezerra, DP},
title = {Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling.},
journal = {Cell death discovery},
volume = {10},
number = {1},
pages = {147},
pmid = {38503729},
issn = {2058-7716},
abstract = {Acute myeloid leukaemia (AML) is a haematological malignancy characterised by the accumulation of transformed myeloid progenitors in the bone marrow. Piplartine (PL), also known as piperlongumine, is a pro-oxidant small molecule extracted from peppers that has demonstrated antineoplastic potential in solid tumours and other haematological malignancies. In this work, we explored the potential of PL to treat AML through the use of a combination of cellular and molecular analyses of primary and cultured leukaemia cells in vitro and in vivo. We showed that PL exhibits in vitro cytotoxicity against AML cells, including CD34[+] leukaemia-propagating cells, but not healthy haematopoietic progenitors, suggesting anti-leukaemia selectivity. Mechanistically, PL treatment increased reactive oxygen species (ROS) levels and induced ROS-mediated apoptosis in AML cells, which could be prevented by treatment with the antioxidant scavenger N-acetyl-cysteine and the pancaspase inhibitor Z-VAD(OMe)-FMK. PL treatment reduced NFKB1 gene transcription and the level of NF-κB p65 (pS536), which was depleted from the nucleus of AML cells, indicating suppression of NF-κB p65 signalling. Significantly, PL suppressed AML development in a mouse xenograft model, and its combination with current AML treatments (cytarabine, daunorubicin and azacytidine) had synergistic effects, indicating translational therapeutic potential. Taken together, these data position PL as a novel anti-AML candidate drug that can target leukaemia stem/progenitors and is amenable to combinatorial therapeutic strategies.},
}
@article {pmid38503013,
year = {2024},
author = {Li, Y and Long, W and Zhang, H and Zhao, M and Gao, M and Guo, W and Yu, L},
title = {Irbesartan ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing NLRP3 inflammasomes in vivo and in vitro.},
journal = {International immunopharmacology},
volume = {131},
number = {},
pages = {111844},
doi = {10.1016/j.intimp.2024.111844},
pmid = {38503013},
issn = {1878-1705},
mesh = {Mice ; Animals ; Male ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Diabetic Nephropathies/drug therapy/metabolism ; Irbesartan/therapeutic use ; NF-E2-Related Factor 2/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism ; Glucose ; *Diabetes Mellitus ; },
abstract = {OBJECTIVES: Diabetic nephropathy (DN) is characterized by albuminuria and renal dysfunction caused by diabetes. At present there is no specific treatment for DN. Irbesartan (IRB) is an angiotensin receptor inhibitor indicated for the treatment of hypertension and DN. However, the underlying molecular mechanisms of IRB on DN remains obscure.<br><br>METHODS: RAW264.7 macrophages were incubated in RPMI-1640, cell viability was evaluated by CCK-8 assays, transcriptional level of proinflammatory cytokines and was measured by ELISA and qPCR, NLRP3 inflammasome and Nrf2/Keap1 related proteins were measured by Western blotting and immunohistochemistry. Streptozotocin (STZ)-induced diabetic male C57BL/6 mice were used to evaluate the therapeutic effect of IRB on DN. Key findings First, we found that IRB improved high glucose-induced cell inflammation by inhibiting the transcription of IL-1&#x3b2; and IL-18. IRB activated the Nrf2/Keap1 pathway and decreased the release of reactive oxygen species (ROS). IRB also suppressed the expression of NLRP3 and caspase-1. IRB combined with the N-acetylcysteine (NAC) significantly inhibited the activation of NLRP3 inflammasomes. Conversely, IRB combined with the Nrf2-related inhibitor ML385 enhanced NLRP3 inflammasome activation, suggesting that IRB suppressed NLRP3 inflammasome via the Nrf2 pathway. In vivo study, HE staining and immunohistochemistry analysis further showed that IRB ameliorated high glucose-induced renal injury by elevating the expression of the Nrf2/Keap1 signaling pathway and suppressing the proinflammatory cytokine and NLRP3 inflammasome activation.<br><br>CONCLUSIONS: Our results suggested that IRB ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing the NLRP3 inflammasomes in vivo and in vitro. These findings provide new therapeutic strategies of diabetic nephropathy.},
}
@article {pmid38500894,
year = {2024},
author = {Harlivasari, AD and Susanto, AD and Taufik, FF and Ginting, TT},
title = {The Role of Twice-Daily N-acetylcysteine (NAC) 2400 mg in Smoking Cessation: A Randomized, Placebo-Controlled Trial in Indonesia.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e54322},
pmid = {38500894},
issn = {2168-8184},
abstract = {INTRODUCTION: Tobacco smoking remains a health concern, especially in developing countries. Nicotine is significantly linked to many cancers and even second-hand exposure. Hence, smoking can increase the risk of lung and heart disease. This makes quitting smoking important and challenging. Success tends to rise by achieving abstinence with assisted pharmacology. These treatments aim to reduce symptoms of nicotine withdrawal. This is a preclinical trial on glutamate modulator in N-acetylcysteine (NAC) as a new potential treatment for smoking cessation. It is based on the administration of NAC related to elevated levels of dopamine in the central nervous system to accomplish successful smoking cessation.<br><br>AIM: This study evaluated the efficacy and tolerability of NAC for smoking cessation. The primary outcome was abstinence rate and the secondary outcomes of the study were to assess carbon monoxide exhalation value (COexh), the withdrawal symptoms, craving score, safety, and tolerability associated with the administration of NAC.<br><br>METHODS: This is a randomized clinical trial. Eligible smokers were treated with NAC 2400 mg twice daily (BID) or placebo to obtain a potential effective abstinence rate.&#xa0;Subjects recruited from the smoking cessation clinic were screened for eligibility and were&#xa0;randomized to either the NAC or placebo group. The trial consisted of a four-week treatment phase and participants were evaluated each week with a brief counseling. Intention to treat data analysis was performed from 2018 to 2019. Smoking cessation status was verified by measuring the amount of carbon monoxide exhaled and by documenting their smoking habits.&#xa0;Adverse events (AEs) have also been observed on each visit.<br><br>RESULTS: A total of 90&#xa0;male smokers with a mean (SD) age of 38.7 (11) years were randomized into two groups to receive NAC (n=45) and placebo (n=45). The primary outcome revealed that the abstinence rate was significantly higher for the NAC&#xa0;group than the placebo group (37.7% vs 6.6%; p=0.02). These findings were supported by data comparison between the NAC group and placebo group of COexh (ppm)&#xa0;(9.59&#xa0;&#xb1;7.4 vs 13,4&#xa0;&#xb1;6.1; p=0.04) and cigarette consumption/week (10 vs 46; p <0.001), which were statistically significant. Comparison of withdrawal with the Minnesota Nicotine Withdrawal Score between the&#xa0;NAC&#xa0;group and the placebo group showed lower values (8 (1-31) vs 11 (0-43); p=0.178), respectively, even though not statistically significant. Compared to the placebo group, the craving score (6 (2-29) vs 12 (6-31); p=0.04) in the NAC group was significantly lower. The most common adverse event was mild gastrointestinal effects (28.9%) and arthralgia (2.2%). No serious adverse events were detected.<br><br>CONCLUSIONS: &#xa0;Despite a small sample size, the data demonstrate the potential benefits of NAC that may help elevate abstinence rates and promote successful smoking cessation pharmacotherapy. Comprehensive treatment combining pharmacologic therapy and counseling increases smoking cessation success rates. It is essential to conduct a randomized multicenter study with a large population to support a sustained abstinence rate using NAC.},
}
@article {pmid38500550,
year = {2024},
author = {Takasaki, T and Hamabe, Y and Touchi, K and Khandakar, GI and Ueda, T and Okada, H and Sakai, K and Nishio, K and Tanabe, G and Sugiura, R},
title = {ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells.},
journal = {Oxidative medicine and cellular longevity},
volume = {2024},
number = {},
pages = {7683793},
pmid = {38500550},
issn = {1942-0994},
mesh = {Humans ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Reactive Oxygen Species/metabolism ; *Melanoma/drug therapy ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; *Pancreatic Neoplasms/drug therapy ; },
abstract = {The extracellular signal-regulated kinase (ERK) MAPK pathway is dysregulated in various human cancers and is considered an attractive therapeutic target for cancer. Therefore, several inhibitors of this pathway are being developed, and some are already used in the clinic. We have previously identified an anticancer compound, ACA-28, with a unique property to preferentially induce ERK-dependent apoptosis in melanoma cells. To comprehensively understand the biological cellular impact induced by ACA-28, we performed a global gene expression analysis of human melanoma SK-MEL-28 cells exposed to ACA-28 using a DNA microarray. The transcriptome analysis identified nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor that combats oxidative stress, as the most upregulated genetic pathway after ACA-28 treatment. Consistently, ACA-28 showed properties to increase the levels of reactive oxygen species (ROS) as well as Nrf2 protein, which is normally repressed by proteasomal degradation and activated in response to oxidative stresses. Furthermore, the ROS scavenger N-acetyl cysteine significantly attenuated the anticancer activity of ACA-28. Thus, ACA-28 activates Nrf2 signaling and exerts anticancer activity partly via its ROS-stimulating property. Interestingly, human A549 cancer cells with constitutively high levels of Nrf2 protein showed resistance to ACA-28, as compared with SK-MEL-28. Transient overexpression of Nrf2 also increased the resistance of cells to ACA-28, while knockdown of Nrf2 exerted the opposite effect. Thus, upregulation of Nrf2 signaling protects cancer cells from ACA-28-mediated cell death. Notably, the Nrf2 inhibitor ML385 substantially enhanced the cell death-inducing property of ACA-28 in pancreatic cancer cells, T3M4 and PANC-1. Our data suggest that Nrf2 plays a key role in determining cancer cell susceptibility to ACA-28 and provides a novel strategy for cancer therapy to combine the Nrf2 inhibitor and ACA-28.},
}
@article {pmid38498979,
year = {2024},
author = {El-Habta, R and Af Bjerkén, S and Virel, A},
title = {N-acetylcysteine increases dopamine release and prevents the deleterious effects of 6-OHDA on the expression of VMAT2, α-synuclein, and tyrosine hydroxylase.},
journal = {Neurological research},
volume = {46},
number = {5},
pages = {406-415},
doi = {10.1080/01616412.2024.2325312},
pmid = {38498979},
issn = {1743-1328},
mesh = {*Vesicular Monoamine Transport Proteins/metabolism ; Humans ; *Oxidopamine/toxicity ; *alpha-Synuclein/metabolism ; *Dopamine/metabolism ; *Acetylcysteine/pharmacology ; *Tyrosine 3-Monooxygenase/metabolism ; Cell Line, Tumor ; Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; },
abstract = {OBJECTIVES: Current treatments for Parkinson's disease using pharmacological approaches alleviate motor symptoms but do not prevent neuronal loss or dysregulation of dopamine neurotransmission. In this article, we have explored the molecular mechanisms underlying the neuroprotective effect of the antioxidant N-acetylcysteine (NAC) on the damaged dopamine system.<br><br>METHODS: SH-SY5Y cells were differentiated towards a dopaminergic phenotype and exposed to 6-hydroxydopamine (6-OHDA) to establish an in vitro model of Parkinson's disease. We examined the potential of NAC to restore the pathological effects of 6-OHDA on cell survival, dopamine synthesis as well as on key proteins regulating dopamine metabolism. Specifically, we evaluated gene- and protein expression of tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and &#x3b1;-synuclein, by using qPCR and Western blot techniques. Moreover, we quantified the effect of NAC on total dopamine levels using a dopamine ELISA assay.<br><br>RESULTS: Our results indicate that NAC has a neuroprotective role in SH-SY5Y cells exposed to 6-OHDA by maintaining cell proliferation and decreasing apoptosis. Additionally, we demonstrated that NAC treatment increases dopamine release and protects SH-SY5Y cells against 6-OHDA dysregulations on the proteins TH, VMAT2, and &#x3b1;-synuclein.<br><br>CONCLUSIONS: Our findings contribute to the validation of compounds capable to restore dopamine homeostasis and shed light on the metabolic pathways that could be targeted to normalize dopamine turnover. Furthermore, our results highlight the effectiveness of the antioxidant NAC in the prevention of dopaminergic neurodegeneration in the present model.<br><br>ABBREVIATIONS: DAT, dopamine transporter; 6-OHDA, 6-hydroxydopamine; NAC, N-acetylcysteine; PARP, poly (ADP-ribose) polymerase; RA; retinoic acid; ROS, reactive oxygen species; TH, tyrosine hydroxylase; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; VMAT2, vesicle monoamine transporter 2.},
}
@article {pmid38497734,
year = {2024},
author = {Li, X and Zou, J and Lin, A and Chi, J and Hao, H and Chen, H and Liu, Z},
title = {Oxidative Stress, Endothelial Dysfunction, and N-Acetylcysteine in Type 2 Diabetes Mellitus.},
journal = {Antioxidants &amp; redox signaling},
volume = {40},
number = {16-18},
pages = {968-989},
pmid = {38497734},
issn = {1557-7716},
support = {RF1 NS132279/NS/NINDS NIH HHS/United States ; R01 HL148196/HL/NHLBI NIH HHS/United States ; R01 HL130845/HL/NHLBI NIH HHS/United States ; R01 HL162367/HL/NHLBI NIH HHS/United States ; R01 HL137229/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/metabolism/drug therapy/complications ; *Acetylcysteine/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; Animals ; *Endothelium, Vascular/metabolism/drug effects/pathology ; *Antioxidants/therapeutic use/pharmacology/metabolism ; Cardiovascular Diseases/metabolism/drug therapy/etiology ; },
abstract = {Significance: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Endothelial dysfunction is closely associated with the development and progression of CVDs. Patients with diabetes mellitus (DM) especially type 2 DM (T2DM) exhibit a significant endothelial cell (EC) dysfunction with substantially increased risk for CVDs. Recent Advances: Excessive reactive oxygen species (ROS) and oxidative stress are important contributing factors to EC dysfunction and subsequent CVDs. ROS production is significantly increased in DM and is critically involved in the development of endothelial dysfunction in diabetic patients. In this review, efforts are made to discuss the role of excessive ROS and oxidative stress in the pathogenesis of endothelial dysfunction and the mechanisms for excessive ROS production and oxidative stress in T2DM. Critical Issues: Although studies with diabetic animal models have shown that targeting ROS with traditional antioxidant vitamins C and E or other antioxidant supplements provides promising beneficial effects on endothelial function, the cardiovascular outcomes of clinical studies with these antioxidant supplements have been inconsistent in diabetic patients. Future Directions: Preclinical and limited clinical data suggest that N-acetylcysteine (NAC) treatment may improve endothelial function in diabetic patients. However, well-designed clinical studies are needed to determine if NAC supplementation would effectively preserve endothelial function and improve the clinical outcomes of diabetic patients with reduced cardiovascular morbidity and mortality. With better understanding on the mechanisms of ROS generation and ROS-mediated endothelial damages/dysfunction, it is anticipated that new selective ROS-modulating agents and effective personalized strategies will be developed for the management of endothelial dysfunction in DM.},
}
@article {pmid38496055,
year = {2024},
author = {R, R and Routray, M},
title = {Management of Yellow Phosphorus-Induced Acute Liver Failure: A Case Report and Review of Literature.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e54223},
pmid = {38496055},
issn = {2168-8184},
abstract = {Three percent (3%) of yellow phosphorus is the active component of the rodenticide Ratol[®]. It is a potent hepatotoxin that leads to acute liver failure (ALF) with high mortality. There is no antidote available; the only definitive management is liver transplantation. Therapeutic plasma exchange, or plasmapheresis, appears to help these patients by removing the toxin, its metabolite, or the inflammatory mediators released in the body in response to the toxin. Here, we report a case of a 19-year-old male with an alleged history of Ratol[®] ingestion and ALF with acute kidney injury. He had a complete reversal of his condition with timely intervention in the form of plasmapheresis.},
}
@article {pmid38495889,
year = {2024},
author = {Gupta, A and Song, MH and Youn, DH and Ku, D and Sasidharan Nair, V and Oh, K},
title = {Prolyl hydroxylase inhibition protects against murine MC903-induced skin inflammation by downregulating TSLP.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1330011},
pmid = {38495889},
issn = {1664-3224},
mesh = {Animals ; Mice ; *Prolyl Hydroxylases ; Interleukin-33 ; Reactive Oxygen Species ; *Dermatitis/drug therapy/etiology/prevention &amp; control ; Anti-Inflammatory Agents ; Inflammation ; Calcitriol/*analogs &amp; derivatives ; },
abstract = {Previously, we reported an anti-inflammatory effect of mTORC1 in a mouse model of type 2 skin inflammation. TSLP, one of the epithelial cell-derived cytokines, was upregulated by Raptor deficiency or rapamycin treatment, which was inhibited by dimethyloxalylglycine (DMOG). However, it remains unclear how DMOG regulates TSLP expression and type 2 skin inflammation. In this study, we investigated the protective effect of DMOG on MC903 (calcipotriol)-induced type 2 skin inflammation. Morphological and immunological changes were assessed by H-E staining, flow cytometry and RT-qPCR. DMOG treatment attenuated MC903-induced skin inflammation in a T cell-independent manner. The anti-inflammatory effect of DMOG was accompanied by downregulation of TSLP and IL-33, and supplementation with recombinant TSLP and IL-33 abolished the effect of DMOG. MC903 increased ROS levels in skin tissue, which was prevented by DMOG. Furthermore, the ROS scavenger N-acetylcysteine (NAC) downregulated TSLP and ameliorated MC903-induced skin inflammation, as did DMOG. Finally, the effect of DMOG on ROS and TSLP was reduced by HIF knockdown. These results suggest that DMOG downregulates TSLP and ROS through the HIF pathway, which reduces MC903-induced skin inflammation.},
}
@article {pmid38494703,
year = {2024},
author = {Miyake, K and Mikami, Y and Asayama, T and Toriumi, T and Shinozuka, K and Tonogi, M and Yonehara, Y and Tsuda, H},
title = {Reactive oxygen species generation required for autophagy induction during butyrate- or propionate-induced release of damage-associated molecular patterns from dying gingival epithelial Ca9-22 cells.},
journal = {Journal of oral science},
volume = {66},
number = {2},
pages = {125-129},
doi = {10.2334/josnusd.23-0421},
pmid = {38494703},
issn = {1880-4926},
mesh = {Humans ; *Butyrates/pharmacology ; *Propionates/pharmacology ; Reactive Oxygen Species/metabolism ; Fatty Acids, Volatile/pharmacology ; Autophagy/physiology ; },
abstract = {PURPOSE: Bacterial cells in mature dental plaque produce a high concentration of short-chain fatty acids (SCFAs) such as butyrate and propionate. SCFA-treatment on human gingival epithelial Ca9-22 cells induced cell death. However, the exact mechanism underlying cell death remains unclear. In this study, the relationship between reactive oxygen species (ROS) and autophagy induction during SCFA-induced cell death was examined.<br><br>METHODS: Human gingival epithelial Ca9-22 cells were treated with butyrate or propionate to induce cell death and the number of dead cells were measured using SYTOX-green dye. A siRNA for ATG5 and N-acetylcysteine (NAC) were used for autophagy reduction and ROS-scavenging, respectively. Release of damage-associated molecular patterns (DAMPs) such as Sin3A-associated protein 130 (SAP130) and high-mobility group box 1 (HMGB1) were detected using western blot.<br><br>RESULTS: Reducing autophagy significantly suppressed SCFA-induced Ca9-22 cell death. ROS generation was observed upon SCFA treatment, and scavenging ROS with NAC decreased cell death. NAC also reduced the SCFA-induced increase in microtubule-associated protein 1 light chain 3B (LC3B)-I and LC3B-II, and mitigated the release of DAMPs.<br><br>CONCLUSION: The findings suggest that ROS generation is necessary for autophagy, which is required for SCFA-induced cell death and accompanying DAMP release.},
}
@article {pmid38488660,
year = {2024},
author = {Cao, S and Yin, H and Li, X and Zeng, X and Liu, J},
title = {Nickel induces epithelial-mesenchymal transition in pulmonary fibrosis in mice via activation of the oxidative stress-mediated TGF-β1/Smad signaling pathway.},
journal = {Environmental toxicology},
volume = {39},
number = {6},
pages = {3597-3611},
doi = {10.1002/tox.24229},
pmid = {38488660},
issn = {1522-7278},
support = {22zx7153//Natural Science Foundation of Southwest University of Science and Technology/ ; },
mesh = {Animals ; Male ; Mice ; *Epithelial-Mesenchymal Transition/drug effects ; Lung/drug effects/pathology/metabolism ; *Nickel/toxicity ; *Oxidative Stress/drug effects ; *Pulmonary Fibrosis/chemically induced/metabolism/pathology ; *Signal Transduction/drug effects ; Smad Proteins/metabolism ; Transforming Growth Factor beta1/metabolism ; },
abstract = {Nickel (Ni) is recognized as a carcinogenic metal, and its widespread use has led to severe environmental and health problems. Although the lung is among the main organs affected by Ni, the precise mechanisms behind this effect remain poorly understood. This study aimed to elucidate the physiological mechanisms underlying Ni-induced pulmonary fibrosis (PF), using various techniques including histopathological detection, biochemical analysis, immunohistochemistry, western blotting, and quantitative real-time PCR. Mice were treated with nickel chloride (NiCl2), which induced PF (detected by Masson staining), up-regulation of α-smooth muscle actin (α-SMA), and collagen-1 mRNA and protein expression. NiCl2 was found to induce PF by: activation of the epithelial-mesenchymal transition (EMT) and the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway; up-regulation of protein and mRNA expression of TGF-β1, p-Smad2, p-Smad3, vimentin, and N-cadherin; and down-regulation of protein and mRNA expression of E-cadherin. In addition, NiCl2 treatment increased malondialdehyde content while inhibiting antioxidant activity, as indicated by decreased catalase, total antioxidant capacity, and superoxide dismutase activities, and glutathione content. Co-treatment with the effective antioxidant and free radical scavenger N-acetyl cysteine (NAC) plus NiCl2 was used to study the effects of oxidative stress in NiCl2-induced PF. The addition of NAC significantly mitigated NiCl2-induced PF, and reversed activation of the TGF-β1/Smad signaling pathway and EMT. NiCl2-induced PF was therefore shown to be due to EMT activation via the TGF-β1/Smad signaling pathway, mediated by oxidative stress.},
}
@article {pmid38480798,
year = {2024},
author = {Zhu, C and Lu, Y and Wang, S and Song, J and Ding, Y and Wang, Y and Dong, C and Liu, J and Qiu, W and Qi, W},
title = {Nortriptyline hydrochloride, a potential candidate for drug repurposing, inhibits gastric cancer by inducing oxidative stress by triggering the Keap1-Nrf2 pathway.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {6050},
pmid = {38480798},
issn = {2045-2322},
support = {No. 202003030451//Science and Technology Development Plan of Shandong Province/ ; No. KC2021-JX-0186-145//Beijing Science and Technology Innovation Medical Development Foundation/ ; No.202103030554//Health Science and Technology Development Plan Project/ ; },
mesh = {Mice ; Animals ; Humans ; Reactive Oxygen Species/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; Nortriptyline/pharmacology ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; *Stomach Neoplasms/drug therapy ; Drug Repositioning ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Oxidative Stress ; Apoptosis ; },
abstract = {Effective drugs for the treatment of gastric cancer (GC) are still lacking. Nortriptyline Hydrochloride (NTP), a commonly used antidepressant medication, has been demonstrated by numerous studies to have antitumor effects. This study first validated the ability of NTP to inhibit GC and preliminarily explored its underlying mechanism. To begin with, NTP inhibits the activity of AGS and HGC27 cells (Human-derived GC cells) in a dose-dependent manner, as well as proliferation, cell cycle, and migration. Moreover, NTP induces cell apoptosis by upregulating BAX, BAD, and c-PARP and downregulating PARP and Bcl-2 expression. Furthermore, the mechanism of cell death caused by NTP is closely related to oxidative stress. NTP increases intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreasing the mitochondrial membrane potential (MMP) and inducing glucose (GSH) consumption. While the death of GC cells can be partially rescued by ROS inhibitor N-acetylcysteine (NAC). Mechanistically, NTP activates the Kelch-like ECH-associated protein (Keap1)-NF-E2-related factor 2 (Nrf2) pathway, which is an important pathway involved in oxidative stress. RNA sequencing and proteomics analysis further revealed molecular changes at the mRNA and protein levels and provided potential targets and pathways through differential gene expression analysis. In addition, NTP can inhibited tumor growth in nude mouse subcutaneous tumor models constructed respectively using AGS and MFC (mouse-derived GC cells), providing preliminary evidence of its effectiveness in vivo. In conclusion, our study demonstrated that NTP exhibits significant anti-GC activity and is anticipated to be a candidate for drug repurposing.},
}
@article {pmid38474543,
year = {2024},
author = {Beloglazkina, EK and Moiseeva, AA and Tsymbal, SA and Guk, DA and Kuzmin, MA and Krasnovskaya, OO and Borisov, RS and Barskaya, ES and Tafeenko, VA and Alpatova, VM and Zaitsev, AV and Finko, AV and Ol'shevskaya, VA and Shtil, AA},
title = {The Copper Reduction Potential Determines the Reductive Cytotoxicity: Relevance to the Design of Metal-Organic Antitumor Drugs.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {5},
pages = {},
pmid = {38474543},
issn = {1420-3049},
support = {19-29-08007//Russian Foundation for Basic Research/ ; },
mesh = {Copper/chemistry ; Reducing Agents ; *Antineoplastic Agents/chemistry ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; *Coordination Complexes/chemistry ; Ligands ; },
abstract = {Copper-organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu[2+] to Cu[1+] triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)-organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu[+2] → Cu[+1] redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper-organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper-organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties.},
}
@article {pmid38472735,
year = {2024},
author = {Farouk, F and Shebl, RI},
title = {LC-MS/MS determination of pyocyanin-N-acetyl cysteine adduct: application for understanding Pseudomonas aeruginosa virulence factor neutralization.},
journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry},
volume = {40},
number = {5},
pages = {891-905},
pmid = {38472735},
issn = {1348-2246},
mesh = {*Acetylcysteine/chemistry/pharmacology ; Anti-Bacterial Agents/pharmacology/chemistry ; Liquid Chromatography-Mass Spectrometry ; *Pseudomonas aeruginosa/drug effects ; *Pyocyanine/metabolism/antagonists &amp; inhibitors/analysis/chemistry ; *Virulence Factors/antagonists &amp; inhibitors/metabolism ; },
abstract = {Combating Pseudomonas aeruginosa infection is challenging. It secretes pyocyanin (PCN) pigment that contributes to its virulence. Neutralizing PCN via reaction with thiol-containing compounds may represent a potential therapeutic option. This study investigates the neutralization reaction between PCN and N-acetyl cysteine (NAC) for bacterial inhibition and explores its mechanism of action. The neutralization adduct (PCN-NAC) was synthesized by reacting the purified PCN and NAC. The adduct was analyzed and its structure was elucidated. LC-MS/MS method was developed for the determination of PCN-NAC in P. aeruginosa cultures post-treatment with NAC (0-5 mg/mL). The corresponding anti-bacterial potential was estimated and compared to nanoparticles (NPs) alone and under stress conditions. In silico studies were performed to support explaining the mechanism of action. Results revealed that PCN-NAC was exclusively detected in NAC-treated cultures in a concentration-dependent manner. PCN-NAC concentration (230-915 µg/mL) was directly proportional to the reduction in the bacterial viable count (28.3% ± 7.1-87.5% ± 5.9) and outperformed all tested NPs, where chitosan NPs induced 56.9% ± 7.9 inhibition, followed by zinc NPs (49.4% ± 0.9) and gold NPs (17.8% ± 7.5) even post-exposure to different stress conditions. A concomitant reduction in PCN concentration was detected. In silico studies revealed possible interactions between key bacterial proteins and PCN-NAC rather than the NAC itself. These results pose NAC as a potential choice for the management of P. aeruginosa infection, where it neutralizes PCN via the formation of PCN-NAC adduct.},
}
@article {pmid38470079,
year = {2024},
author = {Atefi, N and Ziaeifar, E and Seirafianpour, F and Sadeghzadeh-Bazargan, A and Amin, NG and Mozafarpoor, S and Abouie, A and Jafari, MA and Goodarzi, A},
title = {Evaluation of efficacy and safety of vitiligo treatment with micro-needling combined with N-Acetylcysteine and micro-needling alone: A double-blinded randomized controlled clinical trial.},
journal = {Journal of cosmetic dermatology},
volume = {23},
number = {6},
pages = {2220-2230},
doi = {10.1111/jocd.16274},
pmid = {38470079},
issn = {1473-2165},
mesh = {Humans ; *Vitiligo/therapy/drug therapy ; *Acetylcysteine/administration &amp; dosage/adverse effects/therapeutic use ; Double-Blind Method ; Female ; Adult ; Male ; Middle Aged ; Treatment Outcome ; Combined Modality Therapy/adverse effects/methods ; Young Adult ; Severity of Illness Index ; Dry Needling/adverse effects/methods ; Needles/adverse effects ; Adolescent ; Skin Pigmentation/drug effects ; },
abstract = {INTRODUCTION: Vitiligo is a skin pigmentation disorder caused by the selective degradation of melanocytes. This study investigates the therapeutic effects of microneedling with and without N-acetylcysteine (NAC) in patients with persistent and limited vitiligo.<br><br>METHOD: This research employed a clinical trial design with double-blind randomization. Individuals affected by vitiligo and seeking treatment at Rasool Akram Medical Complex were divided into two separate treatment groups. In the intervention group, 24 affected areas underwent meso-microneedling using 5% NAC ampoules over six sessions, in addition to the application of 4.7% NAC cream once daily on the specified area. Conversely, the control group, consisting of 22 lesions, underwent microneedling using distilled water during six sessions. The severity of lesions and the extent of repigmentation were gauged using the Modified VETI Score. Assessment of treatment efficacy was determined through both physician evaluations and patient feedback.<br><br>RESULTS: Twenty patients with a mean age of 36.4&#x2009;years were recruited. The mean percentage of lesions and their intensity were significantly improved 2&#x2009;weeks after the third session and 1&#x2009;month after the end of the treatment (p&#x2009;<&#x2009;0.01). There was no statistically significant difference between the intervention and control groups. Gender, age, family history, duration of disease, duration of disease stability, and history of hypothyroidism had no statistically significant relationship with patients' treatment outcomes (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSION: Microneedling with or without the application of NAC appears to be an effective treatment option for persistent vitiligo lesions. However, despite the higher improvement rate with the application of NAC, the difference was not significant.},
}
@article {pmid38469128,
year = {2024},
author = {Gautam, N and Shrestha, N and Bhandari, S and Thapaliya, S},
title = {Severe dengue infection unmasking drug-induced liver injury: Successful management with N-acetylcysteine.},
journal = {Clinical case reports},
volume = {12},
number = {3},
pages = {e8578},
pmid = {38469128},
issn = {2050-0904},
abstract = {KEY CLINICAL MESSAGE: Clinicians in tuberculosis and dengue endemic regions should have heightened vigilance for drug-induced liver injury (DILI) overlapping with active infections, enabling prompt recognition and life-saving conservative management.<br><br>ABSTRACT: Severe dengue and drug-induced liver injury (DILI) are significant independent risk factors for acute liver failure. The co-occurrence of these conditions significantly complicates clinical management. Here, we describe the case of a 21-year-old Nepali female who developed acute liver failure during antitubercular therapy (ATT). The patient, presenting with fever and nausea after 3&#x2009;weeks of ATT, subsequently received a diagnosis of severe dengue. Laboratory evidence indicated markedly elevated transaminases (AST 4335&#x2009;U/L, ALT 1958&#x2009;U/L), total bilirubin (72&#x2009;&#x3bc;mol/L), and INR (>5). Prompt discontinuation of first-line ATT, initiation of a modified ATT regimen, and N-acetylcysteine (NAC) infusion facilitated the patient's recovery after a week of intensive care. This case underscores the potential for synergistic hepatotoxicity in regions where multiple endemic illnesses coincide. Early recognition of DILI, cessation of offending agents, and comprehensive intensive care are crucial interventions. While the definitive efficacy of NAC remains under investigation, its timely administration in these complex cases warrants exploration for its potential lifesaving benefits.},
}
@article {pmid38467612,
year = {2024},
author = {Zhang, L and Shi, X and Zhang, L and Mi, Y and Zuo, L and Gao, S},
title = {A first-in-class TIMM44 blocker inhibits bladder cancer cell growth.},
journal = {Cell death &amp; disease},
volume = {15},
number = {3},
pages = {204},
pmid = {38467612},
issn = {2041-4889},
support = {81902565//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Mice ; Animals ; Humans ; *Signal Transduction ; Proto-Oncogene Proteins c-akt/metabolism ; Mice, Nude ; Urinary Bladder/metabolism ; Cell Proliferation ; *Urinary Bladder Neoplasms/drug therapy/genetics/metabolism ; Apoptosis ; Adenosine Triphosphate/pharmacology ; Cell Line, Tumor ; Mammals ; Mitochondrial Precursor Protein Import Complex Proteins ; },
abstract = {Mitochondria play a multifaceted role in supporting bladder cancer progression. Translocase of inner mitochondrial membrane 44 (TIMM44) is essential for maintaining function and integrity of mitochondria. We here tested the potential effect of MB-10 (MitoBloCK-10), a first-in-class TIMM44 blocker, against bladder cancer cells. TIMM44 mRNA and protein expression is significantly elevated in both human bladder cancer tissues and cells. In both patient-derived primary bladder cancer cells and immortalized (T24) cell line, MB-10 exerted potent anti-cancer activity and inhibited cell viability, proliferation and motility. The TIMM44 blocker induced apoptosis and cell cycle arrest in bladder cancer cells, but failed to provoke cytotoxicity in primary bladder epithelial cells. MB-10 disrupted mitochondrial functions in bladder cancer cells, causing mitochondrial depolarization, oxidative stress and ATP reduction. Whereas exogenously-added ATP and the antioxidant N-Acetyl Cysteine mitigated MB-10-induced cytotoxicity of bladder cancer cells. Genetic depletion of TIMM44 through CRISPR-Cas9 method also induced robust anti-bladder cancer cell activity and MB-10 had no effect in TIMM44-depleted cancer cells. Contrarily, ectopic overexpression of TIMM44 using a lentiviral construct augmented proliferation and motility of primary bladder cancer cells. TIMM44 is important for Akt-mammalian target of rapamycin (mTOR) activation. In primary bladder cancer cells, Akt-S6K1 phosphorylation was decreased by MB-10 treatment or TIMM44 depletion, but enhanced after ectopic TIMM44 overexpression. In vivo, intraperitoneal injection of MB-10 impeded bladder cancer xenograft growth in nude mice. Oxidative stress, ATP reduction, Akt-S6K1 inhibition and apoptosis were detected in MB-10-treated xenograft tissues. Moreover, genetic depletion of TIMM44 also arrested bladder cancer xenograft growth in nude mice, leading to oxidative stress, ATP reduction and Akt-S6K1 inhibition in xenograft tissues. Together, targeting overexpressed TIMM44 by MB-10 significantly inhibits bladder cancer cell growth in vitro and in vivo.},
}
@article {pmid38467037,
year = {2024},
author = {Gakuba, C and Dumitrascu, AD and Marsan, PE and Legallois, D and Hanouz, JL and Vivien, D and Martinez de Lizarrondo, S and Gauberti, M and Cerasuolo, D},
title = {N-Acetylcysteine to Reduce Mortality for Patients Requiring Cardiac Catheterization or Cardiac Surgery: A Systematic Review and Meta-analysis.},
journal = {Journal of cardiovascular pharmacology},
volume = {83},
number = {6},
pages = {580-587},
doi = {10.1097/FJC.0000000000001551},
pmid = {38467037},
issn = {1533-4023},
mesh = {Humans ; *Cardiac Catheterization/adverse effects/mortality ; *Hospital Mortality ; *Acetylcysteine/adverse effects/therapeutic use/administration &amp; dosage ; *Cardiac Surgical Procedures/adverse effects/mortality ; Treatment Outcome ; Risk Factors ; Risk Assessment ; Female ; Randomized Controlled Trials as Topic ; Male ; Aged ; Middle Aged ; },
abstract = {Multimers of von Willebrand factor play a critical role in various processes inducing morbidity and mortality in cardiovascular-risk patients. With the ability to reduce von Willebrand factor multimers, N-acetylcysteine (NAC) could reduce mortality in patients undergoing coronary catheterization or cardiac surgery. However, its impact in perioperative period has never been studied so far in regard of its potential cardiovascular benefits. Then, 4 databases were searched for randomized controlled trials that compared in-hospital mortality between an experimental group, with NAC, and a control group without NAC, in patients undergoing coronary catheterization or cardiac surgery. The primary efficacy outcome was in-hospital mortality. Secondary outcomes were the occurrence of thrombotic events, major cardiovascular events, myocardial infarction, and contrast-induced nephropathy. The safety outcome was occurrence of hemorrhagic events. Nineteen studies totaling 3718 patients were included. Pooled analysis demonstrated a reduction of in-hospital mortality associated with NAC: odds ratio, 0.60; 95% confidence interval, 0.39-0.92; P = 0.02. The occurrence of secondary outcomes was not significantly reduced with NAC except for contrast-induced nephropathy. No difference was reported for hemorrhagic events. Subgroup analyses revealed a life-saving effect of NAC in a dose-dependent manner with reduction of in-hospital mortality for the NAC high-dose group, but not for the NAC standard-dose (<3500-mg) group. In conclusion, without being able to conclude on the nature of the mechanism involved, our review suggests a benefit of NAC in cardiovascular-risk patients in perioperative period in terms of mortality and supports prospective confirmatory studies.},
}
@article {pmid38465147,
year = {2024},
author = {Martinez-Ortega, JI and Perez Hernandez, FJ and Ortegon Blanco, AE},
title = {Acro-Ischemia Associated With SARS-CoV-2: A Case Report.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e53798},
pmid = {38465147},
issn = {2168-8184},
abstract = {COVID-19 is known to cause various cutaneous lesions, including acro-ischemic lesions (AIL), which are associated with poor prognosis. Anticoagulant therapy has shown positive responses in AIL patients. However, in this case study, we present a fatal AIL case despite anticoagulant therapy. We propose different treatment approaches based on the limited current data on acro-ischemia pathogenesis related to SARS-CoV-2. The clinical case involved a 59-year-old male with severe COVID-19 symptoms, including acrocyanosis and right hemiparesis. Despite receiving anticoagulant therapy, the patient's condition worsened, leading to necrosis in the left foot. The discussion focuses on the high-risk nature of AIL, the potential link between angiotensin-converting enzyme 2 (ACE2) receptors and vasculitis or thromboembolic manifestations, and the role of immune clots in AIL pathogenesis. Behçet syndrome is referenced as a model of inflammation-induced thrombosis, guiding the suggestion for immunosuppressant-based treatment in addition to anticoagulants. Additionally, three substances, N-acetyl cysteine, sulodexide, and hydroxychloroquine, are proposed.},
}
@article {pmid38460408,
year = {2024},
author = {Liu, YL and Liu, JY and Zhu, XX and Wei, JH and Mi, SL and Liu, SY and Li, XL and Zhang, WW and Zhao, LL and Wang, H and Xu, DX and Gao, L},
title = {Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.},
journal = {Ecotoxicology and environmental safety},
volume = {274},
number = {},
pages = {116191},
doi = {10.1016/j.ecoenv.2024.116191},
pmid = {38460408},
issn = {1090-2414},
mesh = {Animals ; Male ; Mice ; Apoptosis ; Cell Proliferation ; DNA Breaks, Double-Stranded/drug effects ; DNA Repair ; *Marine Toxins/metabolism/toxicity ; Mice, Inbred ICR ; *Microcystins/metabolism/toxicity ; Semen ; *Sirtuins/drug effects/metabolism ; *Spermatogonia/drug effects/metabolism ; },
abstract = {The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 μg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.},
}
@article {pmid38460098,
year = {2024},
author = {Nam, Y and Na, J and Ma, SX and Park, H and Park, H and Lee, E and Kim, H and Jang, SM and Ko, HS and Kim, S},
title = {DJ-1 protects cell death from a mitochondrial oxidative stress due to GBA1 deficiency.},
journal = {Genes &amp; genomics},
volume = {46},
number = {5},
pages = {519-529},
pmid = {38460098},
issn = {2092-9293},
support = {2022R1C1C1009937//National Research foundation of korea/ ; },
mesh = {Humans ; Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Antioxidants/metabolism ; Hydrogen Peroxide ; *Neuroblastoma ; Oxidative Stress ; Cell Death/physiology ; Mice, Knockout ; Protein Deglycase DJ-1/genetics/metabolism ; *Parkinson Disease ; },
abstract = {BACKGROUND: GBA1 mutations are the most common genetic risk factor for development of Parkinson's disease (PD). The loss of catalytic activity in GBA1, as well as the reduction of the GBA1 protein in certain cellular compartment, may increase disease progression. However, the mechanisms underlying cellular dysfunction caused by GBA1 deficiency are still mostly unknown.<br><br>OBJECTIVE: In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction.<br><br>METHODS: GBA1 knockout (KO) SH-SY5Y cells were used to assess DJ-1 functions against oxidative stress in vitro. The levels of cellular reactive oxygen species were monitored with MitoSOX reagent. The expression of the PARK7 gene was analyzed using the quantitative real-time PCR (qRT-PCR). To understand the mechanism underlying DJ-1 upregulation in GBA1 KO cells, we assess ROS levels, antioxidant protein, and cell viability in GBA1 KO cells with treatment of ROS inhibitor N-acetyl-cysteine or miglustat, which is an inhibitor of glucosylceramide synthase. Dopaminergic degeneration was assessed from Gba1 L444P heterozygous mice mated with Park7 knockout mice.<br><br>RESULTS: We find that DJ-1 is significantly upregulated in GBA1 KO cells. Elevated levels of DJ-1 are attributed to the transcriptional expression of PARK7 mRNA, but not the inhibition of DJ-1 protein degradation. Because DJ-1 expression is highly linked to oxidative stress, we observe cellular reactive oxygen species (ROS) in GBA1 KO cells. Moreover, several antioxidant gene expressions and protein levels are increased in GBA1 KO cells. To this end, GBA1 KO cells are more susceptible to H2O2-induced cell death. Importantly, there is a significant reduction in dopaminergic neurons in the midbrain from Gba1 L444P heterozygous mice mated with Park7 knockout mice, followed by mild motor dysfunction.<br><br>CONCLUSION: Taken together, our results suggest that DJ-1 upregulation due to GBA1 deficiency has a protective role against oxidative stress. It may be supposed that mutations or malfunctions in the DJ-1 protein may have disadvantages in the survival of dopaminergic neurons in the brains of patients harboring GBA1 mutations.},
}
@article {pmid38455771,
year = {2024},
author = {Aulakh, G and Singh, A},
title = {A Case Report Demonstrating the Favorable Outcomes of Using N-acetylcysteine (NAC) in Managing Hepatic Injury Induced by Amphetamine-Related Drug Toxicity: Do We Underestimate Its Potential?.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e53697},
pmid = {38455771},
issn = {2168-8184},
abstract = {A 59-year-old male with a history of alcohol abuse presented with altered mental status. Upon examination, he was hypertensive and lethargic, and laboratory results revealed severe transaminitis, coagulopathy, and lactic acidosis, despite having normal serum alcohol levels. Additionally, his urine drug screen tested positive for methamphetamine. Following the exclusion of infectious, autoimmune, and other common causes of acute hepatitis, a diagnosis of methamphetamine-induced acute hepatitis was established. A non-acetaminophen toxicity N-acetylcysteine (NAC) protocol was initiated, resulting in a positive response with improvement in mentation and a decrease in liver enzyme levels. This case emphasizes the potential effectiveness of NAC in treating amphetamine-induced liver injury, supported by the limited available literature on the subject.},
}
@article {pmid38455596,
year = {2024},
author = {Alkhattabi, NA and Khalifa, FK and Doghaither, HAA and Al-Ghafari, AB and Tarbiah, NI and Sabban, A},
title = {Protective effects of N-acetylcysteine and S-adenosyl-Lmethionine against nephrotoxicity and immunotoxicity induced by ochratoxin A in rats.},
journal = {International journal of health sciences},
volume = {18},
number = {2},
pages = {17-24},
pmid = {38455596},
issn = {1658-3639},
abstract = {OBJECTIVE: The present study was designed to investigate the nephroprotective and immunoprotective effects of S-adenosyl-L-methionine (SAMe) in comparison to N-acetylcysteine (NAC) against ochratoxin A (OTA) - intoxication.<br><br>METHODS: Forty-eight adult male Sprague-Dawley rats were categorized into four groups: Control; OTA intoxication (5 mg OTA/kg diet); OTA + NAC, rats received 200 mg NAC/day before feeding balanced diet contaminated with OTA; and (OTA + SAMe). Rats received 200 mg SAMe/day dissolved in distilled water orally just before feeding a balanced diet contaminated with OTA.<br><br>RESULTS: OTA administration altered serum kidney function biomarkers. These effects were pronouncedly alleviated by treatment with NAC. Results revealed a correlation between OTA-induced immunotoxicity and the reduced white blood cell (WBC) count. Treatments with SAMe significantly improved the WBCs count and hemoglobin concentration.<br><br>CONCLUSION: NAC and SAMe have a protective role against nephrotoxicity and immunotoxicity induced by continuous administration of OTA. NAC was more effective in reducing OTA nephrotoxicity, whereas SAMe was more potent than NAC in reducing OTA immunotoxicity.},
}
@article {pmid38451349,
year = {2024},
author = {Revand, R and Dontham, A and Sarkar, S and Patil, A},
title = {Subacute Exposure to Gaseous Pollutants from Diesel Engine Exhaust Attenuates Capsaicin-Induced Cardio-Pulmonary Reflex Responses Involving Oxidant Stress Mechanisms in Adult Wistar Rats.},
journal = {Cardiovascular toxicology},
volume = {24},
number = {4},
pages = {396-407},
pmid = {38451349},
issn = {1559-0259},
mesh = {Rats ; Male ; Animals ; Rats, Wistar ; Vehicle Emissions/toxicity ; Capsaicin/pharmacology ; *Environmental Pollutants ; Gases ; Cysteine ; *Air Pollutants/toxicity ; Reflex ; },
abstract = {Intravenous injection of capsaicin produces vagal-mediated protective cardio-pulmonary (CP) reflexes manifesting as tachypnea, bradycardia, and triphasic blood pressure (BP) response in anesthetized rats. Particulate matter from diesel engine exhaust has been reported to attenuate these reflexes. However, the effects of gaseous constituents of diesel exhaust are not known. Therefore, the present study was designed to investigate the effects of gaseous pollutants in diesel exhaust, on capsaicin-induced CP reflexes in rat model. Adult male rats were randomly assigned to three groups: Non-exposed (NE) group, filtered diesel exhaust-exposed (FDE) group and N-acetyl cysteine (NAC)-treated FDE group. FDE group of rats (n = 6) were exposed to filtered diesel exhaust for 5 h a day for 5 days (D1-D5), and were taken for dissection on day 6 (D6), while NE group of rats (n = 6) remained unexposed. On D6, rats were anesthetized, following which jugular vein was cannulated for injection of chemicals, and femoral artery was cannulated to record the BP. Lead II electrocardiogram and respiratory movements were also recorded. Results show that intravenous injection of capsaicin (0.1 ml; 10 µg/kg) produced immediate tachypneic, hyperventilatory, hypotensive, and bradycardiac responses in both NE and FDE groups of rats. However, these capsaicin-induced CP responses were significantly attenuated in FDE group as compared to the NE group of rats. Further, FDE-induced attenuation of capsaicin-evoked CP responses were diminished in the N-acetyl cysteine-treated FDE rats. These findings demonstrate that oxidant stress mechanisms could possibly be involved in inhibition of CP reflexes by gaseous pollutants in diesel engine exhaust.},
}
@article {pmid38450909,
year = {2024},
author = {Yan, H and Ding, J and Li, X and Li, S and Zhang, D},
title = {Arecoline induces neurotoxicity in HT22 cells via the promotion of endoplasmic reticulum stress and downregulation of the Nrf2/HO-1 pathway.},
journal = {Environmental toxicology},
volume = {39},
number = {6},
pages = {3410-3424},
doi = {10.1002/tox.24194},
pmid = {38450909},
issn = {1522-7278},
support = {202301AY070001-262//Science and Technology Foundation of Yunnan Provincial/ ; 2023Y0617//Scientific Research Foundation of the Education Department of Yunnan Province/ ; },
mesh = {Animals ; Mice ; *Apoptosis/drug effects ; *Arecoline/toxicity ; Calcium/metabolism ; Cell Line ; Down-Regulation/drug effects ; *Endoplasmic Reticulum Stress/drug effects ; Heme Oxygenase-1/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; },
abstract = {Arecoline, the predominant bioactive substance extracted from areca nut (AN), is the world's fourth most frequently used psychoactive material. Research has revealed that chewing AN can affect the central nervous system (CNS) and may lead to neurocognitive deficits that are possibly linked to the action of arecoline. However, the mechanism behind the neurotoxicity caused by arecoline remains unclear. This study aimed to investigate the neurotoxic effects of arecoline and its underlying mechanism. The results showed that arecoline caused cytotoxicity against HT22 cells in a dose-dependent manner and induced apoptosis by upregulating the expression of pro-apoptotic caspase and Bcl-2 family proteins. Furthermore, arecoline escalated intracellular reactive oxygen species (ROS) levels and Ca[2+] concentration with increasing doses, thereby motivating endoplasmic reticulum stress (ERS) and ERS-associated apoptotic protein expression. Additionally, the study found that arecoline attenuates intracellular antioxidant defense by inhibiting the translocation of NF-E2-related factor-2 (Nrf2) into the nucleus and decreasing downstream Heme oxygenase-1 (HO-1) levels. The specific inhibitor Sodium 4-phenylbutyrate (4-PBA) can dramatically attenuate arecoline-mediated cell apoptosis and ERS-associated apoptotic pathway expression by blocking ERS. The antioxidant N-Acetylcysteine (NAC) also effectively reverses the arecoline-mediated increase of ERS-related apoptotic pathway protein levels by scavenging intracellular ROS accumulation. In conclusion, this study suggests that arecoline induces neurotoxicity in HT22 cells via ERS mediated by oxidative stress- and Ca[2+] disturbance, as well as by downregulation of the Nrf2/HO-1 pathway.},
}
@article {pmid38446318,
year = {2024},
author = {Yang, R and Yan, F and Shen, J and Wang, T and Li, M and Ni, H},
title = {Geraniol attenuates oxygen-glucose deprivation/reoxygenation-induced ROS-dependent apoptosis and permeability of human brain microvascular endothelial cells by activating the Nrf-2/HO-1 pathway.},
journal = {Journal of bioenergetics and biomembranes},
volume = {56},
number = {3},
pages = {193-204},
pmid = {38446318},
issn = {1573-6881},
mesh = {Humans ; *Apoptosis/drug effects ; *Acyclic Monoterpenes/pharmacology ; *Reactive Oxygen Species/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Endothelial Cells/metabolism/drug effects ; *Glucose/metabolism ; *Heme Oxygenase-1/metabolism ; Oxygen/metabolism ; Brain/metabolism/blood supply ; Microvessels/metabolism/pathology/drug effects ; },
abstract = {Blood-brain barrier breakdown and ROS overproduction are important events during the progression of ischemic stroke aggravating brain damage. Geraniol, a natural monoterpenoid, possesses anti-apoptotic, cytoprotective, anti-oxidant, and anti-inflammatory activities. Our study aimed to investigate the effect and underlying mechanisms of geraniol in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced human brain microvascular endothelial cells (HBMECs). Apoptosis, caspase-3 activity, and cytotoxicity of HBMECs were evaluated using TUNEL, caspase-3 activity, and CCK-8 assays, respectively. The permeability of HBMECs was examined using FITC-dextran assay. Reactive oxygen species (ROS) production was measured using the fluorescent probe DCFH-DA. The protein levels of zonula occludens-1 (ZO-1), occludin, claudin-5, β-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were determined by western blotting. Geraniol showed no cytotoxicity in HBMECs. Geraniol and ROS scavenger N-acetylcysteine (NAC) both attenuated OGD/R-induced apoptosis and increase of caspase-3 activity and the permeability to FITC-dextran in HBMECs. Geraniol relieved OGD/R-induced ROS accumulation and decrease of expression of ZO-1, occludin, claudin-5, and β-catenin in HBMECs. Furthermore, we found that geraniol activated Nrf2/HO-1 pathway to inhibit ROS in HBMECs. In conclusion, geraniol attenuated OGD/R-induced ROS-dependent apoptosis and permeability in HBMECs through activating the Nrf2/HO-1 pathway.},
}
@article {pmid38445814,
year = {2024},
author = {Iepsen, UW and Hjortdal, AR and Thuesen, AD and Finsen, SH and Hansen, PBL and Mortensen, SP},
title = {The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial.},
journal = {Experimental physiology},
volume = {109},
number = {5},
pages = {779-790},
pmid = {38445814},
issn = {1469-445X},
support = {ID 101390//TrygFonden (Tryg Foundation)/ ; ID 20045//TrygFonden (Tryg Foundation)/ ; //The Capital Region of Denmark/ ; //The Beckett Foundation/ ; //The Ehrenreich Foundation/ ; //Dansk Selskab for Anaestesiologi og Intensiv Medicin (DASAIM)/ ; //The Region of Southern Denmark/ ; //The Danish Medical Research Council/ ; //Dansk Selskab for An&#xe6;stesiologi og Intensiv Medicin (DASAIM)/ ; },
mesh = {Humans ; Male ; *Calcium Channels, T-Type/metabolism/drug effects ; Aged ; *Calcium Channel Blockers/pharmacology ; *Nifedipine/pharmacology ; Pilot Projects ; Double-Blind Method ; *Endothelium, Vascular/drug effects/metabolism/physiology ; Dihydropyridines/pharmacology ; Vasodilation/drug effects/physiology ; Vasodilator Agents/pharmacology ; Blood Pressure/drug effects/physiology ; Regional Blood Flow/drug effects/physiology ; Organophosphorus Compounds/pharmacology ; Acetylcholine/pharmacology ; Leg/blood supply ; Nitroprusside/pharmacology ; Middle Aged ; *Nitrophenols ; },
abstract = {Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.},
}
@article {pmid38444903,
year = {2024},
author = {Williams, EE and Quach, D and Daigh, A},
title = {Massive acetaminophen ingestion managed successfully with N-acetylcysteine, fomepizole, and renal replacement therapy.},
journal = {Clinical nephrology. Case studies},
volume = {12},
number = {},
pages = {22-25},
pmid = {38444903},
issn = {2196-5293},
abstract = {Acetaminophen ingestion is routinely managed with the antidote, N-acetylcysteine (NAC). Massive acetaminophen poisoning has been treated successfully with adjunctive therapies such as fomepizole and hemodialysis. Fomepizole functions by inhibiting cytochrome p560, which prevents tylenol from forming its toxic metabolite, NAPQI. Prior cases have demonstrated favorable outcomes and a significant drop in acetaminophen levels after a single session of intermittent hemodialysis and continuous veno-venous hemofiltration (CVVH). However, the recommended dosage adjustments of NAC and fomepizole while a patient is undergoing CVVH has not been well reported. We present a case of an 18-year-old male who presented after ingesting 125 g of tylenol. His 4-hour acetaminophen level was 738.6 µg/mL. He was treated with NAC, fomepizole, and a single 4-hour session of hemodialysis. His acetaminophen level remained elevated at 730 µg/mL despite the hemodialysis session. CVVH was initiated, and he was given intravenous NAC at 12.5 mg/kg/h, oral NAC at 70 mg/kg every 4 hours, and intravenous fomepizole at 10 mg/kg every 6 hours. His tylenol levels became undetectable 57 hours after ingestion, and he did not develop permanent liver toxicity. This case encourages the use of CVVH for massive tylenol ingestion when a single run of intermittent hemodialysis is not effective in lowering the tylenol level. NAC, fomepizole, and CVVH can prevent unfavorable outcomes in massive acetaminophen ingestion when provided at an appropriate dose and frequency.},
}
@article {pmid38444704,
year = {2023},
author = {Rostamabadi, H and Samandari Bahraseman, MR and Esmaeilzadeh-Salestani, K},
title = {Froriepia subpinnata Leaf Extract-Induced Apoptosis in the MCF-7 Breast Cancer Cell Line by Increasing Intracellular Oxidative Stress.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {22},
number = {1},
pages = {e136643},
pmid = {38444704},
issn = {1726-6890},
abstract = {BACKGROUND: Froriepia subpinnata is one of the plants used in the diet of Iranian people. Previous studies have investigated the antioxidant and antibacterial effects of this plant extract, but no study has been conducted on its anticancer properties.<br><br>OBJECTIVES: In this study, we investigated the effect of F. subpinnata extract on MCF-7 breast cancer cells.<br><br>METHODS: The inhibitory effect of F. subpinnata leaf extract was determined on the growth of cancer cells by the MTT test. The ROS (reactive oxygen species) test was used to investigate the impact of the extract on intracellular oxidative stress. Flow cytometry and real-time PCR tests were used to investigate the apoptosis-related molecular processes. The GC-MS analysis was performed to determine the most abundant components.<br><br>RESULTS: The GC-MS analysis showed that phytol, mono-ethylhexyl phthalate (MEHP), cinnamaldehyde, and neophytadiene constituted 60% of the extracted content. The MTT assay demonstrated that F. subpinnata leaf extract caused 50% lethality at a 400 &#x3bc;g/mL dose in MCF7 cells. The F. subpinnata extract at low doses decreased the ROS level for 24 hours in MCF-7, but by increasing the concentration, the ROS levels increased. At the IC50 dose (inhibitory concentration (IC) associated with 50% impact), the ROS level increased 3.5 times compared to the control group. Examining the effect of N-acetyl cysteine (NAC) showed that this antioxidant agent could prevent the lethal impact of the extract and eliminate the ROS increase in MCF7 cells. Flow cytometry and real-time PCR results showed that the extract specifically induced apoptosis through the internal apoptosis pathway in this cancer cell line.<br><br>CONCLUSIONS: The F. subpinnata extract induced apoptosis by increasing ROS in MCF-7 cancer cells and can be considered for further studies.},
}
@article {pmid38438412,
year = {2024},
author = {Park, WH},
title = {Propyl gallate induces cell death in human pulmonary fibroblast through increasing reactive oxygen species levels and depleting glutathione.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {5375},
pmid = {38438412},
issn = {2045-2322},
mesh = {Humans ; *Propyl Gallate/pharmacology ; Antioxidants/pharmacology ; Reactive Oxygen Species ; Catalase ; Cell Death ; Fibroblasts ; Glutathione ; Buthionine Sulfoximine/pharmacology ; *Chrysanthemum ; RNA, Small Interfering/genetics ; },
abstract = {Propyl gallate (PG) exhibits an anti-growth effect on various cell types. The present study investigated the impact of PG on the levels of reactive oxygen species (ROS) and glutathione (GSH) in primary human pulmonary fibroblast (HPF) cells. Moreover, the effects of N-acetyl cysteine (NAC, an antioxidant), L-buthionine sulfoximine (BSO, a GSH synthesis inhibitor), and small interfering RNA (siRNAs) against various antioxidant genes on ROS and GSH levels and cell death were examined in PG-treated HPF cells. PG (100-800 μM) increased the levels of total ROS and O2[·-] at early time points of 30-180 min and 24 h, whereas PG (800-1600 μM) increased GSH-depleted cell number at 24 h and reduced GSH levels at 30-180 min. PG downregulated the activity of superoxide dismutase (SOD) and upregulated the activity of catalase in HPF cells. Treatment with 800 μM PG increased the number of apoptotic cells and cells that lost mitochondrial membrane potential (MMP; ΔΨm). NAC treatment attenuated HPF cell death and MMP (ΔΨm) loss induced by PG, accompanied by a decrease in GSH depletion, whereas BSO exacerbated the cell death and MMP (ΔΨm) loss without altering ROS and GSH depletion levels. Furthermore, siRNA against SOD1, SOD2, or catalase attenuated cell death in PG-treated HPF cells, whereas siRNA against GSH peroxidase enhanced cell death. In conclusion, PG induced cell death in HPF cells by increasing ROS levels and depleting GSH. NAC was found to decrease HPF cell death induced by PG, while BSO enhanced cell death. The findings shed light on how manipulating the antioxidant system influence the cytotoxic effects of PG in HPF cells.},
}
@article {pmid38435146,
year = {2024},
author = {Khan, S and Hughes, S and Hill, O},
title = {N-acetyl Cysteine Supplementation to Alleviate Skin Picking Disorder: A Case Report.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e53440},
pmid = {38435146},
issn = {2168-8184},
abstract = {There are body-focused repetitive behaviors, such as skin picking, trichotillomania, or nail biting, for which therapeutic interventions are available and can be tried, but unfortunately, there are no FDA-approved medications specifically for them. These disorders can cause functional impairment, disrupt activities of daily living, and be burdensome for both the patients and their loved ones. This case report will discuss an over-the-counter vitamin supplement, N-acetyl cysteine (NAC), that can be used safely but is often overlooked.},
}
@article {pmid38434559,
year = {2024},
author = {Zeng, H and Zou, P and Chen, Y and Zhang, P and Shao, L},
title = {NOX4 aggravates doxorubicin-induced cardiomyocyte pyroptosis by increasing reactive oxygen species content and activating the NLRP3 inflammasome.},
journal = {Cardiovascular diagnosis and therapy},
volume = {14},
number = {1},
pages = {84-100},
pmid = {38434559},
issn = {2223-3652},
abstract = {BACKGROUND: Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4)-mediated reactive oxygen species (ROS) has been reported to induce cardiomyocyte apoptosis, but its effect on pyroptosis of cardiomyocytes has been rarely reported. This paper aimed to explore the effects of NOX4-mediated ROS production on doxorubicin (DOX)-induced myocardial injury and pyroptosis through nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome.<br><br>METHODS: HL-1 cells were treated with DOX or mice (30 mice were divided into five groups with six mice/group) underwent intraperitoneal injection with DOX (5 mg/kg, once a week, five times) to induce myocardial injury, followed by assessment of NOX4 and NLRP3 expression in cell supernatant and myocardial tissues. In cardiomyocyte HL-1 cells, cell proliferation was tested by MTT assay and the activity of ROS by probes. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and glutathione (GSH) activity were evaluated by kits. The expression of pyroptosis proteins was assessed by western blotting. Subsequently, the expression of NOX4 or NLRP3 was altered to determine the effect of NOX4 or NLRP3 expression on cardiomyocyte injury and pyroptosis. The animal models were utilized to evaluate the changes in the cardiac function of mice using an echocardiographic system, with these parameters measured including left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular end-diastolic diameter (LVEDD). Furthermore, the content of myocardial injury markers and the protein expression of pyroptosis proteins were determined to evaluate myocardial injury in the mice.<br><br>RESULTS: DOX treatment led to cardiomyocyte injury and pyroptosis, as evidenced by weakened LVEF, LVFS, and cell proliferation (P<0.05), elevated LVEDD, ROS, and MDA (P<0.05), increased expression of pyroptosis proteins (P<0.05), and decreased SOD and GSH (P<0.05). Additionally, NOX4 and NLRP3 were highly-expressed (P<0.05) in cell supernatant and myocardial tissues. In DOX-induced HL-1 cells, the overexpression of NOX4 intensified ROS levels to aggravate cardiomyocyte injury and pyroptosis, which was reversed by treatment of the ROS scavenger N-acetyl-cysteine. Furthermore, it was revealed that the combination of short hairpin RNA (sh)-NOX4 and overexpressed (oe)-NLRP3 reversed the cardioprotective effects of sh-NOX4 and increased myocardial tissue or cell injury and pyroptosis in vitro and in vivo. No mice died during the animal experiments, and only two were ruled out due to a weight loss greater than 20%.<br><br>CONCLUSIONS: NOX4-mediated ROS production activated NLRP3 inflammasome, thereby aggravating DOX-induced myocardial injury in vitro and in vivo.},
}
@article {pmid38432679,
year = {2024},
author = {Roydeva, A and Milanova, A},
title = {LC-MS/MS determination of N-acetyl-l-cysteine in chicken plasma.},
journal = {Biomedical chromatography : BMC},
volume = {38},
number = {6},
pages = {e5854},
doi = {10.1002/bmc.5854},
pmid = {38432679},
issn = {1099-0801},
support = {BG-RRP-2.004-0006-C02//Bulgarian Ministry of Education and Science (MES) in the frames of Bulgarian National Recovery and Resilience Plan, Component "Innovative Bulgaria"/ ; //Trakia University, Bulgaria/ ; },
mesh = {Animals ; *Acetylcysteine/blood ; *Chickens ; Limit of Detection ; Linear Models ; Liquid Chromatography-Mass Spectrometry ; Reproducibility of Results ; Tandem Mass Spectrometry ; },
abstract = {N-acetyl-l-cysteine (NAC) shows beneficial effects in cases of aflatoxicosis and heat stress in poultry but little is known about its pharmacokinetics in chickens. Therefore, the study aimed to develop and validate a sensitive LC-MS/MS analytical method for quantitative analysis of NAC in chicken plasma. A split calibration curve approach was used for determination of NAC in chicken plasma. Standard curves for low (0.05-2.5 μg/ml) and high (2.5-100 μg/ml) ranges of concentrations were prepared. The standard curves for low (r[2] = 0.9987) and high (r[2] = 0.9899) concentrations were linear within the tested range. The limits of detection (LOD) and of quantification (LOQ) for the standard at low concentrations were 0.093 and 0.28 μg/ml, respectively. The accuracy was from 97.35 to 101.33%. The values of LOD and LOQ for the standard at high concentrations were 0.76 and 2.30 μg/ml, respectively. The accuracy was between 99.77 and 112.14%. The intra- and inter-day precisions for all concentrations from both standards did not exceed 8.57% and 10.69%, respectively. The recovery for all concentrations was between 92.45 and 105.52%. The validated method for determination of NAC in chicken plasma can be applied in future pharmacokinetic studies in chickens without dilution of samples and their repeated analysis.},
}
@article {pmid38431210,
year = {2024},
author = {Stewart, GW},
title = {Pyroglutamate acidosis 2023. A review of 100 cases.},
journal = {Clinical medicine (London, England)},
volume = {24},
number = {2},
pages = {100030},
pmid = {38431210},
issn = {1473-4893},
mesh = {Humans ; *Pyrrolidonecarboxylic Acid ; *Acetaminophen/adverse effects ; *Acidosis/diagnosis/chemically induced ; Floxacillin/adverse effects/therapeutic use ; Anti-Bacterial Agents/adverse effects/therapeutic use ; },
abstract = {This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.},
}
@article {pmid38422239,
year = {2024},
author = {Tuncer, G and Aktas, Z and Basaran, S and Cagatay, A and Eraksoy, H},
title = {Effect of N-acetyl cysteine, rifampicin, and ozone on biofilm formation in pan-resistant Klebsiella pneumoniae: an experimental study.},
journal = {Sao Paulo medical journal = Revista paulista de medicina},
volume = {142},
number = {4},
pages = {e2023113},
pmid = {38422239},
issn = {1806-9460},
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Ozone/pharmacology ; Rifampin/pharmacology ; Klebsiella pneumoniae ; Biofilms ; },
abstract = {BACKGROUND: To the best of our knowledge, this is the first study to evaluate the effectiveness of specific concentrations of antibiofilm agents, such as N-acetyl cysteine (NAC), rifampicin, and ozone, for the treatment of pan-resistant Klebsiella pneumoniae (PRKp).<br><br>OBJECTIVES: We evaluated the effectiveness of antibiofilm agents, such as NAC, rifampicin, and ozone, on biofilm formation in PRKp at 2, 6, 24, and 72 h.<br><br>DESIGN AND SETTING: This single-center experimental study was conducted on June 15, 2017, and July 15, 2018, at Istanbul Faculty of Medicine, Istanbul University, Turkey.<br><br>METHODS: Biofilm formation and the efficacy of these agents on the biofilm layer were demonstrated using colony counting and laser-screened confocal microscopy.<br><br>RESULTS: NAC at a final concentration of 2 &#x3bc;g/mL was administered to bacteria that formed biofilms (24 h), and no significant decrease was detected in the bacterial counts of all isolates (all P > 0.05). Rifampicin with a final concentration of 0.1 &#x3bc;g/mL was administered to bacteria that formed biofilm (24 h), and no significant decrease was detected in bacterial count (all P > 0.05). Notably, ozonated water of even 4.78 mg/L concentration for 72 h decreased the bacterial count by &#x2265; 2 log10.<br><br>CONCLUSION: Different approaches are needed for treating PRKp isolates. We demonstrate that PRKp isolates can be successfully treated with higher concentrations of ozone.},
}
@article {pmid38420829,
year = {2024},
author = {Liao, L and Tao, P and Xu, Q and Chen, W and Chen, J and Liu, W and Liu, W and Hu, J and Lu, J},
title = {TRIM6 Promotes ROS-Mediated Inflammasome Activation and Pyroptosis in Renal Tubular Epithelial Cells via Ubiquitination and Degradation of GPX3 Protein.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {29},
number = {2},
pages = {58},
doi = {10.31083/j.fbl2902058},
pmid = {38420829},
issn = {2768-6698},
support = {NSFC-82074261//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Interleukin-18/metabolism/pharmacology ; Pyroptosis ; Interleukin-6/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Signal Transduction ; Inflammation ; Acetylcysteine/metabolism/pharmacology ; Superoxide Dismutase/metabolism ; Epithelial Cells/metabolism ; Glutathione Peroxidase/metabolism/pharmacology ; Ubiquitination ; Malondialdehyde/metabolism ; RNA, Messenger/metabolism ; *Tripartite Motif Proteins ; *Ubiquitin-Protein Ligases ; },
abstract = {BACKGROUND: Pyroptosis is a critical form of cell death during the development of chronic kidney disease (CKD). Tripartite motif 6 (TRIM6) is an E3-ubiquitin ligase that participates in the progression renal fibrosis (RF). The aim of this study was to investigate the roles of TRIM6 and Glutathione peroxidase 3 (GPX3) in oxidative stress-induced inflammasome activation and pyroptosis in Ang-II treated renal tubular epithelial cells.<br><br>METHODS: To study its role in RF, TRIM6 expression was either reduced or increased in human kidney-2 (HK2) cells using lentivirus, and Ang-II, NAC and BMS-986299 were served as reactive oxygen species (ROS) inducer, ROS scavenger and NLRP3 agonist respectively. Pyroptosis and mitochondrial ROS were measured by flow cytometry. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were determined using commercial kits, while the levels of IL-1&#x3b2;, IL-18, IL-6, and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). Co-immunoprecipitation (Co-IP) assay was used to evaluate the interaction between TRIM6 and GPX3. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to measure mRNA and protein expression, respectively.<br><br>RESULTS: Treatment with Angiotensin II (Ang II) increased the protein and mRNA levels of TRIM6 in HK2 cells. Ang II also increased mitochondrial ROS production and the malondialdehyde (MDA) level, but decreased the levels of GSH and SOD. In addition, Ang II enhanced HK2 cell pyroptosis, increased the levels of IL-1&#x3b2;, IL-18, IL-6, and TNF-&#x3b1;, and promoted the expression of active IL-1&#x3b2;, NLRP3, caspase-1, and GSDMD-N proteins. These effects were reversed by knockdown of TRIM6 and by treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. BMS-986299, an NLRP3 agonist treatment, did not affect ROS production in HK2 cells exposed to Ang II combined with NAC, but cell pyroptosis and inflammation were aggravated. Moreover, the overexpression of TRIM6 in HK2 cells resulted in similar effects to Ang II. NAC and GPX3 overexpression in HK2 cells could reverse ROS production, inflammation, and pyroptosis induced by TRIM6 overexpression. TRIM6 overexpression decreased the GPX3 protein level by promoting its ubiquitination, without affecting the GPX3 mRNA level. Thus, TRIM6 facilitates GPX3 ubiquitination, contributing to increased ROS levels and pyroptosis in HK2 cells.<br><br>CONCLUSIONS: TRIM6 increases oxidative stress and promotes the pyroptosis of HK2 cells by regulating GPX3 ubiquitination. These findings could contribute to the development of novel drugs for the treatment of RF.},
}
@article {pmid38420067,
year = {2024},
author = {Ahmed Attari, MB and Zaman, T and Amjad, A and Khan, MH and Waqar, Z and Jabeen, S},
title = {Comparative Analysis of Outcomes in Acute Organophosphate Poisoning With and Without N-acetyl Cysteine Intervention.},
journal = {Cureus},
volume = {16},
number = {1},
pages = {e53155},
pmid = {38420067},
issn = {2168-8184},
abstract = {INTRODUCTION: Organophosphorus poisoning (OPP) stands as a significant health concern in numerous regions, especially in developing nations. Despite the rising complexities and case fatalities associated with exposure, the treatment approach has remained unchanged for many years. Based on clinical insights, certain pharmacologic agents have demonstrated utility in enhancing outcomes and reducing complications arising from this type of exposure.<br><br>OBJECTIVES: The objective of this study is to compare the outcome of N-acetyl cysteine in the treatment of acute organophosphate poisoning cases. In terms of a) its impact on the requirement of atropine, b) Length of hospital stay, and mortality.<br><br>METHODS: The study was conducted in the intensive care unit (ICU) of the General Hospital Lahore. Thirty patients with a history and clinical presentation indicative of acute organophosphorus poisoning were randomly divided into two groups in a 1:1 ratio. The treatment group received parenteral administration of atropine, pralidoxime, and N-acetylcysteine (NAC) as an adjuvant, and the control group received standard treatment for acute organophosphate (OP) toxicity.<br><br>RESULT: Throughout the study duration, 30 patients suffering acute organophosphate (OP) toxicity (14 men, 16 women) were examined, with an age mean of (25.83&#xb1;11.59) years. In the interventional group, only four patients required ICU admission, but in the control group, eight patients were admitted to ICU. The correlation result between the dose of atropine and length of hospital stays was not statistically significant between both study groups (<0.005). Plasma Cholinesterase (PChE) level (KU L-1) and total dose of Pralidoxime (g) were statistically significant in the length of hospital stay. The data was not normally distributed, so the non-parametric tests were applied. The Wilcoxon ranked test showed significant improvement in both the controlled and interventional groups because the p-value was (<0.005). Intergroup comparison analyzed by using the Mann-Whitney U test showed a significant reduction in the severity and other associated symptoms in the interventional group because the p-value was (0.001).<br><br>CONCLUSION: The outcome demonstrated that the NAC group had a decreased demand for atropine rather than Pralidoxime. In the NAC group, the length of hospital stay and mortality was decreased. The administration of NAC to the present study procedure for acute organophosphate (OP) poisoning is suggested.},
}
@article {pmid38417537,
year = {2024},
author = {Yang, Y and Zhou, M and Huang, Y and Ye, X and Mo, Y and Huang, Y and Wang, S},
title = {LCP1-mediated cytoskeleton alterations involve in arsenite-triggered malignant phenotype of human immortalized prostate stromal cells.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {186},
number = {},
pages = {114548},
doi = {10.1016/j.fct.2024.114548},
pmid = {38417537},
issn = {1873-6351},
mesh = {Male ; Humans ; Cell Line ; Prostate ; Reactive Oxygen Species ; *Arsenic ; *Arsenites/toxicity ; Stromal Cells ; *Prostatic Neoplasms ; Phenotype ; Cytoskeleton ; Tumor Microenvironment ; Microfilament Proteins ; HMGB Proteins ; },
abstract = {The connection between continuous arsenic exposure and prostate cancer is already established. However, the exact mechanisms of arsenic tumorigenesis are far from clear. Here, we employed human prostate stromal immortalized cells (WPMY-1) continuous exposure to 1 and 2 μM arsenite for 29 weeks to identify the malignant phenotype and explore the underlying molecular mechanism. As expected, continuous low-dose arsenite exposure led to the malignant phenotype of WPMY-1 cells. Quantitative proteomics identified 517 differentially expressed proteins (DEPs), of which the most remarkably changed proteins (such as LCP1 and DDX58, etc.) and the bioinformatic analysis were focused on the regulation of cytoskeleton, cell adhesion, and migration. Further, cell experiments showed that continuous arsenite exposure altered cytoskeleton structure, enhanced cell adhesive capability, and raised the levels of reactive oxygen species (ROS), ATM, p-ATM, p-ERK1/2, and LCP1 proteins. N-acetylcysteine (NAC) treatment antagonized the increase of LCP1 proteins, and LCP1 knockdown partially restored F-actin organization caused by arsenic. Overall, the results demonstrated that ROS-ATM-ERK1/2 signaling pathway was involved in the activation of LCP1, leading to cytoskeleton alterations. These alterations are believed to play a significant role in arsenite-triggered tumor microenvironment cell-acquired malignant phenotype, which could provide potential biomarkers with therapeutic implications for prostate cancer.},
}
@article {pmid38414064,
year = {2024},
author = {Smabers, LP and Wensink, E and Verissimo, CS and Koedoot, E and Pitsa, KC and Huismans, MA and Higuera Barón, C and Doorn, M and Valkenburg-van Iersel, LB and Cirkel, GA and Brousali, A and Overmeer, R and Koopman, M and Braat, MN and Penning de Vries, B and Elias, SG and Vries, RG and Kranenburg, O and Boj, SF and Roodhart, JM},
title = {Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response.},
journal = {Journal of experimental &amp; clinical cancer research : CR},
volume = {43},
number = {1},
pages = {61},
pmid = {38414064},
issn = {1756-9966},
mesh = {Humans ; Irinotecan/pharmacology/therapeutic use ; Oxaliplatin/pharmacology/therapeutic use ; *Colorectal Neoplasms/drug therapy/genetics ; Acetylcysteine/therapeutic use ; Precision Medicine ; Fluorouracil/pharmacology/therapeutic use ; *Colonic Neoplasms/drug therapy ; Organoids ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; },
abstract = {BACKGROUND: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies.<br><br>METHODS: We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness.<br><br>RESULTS: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU &amp; oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU &amp; oxaliplatin was screened in a ratio, and 5-FU &amp; SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n&#x2009;=&#x2009;6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n&#x2009;=&#x2009;10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n&#x2009;=&#x2009;11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9&#x2009;months, p&#x2009;=&#x2009;0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p&#x2009;=&#x2009;0.003).<br><br>CONCLUSIONS: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.},
}
@article {pmid38408632,
year = {2024},
author = {Guan, S and Qu, X and Wang, J and Zhang, D and Lu, J},
title = {3-Monochloropropane-1,2-diol esters induce HepG2 cells necroptosis via CTSB/TFAM/ROS pathway.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {186},
number = {},
pages = {114525},
doi = {10.1016/j.fct.2024.114525},
pmid = {38408632},
issn = {1873-6351},
mesh = {Humans ; *alpha-Chlorohydrin/toxicity/*analogs &amp; derivatives ; Reactive Oxygen Species/metabolism ; Necroptosis ; Esters/toxicity ; Hep G2 Cells ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; },
abstract = {3-monochloropropane-1,2-diol esters (3-MCPDE) are toxic substances that form in food thermal processing and have a diverse range of toxicities. In this study, we found that 3-MCPDE triggered necroptosis by RIPK1/RIPK3/MLKL pathway in HepG2 cells. Previous studies have shown that ROS is an important activator of RIPK1 and RIPK3. The data showed that 3-MCPDE induced excessive ROS production through mitochondrial damage. After treatment with ROS inhibitor N-acetylcysteine (NAC), 3-MCPDE-induced necroptosis was relieved. Further, we explored how 3-MCPDE destroys mitochondria. The data suggested that 3-MCPDE induced mitochondrial dysfunction through the CTSB/TFAM pathway. Overall, the results indicated that 3-MCPDE induced necroptosis through CTSB/TFAM/ROS pathway in HepG2 cells. Our study provided a new mechanism for 3-MCPDE hepatotoxicity.},
}
@article {pmid38408264,
year = {2024},
author = {Doumi, I and Lang, L and Vileno, B and Deponte, M and Faller, P},
title = {Glutathione Protects other Cellular Thiols against Oxidation by Cu[II]-Dp44mT.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {30},
number = {21},
pages = {e202304212},
doi = {10.1002/chem.202304212},
pmid = {38408264},
issn = {1521-3765},
support = {ANR-10-IDEX-0002//Agence Nationale de la Recherche/ ; ITI-CSC-PFA-22//ITI LabEx Chimie des Syst&#xe8;mes Complexes/ ; DE 1431/20-1//Deutsche Forschungsgemeinschaft/ ; },
mesh = {*Copper/metabolism ; Sulfhydryl Compounds ; Oxidation-Reduction ; *Thiosemicarbazones ; Glutathione/metabolism ; Penicillamine/metabolism ; Acetylcysteine/metabolism ; },
abstract = {Cu-thiosemicarbazones have been intensively investigated for their application in cancer therapy or as antimicrobials. Copper(II)-di-2-pyridylketone-4,4-dimethyl-thiosemicarbazone (Cu[II]-Dp44mT) showed anticancer activity in the submicromolar concentration range in cell culture. The interaction of Cu[II]-Dp44mT with thiols leading to their depletion or inhibition was proposed to be involved in this activity. Indeed, Cu[II]-Dp44mT can catalyze the oxidation of thiols although with slow kinetics. The present work aims to obtain insights into the catalytic activity and selectivity of Cu[II]-Dp44mT toward the oxidation of different biologically relevant thiols. Reduced glutathione (GSH), L-cysteine (Cys), N-acetylcysteine (NAC), D-penicillamine (D-Pen), and the two model proteins glutaredoxin (Grx) and thioredoxin (Trx) were investigated. Cu[II]-Dp44mT catalyzed the oxidation of these thiols with different kinetics, with rates in the following order D-Pen>Cys≫NAC>GSH and Trx>Grx. Cu[II]-Dp44mT was more efficient than Cu[II] chloride for the oxidation of NAC and GSH, but not D-Pen and Cys. In mixtures of biologically relevant concentrations of GSH and either Cys, Trx, or Grx, the oxidation kinetics and spectral properties were similar to that of GSH alone, indicating that the interaction of these thiols with Cu[II]-Dp44mT is dominated by GSH. Hence GSH could protect other thiols against potential deleterious oxidation by Cu[II]-Dp44mT.},
}
@article {pmid38407768,
year = {2024},
author = {Jimenez-Chavez, A and Pedroza-Herrera, G and Betancourt-Reyes, I and De Vizcaya Ruiz, A and Masuoka-Ito, D and Zapien, JA and Medina-Ramirez, IE},
title = {Aluminum enhances the oxidative damage of ZnO NMs in the human neuroblastoma SH-SY5Y cell line.},
journal = {Discover nano},
volume = {19},
number = {1},
pages = {36},
pmid = {38407768},
issn = {2731-9229},
support = {Fordecyt-Pronaces/568494/2020 and C-104/2021//CONAHCYT/ ; },
abstract = {Bare and doped zinc oxide nanomaterials (ZnO NMs) are of great interest as multifunctional platforms for biomedical applications. In this study, we systematically investigate the physicochemical properties of Aluminum doped ZnO (AZO) and its bio-interactions with neuroblastoma (SH-SY5Y) and red blood (RBCs) cells. We provide a comprehensive chemical and structural characterization of the NMs. We also evaluated the biocompatibility of AZO NMs using traditional toxicity assays and advanced microscopy techniques. The toxicity of AZO NMs towards SH-SY5Y cells, decreases as a function of Al doping but is higher than the toxicity of ZnO NMs. Our results show that N-acetyl cysteine protects SH-SY5Y cells against reactive oxygen species toxicity induced by AZO NMs. ZnO and AZO NMs do not exert hemolysis in human RBCs at the doses that cause toxicity (IC50) in neuroblastoma cells. The Atomic force microscopy qualitative analysis of the interaction of SH-SY5Y cells with AZO NMs shows evidence that the affinity of the materials with the cells results in morphology changes and diminished interactions between neighboring cells. The holotomographic microscopy analysis demonstrates NMs' internalization in SH-SY5Y cells, changes in their chemical composition, and the role of lipid droplets in the clearance of toxicants.},
}
@article {pmid38405665,
year = {2024},
author = {Abdallah, R and Shaito, AA and Badran, A and Baydoun, S and Sobeh, M and Ouchari, W and Sahri, N and Eid, AH and Mesmar, JE and Baydoun, E},
title = {Fractionation and phytochemical composition of an ethanolic extract of Ziziphus nummularia leaves: antioxidant and anticancerous properties in human triple negative breast cancer cells.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1331843},
pmid = {38405665},
issn = {1663-9812},
abstract = {Natural products have long been utilized in traditional medicine as remedies to improve health and treat illnesses, and have had a key role in modern drug discovery. Recently, there has been a revived interest in the search for bioactives from natural sources as alternative or complementary modalities to synthetic medicines; especially for cancer treatment, which incidence and mortality rates are on the rise worldwide. Ziziphus nummularia has been widely used in traditional medicine for the treatment of various diseases. Its traditional uses and numerous ethnopharmacological properties may be attributed to its richness in bioactive metabolites. However, its phytochemical composition or chemopreventive effects against the aggressive triple-negative breast cancer (TNBC) are still poorly explored. Here, phytochemical composition of an ethanolic extract of Z. nummularia leaves (ZNE) and its chromatographically isolated fractions was identified both qualitatively by spectrophotometric assays and analytically by HPLC-PDA-MS/MS. The anti-proliferative effects of ZNE were tested in several cancer cell lines, but we focused on its anti-TNBC effects since they were not explored yet. The anti-cancerous potential of ZNE and its fractions was tested in vitro in MDA-MB-231, a TNBC cell line. Results showed that ZNE and its Fraction 6 (F6) reduced the viability of MDA-MB-231 cells. F6 decreased MDA-MB-231 viability more than crude ZNE or its other fractions. ZNE and F6 are rich in phytochemicals and HPLC-PDA-MS/MS analysis identified several metabolites that were previously reported to have anti-cancerous effects. Both ZNE and F6 showed potent antioxidant capacity in the DPPH assay, but promoted reactive oxygen species (ROS) production in MDA-MB-231 cells; an effect which was blunted by the antioxidant N-acetyl cysteine (NAC). NAC also blunted ZNE- and F6-induced reduction in TNBC cell viability. We also demonstrated that ZNE and F6 induced an arrest of the cell cycle, and triggered apoptosis- and autophagy-mediated cell death. ZNE and F6 inhibited metastasis-related cellular processes by modifying cell migration, invasion, and adhesion. Taken together, our findings reveal that Z. nummularia is rich in phytochemicals that can attenuate the malignant phenotype of TNBC and may offer innovative avenues for the discovery of new drug leads for treatment of TNBC and other cancers.},
}
@article {pmid38399445,
year = {2024},
author = {Lu, HI and Chen, KL and Yen, CY and Chen, CY and Chien, TM and Shu, CW and Chen, YH and Jeng, JH and Chen, BH and Chang, HW},
title = {Michelia compressa-Derived Santamarine Inhibits Oral Cancer Cell Proliferation via Oxidative Stress-Mediated Apoptosis and DNA Damage.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {2},
pages = {},
pmid = {38399445},
issn = {1424-8247},
support = {MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology/ ; #NSYSUKMU 112-P06//National Sun Yat-sen University-KMU Joint Research Project/ ; 111CM-KMU-05, 112CM-KMU-05//Chimei-KMU jointed project/ ; KMU-DK(A)112008//Kaohsiung Medical University/ ; KMU-TC112A04//Kaohsiung Medical University Research Center/ ; },
abstract = {The anti-oral cancer effects of santamarine (SAMA), a Michelia compressa var. compressa-derived natural product, remain unclear. This study investigates the anticancer effects and acting mechanism of SAMA against oral cancer (OC-2 and HSC-3) in parallel with normal (Smulow-Glickman; S-G) cells. SAMA selectively inhibits oral cancer cell viability more than normal cells, reverted by the oxidative stress remover N-acetylcysteine (NAC). The evidence of oxidative stress generation, such as the induction of reactive oxygen species (ROS) and mitochondrial superoxide and the depletion of mitochondrial membrane potential and glutathione, further supports this ROS-dependent selective antiproliferation. SAMA arrests oral cancer cells at the G2/M phase. SAMA triggers apoptosis (annexin V) in oral cancer cells and activates caspases 3, 8, and 9. SAMA enhances two types of DNA damage in oral cancer cells, such as γH2AX and 8-hydroxy-2-deoxyguanosine. Moreover, all of these anticancer mechanisms of SAMA are more highly expressed in oral cancer cells than in normal cells in concentration and time course experiments. These above changes are attenuated by NAC, suggesting that SAMA exerts mechanisms of selective antiproliferation that depend on oxidative stress while maintaining minimal cytotoxicity to normal cells.},
}
@article {pmid38397782,
year = {2024},
author = {Tuell, D and Ford, G and Los, E and Stone, W},
title = {The Role of Glutathione and Its Precursors in Type 2 Diabetes.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {2},
pages = {},
pmid = {38397782},
issn = {2076-3921},
support = {C06RR0306551/NH/NIH HHS/United States ; },
abstract = {Type 2 diabetes (T2D) is a major worldwide health crisis affecting about 6.2% of the world's population. Alarmingly, about one in five children in the USA have prediabetes. Glutathione (GSH) and its precursors play a promising role in the prevention and management of type T2D. Oxidative stress (OxS) is a probable factor in both T2D initiation and progression. GSH is the major cytosolic water-soluble chemical antioxidant and emerging evidence supports its role in improving T2D outcomes. Dietary supplementation with N-acetyl-cysteine (NAC) and/or glycine (GLY), which are GSH precursors, has also been studied for possible beneficial effects on T2D. This review will focus on the underlying pathophysiological and molecular mechanisms linking GSH and its precursors with T2D and OxS. In addition to their traditional antioxidant roles, the in vivo effects of GSH/NAC/GLY supplements will be evaluated for their potential abilities to modulate the complex pro-oxidant pathophysiological factors (e.g., hyperglycemia) driving T2D progression. Positive feedback loops that amplify OxS over long time intervals are likely to result in irreversible T2D micro- and macro-vascular damage. Most clinical studies with GSH/NAC/GLY have focused on adults or the elderly. Future research with pediatric populations should be a high priority since early intervention is critical.},
}
@article {pmid38397769,
year = {2024},
author = {Khan, S and Wang, T and Cobo, ER and Liang, B and Khan, MA and Xu, M and Qu, W and Gao, J and Barkema, HW and Kastelic, JP and Liu, G and Han, B},
title = {Antioxidative Sirt1 and the Keap1-Nrf2 Signaling Pathway Impair Inflammation and Positively Regulate Autophagy in Murine Mammary Epithelial Cells or Mammary Glands Infected with Streptococcus uberis.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {2},
pages = {},
pmid = {38397769},
issn = {2076-3921},
support = {32172928//National Natural Science Foundation of China/ ; 31772813//National Natural Science Foundation of China/ ; G2022108009L//High-end Foreign Experts Recruitment Program/ ; 2019BBF02027//Ningxia Key Development Programs/ ; 6222031//Beijing Natural Science Foundation/ ; },
abstract = {Streptococcus uberis mastitis in cattle infects mammary epithelial cells. Although oxidative responses often remove intracellular microbes, S. uberis survives, but the mechanisms are not well understood. Herein, we aimed to elucidate antioxidative mechanisms during pathogenesis of S. uberis after isolation from clinical bovine mastitis milk samples. S. uberis's in vitro pathomorphology, oxidative stress biological activities, transcription of antioxidative factors, inflammatory response cytokines, autophagosome and autophagy functions were evaluated, and in vivo S. uberis was injected into the fourth mammary gland nipple of each mouse to assess the infectiousness of S. uberis potential molecular mechanisms. The results showed that infection with S. uberis induced early oxidative stress and increased reactive oxygen species (ROS). However, over time, ROS concentrations decreased due to increased antioxidative activity, including total superoxide dismutase (T-SOD) and malondialdehyde (MDA) enzymes, plus transcription of antioxidative factors (Sirt1, Keap1, Nrf2, HO-1). Treatment with a ROS scavenger (N-acetyl cysteine, NAC) before infection with S. uberis reduced antioxidative responses and the inflammatory response, including the cytokines IL-6 and TNF-α, and the formation of the Atg5-LC3II/LC3I autophagosome. Synthesis of antioxidants determined autophagy functions, with Sirt1/Nrf2 activating autophagy in the presence of S. uberis. This study demonstrated the evasive mechanisms of S. uberis in mastitis, including suppressing inflammatory and ROS defenses by stimulating antioxidative pathways.},
}
@article {pmid38396357,
year = {2024},
author = {Kamel, AA and Nassar, AY and Meligy, FY and Omar, YA and Nassar, GAY and Ezzat, GM},
title = {Acetylated oligopeptide and N-acetylcysteine protect against iron overload-induced dentate gyrus hippocampal degeneration through upregulation of Nestin and Nrf2/HO-1 and downregulation of MMP-9/TIMP-1 and GFAP.},
journal = {Cell biochemistry and function},
volume = {42},
number = {2},
pages = {e3958},
doi = {10.1002/cbf.3958},
pmid = {38396357},
issn = {1099-0844},
mesh = {Animals ; Male ; Rats ; *Acetylcysteine/pharmacology/metabolism ; Caspases/metabolism ; Claudins/genetics ; Dentate Gyrus/metabolism/pathology ; Dextrans/metabolism/pharmacology ; Down-Regulation ; Glutathione/metabolism ; Hippocampus/metabolism/pathology ; Iron/metabolism/pharmacology ; *Iron Overload/complications/drug therapy ; Matrix Metalloproteinase 9/genetics/metabolism/pharmacology ; Nestin/genetics/metabolism/pharmacology ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism/pharmacology ; Up-Regulation ; *Oligopeptides/pharmacology ; Heme Oxygenase-1/drug effects ; Glial Fibrillary Acidic Protein/drug effects/metabolism ; },
abstract = {Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.},
}
@article {pmid38392216,
year = {2024},
author = {Shih, LJ and Hsu, PC and Chuu, CP and Shui, HA and Yeh, CC and Chen, YC and Kao, YH},
title = {Epigallocatechin-3-gallate Synergistically Enhanced Arecoline-Induced Cytotoxicity by Redirecting Cycle Arrest to Apoptosis.},
journal = {Current issues in molecular biology},
volume = {46},
number = {2},
pages = {1516-1529},
pmid = {38392216},
issn = {1467-3045},
support = {MOST106-2320-B-008-008-MY3, MOST109-2320-B-008-001-MY3//National Science and Technology Council/ ; 11001-62-021, TPCH-110-05//Taipei City Hospital; Department of Health, Taipei City Government/ ; TYAFGH-E-111053, TYAFGH-E-112050//Taoyuan Armed Forces General Hospital/ ; MND-MAB-110-025, MND-MAB-C-11107-111026//National Defense Medical Center/ ; },
abstract = {Carcinogens, such as arecoline, play a crucial role in cancer progression and continuous gene mutations by generating reactive oxygen species (ROS). Antioxidants can reduce ROS levels and potentially prevent cancer progression but may paradoxically enhance the survival of cancer cells. This study investigated whether epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, could resolve this paradox. Prostate cancer cells (PC-3 cell line) were cultured and treated with arecoline combined with NAC (N-acetylcysteine) or EGCG; the combined effects on intracellular ROS levels and cell viability were examined using the MTT and DCFDA assays, respectively. In addition, apoptosis, cell cycle, and protein expression were investigated using flow cytometry and western blot analysis. Our results showed that EGCG, similar to NAC (N-acetylcysteine), reduced the intracellular ROS levels, which were elevated by arecoline. Moreover, EGCG not only caused cell cycle arrest but also facilitated cell apoptosis in arecoline-treated cells in a synergistic manner. These were evidenced by elevated levels of cyclin B1 and p27, and increased fragmentation of procaspase-3, PARP, and DNA. Our findings highlight the potential use of EGCG for cancer prevention and therapy.},
}
@article {pmid38390944,
year = {2024},
author = {Alvarez, IA and Lee, M and Eshaq, RS and Leskova, W and Harris, NR},
title = {High Glucose Induces Oxidative Stress That Alters Glycocalyx Proteoglycan Levels in Primary Rat Retinal Microvascular Endothelial Cells and in Isolated Ophthalmic Arteries.},
journal = {Pathophysiology : the official journal of the International Society for Pathophysiology},
volume = {31},
number = {1},
pages = {89-99},
pmid = {38390944},
issn = {1873-149X},
support = {R01 EY025632/EY/NEI NIH HHS/United States ; NEI EY025632/NH/NIH HHS/United States ; },
abstract = {Our purpose in this study was to identify the role played by oxidative stress in the changes to proteoglycans that occur under hyperglycemic conditions, using primary rat retinal microvascular endothelial cells (RRMEC) and cultured ophthalmic arteries. The cells and blood vessels obtained from rats were cultured in normal glucose (5.6 mM) and high glucose (25 mM) with or without N-acetylcysteine (NAC), an antioxidant. Intracellular oxidative stress was determined by measuring dihydroethidium (DHE) fluorescence and malondialdehyde (MDA)-modified protein levels. mRNA and protein levels were evaluated using quantitative real-time polymerase chain reaction and immunoblot, respectively. High glucose increased levels of glypican-1 mRNA and protein. The level of syndecan-1 mRNA also was increased, but its protein level was decreased, by high glucose. Evaluation of DHE and MDA showed that high glucose increased oxidative stress. These changes caused by high glucose were significantly reversed by NAC treatment. Matrix metalloproteinase-9 (MMP-9) levels, which increased under high glucose conditions, were suppressed by NAC treatment. Oxidative stress caused by hyperglycemia may be responsible for significant changes to the ocular endothelial glycocalyx.},
}
@article {pmid38385491,
year = {2025},
author = {Zhao, X and Shan, G and Xing, D and Gao, H and Xiong, Z and Hui, W and Gong, M},
title = {UBE2L3 Suppresses Oxidative Stress-regulated Necroptosis to Accelerate Osteosarcoma Progression.},
journal = {Recent patents on anti-cancer drug discovery},
volume = {20},
number = {1},
pages = {102-112},
pmid = {38385491},
issn = {2212-3970},
mesh = {Humans ; *Osteosarcoma/pathology/genetics/metabolism ; *Oxidative Stress/physiology ; *Necroptosis/physiology ; Cell Line, Tumor ; *Ubiquitin-Conjugating Enzymes/genetics/metabolism ; *Bone Neoplasms/pathology/genetics/metabolism ; Cell Proliferation ; Cell Movement ; Disease Progression ; Cell Survival ; Apoptosis ; },
abstract = {BACKGROUND: Osteosarcoma is a highly invasive bone marrow stromal tumor with limited treatment options. Oxidative stress plays a crucial role in the development and progression of tumors, but the underlying regulatory mechanisms are not fully understood. Recent studies have revealed the significant involvement of UBE2L3 in oxidative stress, but its specific role in osteosarcoma remains poorly investigated.<br><br>OBJECTIVE: This study aimed to explore the molecular mechanisms by which UBE2L3 promotes oxidative stress-regulated necroptosis to accelerate the progression of osteosarcoma using in vitro cell experiments.<br><br>METHODS: Human osteoblast hFOB1.19 cells and various human osteosarcoma cell lines (MG-63, U2OS, SJSA-1, HOS, and 143B) were cultured in vitro. Plasmids silencing UBE2L3 and negative control plasmids were transfected into U2OS and HOS cells. The cells were divided into the following groups: U2OS cell group, HOS cell group, si-NC-U2OS cell group, si-UBE2L3-U2OS cell group, si-NC-HOS cell group, and si-UBE2L3-HOS cell group. Cell viability and proliferation capacity were measured using the Tunnel method and clonogenic assay. Cell migration and invasion abilities were assessed by Transwell and scratch assays. Cell apoptosis was analyzed by flow cytometry, and ROS levels were detected using immunofluorescence. The oxidative stress levels in various cell groups and the expression changes of necroptosis-related proteins were assessed by PCR and WB. Through these experiments, we aim to evaluate the impact of oxidative stress on necroptosis and uncover the specific mechanisms by which targeted regulation of oxidative stress promotes tumor cell necroptosis as a potential therapeutic strategy for osteosarcoma.<br><br>RESULTS: The mRNA expression levels of UBE2L3 in human osteosarcoma cell lines were significantly higher than those in human osteoblast hFOB1.19 cells (p <0.01). UBE2L3 expression was significantly decreased in U2OS and HOS cells transfected with si-UBE2L3, indicating the successful construction of stable cell lines with depleted UBE2L3. Tunnel assay results showed a significant increase in the number of red fluorescent-labeled cells in si-UBE2L3 groups compared to si-NC groups in both cell lines, suggesting a pronounced inhibition of cell viability. Transwell assay demonstrated a significant reduction in invasion and migration capabilities of si-UBE2L3 groups in osteosarcoma cells. The clonogenic assay revealed significant suppression of proliferation and clonogenic ability in both U2OS and HOS cells upon UBE2L3 knockdown. Flow cytometry confirmed that UBE2L3 knockdown significantly enhanced apoptosis in U2OS and HOS cells. Immunofluorescence results showed that UBE2L3 silencing promoted oxidative stress levels in osteosarcoma cells and facilitated tumor cell death. WB analysis indicated a significant increase in phosphorylation levels of necroptosis-related proteins, RIP1, RIP3, and MLKL, in both osteosarcoma cell lines after UBE2L3 knockdown. In addition, the expression of necrosis-associated proteins was inhibited by the addition of the antioxidant N-acetylcysteine (NAC).<br><br>CONCLUSION: UBE2L3 is upregulated in osteosarcoma cells, and silencing of UBE2L3 promotes oxidative stress in these cells, leading to enhanced necroptosis and delayed progression of osteosarcoma.},
}
@article {pmid38381146,
year = {2024},
author = {Rasouli, H and Razavi, BM and Ghasemzadeh Rahbardar, M and Sadeghian, H and Tabatabaee Yazdi, SA and Hosseinzadeh, H},
title = {Hepatoprotective effect of amifostine and WR-1065 on acetaminophen-induced liver toxicity on Wistar rats.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {397},
number = {8},
pages = {6001-6015},
pmid = {38381146},
issn = {1432-1912},
support = {910351//Pharmaceutical Research Center and the Vice-Chancellor of Research, Mashhad University of Medical Sciences/ ; },
mesh = {Animals ; *Acetaminophen/toxicity ; *Amifostine/pharmacology ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/pathology/metabolism/drug therapy ; *Rats, Wistar ; Male ; *Liver/drug effects/metabolism/pathology ; Mercaptoethylamines/pharmacology ; Acetylcysteine/pharmacology ; Rats ; Antioxidants/pharmacology ; Analgesics, Non-Narcotic/toxicity ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Protective Agents/pharmacology/therapeutic use ; },
abstract = {PURPOSE: The most important problem with acetaminophen is its hepatotoxicity. N-acetylcysteine (NAC) is used to treat the hepatotoxicity of acetaminophen. Due to the structural similarities of this compound with amifostine, we decided to test the effect of this substance and its metabolite, WR-1065, on the hepatotoxicity of acetaminophen.<br><br>METHODS: The single-dose method contained 1. Control; 2. Acetaminophen (1 g/kg, gavage); 3-5. Acetaminophen&#x2009;+&#x2009;amifostine (100, 200, 400 mg/kg, i.p.); 6-8. Acetaminophen&#x2009;+&#x2009;WR-1065 (50, 100, 200 mg/kg, i.p.); and 9. Acetaminophen&#x2009;+&#x2009;NAC (100, 200 mg/kg, i.p.). The multiple-dose method included the same groups: amifostine (50, 100, 200 mg/kg), WR-1065 (25, 50, 100 mg/kg), and NAC (100 mg/kg). Then, animals were sacrificed, and blood samples were collected for measuring ALT, AST, ALP, and T-Bil, liver tissue for histopathological examination, MDA, and GSH amounts.<br><br>RESULTS: Acetaminophen increased the levels of MDA, T-Bil, ALT, AST, and ALP, decreased GSH levels, and augmented necrosis, neutrophils, lymphocytes, and macrophages in the port space in single-dose and multiple-dose studies. Amifostine and WR-1065 significantly reduced the levels of MDA, T-Bil, ALT, AST, ALP, increased GSH content, and ameliorated histopathological alterations in a single-dose and multiple-dose method compared to the acetaminophen group. Moreover, NAC caused a significant decrease in the levels of MDA, T-Bil, ALT, AST, and ALP, and reduced GSH amounts in single-dose and multiple-dose studies.<br><br>CONCLUSION: Amifostine and WR-1065 as antioxidant and hepatoprotective compounds are effective in reducing acetaminophen-induced hepatotoxicity with a similar effect to NAC and can be administered as an adjunct in the treatment of acetaminophen overdose.},
}
@article {pmid38379848,
year = {2024},
author = {Lee, KI and Fang, KM and Kuo, CY and Huang, CF and Liu, SH and Liu, JM and Lai, WC and Chang, KC and Su, CC and Chen, YW},
title = {Roles of oxidative stress/JNK/ERK signals in paraquat-triggered hepatic apoptosis.},
journal = {Current research in toxicology},
volume = {6},
number = {},
pages = {100155},
pmid = {38379848},
issn = {2666-027X},
abstract = {Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1-2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome c release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant N-Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway.},
}
@article {pmid38376812,
year = {2024},
author = {Radan, M and Abol Nejadian, F and Bayati, V and Hemmati, AA and Hoseinynejad, K and Mard, SA},
title = {N-acetyl cysteine augments adipose tissue-derived stem cell efficacy on inflammatory markers and regulatory T cell system balance in an allergic asthma model.},
journal = {The Journal of asthma : official journal of the Association for the Care of Asthma},
volume = {61},
number = {9},
pages = {1029-1041},
doi = {10.1080/02770903.2024.2321296},
pmid = {38376812},
issn = {1532-4303},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Asthma/drug therapy/immunology/therapy ; *T-Lymphocytes, Regulatory/immunology/drug effects ; *Rats, Sprague-Dawley ; Rats ; *Adipose Tissue/cytology ; Disease Models, Animal ; Bronchoalveolar Lavage Fluid/cytology/immunology ; Male ; Cytokines/metabolism ; Lung/immunology/pathology ; Immunoglobulin E/blood ; },
abstract = {BACKGROUND: Allergic asthma is a destructive inflammatory process in the respiratory system. The anti-inflammatory and antioxidant effects of N-acetylcysteine (NAC) have been reported in patients with obstructive pulmonary disease. On the other hand, several studies have shown the modulatory effects of mesenchymal stem cells on the immune system and inflammatory responses. Accordingly, the purpose of the current study was to evaluate the effect of administration of adipose tissue-derived stem cells (ADSCs) plus NAC on regulatory T cell system balance in an allergic asthma model.<br><br>METHODS: Eighty Sprague- Dawley rats were randomly divided into the following groups: Control, Plasmalite, Allergic asthma, Allergic asthma&#x2009;+&#x2009;ADSCs, NAC, Allergic asthma&#x2009;+&#x2009;NAC, Allergic asthma&#x2009;+&#x2009;ADSCs&#x2009;+&#x2009;NAC and Allergic asthma&#x2009;+&#x2009;Prednisolone. at the end of the experiment, arterial blood gas analysis, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), inflammatory cytokine concentration, total IgE and specific OVA-IgE levels, gene expression levels of CD4+-T cell subsets, pulmonary indicators, edema, and lung histopathology were evaluated in all groups.<br><br>RESULTS: Administration of NAC plus ADSCs demonstrated a significant decrease in total WBC and eosinophil counts, which was in line with remarkable decrease in IL-17 and TNF-&#x3b1; concentrations and increases in IL-10 level compared with other treated groups. NAC plus ADSC treatment showed significant increases in Treg gene expression, although Th17 and Th2 expression significantly decreased compared with that in prednisolone- treated rats.<br><br>CONCLUSION: The results of the present study documented that the administration of ADSCs plus NAC has an inhibitory effect on the inflammation caused by allergic asthma in a rat model. The improvement of inflammatory indexes was significantly higher than that with prednisolone treatment.},
}
@article {pmid38376368,
year = {2024},
author = {Ghani, H and Podwojniak, A and Tan, IJ and Fliorent, R and Jafferany, M},
title = {From tugs to treatments: a systematic review on pharmacological interventions for trichotillomania.},
journal = {Clinical and experimental dermatology},
volume = {49},
number = {8},
pages = {774-782},
doi = {10.1093/ced/llae052},
pmid = {38376368},
issn = {1365-2230},
mesh = {*Trichotillomania/drug therapy ; Humans ; *Acetylcysteine/therapeutic use ; *Selective Serotonin Reuptake Inhibitors/therapeutic use ; Aripiprazole/therapeutic use ; Behavior Therapy/methods ; },
abstract = {BACKGROUND: Trichotillomania (TTM) is a psychiatric disorder with dermatological consequences, characterized by recurrent hair pulling. It affects 1-3% of the population, and often coexists with other psychiatric disorders, leading to emotional distress. Effective management of TTM can be challenging because of underdiagnosis, symptom heterogeneity and stigma. Pharmacological interventions, including selective serotonin reuptake inhibitors and N-acetyl cysteine (NAC) are commonly used.<br><br>OBJECTIVES: To assess the existing literature on pharmacotherapy for TTM and identify potential avenues for future research and treatment advancements.<br><br>METHODS: A systematic review of the literature was performed using PubMed and Scopus databases within the past 10 years (PROSPERO: CRD42023454009). Included studies assessed pharmacotherapy for TTM and provided insights into current evidence and potential directions for future research and treatment advancements.<br><br>RESULTS: In total, 23 articles were identified that met inclusion criteria. The most successful interventions were NAC, aripiprazole and monoamine oxidase inhibitors. NAC was identified as the most impressive adjunctive therapy to selective serotonin reuptake inhibitors and behavioural therapies in treatment through its mechanism of decreased glutamate-induced excitatory neuronal damage, with adjunctive antioxidant properties. Most of the other therapeutics that were identified require further research and controlled trials to validate their findings.<br><br>CONCLUSIONS: Even if successful therapeutic outcomes are achieved, it is important to consider the patient's comorbidities and to combine pharmacological interventions with behavioural therapy interventions to comprehensively manage TTM.},
}
@article {pmid38373369,
year = {2024},
author = {Yuce, M and Yildirim, E and Ekinci, M and Turan, M and Ilhan, E and Aydin, M and Agar, G and Ucar, S},
title = {N-acetyl-cysteine mitigates arsenic stress in lettuce: Molecular, biochemical, and physiological perspective.},
journal = {Plant physiology and biochemistry : PPB},
volume = {207},
number = {},
pages = {108390},
doi = {10.1016/j.plaphy.2024.108390},
pmid = {38373369},
issn = {1873-2690},
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Arsenic/toxicity ; Lactuca ; Hydrogen Peroxide/metabolism ; Antioxidants/metabolism ; Soil ; },
abstract = {Agricultural land contaminated with heavy metals such as non-biodegradable arsenic (As) has become a serious global problem as it adversely affects agricultural productivity, food security and human health. Therefore, in this study, we investigated how the administration of N-acetyl-cysteine (NAC), regulates the physio-biochemical and gene expression level to reduce As toxicity in lettuce. According to our results, different NAC levels (125, 250 and 500 μM) significantly alleviated the growth inhibition and toxicity induced by As stress (20 mg/L). Shoot fresh weight, root fresh weight, shoot dry weight and root dry weight (33.05%, 55.34%, 17.97% and 46.20%, respectively) were decreased in plants grown in As-contaminated soils compared to lettuce plants grown in soils without the addition of As. However, NAC applications together with As stress increased these growth parameters. While the highest increase in shoot fresh and dry weight (58.31% and 37.85%, respectively) was observed in 250 μM NAC application, the highest increase in root fresh and dry weight (75.97% and 63.07%, respectively) was observed in 125 μM NAC application in plants grown in As-polluted soils. NAC application decreased the amount of ROS, MDA and H2O2 that increased with As stress, and decreased oxidative damage by regulating hormone levels, antioxidant and enzymes involved in nitrogen metabolism. According to gene expression profiles, LsHIPP28 and LsABC3 genes have shown important roles in reducing As toxicity in leaves. This study will provide insight for future studies on how NAC applications develop resistance to As stress in lettuce.},
}
@article {pmid38369618,
year = {2024},
author = {Sun, C and Zhang, M and Guan, C and Li, W and Peng, Y and Zheng, J},
title = {In vitro and in vivo metabolic activation and hepatotoxicity of chlorzoxazone mediated by CYP3A.},
journal = {Archives of toxicology},
volume = {98},
number = {4},
pages = {1095-1110},
pmid = {38369618},
issn = {1432-0738},
mesh = {Humans ; Rats ; Animals ; *Chlorzoxazone ; Cytochrome P-450 CYP3A/metabolism ; Activation, Metabolic ; Rats, Sprague-Dawley ; Microsomes, Liver/metabolism ; *Chemical and Drug Induced Liver Injury/etiology/metabolism ; Epoxy Compounds/metabolism ; Glutathione/metabolism ; },
abstract = {Chlorzoxazone (CZX), a benzoxazolone derivative, has been approved for the treatment of musculoskeletal disorders to relieve localized muscle spasm. However, its idiosyncratic toxicity reported in patients brought attention, particularly for hepatotoxicity. The present study for the first time aimed at the relationship between CZX-induced hepatotoxicity and identification of oxirane intermediate resulting from metabolic activation of CZX. Two N-acetylcysteine (NAC) conjugates (namely M1 and M2) and two glutathione (GSH) conjugates (namely M3 and M4) were detected in rat &amp; human microsomal incubations with CZX (200 μM) fortified with NAC or GSH, respectively. The formation of M1-M4 was NADPH-dependent and these metabolites were also observed in urine or bile of SD rats given CZX intragastrically at 10 mg/kg or 25 mg/kg. NAC was found to attach at C-6' of the benzo group of M1 by sufficient NMR data. CYPs3A4 and 3A5 dominated the metabolic activation of CZX. The two GSH conjugates were also observed in cultured rat primary hepatocytes after exposure to CZX. Inhibition of CYP3A attenuated the susceptibility of hepatocytes to the cytotoxicity of CZX (10-400 μM). The in vitro and in vivo studies provided solid evidence for the formation of oxirane intermediate of CZX. This would facilitate the understanding of the underlying mechanisms of toxic action of CZX.},
}
@article {pmid38369538,
year = {2024},
author = {Wu, T and Liu, W and Chen, H and Hou, L and Ren, W and Zhang, L and Hu, J and Chen, H and Chen, C},
title = {Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {4008},
pmid = {38369538},
issn = {2045-2322},
support = {2023M731448//China Postdoctoral Science Foundation/ ; 2023M731011//China Postdoctoral Science Foundation/ ; 82203878//National Science Foundation of China/ ; U2102203//National Science Foundation of China/ ; 2023J01385//the Natural Science Foundation of Fujian Province/ ; 2020YFA0112300//National Key R&amp;D Program of China/ ; 202302AA310046//Biomedical Projects of Yunnan Key Science and Technology Program/ ; 202101AS070050//Yunnan Fundamental Research Projects/ ; YSZJGZZ-2020025//Yunnan (Kunming) Academician Expert Workstation/ ; },
mesh = {Humans ; *Triple Negative Breast Neoplasms/genetics ; Reactive Oxygen Species/metabolism ; Cell Proliferation ; Cell Line, Tumor ; Apoptosis ; DNA Damage ; *Pyrimidinones ; *Triazines ; },
abstract = {Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.},
}
@article {pmid38363806,
year = {2024},
author = {Wu, T and Zhang, H and Zhang, P and James, TD and Sun, X},
title = {A Rationally Designed Prodrug for the Fluorogenic Labeling of Albumin and Theranostic Effects on Drug-Induced Liver Injury.},
journal = {Analytical chemistry},
volume = {96},
number = {8},
pages = {3498-3507},
doi = {10.1021/acs.analchem.3c05272},
pmid = {38363806},
issn = {1520-6882},
mesh = {Humans ; Antioxidants/pharmacology ; *Prodrugs/pharmacology/chemistry ; Precision Medicine ; Serum Albumin/chemistry ; Acetylcysteine ; Serum Albumin, Human ; *Chemical and Drug Induced Liver Injury ; },
abstract = {The development of small-molecular fluorogenic tools for the chemo-selective labeling of proteins in live cells is important for the evaluation of intracellular redox homeostasis. Dynamic imaging of human serum albumin (HSA), an antioxidant protein under oxidative stress with concomitant release of antioxidant drugs to maintain redox homeostasis, affords potential opportunities for disease diagnosis and treatment. In this work, we developed a nonfluorogenic prodrug named TPA-NAC, by introducing N-acetyl-l-cysteine (NAC) into a conjugated acceptor skeleton. Through combined thiol and amino addition, coupling with HSA results in fluorescence turn-on and drug release. It was reasoned that the restricted intramolecular motion of the probe under an HSA microenvironment after covalent bonding inhibited the nonradiative transitions. Furthermore, the biocompatibility and photochemical properties of TPA-NAC enabled it to image exogenous and endogenous HSA in living cells in a wash-free manner. Additionally, the released drug evoked upregulation of superoxide dismutase (SOD), which synergistically eliminated reactive oxygen species in a drug-induced liver injury model. This study provides insights into the design of new theranostic fluorescent prodrugs for chemo-selective protein labeling and disease treatments.},
}
@article {pmid38363133,
year = {2024},
author = {Guzman, RM and Savolainen, NG and Hayden, OM and Lee, M and Osbron, CA and Liu, Z and Yang, H and Shaw, DK and Omsland, A and Goodman, AG},
title = {Drosophila melanogaster Sting mediates Coxiella burnetii infection by reducing accumulation of reactive oxygen species.},
journal = {Infection and immunity},
volume = {92},
number = {3},
pages = {e0056022},
pmid = {38363133},
issn = {1098-5522},
support = {R01 AI139051/AI/NIAID NIH HHS/United States ; R01 AI162819/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; *Coxiella burnetii ; Drosophila melanogaster/genetics/metabolism ; NF-kappa B/metabolism ; *Q Fever/microbiology ; Reactive Oxygen Species/metabolism ; Drosophila Proteins ; STING Protein ; },
abstract = {The Gram-negative bacterium Coxiella burnetii is the causative agent of query fever in humans and coxiellosis in livestock. C. burnetii infects a variety of cell types, tissues, and animal species including mammals and arthropods, but there is much left to be understood about the molecular mechanisms at play during infection in distinct species. Human stimulator of interferon genes (STING) induces an innate immune response through the induction of type I interferons (IFNs), and IFN promotes or suppresses C. burnetii replication, depending on tissue type. Drosophila melanogaster contains a functional STING ortholog (Sting) which activates NF-κB signaling and autophagy. Here, we sought to address the role of D. melanogaster Sting during C. burnetii infection to uncover how Sting regulates C. burnetii infection in flies. We show that Sting-null flies exhibit higher mortality and reduced induction of antimicrobial peptides following C. burnetii infection compared to control flies. Additionally, Sting-null flies induce lower levels of oxidative stress genes during infection, but the provision of N-acetyl-cysteine (NAC) in food rescues Sting-null host survival. Lastly, we find that reactive oxygen species levels during C. burnetii infection are higher in Drosophila S2 cells knocked down for Sting compared to control cells. Our results show that at the host level, NAC provides protection against C. burnetii infection in the absence of Sting, thus establishing a role for Sting in protection against oxidative stress during C. burnetii infection.},
}
@article {pmid38361325,
year = {2024},
author = {Angeli, SI and Brown, CS and Holcomb, MA and Velandia, SL and Eshraghi, AA and Chiossone-Kerdel, JA and Hoffer, ME and Sanchez, C and Telischi, FF},
title = {Functional Hearing Preservation in Cochlear Implantation: The Miami Cocktail Effect.},
journal = {Otology &amp; neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology},
volume = {45},
number = {4},
pages = {376-385},
doi = {10.1097/MAO.0000000000004134},
pmid = {38361325},
issn = {1537-4505},
mesh = {Adult ; Humans ; Child ; *Cochlear Implantation/methods ; Case-Control Studies ; Prednisone ; Acetylcysteine ; Retrospective Studies ; Auditory Threshold ; Audiometry, Pure-Tone ; Hearing ; *Cochlear Implants ; Treatment Outcome ; },
abstract = {OBJECTIVE: To investigate if pharmacological treatment with prednisone and L-N-acetylcysteine (STE + NAC) influence functional hearing preservation in cochlear implant (CI) surgery.<br><br>STUDY DESIGNS: Preimplantation and postimplantation longitudinal case-control study.<br><br>SETTING: Tertiary referral center.<br><br>PATIENTS: Pediatric and adult recipients of CI with preimplantation functional hearing defined as an average of air-conducted thresholds at 125, 250, and 500 Hz (low-frequency pure-tone average [LFPTA]) <80 dB.<br><br>INTERVENTIONS: Preimplantation and postimplantation audiometry. Weight-adjusted oral prednisone and L-N-acetylcysteine starting 2 days before surgery (Miami cocktail). Prednisone was continued for 3 days and L-N-acetylcysteine for 12 days after surgery, respectively. Cochlear implantation with conventional length electrodes.<br><br>MAIN OUTCOME MEASURES: Proportion of patients with LFPTA <80 dB, and LFPTA change at 1-year postimplantation.<br><br>RESULTS: All 61 patients received intratympanic and intravenous dexamethasone intraoperatively, with 41 patients receiving STE + NAC and 20 patients not receiving STE + NAC. At 1-year postimplantation, the proportion of functional hearing preservation was 83% in the STE + NAC group compared with 55% of subjects who did not receive STE + NAC (p = 0.0302). The median LFPTA change for STE + NAC-treated and not treated subjects was 8.33 dB (mean, 13.82 &#xb1; 17.4 dB) and 18.34 dB (mean, 26.5 &#xb1; 23.4 dB), respectively (p = 0.0401, Wilcoxon rank test). Perioperative STE + NAC treatment resulted in 10 dB of LFPTA better hearing than when not receiving this treatment. Better low-frequency preimplantation hearing thresholds were predictive of postimplantation functional hearing. No serious side effects were reported.<br><br>CONCLUSION: Perioperative STE + NAC, "The Miami Cocktail," was safe and superior to intraoperative steroids alone in functional hearing preservation 1-year after cochlear implantation.},
}
@article {pmid38359293,
year = {2024},
author = {Noch, EK and Palma, L and Yim, I and Bullen, N and Barnett, D and Walsh, A and Bhinder, B and Benedetti, E and Krumsiek, J and Gurvitch, J and Khwaja, S and Atlas, D and Elemento, O and Cantley, LC},
title = {Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {121},
number = {8},
pages = {e2317343121},
pmid = {38359293},
issn = {1091-6490},
support = {R35 CA197588/CA/NCI NIH HHS/United States ; S10 RR027699/RR/NCRR NIH HHS/United States ; },
mesh = {Humans ; Mice ; Animals ; Hydrogen Peroxide ; Peroxides ; *Glioblastoma/drug therapy/genetics/metabolism ; Proteomics ; Acetylcysteine/pharmacology ; Glucose ; Cell Line, Tumor ; *Brain Neoplasms/drug therapy/genetics ; },
abstract = {Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.},
}
@article {pmid38357896,
year = {2024},
author = {Mestre-Bach, G and Potenza, MN},
title = {Pharmacological management of gambling disorder: an update of the literature.},
journal = {Expert review of neurotherapeutics},
volume = {24},
number = {4},
pages = {391-407},
doi = {10.1080/14737175.2024.2316833},
pmid = {38357896},
issn = {1744-8360},
mesh = {Humans ; *Gambling/drug therapy ; Naltrexone/therapeutic use ; *Behavior, Addictive/drug therapy/psychology ; Narcotic Antagonists/therapeutic use ; Selective Serotonin Reuptake Inhibitors ; },
abstract = {INTRODUCTION: Gambling disorder (GD) is a mental health condition characterized by persistent and problematic betting behavior. GD generates distress and impairment, and treatment options include psychological and pharmacological interventions.<br><br>AREAS COVERED: This narrative review explores existing pharmacological treatments for GD. The following classes of medications were considered: opioid-receptor antagonists (e.g. naltrexone and nalmefene), serotonin reuptake inhibitors (e.g. fluvoxamine, paroxetine, sertraline, escitalopram, and citalopram), glutamatergic agents (e.g. N-acetylcysteine (NAC), acamprosate, and memantine), mood stabilizers (e.g. topiramate, carbamazepine, lithium), and other medications (e.g. modafinil, nefazodone, olanzapine, haloperidol, tolcapone, and bupropion).<br><br>EXPERT OPINION: Due to the limitations of the studies reviewed, solid conclusions regarding the optimal choice of pharmacotherapy for individuals with GD are challenging to draw at this time. Despite some medications, such as naltrexone and nalmefene, showing promising results, efficacy has varied across studies. The review highlights current gaps/limitations, including small sample sizes, limited diversity in participant demographics, the need for exploring different gambling subtypes and treatment responses, high placebo response rates, lack of longer-term longitudinal information, limited investigation of neurobiological correlates and co-occurring disorders, and the importance of implementation research. Further research is needed to address these gaps and explore additional medications, as well as interventions like neuromodulation.},
}
@article {pmid38357503,
year = {2024},
author = {Raas, Q and Wood, A and Stevenson, TJ and Swartwood, S and Liu, S and Kannan, RM and Kannan, S and Bonkowsky, JL},
title = {Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model.},
journal = {Frontiers in pediatrics},
volume = {12},
number = {},
pages = {1326886},
pmid = {38357503},
issn = {2296-2360},
abstract = {BACKGROUND: Mitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected patients present with leukodystrophy, seizures, and hearing loss. ACOX1 serves as the rate-limiting enzyme in peroxisomal beta-oxidation of very long-chain fatty acids. The N237S substitution has been shown to stabilize the active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage. Mitchell syndrome lacks a vertebrate model, limiting insights into the pathophysiology of ACOX1-driven white matter damage and neuroinflammatory insults.<br><br>METHODS: We report a patient presenting with rapidly progressive white matter damage and neurological decline, who was eventually diagnosed with an ACOX1 N237S mutation through whole genome sequencing. We developed a zebrafish model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant tagged with GFP. We assayed zebrafish behavior, oligodendrocyte numbers, expression of white matter and inflammatory transcripts, and analysis of peroxisome counts.<br><br>RESULTS: The patient experienced progressive leukodystrophy and died 2 years after presentation. The transgenic zebrafish showed a decreased swimming ability, which was restored with the reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate. The mutants showed no effect on oligodendrocyte counts but did display activation of the integrated stress response (ISR). Using a novel SKL-targeted mCherry reporter, we found that mutants had reduced density of peroxisomes.<br><br>CONCLUSIONS: We developed a vertebrate (zebrafish) model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant. The transgenic mutants exhibited motor impairment and showed signs of activated ISR, but interestingly, there were no changes in oligodendrocyte counts. However, the mutants exhibited a deficiency in the number of peroxisomes, suggesting a possible shared mechanism with the Zellweger spectrum disorders.},
}
@article {pmid38354685,
year = {2024},
author = {Cheng, C and Li, W and Ye, Y and Zhu, Y and Tang, M and Hu, Z and Su, H and Dang, C and Wan, J and Liu, Z and Gong, Y and Yao, LH},
title = {Lactate induces C2C12 myoblasts differentiation by mediating ROS/p38 MAPK signalling pathway.},
journal = {Tissue &amp; cell},
volume = {87},
number = {},
pages = {102324},
doi = {10.1016/j.tice.2024.102324},
pmid = {38354685},
issn = {1532-3072},
mesh = {Reactive Oxygen Species/metabolism ; *Lactic Acid/metabolism/pharmacology ; Cell Differentiation ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Myoblasts/metabolism ; },
abstract = {Lactate serves not merely as an energy substrate for skeletal muscle but also regulates myogenic differentiation, leading to an elevation of reactive oxygen species (ROS) levels. The present study was focused on exploring the effects of lactate and ROS/p38 MAPK in promoting C2C12 myoblasts differentiation. Our results demonstrated that lactate increased C2C12 myoblasts differentiation at a range of physiological concentrations, accompanied by enhanced ROS contents. We used n-acetylcysteine (NAC, a ROS scavenger) pretreatment and found that it delayed lactate-induced C2C12 myoblast differentiation by upregulating Myf5 expression on days 5 and 7 and lowering MyoD and MyoG expression. The finding implies that lactate accompanies ROS-dependent manner to promote C2C12 myoblast differentiation. Additionally, lactate significantly increased p38 MAPK phosphorylation to promote C2C12 cell differentiation, but pretreatment with SB203580 (p38 MAPK inhibitor) reduced lactate-induced C2C12 myoblasts differentiation. whereas lactate pretreatment with NAC inhibited p38 MAPK phosphorylation in C2C12 cells, demonstrating that lactate mediated ROS and regulated the p38 MAPK signalling pathway to promote C2C12 cell differentiation. In conclusion, our results suggest that the promotion of C2C12 myoblasts differentiation by lactate is dependent on ROS and the p38 MAPK signalling pathway. These observations reveal a beneficial role for lactate in increasing myogenesis through ROS-sensitive mechanisms as well as providing new ideas regarding the positive impact of ROS in improving the function of skeletal muscle.},
}
@article {pmid38347533,
year = {2024},
author = {Yang, Y and Wang, L and Huang, Z and Ge, L and Shi, J},
title = {N-acetylcysteine as a novel methacrylate-based resin cement component: effect on cell apoptosis and genotoxicity in human gingival fibroblasts.},
journal = {BMC oral health},
volume = {24},
number = {1},
pages = {222},
pmid = {38347533},
issn = {1472-6831},
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Methacrylates/toxicity ; Resin Cements ; Reactive Oxygen Species ; Apoptosis ; DNA/pharmacology ; Fibroblasts ; Cell Survival ; },
abstract = {BACKGROUND: N-acetylcysteine (NAC) reduces the cytotoxicity and genotoxicity induced by monomers leached from dental composite resins. Herein, we investigated the effects of methacrylate-based resin cement used in dental implant restoration on apoptosis and genotoxicity, as well as the antiapoptotic and antigenotoxic capabilities of its component, NAC.<br><br>METHODS: The antioxidant NAC (0.1 or 1&#x2009;wt.%) was experimentally incorporated into the methacrylate-based dental resin cement Premier&#xae;. The Premier&#xae;&#x2009;+&#x2009;NAC (0.1 or 1&#x2009;wt.%) mixture was subsequently immersed into Dulbecco's modified Eagle's medium for 72&#x2009;h, and used to treat human gingival fibroblasts (HGFs). The viability of HGFs was determined using the XTT assay. The formation of deoxyribonucleic acid (DNA) double-strand breaks (DNA-DSBs) was determined using a &#x3b3;-H2AX assay. Reactive oxygen species (ROS), apoptosis, necrosis, and cell cycles were detected and analyzed using flow cytometry.<br><br>RESULTS: The eluate of Premier&#xae; significantly inhibited HGF proliferation in vitro by promoting a G1-phase cell cycle arrest, resulting in cell apoptosis. Significant ROS production and DNA-DSB induction were also found in HGFs exposed to the eluate. Incorporating NAC (1&#x2009;wt.%) into Premier&#xae; was found to reduce cell cytotoxicity, the percentage of G1-phase cells, cell apoptosis, ROS production, and DNA-DSB induction.<br><br>CONCLUSION: Incorporating NAC (1&#x2009;wt.%) into methacrylate-based resin cement Premier&#xae; decreases the cell cytotoxicity, ROS production, and DNA-DSBs associated with resin use, and further offers protective effects against the early stages of cell apoptosis and G1-phase cell cycle arrest in HGFs. Overall, our in vitro results indicate that the addition of NAC into methacrylate-based resin cements may have clinically beneficial effects on the cytotoxicity and genotoxicity of these materials.},
}
@article {pmid38340270,
year = {2024},
author = {Ali, J and Thompson, M and Mackenzie, C},
title = {Assessing the frequency and types of errors involved in the use of a modified intravenous N-acetylcysteine protocol for acetaminophen overdose.},
journal = {CJEM},
volume = {26},
number = {3},
pages = {174-178},
pmid = {38340270},
issn = {1481-8043},
mesh = {Humans ; Acetylcysteine/therapeutic use ; Acetaminophen/therapeutic use ; Antidotes ; *Drug Overdose/drug therapy/epidemiology ; *Poisons/therapeutic use ; Retrospective Studies ; },
abstract = {BACKGROUND: Acetaminophen overdose is a leading cause of acute liver failure in developing countries. N-acetylcysteine (NAC) is a highly effective antidote for acetaminophen hepatotoxicity, typically initiated in the emergency department. Due to a known high rate of errors with the standard three-bag IV NAC protocol, in 2019, the Ontario Poison Center changed to a modified 3% IV NAC one-bag protocol. This study was undertaken to determine the frequency and types of errors associated with the use of this protocol.<br><br>METHODS: Data were gathered via chart review of Ontario Poison Centre electronic medical record cases identified as receiving IV NAC for acetaminophen overdose between August 1 and September 30, 2022. 218 total charts were identified, and 188 were deemed eligible based on inclusion and exclusion criteria.<br><br>RESULTS: Errors were identified in 25% of charts, consisting of dosing errors in 11.7%, stopping errors in 9.0%, initiation errors in 3.7%, and interruptions in therapy in 3.2%. Dosing errors were the most common type of error (44.4%), with overdoses occurring three times more than underdoses. Errors were identified at 39% of geographic locations in the charts reviewed, with similar frequency in Ontario, Manitoba, and Nunavut. Clinical outcomes were similar in charts with and without errors.<br><br>INTERPRETATION: The rate of errors identified with this 3% IV NAC one-bag protocol is lower than reported for the standard three-bag protocol, but remains high due to dosing errors. Previously reported issues with prolonged interruptions in therapy with the standard three-bag protocol were low with the current 3% one-bag protocol. Although severe outcomes are rare, IV NAC overdose can be fatal. Identifying local factors in emergency departments that can contribute to administration errors (i.e., dose calculation, pump programming issues) can enhance the safety of this important antidote.},
}
@article {pmid38336380,
year = {2024},
author = {Sams, MP and Iansavitchous, J and Astridge, M and Rysan, H and Xu, LS and Rodrigues de Oliveira, B and DeKoter, RP},
title = {N-Acetylcysteine Alters Disease Progression and Increases Janus Kinase Mutation Frequency in a Mouse Model of Precursor B-Cell Acute Lymphoblastic Leukemia.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {389},
number = {1},
pages = {40-50},
doi = {10.1124/jpet.123.002000},
pmid = {38336380},
issn = {1521-0103},
support = {//CIHR/Canada ; },
mesh = {Child ; Humans ; Mice ; Animals ; Child, Preschool ; Acetylcysteine/pharmacology/therapeutic use ; Janus Kinases ; Mutation Rate ; Reactive Oxygen Species/metabolism ; Precursor Cells, B-Lymphoid/metabolism ; *Drinking Water ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Janus Kinase 1/genetics/metabolism ; Mutation ; Janus Kinase 3/genetics/metabolism ; Disease Progression ; },
abstract = {B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was tested for its ability to alter disease progression in a mouse model of B-ALL. Mb1-CreΔPB mice have deletions in genes encoding PU.1 and Spi-B in B cells and develop B-ALL at 100% incidence. Treatment of Mb1-CreΔPB mice with NAC in drinking water significantly reduced the frequency of CD19[+] pre-B-ALL cells infiltrating the thymus at 11 weeks of age. However, treatment with NAC did not reduce leukemia progression or increase survival by a median 16 weeks of age. NAC significantly altered gene expression in leukemias in treated mice. Mice treated with NAC had increased frequencies of activating mutations in genes encoding Janus kinases 1 and 3. In particular, frequencies of Jak3 R653H mutations were increased in mice treated with NAC compared with control drinking water. NAC opposed oxidization of PTEN protein ROS in cultured leukemia cells. These results show that NAC alters leukemia progression in this mouse model, ultimately selecting for leukemias with high Jak3 R653H mutation frequencies. SIGNIFICANCE STATEMENT: In a mouse model of precursor B-cell acute lymphoblastic leukemia associated with high levels of reactive oxygen species, treatment with N-acetylcysteine did not delay disease progression but instead selected for leukemic clones with activating R653H mutations in Janus kinase 3.},
}
@article {pmid38335769,
year = {2024},
author = {Świętek, M and Marková, I and Malínská, H and Hüttl, M and Miklánková, D and Černá, K and Konefał, R and Horák, D},
title = {Tannic acid- and N-acetylcysteine-chitosan-modified magnetic nanoparticles reduce hepatic oxidative stress in prediabetic rats.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {235},
number = {},
pages = {113791},
doi = {10.1016/j.colsurfb.2024.113791},
pmid = {38335769},
issn = {1873-4367},
mesh = {Rats ; Animals ; Antioxidants/pharmacology/metabolism ; Acetylcysteine/pharmacology ; *Chitosan/pharmacology ; *Magnetite Nanoparticles ; *Prediabetic State/metabolism ; Silicon Dioxide/pharmacology ; Glutathione/metabolism ; Rats, Wistar ; Oxidative Stress ; Liver ; Superoxide Dismutase/metabolism ; *Polyphenols ; },
abstract = {Magnetic nanoparticles (MNPs) modified with tannic acid (TA) have shown remarkable success as an antioxidant and antimicrobial therapeutic agent. Herein, we report a synthetic procedure for the preparation of silica-coated MNPs modified with N-acetylcysteine-modified chitosan and TA. This was achieved by free-radical grafting of NAC onto chitosan (CS), a layer-by-layer technique for modifying negatively charged MNP@SiO2 nanoparticles with positively charged CS-NAC, and crosslinking CS with TA. The antioxidant and metabolic effects of MNP@SiO2-CS-NAC and MNP@SiO2-CS-NAC-TA nanoparticles were tested in a model of prediabetic rats with hepatic steatosis, the hereditary hypertriglyceridemic rats (HHTg). The particles exhibited significant antioxidant properties in the liver, increasing the activity of the antioxidant enzymes superoxide dismutase (SOD), glutathione reductase (GR) and glutathione peroxidase (GPx), decreasing the concentration of the lipoperoxidation product malondialdehyde (MDA), and improving the antioxidant status determined as the ratio of reduced to oxidized glutathione; in particular, TA increased some antioxidant parameters. MNPs carrying antioxidants such as NAC and TA could thus represent a promising therapeutic agent for the treatment of various diseases accompanied by increased oxidative stress.},
}
@article {pmid38330258,
year = {2024},
author = {Mao, X and Zhao, G and Wang, Q and He, J and Liu, Y and Liu, T and Li, W and Peng, Y and Zheng, J},
title = {Chelerythrine Chloride is an Affinity-Labeling Inactivator of CYP3A4 by Modification of Cysteine239.},
journal = {Journal of medicinal chemistry},
volume = {67},
number = {4},
pages = {2802-2811},
doi = {10.1021/acs.jmedchem.3c01943},
pmid = {38330258},
issn = {1520-4804},
mesh = {Cytochrome P-450 CYP3A ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; *Alkaloids ; *Antineoplastic Agents ; *Benzophenanthridines ; },
abstract = {Chelerythrine chloride (CHE) is a quaternary benzo[c]phenanthridine alkaloid with an iminium group that was found to cause time- and concentration-dependent inhibition of CYP3A4. The loss of CYP3A4 activity was independent of NADPH. CYP3A4 competitive inhibitor ketoconazole and nucleophile N-acetylcysteine (NAC) slowed the inactivation. No recovery of CYP3A4 activity was observed after dialysis. Dihydrochelerythrine hardly inhibited CYP3A4, suggesting that the iminium group was primarily responsible for the inactivation. UV spectral analysis revealed that the maximal absorbance of CHE produced a significant red-shift after being mixed with NAC, suggesting that 1,2-addition possibly took place between the sulfhydryl group of NAC and iminium group of CHE. Molecular dynamics simulation and site-direct mutagenesis studies demonstrated that modification of Cys239 by the iminium group of CHE attributed to the inactivation. In conclusion, CHE is an affinity-labeling inactivator of CYP3A4. The observed enzyme inactivation resulted from the modification of Cys239 of CYP3A4 by the iminium group of CHE.},
}
@article {pmid38325272,
year = {2024},
author = {Tian, T and Pang, H and Li, X and Ma, K and Liu, T and Li, J and Luo, Z and Li, M and Hou, Q and Hao, H and Dong, J and Du, H and Liu, X and Sun, Z and Zhao, C and Song, X and Jin, M},
title = {The role of DRP1 mediated mitophagy in HT22 cells apoptosis induced by silica nanoparticles.},
journal = {Ecotoxicology and environmental safety},
volume = {272},
number = {},
pages = {116050},
doi = {10.1016/j.ecoenv.2024.116050},
pmid = {38325272},
issn = {1090-2414},
mesh = {Adenosine Triphosphate ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; *Dynamins/metabolism ; *Mitophagy ; *Nanoparticles/toxicity ; Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; *Silicon Dioxide/pharmacology ; Superoxide Dismutase/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Animals ; Mice ; Cell Line, Tumor ; },
abstract = {Silica nanoparticles (SiNPs) are widely used in the biomedical field and can enter the central nervous system through the blood-brain barrier, causing damage to hippocampal neurons. However, the specific mechanism remains unclear. In this experiment, HT22 cells were selected as the experimental model in vitro, and the survival rate of cells under the action of SiNPs was detected by MTT method, reactive oxygen species (ROS), lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and adenosine triphosphate (ATP) were tested by the kit, the ultrastructure of the cells was observed by transmission electron microscope, membrane potential (MMP), calcium ion (Ca[2+]) and apoptosis rate were measured by flow cytometry, and the expressions of mitochondrial functional protein, mitochondrial dynein, mitochondrial autophagy protein as well as apoptosis related protein were detected by Western blot. The results showed that cell survival rate, SOD, CAT, GSH-Px, ATP and MMP gradually decreased with the increase of SiNPs concentration, while intracellular ROS, Ca[2+], LDH and apoptosis rate increased with the increase of SiNPs concentration. In total cellular proteins,the expressions of mitochondrial functional proteins VDAC and UCP2 gradually increased, the expression of mitochondrial dynamic related protein DRP1 increased while the expressions of OPA1 and Mfn2 decreased. The expressions of mitophagy related proteins PINK1, Parkin and LC3Ⅱ/LC3Ⅰ increased and P62 gradually decreased, as well as the expressions of apoptosis related proteins Apaf-1, Cleaved-Caspase-3, Caspase-3, Caspase-9, Bax and Cyt-C. In mitochondrial proteins, the expressions of mitochondrial dynamic related proteins DRP1 and p-DRP1 were increased, while the expressions of OPA1 and Mfn2 were decreased. Expressions of mitochondrial autophagy associated proteins PINK1, Parkin, LC3II/LC3I increased, P62 decreased gradually, as well as the expressions of apoptosis related proteins Cleaved-Caspase-3, Caspase-3, and Caspase-9 increased, and Cyt-C expressions decreased. To further demonstrate the role of ROS and DRP1 in HT22 cell apoptosis induced by SiNPs, we selected the ROS inhibitor N-Acetylcysteine (NAC) and Dynamin-related protein 1 (DRP1) inhibitor Mdivi-1. The experimental results indicated that the above effects were remarkably improved after the use of inhibitors, further confirming that SiNPs induce the production of ROS in cells, activate DRP1, cause excessive mitochondrial division, induce mitophagy, destroy mitochondrial function and eventually lead to apoptosis.},
}
@article {pmid38325270,
year = {2024},
author = {Xiong, A and He, X and Liu, S and Ran, Q and Zhang, L and Wang, J and Jiang, M and Niu, B and Xiong, Y and Li, G},
title = {Oxidative stress-mediated activation of FTO exacerbates impairment of the epithelial barrier by up-regulating IKBKB via N6-methyladenosine-dependent mRNA stability in asthmatic mice exposed to PM2.5.},
journal = {Ecotoxicology and environmental safety},
volume = {272},
number = {},
pages = {116067},
doi = {10.1016/j.ecoenv.2024.116067},
pmid = {38325270},
issn = {1090-2414},
mesh = {Animals ; Mice ; *Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics/metabolism ; *Asthma/chemically induced/genetics ; *I-kappa B Kinase/metabolism ; Obesity ; Oxidative Stress/genetics ; Particulate Matter/toxicity ; RNA Stability ; RNA, Messenger/metabolism ; },
abstract = {In order to comprehend the underlying mechanisms contributing to the development and exacerbation of asthma resulting from exposure to fine particulate matter (PM2.5), we established an asthmatic model in fat mass and obesity-associated gene knockdown mice subjected to PM2.5 exposure. Histological analyses using hematoxylin-eosin (HE) and Periodic Acid-Schiff (PAS) staining revealed that the down-regulation of the fat mass and obesity-associated gene (Fto) expression significantly ameliorated the pathophysiological alterations observed in asthmatic mice exposed to PM2.5. Furthermore, the down-regulation of Fto gene expression effectively attenuated damage to the airway epithelial barrier. Additionally, employing in vivo and in vitro models, we elucidated that PM2.5 modulated FTO expression by inducing oxidative stress. Asthmatic mice exposed to PM2.5 exhibited elevated Fto expression, which correlated with increased levels of reactive oxygen species. Similarly, when cells were exposed to PM2.5, FTO expression was up-regulated in a ROS-dependent manner. Notably, the administration of N-acetyl cysteine successfully reversed the PM2.5-induced elevation in FTO expression. Concurrently, we performed transcriptome-wide Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) analysis subsequent to PM2.5 exposure. Through the implementation of Gene Set Enrichment Analysis and m6A-IP-qPCR, we successfully identified inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB) as a target gene regulated by FTO. Interestingly, exposure to PM2.5 led to increased expression of IKBKB, while m6A modification on IKBKB mRNA was reduced. Furthermore, our investigation revealed that PM2.5 also regulated IKBKB through oxidative stress. Significantly, the down-regulation of IKBKB effectively mitigated epithelial barrier damage in cells exposed to PM2.5 by modulating nuclear factor-kappa B (NF-κB) signaling. Importantly, we discovered that decreased m6A modification on IKBKB mRNA facilitated by FTO enhanced its stability, consequently resulting in up-regulation of IKBKB expression. Collectively, our findings propose a novel role for FTO in the regulation of IKBKB through m6A-dependent mRNA stability in the context of PM2.5-induced oxidative stress. Therefore, it is conceivable that the utilization of antioxidants or inhibition of FTO could represent potential therapeutic strategies for the management of asthma exacerbated by PM2.5 exposure.},
}
@article {pmid38323079,
year = {2024},
author = {Hashmi, HZ and Khowaja, A and Moheet, A},
title = {Experimental pharmacological approaches to reverse impaired awareness of hypoglycemia-a review.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1349004},
pmid = {38323079},
issn = {1663-9812},
abstract = {The colossal global burden of diabetes management is compounded by the serious complication of hypoglycemia. Protective physiologic hormonal and neurogenic counterregulatory responses to hypoglycemia are essential to preserve glucose homeostasis and avert serious morbidity. With recurrent exposure to hypoglycemic episodes over time, these counterregulatory responses to hypoglycemia can diminish, resulting in an impaired awareness of hypoglycemia (IAH). IAH is characterized by sudden neuroglycopenia rather than preceding cautionary autonomic symptoms. IAH increases the risk of subsequent sudden and severe hypoglycemic episodes in patients with diabetes. The postulated causative mechanisms behind IAH are complex and varied. It is therefore challenging to identify a single effective therapeutic strategy. In this review, we closely examine the efficacy and feasibility of a myriad of pharmaceutical interventions in preventing and treating IAH as described in clinical and preclinical studies. Pharmaceutical agents outlined include N-acetyl cysteine, GABA A receptor blockers, opioid receptor antagonists, AMP activated protein kinase agonists, potassium channel openers, dehydroepiandrosterone, metoclopramide, antiadrenergic agents, antidiabetic agents and glucagon.},
}
@article {pmid38318818,
year = {2024},
author = {Liu, J and Li, SM and Tang, YJ and Cao, JL and Hou, WS and Wang, AQ and Wang, C and Jin, CH},
title = {Jaceosidin induces apoptosis and inhibits migration in AGS gastric cancer cells by regulating ROS-mediated signaling pathways.},
journal = {Redox report : communications in free radical research},
volume = {29},
number = {1},
pages = {2313366},
pmid = {38318818},
issn = {1743-2928},
mesh = {Humans ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Flavonoids/pharmacology ; Glycogen Synthase Kinase 3 beta/metabolism/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; *Stomach Neoplasms/drug therapy/metabolism/pathology ; },
abstract = {Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways. Furthermore, JAC accumulated ROS to up-regulate p-JNK, p-p38, and IκB-α protein expressions and down-regulate the p-ERK, p-STAT3, and NF-κB protein expressions. Cell cycle assay results showed that JAC accumulated ROS to up-regulate p21 and p27 protein expressions and down-regulate p-AKT, CDK2, CDK4, CDK6, Cyclin D1, and Cyclin E protein expressions to induce G0/G1 phase arrest. Cell migration assay results showed JAC accumulated ROS to down-regulate Wnt-3a, p-GSK-3β, N-cadherin, and β-catenin protein expressions and up-regulate E-cadherin protein expression to inhibit migration. Furthermore, N-acetyl cysteine pre-treatment prevented the change of these protein expressions. In summary, JAC induced apoptosis and G0/G1 phase arrest and inhibited migration through ROS-mediated signaling pathways in AGS cells.},
}
@article {pmid38318025,
year = {2024},
author = {Liu, TH and Wu, JY and Huang, PY and Tsai, YW and Hsu, WH and Chuang, MH and Tang, HJ and Lai, CC},
title = {Clinical efficacy of N-acetylcysteine for COVID-19: A systematic review and meta-analysis of randomized controlled trials.},
journal = {Heliyon},
volume = {10},
number = {3},
pages = {e25179},
pmid = {38318025},
issn = {2405-8440},
abstract = {BACKGROUND: The association between N-acetylcysteine (NAC) and COVID-19 remains undetermined; therefore, this meta-analysis assessed the clinical efficacy of NAC in the treatment of patients with COVID-19.<br><br>METHODS: This study searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for studies published from their inception to December 17, 2022. Only randomized controlled trials (RCTs) that assessed the clinical efficacy of NAC for patients with COVID-19 were included.<br><br>RESULTS: Five RCTs involving 651 patients were included. There was no significant difference in mortality between the study group receiving NAC and the control group (15.6&#xa0;% [50/320] vs. 32.3&#xa0;%, [107/331]; risk ratio [RR]: 0.58; 95&#xa0;% confidence interval [CI]: 0.24-1.40). In addition, the two groups did not differ with respect to the incidence of invasive mechanical ventilation (RR: 0.93; 95&#xa0;% CI: 0.65-1.33), the risk of intensive care unit (ICU) admission (RR: 0.86; 95&#xa0;% CI: 0.62-1.21), the length of hospital stay (mean difference [MD]: 0.17 days; 95&#xa0;% CI: -0.67-1.01), and the length of ICU stay (MD: -0.77 days; 95&#xa0;% CI: -2.97-1.42).<br><br>CONCLUSIONS: The administration of NAC did not improve the clinical outcomes of patients with COVID-19; its routine use is not recommended for patients with SARS-CoV-2 infections.},
}
@article {pmid38317753,
year = {2024},
author = {Jerome, RN and Zahn, LA and Abner, JJ and Joly, MM and Shirey-Rice, JK and Wallis, RS and Bernard, GR and Pulley, JM},
title = {Repurposing N-acetylcysteine for management of non-acetaminophen induced acute liver failure: an evidence scan from a global health perspective.},
journal = {Translational gastroenterology and hepatology},
volume = {9},
number = {},
pages = {2},
pmid = {38317753},
issn = {2415-1289},
support = {UL1 TR002243/TR/NCATS NIH HHS/United States ; },
abstract = {BACKGROUND: The World Health Organization (WHO)'s Essential Medicines List (EML) plays an important role in advocating for access to key treatments for conditions affecting people in all geographic settings. We applied our established drug repurposing methods to one EML agent, N-acetylcysteine (NAC), to identify additional uses of relevance to the global health community beyond its existing EML indication (acetaminophen toxicity).<br><br>METHODS: We undertook a phenome-wide association study (PheWAS) of a variant in the glutathione synthetase (GSS) gene in approximately 35,000 patients to explore novel indications for use of NAC, which targets glutathione. We then evaluated the evidence regarding biologic plausibility, efficacy, and safety of NAC use in the new phenotype candidates.<br><br>RESULTS: PheWAS of GSS variant R418Q revealed increased risk of several phenotypes related to non-acetaminophen induced acute liver failure (ALF), indicating that NAC may represent a therapeutic option for treating this condition. Evidence review identified practice guidelines, systematic reviews, clinical trials, retrospective cohorts and case series, and case reports. This evidence suggesting benefit of NAC use in this subset of ALF patients. The safety profile of NAC in this literature was also concordant with existing evidence on safety of this agent in acetaminophen-induced ALF.<br><br>CONCLUSIONS: This body of literature indicates efficacy and safety of NAC in non-acetaminophen induced ALF. Given the presence of NAC on the EML, this medication is likely to be available across a range of resource settings; promulgating its use in this novel subset of ALF can provide healthcare professionals and patients with a valuable and safe complement to supportive care for this disease.},
}
@article {pmid38315254,
year = {2024},
author = {Rodrigues, JP and da Costa Silva, JR and Ferreira, BA and Veloso, LI and Quirino, LS and Rosa, RR and Barbosa, MC and Rodrigues, CM and Gaspari, PBF and Beletti, ME and Goulart, LR and Corrêa, NCR},
title = {Development of collagenous scaffolds for wound healing: characterization and in vivo analysis.},
journal = {Journal of materials science. Materials in medicine},
volume = {35},
number = {1},
pages = {12},
pmid = {38315254},
issn = {1573-4838},
mesh = {Animals ; Mice ; *Acetylcysteine ; *Anti-Infective Agents/pharmacology ; Biocompatible Materials/chemistry ; *Chitosan/chemistry ; Collagen/chemistry ; Tissue Scaffolds/chemistry ; Wound Healing ; Polylysine/chemistry ; },
abstract = {The development of wound dressings from biomaterials has been the subject of research due to their unique structural and functional characteristics. Proteins from animal origin, such as collagen and chitosan, act as promising materials for applications in injuries and chronic wounds, functioning as a repairing agent. This study aims to evaluate in vitro effects of scaffolds with different formulations containing bioactive compounds such as collagen, chitosan, N-acetylcysteine (NAC) and ε-poly-lysine (ε-PL). We manufactured a scaffold made of a collagen hydrogel bioconjugated with chitosan by crosslinking and addition of NAC and ε-PL. Cell viability was verified by resazurin and live/dead assays and the ultrastructure of biomaterials was evaluated by SEM. Antimicrobial sensitivity was assessed by antibiogram. The healing potential of the biomaterial was evaluated in vivo, in a model of healing of excisional wounds in mice. On the 7th day after the injury, the wounds and surrounding skin were processed for evaluation of biochemical and histological parameters associated with the inflammatory process. The results showed great cell viability and increase in porosity after crosslinking while antimicrobial action was observed in scaffolds containing NAC and ε-PL. Chitosan scaffolds bioconjugated with NAC/ε-PL showed improvement in tissue healing, with reduced lesion size and reduced inflammation. It is concluded that scaffolds crosslinked with chitosan-NAC-ε-PL have the desirable characteristics for tissue repair at low cost and could be considered promising biomaterials in the practice of regenerative medicine.},
}
@article {pmid38314899,
year = {2024},
author = {Li, L and Chen, D and Lin, X and Luo, J and Tan, J and Ding, D and Li, P},
title = {Antioxidative Stress-Induced Destruction to Cochlear Cells Caused by Blind Antioxidant Therapy.},
journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery},
volume = {170},
number = {5},
pages = {1421-1429},
doi = {10.1002/ohn.659},
pmid = {38314899},
issn = {1097-6817},
mesh = {*Antioxidants/pharmacology ; *Acetylcysteine/pharmacology ; *Ubiquinone/*analogs &amp; derivatives/pharmacology/therapeutic use ; *Cell Survival/drug effects ; Animals ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; Mice ; Cochlea/drug effects/pathology ; Hair Cells, Auditory/drug effects/pathology ; Cell Count ; *Oligopeptides ; },
abstract = {OBJECTIVE: Verification that blind and excessive use of antioxidants leads to antioxidant stress which exacerbates cochlear cell damage.<br><br>STUDY DESIGN: Basic research.<br><br>SETTING: The Third Affiliated Hospital of Sun Yat-Sen University.<br><br>METHODS: We compared and quantified hair cell-like house ear institute-organ of corti 1 (HEI-OC1) cell density, cell viability, and apoptosis caused by different concentrations of N-acetylcysteine&#xa0;(NAC) via Hoechst staining, Cell Counting Kit 8, Hoechst with propidium iodide staining, and Annexin V with propidium iodide (PI) staining. Apoptosis induced by high concentrations of M40403 and coenzyme Q10 in cochlear explants was analyzed and compared by cochlear dissection and activated caspase 3 labeling.<br><br>RESULTS: With the increase of NAC concentration (0-1000&#x2009;&#x3bc;mol/L), cell density decreased consequently and reached the lowest at 1000&#x2009;&#x3bc;mol/L (****P&#x2009;&#x2264;&#x2009;.0001). Cell viability is also declining (**P&#x2009;<&#x2009;.01). The number of Annexin V-fluorescein isothiocyanate-labeled cells and PI-labeled cells increased with increasing NAC concentration after treatment of HEI-OC1 cells for 48&#x2009;hours. The proportion of apoptotic cells also rose (*P&#x2009;<&#x2009;.05, **P&#x2009;<&#x2009;.01). Cochlear hair cells (HCs) treated with low concentrations of M40403 and coenzyme Q10 for 48&#x2009;hours showed no damage. When the concentrations of M40403 and coenzyme Q10 were increased (concentrations&#xff1e;30&#x2009;&#x3bc;mol/L), HC damage began, followed by a dose-dependent increase in HC loss (*P&#x2009;<&#x2009;.001, **P&#x2009;<&#x2009;.0001). Activated caspase-3 was clearly apparent in cochlear explants treated with 50&#x2009;&#x3bc;mol/L M40403 and coenzyme Q10 compared with cochlear explants without added M40403 and coenzyme Q10.<br><br>CONCLUSION: These experimental results suggest that inappropriate application of antioxidants can cause severe damage to normal cochlear HCs.},
}
@article {pmid38309383,
year = {2024},
author = {La Sala, L and Carlini, V and Conte, C and Macas-Granizo, MB and Afzalpour, E and Martin-Delgado, J and D'Anzeo, M and Pedretti, RFE and Naselli, A and Pontiroli, AE and Cappato, R},
title = {Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?.},
journal = {Pharmacological research},
volume = {201},
number = {},
pages = {107083},
doi = {10.1016/j.phrs.2024.107083},
pmid = {38309383},
issn = {1096-1186},
mesh = {Humans ; *MicroRNAs/genetics/therapeutic use ; *Non-alcoholic Fatty Liver Disease/drug therapy/genetics ; *Diabetes Mellitus, Type 2/drug therapy/genetics ; *Metabolic Diseases/drug therapy/genetics ; *Heart Diseases ; Oligonucleotides, Antisense/therapeutic use ; },
abstract = {Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.},
}
@article {pmid38305139,
year = {2024},
author = {Frasson, I and Diamante, L and Zangrossi, M and Carbognin, E and Pietà, AD and Penna, A and Rosato, A and Verin, R and Torrigiani, F and Salata, C and Dizanzo, MP and Vaccaro, L and Cacchiarelli, D and Richter, SN and Montagner, M and Martello, G},
title = {Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern.},
journal = {Journal of molecular cell biology},
volume = {16},
number = {3},
pages = {},
pmid = {38305139},
issn = {1759-4685},
support = {PRIN-2020KSY3KL//Ministry of Education, University and Research/ ; RCR-2019 23669115//Italian Ministry of Health/ ; PO-FESR 2014-2020/ERC_/European Research Council/International ; 871029//European Union's Horizon 2020 Research and Innovation Programme/ ; OPP1035881//Bill and Melinda Gates Foundation/ ; TCP13013//Telethon Foundation/ ; NewTarCoV2//CaRiPaRo Foundation/ ; 615879//ERC/ ; },
mesh = {*SARS-CoV-2/genetics/drug effects/physiology/metabolism ; Humans ; Animals ; *Virus Replication/drug effects ; *COVID-19/virology ; *Antiviral Agents/pharmacology ; Mice ; COVID-19 Drug Treatment ; Reactive Oxygen Species/metabolism ; Chlorocebus aethiops ; Acetylcysteine/pharmacology ; Vero Cells ; Host-Pathogen Interactions/genetics/drug effects ; Drug Repositioning ; Mutation/genetics ; },
abstract = {The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants, some of which are resistant to vaccines and drugs targeting viral elements. Targeting host dependency factors, e.g. cellular proteins required for viral replication, would help prevent the development of resistance. However, it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors. To this end, we compared three variants of concern and found that the host transcriptional response was conserved, differing only in kinetics and magnitude. Clustered regularly interspaced short palindromic repeats screening identified host genes required for each variant during infection. Most of the genes were shared by multiple variants. We validated our hits with small molecules and repurposed the US Food and Drug Administration-approved drugs. All the drugs were highly active against all the tested variants, including new variants that emerged during the study (Delta and Omicron). Mechanistically, we identified reactive oxygen species production as a key step in early viral replication. Antioxidants such as N-acetyl cysteine (NAC) were effective against all the variants in both human lung cells and a humanized mouse model. Our study supports the use of available antioxidant drugs, such as NAC, as a general and effective anti-COVID-19 approach.},
}
@article {pmid38304461,
year = {2023},
author = {Balmuri, SR and Noaman, S and Usman, H and Niepa, THR},
title = {Altering the interfacial rheology of Pseudomonas aeruginosa and Staphylococcus aureus with N-acetyl cysteine and cysteamine.},
journal = {Frontiers in cellular and infection microbiology},
volume = {13},
number = {},
pages = {1338477},
pmid = {38304461},
issn = {2235-2988},
mesh = {Humans ; Acetylcysteine/pharmacology/metabolism ; *Cystic Fibrosis/complications/microbiology ; Staphylococcus aureus ; Pseudomonas aeruginosa ; Cysteamine/pharmacology/metabolism ; *Staphylococcal Infections/microbiology ; Anti-Bacterial Agents/pharmacology ; Biofilms ; Lung ; *Pseudomonas Infections/microbiology ; *Cysts ; },
abstract = {INTRODUCTION: Chronic lung infection due to bacterial biofilms is one of the leading causes of mortality in cystic fibrosis (CF) patients. Among many species colonizing the lung airways, Pseudomonas aeruginosa and Staphylococcus aureus are two virulent pathogens involved in mechanically robust biofilms that are difficult to eradicate using airway clearance techniques like lung lavage. To remove such biological materials, glycoside hydrolase-based compounds are commonly employed for targeting and breaking down the biofilm matrix, and subsequently increasing cell susceptibility to antibiotics.<br><br>MATERIALS AND METHODS: In this study, we evaluate the effects of N-acetyl cysteine (NAC) and Cysteamine (CYST) in disrupting interfacial bacterial films, targeting different components of the extracellular polymeric substances (EPS). We characterize the mechanics and structural integrity of the interfacial bacterial films using pendant drop elastometry and scanning electron microscopy.<br><br>RESULTS AND DISCUSSION: Our results show that the film architectures are compromised by treatment with disrupting agents for 6 h, which reduces film elasticity significantly. These effects are profound in the wild type and mucoid P. aeruginosa, compared to S. aureus. We further assess the effects of competition and cooperation between S. aureus and P. aeruginosa on the mechanics of composite interfacial films. Films of S. aureus and wild-type P. aeruginosa cocultures lose mechanical strength while those of S. aureus and mucoid P. aeruginosa exhibit improved storage modulus. Treatment with NAC and CYST reduces the elastic property of both composite films, owing to the drugs' ability to disintegrate their EPS matrix. Overall, our results provide new insights into methods for assessing the efficacy of mucolytic agents against interfacial biofilms relevant to cystic fibrosis infection.},
}
@article {pmid38299014,
year = {2024},
author = {Vedaei, F and Newberg, AB and Alizadeh, M and Zabrecky, G and Navarreto, E and Hriso, C and Wintering, N and Mohamed, FB and Monti, D},
title = {Treatment effects of N-acetyl cysteine on resting-state functional MRI and cognitive performance in patients with chronic mild traumatic brain injury: a longitudinal study.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1282198},
pmid = {38299014},
issn = {1664-2295},
abstract = {Mild traumatic brain injury (mTBI) is a significant public health concern, specially characterized by a complex pattern of abnormal neural activity and functional connectivity. It is often associated with a broad spectrum of short-term and long-term cognitive and behavioral symptoms including memory dysfunction, headache, and balance difficulties. Furthermore, there is evidence that oxidative stress significantly contributes to these symptoms and neurophysiological changes. The purpose of this study was to assess the effect of N-acetylcysteine (NAC) on brain function and chronic symptoms in mTBI patients. Fifty patients diagnosed with chronic mTBI participated in this study. They were categorized into two groups including controls (CN, n = 25), and patients receiving treatment with N-acetyl cysteine (NAC, n = 25). NAC group received 50 mg/kg intravenous (IV) medication once a day per week. In the rest of the week, they took one 500 mg NAC tablet twice per day. Each patient underwent rs-fMRI scanning at two timepoints including the baseline and 3 months later at follow-up, while the NAC group received a combination of oral and IV NAC over that time. Three rs-fMRI metrics were measured including fractional amplitude of low frequency fluctuations (fALFF), degree centrality (DC), and functional connectivity strength (FCS). Neuropsychological tests were also assessed at the same day of scanning for each patient. The alteration of rs-fMRI metrics and cognitive scores were measured over 3 months treatment with NAC. Then, the correlation analysis was executed to estimate the association of rs-fMRI measurements and cognitive performance over 3 months (p < 0.05). Two significant group-by-time effects demonstrated the changes of rs-fMRI metrics particularly in the regions located in the default mode network (DMN), sensorimotor network, and emotional circuits that were significantly correlated with cognitive function recovery over 3 months treatment with NAC (p < 0.05). NAC appears to modulate neural activity and functional connectivity in specific brain networks, and these changes could account for clinical improvement. This study confirmed the short-term therapeutic efficacy of NAC in chronic mTBI patients that may contribute to understanding of neurophysiological effects of NAC in mTBI. These findings encourage further research on long-term neurobehavioral assessment of NAC assisting development of therapeutic plans in mTBI.},
}
@article {pmid38294834,
year = {2024},
author = {Feng, R and Fan, Y and Zhang, X and Chen, L and Zhong, ZF and Wang, Y and Yu, H and Zhang, QW and Li, G},
title = {A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure.},
journal = {ACS nano},
volume = {18},
number = {7},
pages = {5951-5964},
pmid = {38294834},
issn = {1936-086X},
abstract = {Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.},
}
@article {pmid38291912,
year = {2024},
author = {Akakpo, JY and Olivos, H and Shrestha, B and Midey, A and Jaeschke, H and Ramachandran, A},
title = {Spatial analysis of renal acetaminophen metabolism and its modulation by 4-methylpyrazole with DESI mass spectrometry imaging.},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {198},
number = {2},
pages = {328-346},
pmid = {38291912},
issn = {1096-0929},
support = {R01 DK102142/DK/NIDDK NIH HHS/United States ; TL1 TR002368/TR/NCATS NIH HHS/United States ; R21 AG073892/AG/NIA NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Mice ; Animals ; Acetaminophen/toxicity/metabolism ; Fomepizole/therapeutic use ; Glutathione/metabolism ; Mice, Inbred C57BL ; Kidney/metabolism ; Mass Spectrometry ; Spatial Analysis ; *Acute Kidney Injury/chemically induced ; *Chemical and Drug Induced Liver Injury/drug therapy ; },
abstract = {Acute kidney injury (AKI) is a common complication in acetaminophen (APAP) overdose patients and can negatively impact prognosis. Unfortunately, N-acetylcysteine, which is the standard of care for the treatment of APAP hepatotoxicity does not prevent APAP-induced AKI. We have previously demonstrated the renal metabolism of APAP and identified fomepizole (4-methylpyrazole, 4MP) as a therapeutic option to prevent APAP-induced nephrotoxicity. However, the kidney has several functionally distinct regions, and the dose-dependent effects of APAP on renal response and regional specificity of APAP metabolism are unknown. These aspects were examined in this study using C57BL/6J mice treated with 300-1200 mg/kg APAP and mass spectrometry imaging (MSI) to provide spatial cues relevant to APAP metabolism and the effects of 4MP. We find that renal APAP metabolism and generation of the nonoxidative (APAP-GLUC and APAP-SULF) and oxidative metabolites (APAP-GSH, APAP-CYS, and APAP-NAC) were dose-dependently increased in the kidney. This was recapitulated on MSI which revealed that APAP overdose causes an accumulation of APAP and APAP GLUC in the inner medulla and APAP-CYS in the outer medulla of the kidney. APAP-GSH, APAP-NAC, and APAP-SULF were localized mainly to the outer medulla and the cortex where CYP2E1 expression was evident. Interestingly, APAP also induced a redistribution of reduced GSH, with an increase in oxidized GSH within the kidney cortex. 4MP ameliorated these region-specific variations in the formation of APAP metabolites in renal tissue sections. In conclusion, APAP metabolism has a distinct regional distribution within the kidney, the understanding of which provides insight into downstream mechanisms of APAP-induced nephrotoxicity.},
}
@article {pmid38290605,
year = {2024},
author = {He, J and Ma, Y and Niu, X and Pei, J and Yan, R and Xu, F and Ma, J and Ma, X and Jia, S and Ma, W},
title = {Silver nanoparticles induce endothelial cytotoxicity through ROS-mediated mitochondria-lysosome damage and autophagy perturbation: The protective role of N-acetylcysteine.},
journal = {Toxicology},
volume = {502},
number = {},
pages = {153734},
doi = {10.1016/j.tox.2024.153734},
pmid = {38290605},
issn = {1879-3185},
mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Silver/toxicity ; *Metal Nanoparticles/toxicity ; Autophagy ; Human Umbilical Vein Endothelial Cells ; Lysosomes/metabolism ; Mitochondria/metabolism ; Cell Survival ; },
abstract = {Silver nanoparticles (AgNPs) are used increasingly often in the biomedical field, but their potential deleterious effects on the cardiovascular system remain to be elucidated. The primary aim of this study was to evaluate the toxic effects, and the underlying mechanisms of these effects, of AgNPs on human umbilical vein endothelial cells (HUVECs), as well as the protective role of N-acetylcysteine (NAC) against cytotoxicity induced by AgNPs. In this study, we found that exposure to AgNPs affects the morphology and function of endothelial cells which manifests as decreased cell proliferation, migration, and angiogenesis ability. Mechanistically, AgNPs can induce excessive cellular production of reactive oxygen species (ROS), leading to damage to cellular sub-organs such as mitochondria and lysosomes. More importantly, our data suggest that AgNPs causes autophagy defect, inhibits mitophagy, and finally activates the mitochondria-mediated apoptosis signaling pathway and evokes cell death. Interestingly, treatment with ROS scavenger-NAC can effectively suppress AgNP-induced endothelial damage.Our results indicate that ROS-mediated mitochondria-lysosome injury and autophagy dysfunction are potential factors of endothelial toxicity induced by AgNPs. This study may provide new evidence for the cardiovascular toxicity of AgNPs and serve as a reference for the safe use of nanoparticles(NPs) in the future.},
}
@article {pmid38290315,
year = {2024},
author = {Li, L and Xu, H and Wang, Y and Zhang, Y and Ye, R and Li, W and Yang, J and Wu, J and Li, J and Jin, E and Cao, M and Li, X and Li, S and Liu, C},
title = {From inflammation to pyroptosis: Understanding the consequences of cadmium exposure in chicken liver cells.},
journal = {Ecotoxicology and environmental safety},
volume = {272},
number = {},
pages = {116004},
doi = {10.1016/j.ecoenv.2024.116004},
pmid = {38290315},
issn = {1090-2414},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Inflammasomes/metabolism ; Pyroptosis ; Cadmium/toxicity ; Chickens/metabolism ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2 ; *Chemical and Drug Induced Liver Injury, Chronic ; Inflammation/chemically induced ; },
abstract = {Hepatotoxicity is frequently observed following acute cadmium (Cd) exposure in chicken. Oxidative stress and subsequent inflammation are regarded as the main reasons for cadmium-induced liver injury. NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome-induced pyroptosis is involved in various inflammatory diseases, including liver injury. Poultry are more susceptible to harmful effects of heavy metals. However, the mechanism of cadmium-induced liver injury in chicken is still elusive. In this study, the effect of cadmium on chicken liver cells and the underlying mechanisms were investigated. The results showed mitochondria was damaged and excessive reactive oxygen species (ROS) were generated in chicken liver cell line LMH after cadmium exposure. Furthermore, cadmium-induced NLRP3 inflammasome activation and the cell membrane rupture indicated LMH cells pyroptosis. The ROS scavengers, acetylcysteine (NAC) and Mito-TEMPO prevented pyroptosis in LMH cells, suggesting that ROS were responsible for the activation of the NLRP3 inflammasome induced by cadmium. Additionally, anti-oxidative transcription factor Nrf2 was inhibited after cadmium exposure, explaining the excessive ROS generation. In summary, our study showed that cadmium leads to ROS generation by inducing mitochondrial damage and inhibiting Nrf2 activity, which promotes NLRP3 inflammasome activation and eventually induces pyroptosis in LMH cells.},
}
@article {pmid38288173,
year = {2023},
author = {Shuka, N and Hasimi, E and Kristo, A and Simoni, L and Gishto, T and Shirka, E and Zaimi Petrela, E and Goda, A},
title = {Contrast-Induced Nephropathy in Interventional Cardiology: Incidence, Risk Factors, and Identification of High-Risk Patients.},
journal = {Cureus},
volume = {15},
number = {12},
pages = {e51283},
pmid = {38288173},
issn = {2168-8184},
abstract = {AIM: This study aimed to study contrast-induced nephropathy (CIN) or more recent nomenclature contrast-associated acute kidney injury (CI-AKI) in patients undergoing percutaneous coronary procedures, evaluating CIN incidence, risk factors (RFs), and high-risk patients with CIN. Methods: This is a prospective, observational, unicentric trial of patients who underwent coronary angiography and/or percutaneous coronary intervention (PCI) in the University Hospital Center (UHC) "Mother Teresa" in Tirana, Albania, during 2016-2018. CIN was defined as an increase of 25% and/or by 0.5 mg/dL of serum creatinine (SCr) and high-risk patients with CIN as an increase by 50% and/or by 2 mg/dL and/or need for dialysis compared to the basal pre-procedural values. We evaluated RFs for CIN: preexisting renal lesion (PRL), heart failure (HF), age, diabetes mellitus (DM), anemia, and contrast quantity. Results: The incidence of CIN resulted in 14.4%. HF, PRL, and age ≥65 years resulted in independent RFs for CIN, whereas anemia, DM, and contrast quantity >100 mL did not. PRL proved to be the most important RF for CIN, whereas HF was the only independent RF for high-risk CIN patients.<br><br>CONCLUSIONS: The incidence of CIN coincides with the results in the literature. PRL, HF, and age &#x2265;65 years resulted in independent RFs for CIN; more and larger trials are needed to evaluate DM, anemia, and contrast quantity related to their impact on CIN. High-risk patients with CIN represent the most problematic patients of this pathology.},
}
@article {pmid38287817,
year = {2024},
author = {Patil, K and Khan, AQ and Ahmad, F and Kuttikrishnan, S and Anver, R and Mateo, JM and Ahmad, A and Bhat, AA and Buddenkotte, J and Steinhoff, M and Uddin, S},
title = {Sanguinarine Triggers Apoptosis in Cutaneous Squamous Cell Carcinoma Cells through Reactive Oxygen Species-Dependent c-Jun N-Terminal Kinase Signaling Pathway.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {29},
number = {1},
pages = {40},
doi = {10.31083/j.fbl2901040},
pmid = {38287817},
issn = {2768-6698},
support = {MRC-01-23-065//Medical Research Center, Hamad Medical Corporation/ ; },
mesh = {Humans ; Reactive Oxygen Species/metabolism ; Benzophenanthridines/pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Carcinoma, Squamous Cell/drug therapy ; *Skin Neoplasms/drug therapy ; Signal Transduction ; Apoptosis ; MAP Kinase Signaling System ; Cell Line, Tumor ; *Anthracenes ; *Isoquinolines ; },
abstract = {BACKGROUND: The benzophenanthridine Sanguinarine (Sng) is one of the most abundant root alkaloids with a long history of investigation and pharmaceutical applications. The cytotoxicity of Sng against various tumor cells is well-established; however, its antiproliferative and apoptotic potential against the cutaneous squamous cell carcinoma (cSCC) cells remains unknown. In the present study, we investigated the anti-cancer potential of Sng against cSCC cells and elucidated the underlying mechanisms relevant to the drug action.<br><br>METHODS: The inhibitory effect of Sng on cSCC cells was evaluated by analyzing cell viability, colony-forming ability and multi-caspase activity. Apoptosis was quantified through Annexin-V/Propidium iodide flow cytometric assay and antagonized by pan-caspase inhibitor z-VAD-FMK. Mitochondrial membrane potential (&#x394;&#x3a8;m) dysfunction was analyzed by JC-1 staining, whereas reactive oxygen species (ROS) generation was confirmed by pretreatment with N-acetylcysteine (NAC) and fluorogenic probe-based flow cytometric detection. The expression of cell cycle regulatory proteins, apoptotic proteins and MAPK signaling molecules was determined by Western blotting. Involvement of JNK, p38-MAPK and MEK/ERK in ROS-mediated apoptosis was investigated by pretreatment with SP600125 (JNK inhibitor), SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor), respectively. The stemness-targeting potential of Sng was assessed in tumor cell-derived spheroids.<br><br>RESULTS: Treatment with Sng decreased cell viability and colony formation in primary (A431) and metastatic (A388) cSCC cells in a time- and dose-dependent manner. Sng significantly inhibited cell proliferation by inducing sub-G0/G1 cell-cycle arrest and apoptosis in cSCC cells. Sng evoked ROS generation, intracellular glutathione (GSH) depletion, &#x394;&#x3a8;m depolarization and the activation of JNK pathway as well as that of caspase-3, -8, -9, and PARP. Antioxidant NAC inhibited ROS production, replenished GSH levels, and abolished apoptosis induced by Sng by downregulating JNK. Pretreatment with z-VAD-FMK inhibited Sng-mediated apoptosis. The pharmacological inhibition of JNK by SP600125 mitigated Sng-induced apoptosis in metastatic cSCC cells. Finally, Sng ablated the stemness of metastatic cSCC cell-derived spheroids.<br><br>CONCLUSION: Our results indicate that Sng exerts a potent cytotoxic effect against cSCC cells that is underscored by a mechanism involving multiple levels of cooperation, including cell-cycle sub-G0/G1 arrest and apoptosis induction through ROS-dependent activation of the JNK signaling pathway. This study provides insight into the potential therapeutic application of Sng targeting cSCC.},
}
@article {pmid38283455,
year = {2023},
author = {Mohammed, HMI and Ahmad, F},
title = {Mushroom Poisoning: A Rare Etiology of Acute Liver Failure.},
journal = {Cureus},
volume = {15},
number = {12},
pages = {e51144},
pmid = {38283455},
issn = {2168-8184},
abstract = {Acute liver failure is defined as a rapid deterioration in liver function, manifested by symptoms and signs of hepatic encephalopathy and disturbed synthetic function in a patient without Pre-existing cirrhosis and with an illness of less than 26 weeks duration. Mushroom poisoning as a cause of acute liver injury is rare but associated with deadly outcomes if not early recognized and treated. The mortality is very high in the case of amatoxin-containing mushrooms ingestion and liver transplantation is the only lifesaving option. Therefore, early recognition of a suspected patient who came with features of mushroom-related food poisoning, timely referral to a liver transplantation center, and adequate supportive management remain the main approaches of management in a patient with acute liver injury. We present a patient with gastroenteritis who ingested wild mushroom 14 hours prior to hospital admission with subsequent severe acute liver failure due to mushroom poisoning, successfully treated with urgent liver transplantation. This case study highlighted that careful evaluation of the symptoms and signs of acute liver failure in a patient with a history of mushroom ingestion can result in early referral to a liver transplant center, especially if the patient is systemically unwell.},
}
@article {pmid38282602,
year = {2024},
author = {Park, HR and Harris, SM and Boldenow, E and Aronoff, DM and Rea, M and Xi, C and Loch-Caruso, R},
title = {The antioxidant N-acetyl cysteine inhibits cytokine and prostaglandin release in human fetal membranes stimulated ex vivo with lipoteichoic acid or live group B streptococcus.},
journal = {American journal of reproductive immunology (New York, N.Y. : 1989)},
volume = {91},
number = {1},
pages = {e13807},
pmid = {38282602},
issn = {1600-0897},
support = {P42 ES017198/ES/NIEHS NIH HHS/United States ; P30 ES001247/ES/NIEHS NIH HHS/United States ; R01 ES007062/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; R00 ES029548/ES/NIEHS NIH HHS/United States ; UL1 TR000433/TR/NCATS NIH HHS/United States ; UM1 TR004404/TR/NCATS NIH HHS/United States ; },
mesh = {Pregnancy ; Female ; Infant, Newborn ; Humans ; Cytokines/metabolism ; Lipopolysaccharides/pharmacology ; Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Acetylcysteine/pharmacology/metabolism ; Dinoprostone/metabolism ; Prostaglandins/metabolism ; Streptococcus agalactiae ; Extraembryonic Membranes/metabolism ; *Chorioamnionitis ; *Streptococcal Infections ; *Teichoic Acids ; },
abstract = {BACKGROUNDS: Infection during pregnancy is a significant public health concern due to the increased risk of adverse birth outcomes. Group B Streptococcus or Streptococcus agalactiae (GBS) stands out as a major bacterial cause of neonatal morbidity and mortality. We aimed to explore the involvement of reactive oxygen species (ROS) and oxidative stress pathways in pro-inflammatory responses within human fetal membrane tissue, the target tissue of acute bacterial chorioamnionitis.<br><br>METHODS: We reanalyzed transcriptomic data from fetal membrane explants inoculated with GBS to assess the impact of GBS on oxidative stress and ROS genes/pathways. We conducted pathway enrichment analysis of transcriptomic data using the Database for Annotation, Visualization and Integrated Discovery (DAVID), a web-based functional annotation/pathway enrichment tool. Subsequently, we conducted ex vivo experiments to test the hypothesis that antioxidant treatment could inhibit pathogen-stimulated inflammatory responses in fetal membranes.<br><br>RESULTS: Using DAVID analysis, we found significant enrichment of pathways related to oxidative stress or ROS in GBS-inoculated human fetal membranes, for example, "Response to Oxidative Stress" (FDR&#xa0;=&#xa0;0.02) and "Positive Regulation of Reactive Oxygen Species Metabolic Process" (FDR&#xa0;=&#xa0;2.6*10[-4]). There were 31 significantly changed genes associated with these pathways, most of which were upregulated after GBS inoculation. In ex vivo experiments with choriodecidual membrane explants, our study showed that co-treatment with N-acetylcysteine (NAC) effectively suppressed the release of pro-inflammatory cytokines (IL-6, IL-8, TNF-&#x3b1;) and prostaglandin PGE2, compared to GBS-treated explants (p&#xa0;<&#xa0;.05 compared to GBS-treated samples without NAC co-treatment). Furthermore, NAC treatment inhibited the release of cytokines and PGE2 stimulated by lipoteichoic acid (LTA) and lipopolysaccharide (LPS) in whole membrane explants (p&#xa0;<&#xa0;.05 compared to LTA or LPS-treated samples without NAC co-treatment).<br><br>CONCLUSIONS: Our study sheds light on the potential roles of ROS in governing the innate immune response to GBS infection, offering insights for developing strategies to mitigate GBS-related adverse outcomes.},
}
@article {pmid38279215,
year = {2024},
author = {Castro, MC and Villagarcía, HG and Di Sarli Gutiérrez, L and Arbeláez, LG and Schinella, G and Massa, ML and Francini, F},
title = {Akt Signaling and Nitric Oxide Synthase as Possible Mediators of the Protective Effect of N-acetyl-L-cysteine in Prediabetes Induced by Sucrose.},
journal = {International journal of molecular sciences},
volume = {25},
number = {2},
pages = {},
pmid = {38279215},
issn = {1422-0067},
support = {CONICET (PIP-2021/2023)//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; M-231//National University of La Plata - Argentina/ ; PICT 2017-2993//FONCYT/ ; },
mesh = {Rats ; Male ; Animals ; Acetylcysteine/pharmacology/metabolism ; *Prediabetic State/drug therapy ; Rats, Wistar ; *Diabetes Mellitus, Type 2/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Sucrose/pharmacology ; *Insulin Resistance ; Oxidative Stress ; Insulin/metabolism ; Signal Transduction ; Glucose/pharmacology ; Nitric Oxide/metabolism ; },
abstract = {The aim of this work was to evaluate possible mechanisms involved in the protective effect of N-acetyl-L-cysteine (NAC) on hepatic endocrine-metabolic, oxidative stress, and inflammatory changes in prediabetic rats. For that, normal male Wistar rats (60 days old) were fed for 21 days with 10% sucrose in their drinking water and 5 days of NAC administration (50 mg/kg, i.p.) and thereafter, we determined: serum glucose, insulin, transaminases, uric acid, and triglyceride levels; hepatic fructokinase and glucokinase activities, glycogen content, lipogenic gene expression; enzymatic and non-enzymatic oxidative stress, insulin signaling pathway, and inflammatory markers. Results showed that alterations evinced in sucrose-fed rats (hypertriglyceridemia, hyperinsulinemia, and high liver fructokinase activity together with increased liver lipogenic gene expression and oxidative stress and inflammatory markers) were prevented by NAC administration. P-endothelial nitric oxide synthase (P-eNOS)/eNOS and pAKT/AKT ratios, decreased by sucrose ingestion, were restored after NAC treatment. In conclusion, the results suggest that NAC administration improves glucose homeostasis, oxidative stress, and inflammation in prediabetic rats probably mediated by modulation of the AKT/NOS pathway. Administration of NAC may be an effective complementary strategy to alleviate or prevent oxidative stress and inflammatory responses observed in type 2 diabetes at early stages of its development (prediabetes).},
}
@article {pmid38274165,
year = {2024},
author = {Sun, YL and Chang, HF and Chiang, PH and Lin, MW and Lin, CH and Kuo, CM and Lin, TC and Lin, CS},
title = {Fabrication and application of glutathione biosensing SPCE strips with gold nanoparticle modification.},
journal = {RSC advances},
volume = {14},
number = {6},
pages = {3808-3819},
pmid = {38274165},
issn = {2046-2069},
abstract = {Glutathione (GSH) is a major antioxidant in organisms. An alteration in GSH concentration has been implicated in a number of pathological conditions. Therefore, GSH sensing has become a critical issue. In this study, a disposable strip used for tyrosinase-modified electrochemical testing was fabricated for the detection of GSH levels in vivo. The system is based on tyrosinase as a biorecognition element and a screen-printed carbon electrode (SPCE) as an amperometric transducer. On the tyrosinase-SPCE strips, the oxidation reaction from catechol to o-quinone was catalyzed by tyrosinase. The tyrosinase-SPCE strips were modified with gold nanoparticles (AuNPs). In the presence of AuNPs of 25 nm diameter, the cathodic peak current of cyclic voltammetry (CV) was significantly enhanced by 5.2 fold. Under optimized conditions (250 μM catechol, 50 mM phosphate buffer, and pH 6.5), the linear response of the tyrosinase-SPCE strips ranged from 31.25 to 500 μM GSH, with a detection limit of approximately 35 μM (S/N > 3). The tyrosinase-SPCE strips have been used to detect real samples of plasma and tissue homogenates in a mouse experiment. The mice were orally administrated with N-acetylcysteine (NAC) 100 mg kg[-1] once a day for 7 days; the plasma GSH significantly enhanced 2.8 fold as compared with saline-treated mice (1123 vs. 480 μM μg[-1] protein). NAC administration also could alleviate the adverse effect of GSH reduction in the mice treated with doxorubicin.},
}
@article {pmid38270755,
year = {2024},
author = {Zhang, H and Huang, Y},
title = {Genome-wide identification and characterization of greenbug-inducible NAC transcription factors in sorghum.},
journal = {Molecular biology reports},
volume = {51},
number = {1},
pages = {207},
pmid = {38270755},
issn = {1573-4978},
mesh = {*Sorghum/genetics ; Edible Grain ; Genotype ; Acetylcysteine/analogs &amp; derivatives ; },
abstract = {BACKGROUND: Sorghum (Sorghum bicolor) is an important cereal crop grown worldwide because of its multipurpose uses such as food, forage, and bioenergy feedstock and its wide range of adaption even in marginal environments. Greenbug can cause severe damage to sorghum plants and yield loss. Plant NAC transcription factors (TFs) have been reported to have diverse functions in plant development and plant defense but has not been studied in sorghum yet.<br><br>METHODS AND RESULTS: In this study, a comprehensive analysis of the sorghum NAC (SbNAC) gene family was conducted through genome-wide analysis. A total of 112 NAC genes has been identified in the sorghum genome. These SbNAC genes are phylogenetically clustered into 15 distinct subfamilies and unevenly distribute in clusters at the telomeric ends of each chromosome. Twelve pairs of SbNAC genes are possibly involved in the segmental duplication among nine chromosomes except chromosome 10. Structure analysis showed the diverse structures with a highly variable number of exons in the SbNAC genes. Furthermore, most of the SbNAC genes showed specific temporal and spatial expression patterns according to the results of RNA-seq analysis, suggesting their diverse functions during sorghum growth and development. We have also identified nine greenbug-inducible SbNAC genes by comparing the expression profiles between two sorghum genotypes (susceptible BTx623 and resistant PI607900) in response to greenbug infestation.<br><br>CONCLUSIONS: Our systematic analysis of the NAC gene expression profiles provides both a preliminary survey into their roles in plant defense against insect pests and a useful reference for in-depth characterization of the SbNAC genes and the regulatory network that contributes genetic resistance to aphids.},
}
@article {pmid38269219,
year = {2023},
author = {Schaefer, J and Khanna, D},
title = {Nutritional and Wellness Strategies for Neurological and Psychiatric Recovery From Post-COVID Syndrome and Post-acute Sequelae of COVID-19.},
journal = {Cureus},
volume = {15},
number = {12},
pages = {e51076},
pmid = {38269219},
issn = {2168-8184},
abstract = {The post-COVID syndrome was officially recognized as a disability under the Americans with Disabilities Act, indicating that this syndrome has made a significant impact on our populace. Also, post-acute sequelae of COVID-19 (PASC) is a term that describes the long-term health problems that some people experience after being infected with the virus that causes COVID-19. These problems can last for weeks, months, or even years, and can affect various parts of the body, such as the heart, lungs, brain, and blood vessels. This narrative review paper utilized the PubMed database to explore the pathophysiology of post-COVID syndrome's neurological and psychiatric symptoms and PASC and make therapeutic connections to the known mechanisms of various nutritional, supplemental, and wellness approaches. Searches were queried on the PubMed database between March 29 and April 16, 2022, using the phrases "long-covid," "post-COVID syndrome," "Vitamin D covid," "vitamin C covid," "omega-3 covid," "kynurenine covid," "whole-body hyperthermia," "mushrooms immunity," "n-acetyl cysteine covid," "mushrooms cognition," "sugar consumption inflammation," and "covid microbiome." Articles were screened for their relevance to the discussion of post-COVID syndrome's neurological and psychiatric pathophysiology at the discretion of the principal researcher. There were no limitations regarding publication years, but articles from 2005 to April 2022 were cited. Micro-ischemic disease, neuropathy, autoimmune processes, mast-cell activation, and impaired blood-brain barriers have all been implicated in the pathological processes of this syndrome with varying degrees of supportive evidence. The common denominators, however, are inflammation and oxidative stress. Therefore, a beneficial approach to dealing with the complications of post-COVID syndrome would be to reduce the exacerbations of these common denominators with lifestyle and nutritional changes. Replenishing nutritional deficiencies, supplementing with N-acetylcysteine, decreasing consumption of refined sugars, preventing dysbiosis of the microbiome, performing exercises, increasing dietary intake of mushrooms, utilizing beneficial herbs such as rosemary, and increasing the core body temperature through whole-body hyperthermia seem to show potential for efficacy in this pursuit. Considering the safety and evidence-based connections of the therapies explored for dealing with the post-Covid syndrome, it could be of great benefit and of little harm to our patients to include these considerations in formulating post-Covid treatment plans.},
}
@article {pmid38250216,
year = {2024},
author = {Zavala-Valencia, AC and Velasco-Hidalgo, L and Martínez-Avalos, A and Castillejos-López, M and Torres-Espíndola, LM},
title = {Effect of N-Acetylcysteine on Cisplatin Toxicity: A Review of the Literature.},
journal = {Biologics : targets &amp; therapy},
volume = {18},
number = {},
pages = {7-19},
pmid = {38250216},
issn = {1177-5475},
abstract = {N-acetylcysteine (NAC) is a membrane-permeable cysteine precursor capable of enhancing the intracellular cysteine pool, enhancing cellular glutathione (GSH) synthesis, and thus potentiating the endogenous antioxidant mechanism. Late administration of NAC after cisplatin has been shown in different in vivo studies to reduce the side effects caused by various toxicities at different levels without affecting the antitumor efficacy of platinum, improving total and enzymatic antioxidant capacity and decreasing oxidative stress markers. These characteristics provide NAC with a rationale as a potentially effective chemo protectant in cisplatin-based therapeutic cycles. NAC represents a potential candidate as a chemoprotective agent to decrease toxicities secondary to cisplatin treatment. It suggests that it could be used in clinical trials, whereby the effective dose, timing, and route should be adjusted to optimize chemoprotection. This review provides an overview of the effect of NAC on cisplatin toxicity, a drug widely used in the clinic in adults and children.},
}
@article {pmid38247538,
year = {2024},
author = {Sun, J and Chen, Y and Wang, T and Ali, W and Ma, Y and Liu, Z and Zou, H},
title = {Role of Mitochondrial Reactive Oxygen Species-Mediated Chaperone-Mediated Autophagy and Lipophagy in Baicalin and N-Acetylcysteine Mitigation of Cadmium-Induced Lipid Accumulation in Liver.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {1},
pages = {},
pmid = {38247538},
issn = {2076-3921},
support = {31872533//National Natural Science Foundation of China/ ; 32072933//National Natural Science Foundation of China/ ; 32273086//National Natural Science Foundation of China/ ; },
abstract = {Cadmium (Cd) is a major health concern globally and can accumulate and cause damage in the liver for which there is no approved treatment. Baicalin and N-acetylcysteine (NAC) have been found to have protective effects against a variety of liver injuries, but it is not clear whether their combined use is effective in preventing and treating Cd-induced lipid accumulation. The study found that Cd increased the production of mitochondrial reactive oxygen species (mROS) and elevated the level of chaperone-mediated autophagy (CMA). Interestingly, mROS-mediated CMA exacerbates the Cd-induced inhibition of lipophagy. Baicalin and NAC counteracted inhibition of lipophagy by attenuating Cd-induced CMA, suggesting an interplay between CMA elevation, mitochondrial destruction, and mROS formation. Maintaining the stability of mitochondrial structure and function is essential for alleviating Cd-induced lipid accumulation in the liver. Choline is an essential component of the mitochondrial membrane and is responsible for maintaining its structure and function. Mitochondrial transcriptional factor A (TFAM) is involved in mitochondrial DNA transcriptional activation and replication. Our study revealed that the combination of baicalin and NAC can regulate choline metabolism through TFAM and thereby maintain mitochondrial structure and functionality. In summary, the combination of baicalin and NAC plays a more beneficial role in alleviating Cd-induced lipid accumulation than the drug alone, and the combination of baicalin and NAC can stabilize mitochondrial structure and function and inhibit mROS-mediated CMA through TFAM-choline, thereby promoting lipophagy to alleviate Cd-induced lipid accumulation.},
}
@article {pmid38247506,
year = {2024},
author = {Kyriakou, S and Demosthenous, N and Amery, T and Stewart, KJ and Winyard, PG and Franco, R and Pappa, A and Panayiotidis, MI},
title = {Naturally Derived Phenethyl Isothiocyanate Modulates Induction of Oxidative Stress via Its N-Acetylated Cysteine Conjugated form in Malignant Melanoma.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {1},
pages = {},
pmid = {38247506},
issn = {2076-3921},
abstract = {Phenethyl isothiocyanate (PEITC) is a secondary metabolic product yielded upon the hydrolysis of gluconasturtiin and it is highly accumulated in the flowers of watercress. The aim of the current study was to assess the role of a naturally derived PEITC-enriched extract in the induction of oxidative stress and to evaluate its anti-melanoma potency through the regulation of its metabolism with the concurrent production of the N-acetyl cysteine conjugated by-product. For this purpose, an in vitro melanoma model was utilized consisting of human primary (A375) cells as well as metastatic (COLO-679) malignant melanoma cells together with non-tumorigenic immortalized keratinocytes (HaCaT). Cytotoxicity was assessed via the Alamar Blue assay whereas the antioxidant/prooxidant activity of PEITC was determined via spectrophotometric assays. Finally, kinetic characterization of the end-product of PEITC metabolism was monitored via UPLC coupled to a tandem mass spectrometry (MS/MS). Our results indicate that although PhEF showed very minor antioxidant activity in a cell-free system, in a cell-based system, it can modulate the activity of key enzyme(s) involved in cellular antioxidant defense mechanism(s). In addition, we have shown that PhEF induces lipid and protein oxidation in a concentration-dependent manner, while its cytotoxicity is not only dependent on PEITC itself but also on its N-acetylated cysteine conjugated form.},
}
@article {pmid38246558,
year = {2024},
author = {Hao, X and Liu, M and Zhang, X and Yu, H and Fang, Z and Gao, X and Chen, M and Shao, Q and Gao, W and Lei, L and Song, Y and Li, X and Liu, G and Du, X},
title = {Thioredoxin-2 suppresses hydrogen peroxide-activated nuclear factor kappa B signaling via alleviating oxidative stress in bovine adipocytes.},
journal = {Journal of dairy science},
volume = {107},
number = {6},
pages = {4045-4055},
doi = {10.3168/jds.2023-23465},
pmid = {38246558},
issn = {1525-3198},
mesh = {Animals ; Cattle ; *Hydrogen Peroxide/pharmacology/metabolism ; *Oxidative Stress/drug effects ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; *Adipocytes/drug effects/metabolism ; *Thioredoxins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Female ; },
abstract = {During the periparturient period, both oxidative stress, and inflammation of adipose tissue are considered high risk factors for metabolic disorder of dairy cows. Oxidative stress can activate transcription factor nuclear factor kappa B (NF-κB), which lead to the upregulation of genes involved in inflammatory pathways. Thioredoxin-2 (TXN2) is a mitochondrial protein that regulates cellular redox by suppressing mitochondrial reactive oxygen species (ROS) generation in nonruminant, whereas the function of TXN2 in bovine adipocytes was unclear. Thus, the objective of this study was to evaluate how or by which mechanisms TXN2 regulates oxidative stress and NF-κB signaling pathway in bovine adipocytes. Bovine pre-adipocytes isolated from 5 healthy Holstein cows were differentiated and used for (1) treatment with different concentrations of hydrogen peroxide (H2O2; 0, 25, 50, 100, 200, or 400 μM) for 2 h; (2) transfection with or without TXN2 small interfering RNA (si-TXN2) for 48 h and then treated with or without 200 μM H2O2 for 2 h; (3) transfection with scrambled negative control siRNA (si-control) or si-TXN2 for 48 h, and then treatment with or without 10 mM N-acetylcysteine (NAC) for 2 h; (4) transfection with or without TXN2-overexpressing plasmid for 48 h and then treatment with or without 200 μM H2O2 for 2 h. High concentrations of H2O2 (200 and 400 μM) decreased protein and mRNA abundance of TXN2, reduced total antioxidant capacity (T-AOC) and ATP content in adipocytes. Moreover, 200 and 400 μM H2O2 reduced protein abundance of inhibitor of kappa B α (IκBα), increased phosphorylation of NF-κB and upregulated mRNA abundance of tumor necrosis factor-α (TNFA) and interleukin-1B (IL-1B), suggesting that H2O2-induced oxidative stress and activated NF-κB signaling pathway. Silencing of TXN2 increased intracellular ROS content, phosphorylation of NF-κB and mRNA abundance of TNFA and IL-1B, decreased ATP content and protein abundance of IκBα in bovine adipocytes. Knockdown of TXN2 aggravated H2O2-induced oxidative stress and inflammation. In addition, treatment with antioxidant NAC ameliorated oxidative stress and inhibited NF-κB signaling pathway in adipocytes transfected with si-TXN2. In bovine adipocytes treated with H2O2, overexpression of TXN2 reduced the content of ROS and elevated the content of ATP and T-AOC. Overexpression of TXN2 alleviated H2O2-induced inflammatory response in adipocytes, as demonstrated by decreased expression of phosphorylated NF-κB, TNFA, IL-1B, as well as increased expression of IκBα. Furthermore, the protein and mRNA abundance of TXN2 was lower in adipose tissue of dairy cows with clinical ketosis. Overall, our studies contribute to the understanding of the role of TXN2 in adipocyte oxidative stress and inflammatory response.},
}
@article {pmid38245726,
year = {2024},
author = {Lee, JH and Jaiswal, MS and Jang, YS and Choi, JH and Kim, GC and Hong, JW and Hwang, DS},
title = {No-ozone cold plasma induces apoptosis in human neuroblastoma cell line via increased intracellular reactive oxygen species (ROS).},
journal = {BMC complementary medicine and therapies},
volume = {24},
number = {1},
pages = {46},
pmid = {38245726},
issn = {2662-7671},
mesh = {Humans ; Reactive Oxygen Species/metabolism ; Caspase 3/metabolism ; *Plasma Gases/pharmacology/therapeutic use ; *Ozone/pharmacology/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology/therapeutic use ; Cell Line, Tumor ; Apoptosis ; *Neuroblastoma/drug therapy/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; },
abstract = {BACKGROUND: This study aimed to evaluate the effect of argon-based No-ozone Cold Plasma (NCP) on neuroblastoma cancer cell apoptosis.<br><br>METHODS: Experiments were performed with SK-N-SH and HS 68. Cell cultures were treated with NCP for 1, 3, and 5&#xa0;min. NCP was applied using three different strategies: direct NCP application to cell cultures, to only media, and to only cells. Evaluation of cell viability and the level of the reactive oxygen species (ROS) was performed. N-acetyl-L-cysteine (NAC) was also used to antagonize intracellular ROS. Cleaved caspase 3, PARP, aquaporin (AQP) 3 and 8 were detected.<br><br>RESULTS: NCP induced a gradual decrease in the SK-N-SH cell viability. In contrast, the viability of HS 68 cells did not change. SK-N-SH cells viability was reduced the most when the only media-NCP application strategy was employed. Intracellular ROS levels were significantly increased with time. Cleaved caspase 3 and PARP were increased at 6&#xa0;h after NCP application. SK-N-SH cells remained viable with NAC after NCP application. AQP 3 and 8 were over-expressed in SK-N-SH cells.<br><br>CONCLUSION: These findings demonstrate the anti-cancer effect of NCP on neuroblastoma cells. NCP enhanced the selective apoptosis of neuroblastoma cells due to the increased intracellular ROS.},
}
@article {pmid38236790,
year = {2024},
author = {Tavanaeimanesh, H and Alinia, Z and Sadeghian Chaleshtori, S and Moosavian, H and Mohebi, Z and Daneshi, M},
title = {The efficacy of N-acetylcysteine in decreasing airway inflammation and mucus accumulation in horses with 18 hours of head confinement.},
journal = {Journal of veterinary internal medicine},
volume = {38},
number = {2},
pages = {1224-1231},
pmid = {38236790},
issn = {1939-1676},
mesh = {Animals ; *Acetylcysteine/therapeutic use ; Bronchoalveolar Lavage Fluid ; *Horse Diseases/drug therapy/prevention &amp; control ; Horses ; Inflammation/drug therapy/veterinary ; Mucus ; Prospective Studies ; Trachea ; Cross-Over Studies ; },
abstract = {BACKGROUND: During transportation many horses develop post-transportation infection, which can be life-threatening and end their sport career. Preventing mucus accumulation and inflammation during transportation is vital, emphasizing the need for effective strategies to enhance overall horse health welfare.<br><br>OBJECTIVES: Assess the impact of N-acetylcysteine (NAC) on mucus accumulation and inflammation in horses subjected to 18&#x2009;hours of head confinement.<br><br>ANIMALS: Six healthy crossbred horses, 5.3&#x2009;&#xb1;&#x2009;2.1&#x2009;years of age and weighing 387&#x2009;&#xb1;&#x2009;30&#x2009;kg.<br><br>METHODS: Prospective placebo-controlled cross-over design study. The horses' heads were restrained in their stalls for a period of 18&#x2009;hours. They were studied under 4 conditions: Not confined (NC): before head confinement, placebo (P), and confined head (CH): 18&#x2009;hours of head confinement without treatment, and N-Acetylcysteine (NAC): 18&#x2009;hours of head confinement treated with NAC before confinement (15&#x2009;mg/kg/day NAC PO for 3&#x2009;days). Bronchoalveolar lavage (BAL) was performed in each condition. Mucus accumulation along the trachea was evaluated by endoscopy.<br><br>RESULTS: Endoscopic scores were significantly different between CH and other conditions, whereas no significant differences were found among NC, P, and NAC. The BAL cell count (34&#x2009;291&#x2009;&#xb1;&#x2009;2624 cells/&#x3bc;L), neutrophil and lymphocyte count (18&#x2009;601&#x2009;&#xb1;&#x2009;3193 cells/&#x3bc;L and 3337.4&#x2009;&#xb1;&#x2009;593 cells/&#x3bc;L, respectively) in CH were significantly higher compared to NAC. Neutrophil percentage was significantly higher in CH (53.8&#x2009;&#xb1;&#x2009;8%) compared to horses that received NAC (20.08&#x2009;&#xb1;&#x2009;8%). Conversely, in comparison to NAC (66.33&#x2009;&#xb1;&#x2009;9%), the percentage of macrophages was significantly lower in CH (35.7&#x2009;&#xb1;&#x2009;10%).<br><br>CONCLUSIONS: N-acetylcysteine was found to significantly decrease mucus accumulation and inflammatory cell counts in horses with head confinement.},
}
@article {pmid38236698,
year = {2024},
author = {Li, C and Li, X and Fan, A and He, N and Wu, D and Yu, H and Wang, K and Jiao, W and Zhao, X},
title = {Evidence for cytochrome P450 3A4-mediated metabolic activation of SCO-267.},
journal = {Biopharmaceutics &amp; drug disposition},
volume = {45},
number = {1},
pages = {30-42},
doi = {10.1002/bdd.2381},
pmid = {38236698},
issn = {1099-081X},
mesh = {Humans ; Rats ; Animals ; *Cytochrome P-450 CYP3A/metabolism ; Activation, Metabolic ; *Diabetes Mellitus, Type 2/metabolism ; Quinones/metabolism ; Imines/metabolism ; Microsomes, Liver/metabolism ; Glutathione/metabolism ; *Piperidines ; *Pyridines ; *Benzoquinones ; },
abstract = {SCO-267 is a potent G-protein-coupled receptor 40 agonist that is undergoing clinical development for the treatment of type 2 diabetes mellitus. The current work was undertaken to investigate the bioactivation potential of SCO-267 in vitro and in vivo. Three SCO-267-derived glutathione (GSH) conjugates (M1-M3) were found both in rat and human liver microsomal incubations supplemented with GSH and nicotinamide adenine dinucleotide phosphate. Two GSH conjugates (M1-M2) together with two N-acetyl-cysteine conjugates (M4-M5) were detected in the bile of rats receiving SCO-267 at 10 mg/kg. The identified conjugates suggested the generation of quinone-imine and ortho-quinone intermediates. CYP3A4 was demonstrated to primarily catalyze the bioactivation of SCO-267. In addition, SCO-267 concentration-, time-, and NADPH-dependently inactivated CYP3A in human liver microsomes using testosterone as a probe substrate, along with KI and kinact values of 4.91 μM and 0.036 min[-1] , respectively. Ketoconazole (a competitive inhibitor of CYP3A) displayed no significant protective effect on SCO-267-induced CYP3A inactivation. However, inclusion of GSH showed significant protection. These findings revealed that SCO-267 undergoes a facile CYP3A4-catalyzed bioactivation with the generation of quinone-imine and ortho-quinone intermediates, which were assumed to be involved in SCO-267 induced CYP3A inactivation. These findings provide further insight into the bioactivation pathways involved in the generation of reactive, potentially toxic metabolites of SCO-267. Further studies are needed to evaluate the influence of SCO-267 metabolism on the safety of this drug in vivo.},
}
@article {pmid38234666,
year = {2024},
author = {Yalçin, T and Kuloğlu, T and Tektemur, NK and Tektemur, A and Ozan, &#x130;E},
title = {Effects of N-acetylcysteine on spexin immunoreactivity in kidney tissues of rats treated with adriamycin.},
journal = {Iranian journal of basic medical sciences},
volume = {27},
number = {2},
pages = {233-240},
pmid = {38234666},
issn = {2008-3866},
abstract = {OBJECTIVES: Due to its negative side effects, mainly nephrotoxicity, adriamycin (ADR) is used fairly infrequently. The purpose of this study is to investigate the effects of N-acetyl cysteine (NAC) on the immunoreactivity of spexin (SPX) in the kidney tissues of rats given ADR.<br><br>MATERIALS AND METHODS: A total of 28 male Sprague-Dawley rats were randomly assigned to four groups (n=7): control (no intervention), NAC (150 mg/kg/day, administered intraperitoneally), ADR (single dose of 15 mg/kg, administered intraperitoneally), and ADR+NAC (single dose of 15 mg/kg ADR + 150 mg/kg/day NAC, both administered intraperitoneally). The experiment was concluded on the 15[th] day.<br><br>RESULTS: The administration of ADR resulted in biochemical and histopathological alterations in the kidney. It was found that ADR treatment led to elevated levels of TOS (total oxidative stress), apoptosis, and SPX. Conversely, when NAC was administered as a treatment, it effectively reduced TOS, apoptosis, and SPX levels. These findings suggest that SPX may contribute to the development of ADR-induced kidney damage.<br><br>CONCLUSION: Further investigations are warranted to gain a comprehensive understanding of kidney damage, and specifically to elucidate the role of SPX in this context. Additionally, these studies can pave the way for exploring novel therapeutic strategies targeting SPX to prevent and/or treat the development of kidney damage.},
}
@article {pmid38233317,
year = {2024},
author = {Jung, E and Romero, R and Suksai, M and Gotsch, F and Chaemsaithong, P and Erez, O and Conde-Agudelo, A and Gomez-Lopez, N and Berry, SM and Meyyazhagan, A and Yoon, BH},
title = {Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment.},
journal = {American journal of obstetrics and gynecology},
volume = {230},
number = {3S},
pages = {S807-S840},
pmid = {38233317},
issn = {1097-6868},
support = {HHSN275201300006C/HD/NICHD NIH HHS/United States ; Z01 HD002400/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Female ; Infant, Newborn ; Pregnancy ; Humans ; *Chorioamnionitis/diagnosis/drug therapy/etiology ; Clarithromycin/therapeutic use ; *Postpartum Hemorrhage/drug therapy ; *Neonatal Sepsis/diagnosis/drug therapy ; Anti-Bacterial Agents/therapeutic use ; Amniotic Fluid/microbiology ; Inflammation/metabolism ; Tachycardia ; },
abstract = {Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia. In cases of uncertainty, a definitive diagnosis can be made by analyzing amniotic fluid with methods to detect bacteria (Gram stain, culture, or microbial nucleic acid) and inflammation (white blood cell count, glucose concentration, interleukin-6, interleukin-8, matrix metalloproteinase-8). The most common microorganisms are Ureaplasma species, and polymicrobial infections occur in 70% of cases. The fetal attack rate is low, and the rate of positive neonatal blood cultures ranges between 0.2% and 4%. Intrapartum antibiotic administration is the standard treatment to reduce neonatal sepsis. Treatment with ampicillin and gentamicin have been recommended by professional societies, although other antibiotic regimens, eg, cephalosporins, have been used. Given the importance of Ureaplasma species as a cause of intraamniotic infection, consideration needs to be given to the administration of antimicrobial agents effective against these microorganisms such as azithromycin or clarithromycin. We have used the combination of ceftriaxone, clarithromycin, and metronidazole, which has been shown to eradicate intraamniotic infection with microbiologic studies. Routine testing of neonates born to affected mothers for genital mycoplasmas could improve the detection of neonatal sepsis. Clinical chorioamnionitis is associated with decreased uterine activity, failure to progress in labor, and postpartum hemorrhage; however, clinical chorioamnionitis by itself is not an indication for cesarean delivery. Oxytocin is often administered for labor augmentation, and it is prudent to have uterotonic agents at hand to manage postpartum hemorrhage. Infants born to mothers with clinical chorioamnionitis near term are at risk for early-onset neonatal sepsis and for long-term disability such as cerebral palsy. A frontier is the noninvasive assessment of amniotic fluid to diagnose intraamniotic inflammation with a transcervical amniotic fluid collector and a rapid bedside test for IL-8 for patients with ruptured membranes. This approach promises to improve diagnostic accuracy and to provide a basis for antimicrobial administration.},
}
@article {pmid38230777,
year = {2024},
author = {Nili-Ahmadabadi, A and Abdpour, S and Omidifar, N and Hashemi, SA and Mousavi, SM and Ahmadabadi, MN},
title = {Therapeutic potentials of N-acetylcysteine immobilized polyrhodanine nanoparticles toward acetaminophen-induced acute hepatotoxicity in rat.},
journal = {Chemical biology &amp; drug design},
volume = {103},
number = {1},
pages = {e14430},
doi = {10.1111/cbdd.14430},
pmid = {38230777},
issn = {1747-0285},
support = {//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; },
mesh = {Rats ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; Acetaminophen/toxicity ; Antioxidants/pharmacology/therapeutic use ; Saline Solution/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology ; Liver ; *Nanoparticles ; Sulfhydryl Compounds ; },
abstract = {N-acetylcysteine (NAC) is a recommended drug for treating acetaminophen (APAP) intoxication. Due to NAC's low bioavailability, this study aimed to use polyrhodanine (PR) nanoparticles (NPs) as a drug carrier to improve the effectiveness of NAC. After preparation and characterization of NAC loaded on PR, 30 rats were randomly divided into five groups of six. The first group (control) received normal saline. Groups 2-5 were treated with normal saline, PR, NAC, and NAC loaded on PR, respectively. The treatments were started 4 h after oral administration of APAP (2000 mg kg[-1]). After 48 h, the animals were anesthetized, and liver function indices and oxidative stress were measured in tissue and serum samples. The APAP administration can increase aminotransferases and alkaline phosphatase enzymes in serum, decreasing the total antioxidant capacity and thiol groups and increasing lipid peroxidation in liver tissue. Administration of PR-NAC could effectively improve the level of serum-hepatic enzymes, total antioxidant capacity and thiol groups, lipid peroxidation, and pathological changes in liver tissue in animals poisoned with APAP. PR-NAC has a significant therapeutic effect on preventing acute hepatotoxicity caused by APAP, and its effectiveness can be associated with an improvement in the oxidant/antioxidant balance of liver tissue.},
}
@article {pmid38230207,
year = {2024},
author = {Wang, Q and Lin, B and Wei, H and Wang, X and Nie, X and Shi, Y},
title = {AQP3 Promotes the Invasion and Metastasis in Cervical Cancer by Regulating NOX4-derived H2O2 Activation of Syk/PI3K/Akt Signaling Axis.},
journal = {Journal of Cancer},
volume = {15},
number = {4},
pages = {1124-1137},
pmid = {38230207},
issn = {1837-9664},
abstract = {Unrestrained chronic inflammation leads to the abnormal activity of NOX4 and the subsequent production of excessive hydrogen peroxide (H2O2). Excessive H2O2 signaling triggered by prolonged inflammation is thought to be one of the important reasons for the progression of some types of cancer including cervical cancer. Aquaporin 3 (AQP3) is a member of the water channel protein family, and it remains unknown whether AQP3 can regulate the transmembrane transport of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)-derived H2O2 induced by the stimulation of inflammatory factors to facilitate the malignant progression in cervical cancer. In this study, cervical cancer HeLa cell line was respectively treated with diphenyleneiodonium (DPI), N-Acetylcysteine (NAC) or lentivirus-shRNA- AQP3. Plate cloning, cell migration or transwell invasion assays, etc. were performed to detect the invasive and migration ability of the cells. Western blot and CO-IP were used to analyze the mechanism of AQP3 regulating H2O2 conduction. Finally, in vivo assays were performed for validation in nude mice. AQP3 Knockdown, DPI or NAC treatments all reduced intracellular H2O2 influx, and the activation of Syk/PI3K/Akt signal axis was inhibited, the migration and invasive ability of the cells was attenuated. In vivo assays confirmed that the excessive H2O2 transport through AQP3 enhanced the infiltration and metastasis of cervical cancer. These results suggest that AQP3 activates H2O2/Syk/PI3K/Akt signaling axis through regulating NOX4-derived H2O2 transport to contribute to the progression of cervical cancer, and AQP3 may be a potential target for the clinical treatment of advanced cervical cancer.},
}
@article {pmid38216781,
year = {2024},
author = {Zhao, Q and Yu, M and Li, J and Guo, Y and Wang, Z and Hu, K and Xu, F and Liu, Y and Li, L and Wan, D and Zhao, Y and Shang, J and Zhang, J},
title = {GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis.},
journal = {Discover oncology},
volume = {15},
number = {1},
pages = {8},
pmid = {38216781},
issn = {2730-6011},
support = {No. 212102310124//the Key Scientific and Technological Project of Henan Province/ ; No. 222102310083//the Key Scientific and Technological Project of Henan Province/ ; No. 222300420306//the Natural Science Foundation of Henan/ ; No. 2023BP0206//the Project of Basic Research Fund of Henan Institute of Medical and Pharmacological Sciences/ ; },
abstract = {Glutamate dehydrogenase 1 (GLUD1) is an important enzyme in glutamine metabolism. Previously, we found GLUD1 was down-regulated in tumor tissues of hepatocellular carcinoma (HCC) patients by proteomics study. To explore its role in the progression of HCC, the expressional level of GLUD1 was firstly examined and presented as that both the protein and mRNA levels were down-regulated in tumor tissues compared to the normal liver tissues. GLUD1 overexpression significantly inhibited HCC cells proliferation, migration, invasion and tumor growth both in vitro and in vivo, while GLUD1 knocking-down promoted HCC progression. Metabolomics study of GLUD1 overexpressing and control HCC cells showed that 129 differentially expressed metabolites were identified, which mainly included amino acids, bases, and phospholipids. Moreover, metabolites in mitochondrial oxidative phosphorylation system (OXPHOS) were differentially expressed in GLUD1 overexpressing cells. Mechanistic studies showed that GLUD1 overexpression enhanced mitochondrial respiration activity and reactive oxygen species (ROS) production. Excessive ROS lead to mitochondrial apoptosis that was characterized by increased expression levels of p53, Cytochrome C, Bax, Caspase 3 and decreased expression level of Bcl-2. Furthermore, we found that the p38/JNK MAPK pathway was activated in GLUD1 overexpressing cells. N-acetylcysteine (NAC) treatment eliminated cellular ROS and blocked p38/JNK MAPK pathway activation, as well as cell apoptosis induced by GLUD1 overexpression. Taken together, our findings suggest that GLUD1 inhibits HCC progression through regulating cellular metabolism and oxidative stress state, and provide that ROS generation and p38/JNK MAPK pathway activation as promising methods for HCC treatment.},
}
@article {pmid38216081,
year = {2024},
author = {Zhu, G and Zeng, Y and Peng, W and Lu, C and Cai, H and Abuduxukuer, Z and Chen, Y and Chen, K and Song, X and Song, Y and Ye, L and Wang, J and Jin, M},
title = {Edaravone alleviated allergic airway inflammation by inhibiting oxidative stress and endoplasmic reticulum stress.},
journal = {European journal of pharmacology},
volume = {966},
number = {},
pages = {176317},
doi = {10.1016/j.ejphar.2024.176317},
pmid = {38216081},
issn = {1879-0712},
mesh = {Mice ; Animals ; *Immunity, Innate ; Edaravone/pharmacology/therapeutic use ; Cytokines/metabolism ; Endoribonucleases/metabolism ; Hydrogen Peroxide/pharmacology ; Lymphocytes ; Protein Serine-Threonine Kinases/metabolism ; *Asthma/metabolism ; Lung ; Inflammation/drug therapy/metabolism ; Oxidative Stress ; Oxidants/pharmacology ; Pyroglyphidae/metabolism ; Disease Models, Animal ; },
abstract = {Oxidative stress and endoplasmic reticulum stress (ERS) was associated with the development of asthma. Edaravone (EDA) plays a classical role to prevent the occurrence and development of oxidative stress-related diseases. Herein, we investigated the involvement and signaling pathway of EDA in asthma, with particular emphasis on its impact on type 2 innate lymphoid cells (ILC2) and CD4[+]T cells, and then further elucidated whether EDA could inhibit house dust mite (HDM)-induced allergic asthma by affecting oxidative stress and ERS. Mice received intraperitoneally injection of EDA (10 mg/kg, 30 mg/kg), dexamethasone (DEX) and N-acetylcysteine (NAC), with the latter two used as positive control drugs. DEX and high dose of EDA showed better therapeutic effects in alleviating airway inflammation and mucus secretion in mice, along with decreasing eosinophils and neutrophils in bronchoalveolar lavage fluid (BALF) than NAC. Further, the protein levels of IL-33 in lung tissues were inhibited by EDA, leading to reduced activation of ILC2s in the lung. EDA treatment alleviated the activation of CD4[+] T cells in lung tissues of HDM-induced asthmatic mice and reduced Th2 cytokine secretion in BALF. ERS-related markers (p-eIF2α, IRE1α, CHOP, GRP78) were decreased after treatment of EDA compared to HDM group. Malondialdehyde (MDA), glutathione (GSH), hydrogen peroxide (H2O2), and superoxide dismutase (SOD) were detected to evaluate the oxidant stress in lung tissues. EDA showed a protective effect against oxidant stress. In conclusion, our findings demonstrated that EDA could suppress allergic airway inflammation by inhibiting oxidative stress and ERS, suggesting to serve as an adjunct medication for asthma in the future.},
}
@article {pmid38215974,
year = {2024},
author = {Eslami Ghayour, A and Nazari, S and Keramat, F and Shahbazi, F and Eslami-Ghayour, A},
title = {Evaluation of the efficacy of N-acetylcysteine and bromhexine compared with standard care in preventing hospitalization of outpatients with COVID-19: a double blind randomized clinical trial.},
journal = {Revista clinica espanola},
volume = {224},
number = {2},
pages = {86-95},
doi = {10.1016/j.rceng.2023.12.011},
pmid = {38215974},
issn = {2254-8874},
mesh = {Humans ; *COVID-19 ; Acetylcysteine/therapeutic use ; Outpatients ; COVID-19 Vaccines ; *Bromhexine ; Iran ; Treatment Outcome ; Hospitalization ; },
abstract = {INTRODUCTION AND AIM: Since its emergence in December 2019, the coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 has become a global emergency, spreading rapidly worldwide. In response to the early referral of these patients to outpatient health centers, we decided to seek more effective treatments in the early stages of their referral. This study aims to prevent both the progression and deterioration of the physical conditions of COVID-19 patients, reduce the rate of referrals, and mitigate the risks of hospitalization and death.<br><br>MATERIAL AND METHODS: Conducted at Dibaj Therapeutic Center, Hamadan City, Iran, a double-blind randomized controlled trial encompassed 225 COVID-19 patients from April to September 2022. Ethical approval was obtained from Hamadan University of Medical Sciences (Approval No.: IR.UMSHA.REC.1400.957), with the protocol registered in the Iranian Registry of Clinical Trials (Registration No. : IRCT20220302054167N1). In this study, we included patients who tested positive for COVID-19- PCR and were symptomatic, excluding those who were pregnant or had received a COVID-19 vaccine. Patients with oxygen saturation above 92% were allocated to three groups: Group A received N-acetylcysteine, Group B received Bromhexine, and Group C received standard care. Follow-ups on oxygen levels, symptoms, and hospitalization needs were conducted on days 7 and 14, with hospitalized patients monitored for one month post-hospitalization.<br><br>RESULTS: The study found that both N-acetylcysteine and Bromhexine can effectively reduce hospitalization rates and mortality and shorten the duration of hospitalization. The third visit of patients who received N-acetylcysteine showed an increase of 1.33% in oxygen saturation compared to their first visit, and in patients who received Bromhexine, this increase was 1.19%. The mortality rate was 9.33% in the control group and zero in both groups of patients who received medication.<br><br>CONCLUSION: In conclusion, the results of this study indicate that NAC and bromhexine may be effective in the treatment of patients with positive COVID-19, with a lower hospitalization rate, shorter hospitalization, faster recovery time, and reduced mortality compared to the control group.},
}
@article {pmid38215930,
year = {2024},
author = {Katebi, SN and Torkaman-Boutorabi, A and Riahi, E and Haghparast, A},
title = {N-acetylcysteine attenuates accumbal core neuronal activity in response to morphine in the reinstatement of morphine CPP in morphine extinguished rats.},
journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry},
volume = {131},
number = {},
pages = {110942},
doi = {10.1016/j.pnpbp.2024.110942},
pmid = {38215930},
issn = {1878-4216},
mesh = {Humans ; Rats ; Animals ; *Morphine/pharmacology ; *Acetylcysteine/pharmacology ; Rats, Wistar ; Extinction, Psychological/physiology ; Nucleus Accumbens ; Neurons ; },
abstract = {Numerous studies have suggested that N-acetylcysteine (NAC), has the potential to suppress drug craving in people with substance use disorder and reduce drug-seeking behaviors in animals. The nucleus accumbens (NAc) plays a crucial role in the brain's reward system, with the nucleus accumbens core (NAcore) specifically implicated in compulsive drug seeking and relapse. In this study, we aimed to explore the impact of subchronic NAC administration during the extinction period and acute NAC administration on the electrical activity of NAcore neurons in response to a priming dose of morphine in rats subjected to extinction from morphine-induced place preference (CPP).We conducted single-unit recordings in anesthetized rats on the reinstatement day, following the establishment of morphine-induced conditioned place preference (7 mg/kg, s.c., 3 days), and subsequent drug-free extinction. In the subchronically NAC-treated groups, rats received daily injections of either NAC (50 mg/kg; i.p.) or saline during the extinction period. On the reinstatement day, we recorded the spontaneous activity of NAcore neurons for 15 min, administered a priming dose of morphine, and continued recording for an additional 45 min. While morphine excited most recorded neurons in saline-treated rats, it failed to alter firing rates in NAC-treated rats that had received NAC during the extinction period. For acutely NAC-treated animals, we recorded the baseline activity of NAcore neurons for 10 min before administering a single injection of either NAC (50 mg/kg; i.p.) or saline in rats with no treatment during the extinction. Following 30 min of recording and a priming dose of morphine (1 mg/kg, s.c.), the recording continued for an additional 30 min. The firing activity of NAcore neurons did not show significant changes after morphine or NAC injection. In conclusion, our findings emphasize that daily NAC administration during the extinction period significantly attenuates the morphine-induced increase in firing rates of NAcore neurons during the reinstatement of morphine CPP. However, acute NAC injection does not produce the same effect. These results suggest that modulating glutamate transmission through daily NAC during extinction may effectively inhibit the morphine place preference following the excitatory effects of morphine on NAcore neurons.},
}
@article {pmid38213396,
year = {2023},
author = {Fort, TD and Cain, ME},
title = {Inefficacy of N-acetylcysteine in mitigating cue-induced amphetamine-seeking.},
journal = {Addiction neuroscience},
volume = {8},
number = {},
pages = {},
pmid = {38213396},
issn = {2772-3925},
support = {P20 GM113109/GM/NIGMS NIH HHS/United States ; R15 DA035435/DA/NIDA NIH HHS/United States ; },
abstract = {Glutamatergic imbalances are characteristic of SUDs. Astrocytic and neuronal transporters help regulate glutamate homeostasis and disruptions in this homeostasis engender SUD. The cysteine-glutamate exchanger (xCT) is primarily localized on astrocytes and maintains glutamate concentrations. This process is disrupted by cocaine use, and the therapeutic N-acetylcysteine (NAC) lowers cue-induced relapse to cocaine by restoring xCT function. However, little research has shown how these effects extend to other psychostimulants, such as amphetamine (AMP). Here, we assessed xCT expression following relapse to AMP cues, and if NAC can attenuate relapse via changes to astrocyte and xCT expression. We administered NAC (100 mg/kg ip) daily during a 14-day abstinence period following AMP (0.1 mg/kg/infusion; 2 h sessions) self-administration. Relapse was tested following one (WD 1) or 14 days (WD 14) of withdrawal. The overall number of astrocytes was also quantified within the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb). NAC failed to lower cue-induced AMP craving via cue-induced relapse and reinstatement testing. Cue-induced craving did not increase from WD 1 to WD 14. AMP-exposed rats had greater astrocyte counts in the mPFC and ACb when compared AMP-naïve rats. Repeated injection with NAC decreased xCT expression within the mPFC and ACb. Overall, these results suggest that NAC may be an ineffective treatment option for lowering cue-induced relapse to AMP. Further, the results suggest that stimulating xCT via NAC may not be an effective therapeutic approach for decreasing cue-seeking for AMP.},
}
@article {pmid38212360,
year = {2024},
author = {Komakula, S and Bhatia, R and Sahib, A and Upadhyay, A and S, LJ and Garg, A and Y, VV and Pandit, AK and Vibha, D and Singh, MB and Tripathi, M and Srivastava, MVP},
title = {Safety and efficacy of N-acetylcysteine (NAC) as an adjunct to standard treatment in patients with acute ischemic stroke: a randomized controlled pilot trial (NACTLYS).},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {1103},
pmid = {38212360},
issn = {2045-2322},
mesh = {Humans ; Tissue Plasminogen Activator/adverse effects ; Acetylcysteine/adverse effects ; Pilot Projects ; *Ischemic Stroke/etiology ; Treatment Outcome ; Fibrinolytic Agents/adverse effects ; *Stroke ; Cerebral Hemorrhage/complications ; *Brain Ischemia/complications ; Thrombolytic Therapy/adverse effects ; },
abstract = {There is a pressing clinical need for thrombolytic agents that can effectively disaggregate arterial thrombi in acute ischemic stroke without significantly increasing the risk of bleeding. This pilot study aimed to investigate the safety and efficacy of N-acetylcysteine (NAC) as an adjunctive therapy to intravenous recombinant tissue plasminogen activator (rtPA or alteplase). A randomized, open-label, blinded assessor pilot study was conducted. Patients presenting with an acute ischemic stroke within 4.5 h from onset were randomized into two groups: intravenous NAC and rtPA or rtPA alone. Primary outcomes included intracerebral hemorrhage, symptomatic intracerebral hemorrhage, extracranial bleeding, and adverse reactions. Secondary outcomes comprised major neurological improvement assessed by (National Institute of Health Stroke Scale) NIHSS at 24 h, recanalization on first run of angiography in patients who underwent thrombectomy or on repeat vascular imaging at 24 h, modified Rankin scale, and three-month mortality. Forty patients were enrolled, with 21 receiving only rtPA and 19 receiving NAC with rtPA. Baseline characteristics were comparable among groups. No significant differences were observed in adverse events (p = 0.99), intracranial hemorrhage (p = 0.21), symptomatic intracerebral hemorrhage (p = 0.47), or extracranial bleeding (p = 0.21). Median NIHSS at 24 h was significantly lower in the intervention group (p = 0.03). Functional outcomes and three-month mortality were similar between groups (p = 0.85 and p = 0.99 respectively). The co-administration of N-acetylcysteine with alteplase did not significantly alter safety profiles, morbidity, or mortality at 3 months. While no substantial differences were noted, a slightly improved early neurological outcome was observed in the intervention arm. The study's findings were constrained by a small sample size, emphasizing the necessity for future large-scale trials to comprehensively evaluate the safety and efficacy of N-acetylcysteine as a thrombolytic agent in acute ischemic stroke.Trial Registration Clinical Trials Registry India-CTRI/2019/05/019305.},
}
@article {pmid38212034,
year = {2023},
author = {Ma, TX and Li, JT and Li, J and Zhang, Y and Liang, JQ},
title = {[Guiqi Yiyuan Ointment protects rat left lung from bystander effect of right lung injury induced by ~(12)C~(6+) beam].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {48},
number = {24},
pages = {6740-6748},
doi = {10.19540/j.cnki.cjcmm.20230914.702},
pmid = {38212034},
issn = {1001-5302},
mesh = {Rats ; Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; NF-kappa B/genetics/metabolism ; Inflammasomes/metabolism ; *Lung Injury/etiology/genetics ; Reactive Oxygen Species/metabolism ; Bystander Effect ; Ointments ; Rats, Wistar ; Lung/metabolism ; Caspase 1/metabolism ; RNA, Messenger ; Superoxide Dismutase ; },
abstract = {This study observed the effects of Guiqi Yiyuan Ointment(GQYY) on the left lung subjecting to bystander effect of right lung injury induced by ~(12)C~(6+) beam in rats and decipher the underlying mechanism from NOD-like receptor protein 3(NLRP3)/apoptosis-associated speck-like protein containing a CARD(ASC)/cysteinyl aspartate specific proteinase-1(caspase-1) pathway. Wistar rats were randomized into 7 groups: blank, model, inhibitor [200 mg·kg~(-1), N-acetylcysteine(NAC)], western drug [140 mg·kg~(-1) amifostine(AMI)], and high-, medium-, and low-dose(4.8, 2.4, and 1.2 g·kg~(-1), respectively) GQYY groups. The model of bystander effect damage was established by 4 Gy ~(12)C~(6+) beam irradiation of the right lung(with the other part shielded by a lead plate). The pathological changes in the lung tissue, the level of reactive oxygen species(ROS) in the lung tissue, and the levels of superoxide dismutase(SOD) and malondialdehyde(MDA) in the serum were observed and measured in each group. Furthermore, the mRNA and protein levels of NLRP3, ASC, caspase-1, and phosphorylated nuclear factor-κB p65(p-NF-κB p65)/nuclear factor-κB p65(NF-κB p65) were determined. Compared with the blank group, the model group showed thickened alveolar wall, narrowed alveolar cavity, and presence of massive red blood cells and inflammatory infiltration in the alveolar wall and alveolar cavity. In addition, the model group showed elevated ROS levels in both left and right lungs, elevated MDA level, lowered SOD level, and up-regulated mRNA and protein levels of NLRP3, ASC, caspase-1, and p-NF-κB p65/NF-κB p65. Compared with the model group, the drug administration in all the groups reduced inflammatory cell infiltration in the lung tissue. The inhibitor group and the western drug group showed enlarged alveolar cavity, thinned interstitium, and reduced inflammation. There was a small amount of alveolar wall rupture in the high-and medium-dose GQYY groups and reduced inflammatory cell infiltration in the low dose GQYY group. Compared with the model group, drug administration lowered level of ROS in the left and right lungs, lowered the MDA level, elevated the SOD level, and down-regulated the mRNA and protein levels of NLRP3, ASC, caspase-1, and p-NF-κB p65/NF-κB p65. GQYY can effectively reduce the damage caused by radiation and bystander effect, which may be associated with the ROS-mediated NLRP3 inflammasome activation.},
}
@article {pmid38211826,
year = {2024},
author = {Li, X and Kong, L and Pan, J and Liu, H and Wang, C and Xu, S and Liu, W and Sun, J},
title = {N-acetylcysteine protects against neurodevelopmental injuries induced by methylmercury exposure during pregnancy and lactation.},
journal = {Brain research},
volume = {1827},
number = {},
pages = {148761},
doi = {10.1016/j.brainres.2024.148761},
pmid = {38211826},
issn = {1872-6240},
mesh = {Humans ; Pregnancy ; Female ; Animals ; Mice ; *Acetylcysteine/pharmacology ; *Methylmercury Compounds/toxicity ; Lactation ; Antioxidants/pharmacology ; Brain ; },
abstract = {As an extremely dangerous environmental contaminant, methylmercury (MeHg) results in detrimental health effects in human brain nervous system, one of its main targets. However, as a developmental toxicant, the brain of offspring is vulnerable to MeHg during pregnancy and lactation exposure. Unfortunately, mechanisms of neurodevelopmental injuries induced by MeHg have not been fully elucidated. N-acetylcysteine (NAC) has been used for several decades as an antioxidant to antagonize oxidative stress. However, the molecular mechanisms of NAC alleviating MeHg-induced neurodevelopmental toxicity are not clear. Here, for evaluation of the dose-dependent effects of MeHg exposure on neurodevelopmental injuries of offspring, and the possible protective effects of NAC, the pregnant female mice were exposed to MeHg (4, 8, 12 mg/L, respectively) and NAC (50, 100, 150 mg/kg, respectively) from gestational day 1 (GD1) to postnatal day 21 (PND21). Our results indicated that administering MeHg caused behavioral impairment and neuronal injuries in the cerebral cortex of newborn mice. MeHg dose-dependently caused reactive oxygen species (ROS) overproduction and oxidative stress aggravation, together with expression of Nrf2, HO-1, Notch1, and p21 up-regulation, and CDK2 inhibition. NAC treatment dose-dependently antagonized MeHg-induced oxidative stress that may contribute to alleviating neurobehavioral and neurodevelopmental impairments. These results give insight into that NAC can protect against MeHg-induced neurodevelopmental toxicity by its antioxidation capacity.},
}
@article {pmid38206362,
year = {2024},
author = {Baumel-Alterzon, S and Katz, LS and Lambertini, L and Tse, I and Heidery, F and Garcia-Ocaña, A and Scott, DK},
title = {NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function.},
journal = {Diabetologia},
volume = {67},
number = {3},
pages = {547-560},
pmid = {38206362},
issn = {1432-0428},
support = {R01 DK114338/DK/NIDDK NIH HHS/United States ; UC4 DK104211/DK/NIDDK NIH HHS/United States ; UC4 DK108120/DK/NIDDK NIH HHS/United States ; U01 DK120456/DK/NIDDK NIH HHS/United States ; R01DK130300/DK/NIDDK NIH HHS/United States ; R01DK114338/DK/NIDDK NIH HHS/United States ; R01 DK130300/DK/NIDDK NIH HHS/United States ; P30 DK020541/DK/NIDDK NIH HHS/United States ; P30 DK020593/DK/NIDDK NIH HHS/United States ; K01 DK128387/DK/NIDDK NIH HHS/United States ; R24 DK106755/DK/NIDDK NIH HHS/United States ; DK128387-01A1/DK/NIDDK NIH HHS/United States ; },
mesh = {Male ; Humans ; Mice ; Animals ; Child ; Infant, Newborn ; Infant ; Blood Glucose/metabolism ; Antioxidants/metabolism ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2/genetics ; Animals, Newborn ; Organelle Biogenesis ; *Insulin-Secreting Cells/metabolism ; Glucose/metabolism ; Oxidation-Reduction ; DNA, Mitochondrial/metabolism ; Adenosine Triphosphate/metabolism ; *Insulins ; },
abstract = {AIMS/HYPOTHESIS: All forms of diabetes result from insufficient functional beta cell mass. Due to the relatively limited expression of several antioxidant enzymes, beta cells are highly vulnerable to pathological levels of reactive oxygen species (ROS), which can lead to the reduction of functional beta cell mass. During early postnatal ages, both human and rodent beta cells go through a burst of proliferation that quickly declines with age. The exact mechanisms that account for neonatal beta cell proliferation are understudied but mitochondrial release of moderated ROS levels has been suggested as one of the main drivers. We previously showed that, apart from its conventional role in protecting beta cells from oxidative stress, the nuclear factor erythroid 2-related factor 2 (NRF2) is also essential for beta cell proliferation. We therefore hypothesised that NRF2, which is activated by ROS, plays an essential role in beta cell proliferation at early postnatal ages.<br><br>METHODS: Beta cell NRF2 levels and beta cell proliferation were measured in pancreatic sections from non-diabetic human cadaveric donors at different postnatal ages, childhood and adulthood. Pancreatic sections from 1-, 7-, 14- and 28-day-old beta cell-specific Nrf2 (also known as Nfe2l2)-knockout mice (&#x3b2;Nrf2KO) or control (Nrf2[lox/lox]) mice were assessed for beta cell NRF2 levels, beta cell proliferation, beta cell oxidative stress, beta cell death, nuclear beta cell pancreatic duodenal homeobox protein 1 (PDX1) levels and beta cell mass. Seven-day-old &#x3b2;Nrf2KO and Nrf2[lox/lox] mice were injected daily with N-acetylcysteine (NAC) or saline (154 mmol/l NaCl) to explore the potential contribution of oxidative stress to the phenotypes seen in &#x3b2;Nrf2KO mice at early postnatal ages. RNA-seq was performed on 7-day-old &#x3b2;Nrf2KO and Nrf2[lox/lox] mice to investigate the mechanisms by which NRF2 stimulates beta cell proliferation at early postnatal ages. Mitochondrial biogenesis and function were determined using dispersed islets from 7-day-old &#x3b2;Nrf2KO and Nrf2[lox/lox] mice by measuring MitoTracker intensity, mtDNA/gDNA ratio and ATP/ADP ratio. To study the effect of neonatal beta cell-specific Nrf2 deletion on glucose homeostasis in adulthood, blood glucose, plasma insulin and insulin secretion were determined and a GTT was performed on 3-month-old &#x3b2;Nrf2KO and Nrf2[lox/lox] mice fed on regular diet (RD) or high-fat diet (HFD).<br><br>RESULTS: The expression of the master antioxidant regulator NRF2 was increased at early postnatal ages in both human (1 day to 19 months old, 31%) and mouse (7 days old, 57%) beta cells, and gradually declined with age (8% in adult humans, 3.77% in adult mice). A significant correlation (R[2]=0.568; p=0.001) was found between beta cell proliferation and NRF2 levels in human beta cells. Seven-day-old &#x3b2;Nrf2KO mice showed reduced beta cell proliferation (by 65%), beta cell nuclear PDX1 levels (by 23%) and beta cell mass (by 67%), and increased beta cell oxidative stress (threefold) and beta cell death compared with Nrf2[lox/lox] control mice. NAC injections increased beta cell proliferation in 7-day-old &#x3b2;Nrf2KO mice (3.4-fold) compared with saline-injected &#x3b2;Nrf2KO mice. Interestingly, RNA-seq of islets isolated from 7-day-old &#x3b2;Nrf2KO mice revealed reduced expression of mitochondrial RNA genes and genes involved in the electron transport chain. Islets isolated from 7-day old &#x3b2;Nrf2KO mice presented reduced MitoTracker intensity (by 47%), mtDNA/gDNA ratio (by 75%) and ATP/ADP ratio (by 68%) compared with islets from Nrf2[lox/lox] littermates. Lastly, HFD-fed 3-month-old &#x3b2;Nrf2KO male mice displayed a significant reduction in beta cell mass (by 35%), a mild increase in non-fasting blood glucose (1.2-fold), decreased plasma insulin (by 14%), and reduced glucose tolerance (1.3-fold) compared with HFD-fed Nrf2[lox/lox] mice.<br><br>CONCLUSIONS/INTERPRETATION: Our study highlights NRF2 as an essential transcription factor for maintaining neonatal redox balance, mitochondrial biogenesis and function and beta cell growth, and for preserving functional beta cell mass in adulthood under metabolic stress.<br><br>DATA AVAILABILITY: Sequencing data are available in the NCBI Gene Expression Omnibus, accession number GSE242718 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242718).},
}
@article {pmid38204261,
year = {2024},
author = {ALRashdi, BM and Hussein, MM and Mohammed, RM and Abdelhamed, NW and Asaad, ME and Alruwaili, M and Alrashidi, SM and Habotta, OA and Abdel Moneim, AE and Ramadan, SS},
title = {Turmeric Extract-loaded Selenium Nanoparticles Counter Doxorubicin-induced Hepatotoxicity in Mice via Repressing Oxidative Stress, Inflammatory Cytokines, and Cell Apoptosis.},
journal = {Anti-cancer agents in medicinal chemistry},
volume = {24},
number = {6},
pages = {443-453},
pmid = {38204261},
issn = {1875-5992},
support = {DSR-2021-03-03112//Deanship of Scientific Research at Jouf University/ ; },
mesh = {Animals ; *Doxorubicin/pharmacology ; *Oxidative Stress/drug effects ; Mice ; *Selenium/chemistry/pharmacology ; *Apoptosis/drug effects ; *Plant Extracts/pharmacology/chemistry ; *Cytokines/metabolism ; *Nanoparticles/chemistry ; Male ; Curcuma/chemistry ; Chemical and Drug Induced Liver Injury/drug therapy/metabolism/pathology ; Dose-Response Relationship, Drug ; Structure-Activity Relationship ; Antibiotics, Antineoplastic/pharmacology ; Cell Proliferation/drug effects ; },
abstract = {BACKGROUND: Doxorubicin (DOX) is an antitumor anthracycline used to treat a variety of malignancies; however, its clinical use is associated with noticeable hepatotoxicity. Therefore, the current study was designed to delineate if biosynthesized SeNPs with turmeric extract (Tur-SeNPs) could alleviate DOX-induced hepatic adverse effects.<br><br>METHODS: Mice were orally post-treated with Tur extract, Tur-SeNPs, or N-acetyl cysteine after the intraperitoneal injection of DOX.<br><br>RESULTS: Our findings have unveiled a remarkable liver attenuating effect in DOX-injected mice post-treated with Tur-SeNPs. High serum levels of ALT, AST, ALP, and total bilirubin induced by DOX were significantly decreased by Tur-SeNPs therapy. Furthermore, Tur-SeNPs counteracted DOX-caused hepatic oxidative stress, indicated by decreased MDA and NO levels along with elevated levels of SOD, CAT, GPx, GR, GSH, and mRNA expression levels of Nrf-2. Noteworthily, decreased hepatic IL-1&#x3b2;, TNF-&#x3b1;, and NF-&#x3ba;B p65 levels in addition to downregulated iNOS gene expression in Tur-SeNPs-treated mice have indicated their potent antiinflammatory impact. Post-treatment with Tur-SeNPs also mitigated the hepatic apoptosis evoked by DOX injection. A liver histological examination confirmed the biochemical and molecular findings.<br><br>CONCLUSIONS: In brief, the outcomes have demonstrated Tur loaded with nanoselenium to successfully mitigate the liver damage induced by DOX via blocking oxidative stress, and inflammatory and apoptotic signaling.},
}
@article {pmid38203377,
year = {2023},
author = {Govoni, S and Fantucci, P and Marchesi, N and Vertemara, J and Pascale, A and Allegri, M and Calvillo, L and Vanoli, E},
title = {N-Acetylcysteine Antagonizes NGF Activation of TrkA through Disulfide Bridge Interaction, an Effect Which May Contribute to Its Analgesic Activity.},
journal = {International journal of molecular sciences},
volume = {25},
number = {1},
pages = {},
pmid = {38203377},
issn = {1422-0067},
support = {GU Serie Generale n. 92 , April 19, 2014//MIUR (ministry of University and Research) GU Serie Generale n. 92 , April 19, 2014, funding Neuheart S.r.l. (516.456 &#x20ac;) for the project having the title "Sviluppo di farmaci agonisti ed antagonisti delle neurotrofine (Development of neurotrophin-receptor/ ; },
mesh = {Humans ; *Acetylcysteine/pharmacology ; Nerve Growth Factor/pharmacology ; *Neuroblastoma ; Analgesics/pharmacology ; Disulfides ; },
abstract = {N-acetylcysteine (NAC), a mucolytic agent and an antidote to acetaminophen intoxication, has been studied in experimental conditions and trials exploring its analgesic activity based on its antioxidant and anti-inflammatory properties. The purpose of this study is to investigate additional mechanisms, namely, the inhibition of nerve growth factor (NGF) and the activation of the Tropomyosin receptor kinase A (TrkA) receptor, which is responsible for nociception. In silico studies were conducted to evaluate dithiothreitol and NAC's interaction with TrkA. We also measured the autophosphorylation of TrkA in SH-SY5Y cells via ELISA to assess NAC's in vitro activity against NGF-induced TrkA activation. The in silico and in vitro tests show that NAC interferes with NGF-induced TrkA activation. In particular, NAC breaks the disulfide-bound Cys 300-345 of TrkA, perturbing the NGF-TrkA interaction and producing a rearrangement of the binding site, inducing a consequent loss of their molecular recognition and spatial reorganization, which are necessary for the induction of the autophosphorylation process. The latter was inhibited by 40% using 20 mM NAC. These findings suggest that NAC could have a role as a TrkA antagonist, an action that may contribute to the activity and use of NAC in various pain states (acute, chronic, nociplastic) sustained by NGF hyperactivity and/or accompanied by spinal cord sensitization.},
}
@article {pmid38203359,
year = {2023},
author = {Boguszewicz, &#x141; and Bieleń, A and Ciszek, M and Skorupa, A and Mrochem-Kwarciak, J and Składowski, K and Sokół, M},
title = {Metabolomic Insight into Implications of Induction Chemotherapy Followed by Concomitant Chemoradiotherapy in Locally Advanced Head and Neck Cancer.},
journal = {International journal of molecular sciences},
volume = {25},
number = {1},
pages = {},
pmid = {38203359},
issn = {1422-0067},
mesh = {Humans ; Squamous Cell Carcinoma of Head and Neck/therapy ; *Induction Chemotherapy ; Phosphorylcholine ; *Head and Neck Neoplasms/therapy ; Chemoradiotherapy/adverse effects ; Betaine ; Serine ; Tyrosine ; Lipids ; },
abstract = {The present study compares two groups of locally advanced patients with head and neck squamous cell carcinoma (LA-HNSCC) undergoing concurrent chemoradiotherapy (cCHRT), specifically those for whom it is a first-line treatment and those who have previously received induction chemotherapy (iCHT). The crucial question is whether iCHT is a serious burden during subsequent treatment for LA-HNSCC and how iCHT affects the tolerance to cCHRT. Of the 107 LA-HNSCC patients, 54 received cisplatin-based iCHT prior to cCHRT. The patients were clinically monitored at weekly intervals from the day before until the completion of the cCHRT. The 843 blood samples were collected and divided into two aliquots: for laboratory blood tests and for nuclear magnetic resonance (NMR) spectroscopy (a Bruker 400 MHz spectrometer). The NMR metabolites and the clinical parameters from the laboratory blood tests were analyzed using orthogonal partial least squares analysis (OPLS) and the Mann-Whitney U test (MWU). After iCHT, the patients begin cCHRT with significantly (MWU p-value < 0.05) elevated blood serum lipids, betaine, glycine, phosphocholine, and reticulocyte count, as well as significantly lowered NMR inflammatory markers, serine, hematocrit, neutrophile, monocyte, red blood cells, hemoglobin, and CRP. During cCHRT, a significant increase in albumin and psychological distress was observed, as well as a significant decrease in platelet, N-acetyl-cysteine, tyrosine, and phenylalanine, in patients who received iCHT. Importantly, all clinical symptoms (except the decreased platelets) and most metabolic alterations (except for betaine, serine, tyrosine, glucose, and phosphocholine) resolve until the completion of cCHRT. In conclusion, iCHT results in hematological toxicity, altered lipids, and one-carbon metabolism, as well as downregulated inflammation, as observed at the beginning and during cCHRT. However, these complications are temporary, and most of them resolve at the end of the treatment. This suggests that iCHT prior to cCHRT does not pose a significant burden and should be considered as a safe treatment option for LA-HNSCC.},
}
@article {pmid38199597,
year = {2024},
author = {Yuan, Z and Yi, G and Ma, R and Wang, Z and Hu, J and Zhao, W and Hu, Y},
title = {Aldehyde oxidase 1 promotes gallbladder carcinogenesis through ROS-mediated activation of the Wnt/β-catenin pathway.},
journal = {Cellular signalling},
volume = {116},
number = {},
pages = {111042},
doi = {10.1016/j.cellsig.2024.111042},
pmid = {38199597},
issn = {1873-3913},
mesh = {Animals ; Humans ; Mice ; Aldehyde Oxidase ; beta Catenin ; Carcinogenesis ; *Gallbladder Neoplasms ; Reactive Oxygen Species ; Wnt Signaling Pathway ; },
abstract = {BACKGROUND: Aldehyde oxidase 1 (AOX1) is associated with various pathophysiological processes, including cancer. Specifically, AOX1 has been demonstrated to have a close relationship with the progression of certain cancers. However, the expression, function, and mechanisms of action of AOX1 in gallbladder cancer (GBC) remain unclear.<br><br>METHODS: Utilizing immunohistochemistry, the study quantified the prevalence of AOX1 within tissues of gallbladder carcinoma and those of the surrounding non-cancerous regions. In vitro assays using gallbladder carcinoma cell lines with modulated AOX1 expression levels were performed to assess the protein's role in cell proliferation, migration, and invasion. Furthermore, flow cytometry techniques were harnessed to determine the influence of AOX1 on the content of reactive oxygen species (ROS) in these cells. Additionally, the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt/&#x3b2;-catenin signaling pathway markersin cells with varied AOX1 expression, detected through Western blot analyses. An in vivo xenograft model involving athymic mice was implemented to explore the influence of AOX1 on gallbladder tumor growth, with Western blot analysis applied to measure EMT marker expression in the resulting tumours.<br><br>RESULTS: Elevated AOX1 protein levels have been observed in gallbladder carcinoma tissues, with such upregulation linked to a negative prognostic outlook for patients. In vitro analyses demonstrate that enhanced AOX1 expression facilitates gallbladder carcinoma cell proliferation, migration, and invasion, while AOX1 suppression yields an inhibitory effect on these cellular behaviors. Western blot results reveal an inverse relationship between AOX1 and E-cadherin levels, yet was positively correlation with N-cadherin, Vimentin, and Snail within both gallbladder cancer cells and in vivo xenograft tumours. Further mechanistic investigation indicates that AOX1 elevation augments reactive oxygen species (ROS) production and initiates the Wnt/&#x3b2;-catenin signaling pathway in these cells. The application of N-acetylcysteine (NAC) and/or KY1797K attenuates the proliferative, migratory, and invasive enhancements imparted by AOX1 overexpression and reinforces these effects when AOX1 is silenced-achieved through ROS mitigation and the obstruction of the Wnt/&#x3b2;-catenin pathway. In vivo studies corroborate these findings, showing AOX1 overexpression to amplify xenograft tumor growth and mesenchymal marker expression, whereas AOX1 interference did the opposite.<br><br>CONCLUSIONS: The study indicates that AOX1 functions as a carcinogenic factor in gallbladder carcinoma, enhancing cell proliferation, migration, invasion, and the EMT. These effects are driven by the activation of the Wnt/&#x3b2;-catenin pathway mediated by reactive oxygen species (ROS). Therefore,AOX1 presents potential as a valuable prognostic and diagnostic marker as well as a target for therapeutic intervention in the gallbladder cancer.},
}
@article {pmid38194754,
year = {2024},
author = {Yang, D and Yu, X and Li, X and Yu, B and Peng, H},
title = {Protective effects of l-cysteine and N-acetyl-l-cysteine on boar sperm quality during hypothermic liquid storage with bovine serum albumin as a protectant.},
journal = {Theriogenology},
volume = {216},
number = {},
pages = {185-195},
doi = {10.1016/j.theriogenology.2023.12.030},
pmid = {38194754},
issn = {1879-3231},
mesh = {Male ; Swine ; Animals ; *Semen ; Acetylcysteine/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Serum Albumin, Bovine/pharmacology/metabolism ; Antioxidants/pharmacology/metabolism ; AMP-Activated Protein Kinases/metabolism ; Sperm Motility ; Spermatozoa/physiology ; Semen Analysis/veterinary ; Glutathione/metabolism ; Adenosine Triphosphate/metabolism ; *Semen Preservation/veterinary/methods ; },
abstract = {Hypothermic liquid storage at 4-5 °C has emerged as a novel approach for preserving boar semen, offering innovative possibilities for semen preservation. However, this method also presents challenges, including cold shock and excessive reactive oxygen species (ROS) production. Therefore, reducing oxidative damage induced by low temperatures becomes essential while supplementing appropriate protectants. In this study, we investigated the efficacy of Bovine Serum Albumin (BSA) compared to Polyvinylpyrrolidone (PVP) and Skim Milk Powder (SMP) in maintaining boar sperm motility and progressive motility using computer-assisted sperm analysis (CASA). Among the tested concentrations, 4 g/L of BSA exhibited the best protective effect. Subsequently, we supplemented different concentrations of l-cysteine (LC) and N-acetyl-l-cysteine (NAC) as additives in the presence of BSA as a protectant. Our results demonstrated that 1 mmol/L of LC and 0.5 mmol/L of NAC exhibited superior protection of sperm quality compared to other concentrations. Furthermore, the 1 mmol/L LC and 0.5 mmol/L NAC groups showed significantly improved plasma membrane integrity and acrosome integrity compared to the control group. These groups also exhibited enhanced antioxidant capacity, evidenced by increased mitochondrial membrane potential (MMP), ATP production, total superoxide dismutase (T-SOD) activity, total antioxidant capacity (T-AOC), glutathione (GSH), glutathione peroxidase (GSH-PX), and GPX-4 levels. Additionally, they demonstrated decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as reduced oxidized glutathione (GSSG) and glutathione reductase (GR) levels. Furthermore, LC and NAC treatment enhanced AMP-activated protein kinase (AMPK) phosphorylation. However, inhibiting AMPK using compound C did not inhibit the protective effects of LC and NAC on low-temperature preserved boar sperm. These findings suggest that 4 g/L BSA can serve as an effective protectant for hypothermic liquid storage of boar semen. Additionally, LC and NAC supplementation reduces oxidative damage by enhancing antioxidant capacity rather than through AMPK-mediated ATP supplementation. These results contribute to advancing the application of LC and NAC in hypothermic liquid storage of boar semen.},
}
@article {pmid38191622,
year = {2024},
author = {Romero-Miguel, D and Casquero-Veiga, M and Lamanna-Rama, N and Torres-Sánchez, S and MacDowell, KS and García-Partida, JA and Santa-Marta, C and Berrocoso, E and Leza, JC and Desco, M and Soto-Montenegro, ML},
title = {N-acetylcysteine during critical neurodevelopmental periods prevents behavioral and neurochemical deficits in the Poly I:C rat model of schizophrenia.},
journal = {Translational psychiatry},
volume = {14},
number = {1},
pages = {14},
pmid = {38191622},
issn = {2158-3188},
mesh = {Female ; Pregnancy ; Rats ; Animals ; Rats, Wistar ; *Acetylcysteine/pharmacology ; *Schizophrenia/drug therapy/prevention &amp; control ; Poly I-C ; Inflammation ; },
abstract = {Schizophrenia is a chronic neurodevelopmental disorder with an inflammatory/prooxidant component. N-acetylcysteine (NAC) has been evaluated in schizophrenia as an adjuvant to antipsychotics, but its role as a preventive strategy has not been sufficiently explored. We aimed to evaluate the potential of NAC administration in two-time windows before the onset of symptoms in a schizophrenia-like maternal immune stimulation (MIS) rat model. Pregnant Wistar rats were injected with Poly I:C or Saline on gestational day (GD) 15. Three different preventive approaches were evaluated: 1) NAC treatment during periadolescence in the offspring (from postnatal day [PND] 35 to 49); 2) NAC treatment during pregnancy after MIS challenge until delivery (GD15-21); and 3) NAC treatment throughout all pregnancy (GD1-21). At postnatal day (PND) 70, prepulse inhibition (PPI) and anxiety levels were evaluated. In vivo magnetic resonance (MR) imaging was acquired on PND100 to assess structural changes in gray and white matter, and brain metabolite concentrations. Additionally, inflammation and oxidative stress (IOS) markers were measured ex vivo in selected brain regions. MIS offspring showed behavioral, neuroanatomical, and biochemical alterations. Interestingly, NAC treatment during periadolescence prevented PPI deficits and partially counteracted some biochemical imbalances. Moreover, NAC treatments during pregnancy not only replicated the beneficial outcomes reported by the treatment in periadolescence, but also prevented some neuroanatomical deficits, including reductions in hippocampal and corpus callosum volumes. This study suggests that early reduction of inflammation and prooxidation could help prevent the onset of schizophrenia-like symptoms, supporting the importance of anti-IOS compounds in ameliorating this disorder.},
}
@article {pmid38190586,
year = {2024},
author = {Lebrun, F and Levard, D and Lemarchand, E and Yetim, M and Furon, J and Potzeha, F and Marie, P and Lesept, F and Blanc, M and Haelewyn, B and Rubio, M and Letourneur, A and Violle, N and Orset, C and Vivien, D},
title = {Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages.},
journal = {Blood advances},
volume = {8},
number = {5},
pages = {1330-1344},
pmid = {38190586},
issn = {2473-9537},
support = {EP-D-14-002/EPA/EPA/United States ; },
mesh = {Mice ; Animals ; Humans ; Tissue Plasminogen Activator/pharmacology/therapeutic use ; Mice, Obese ; *Stroke/drug therapy/etiology ; Hemorrhage ; Inflammation/drug therapy ; *Ischemic Stroke/complications/drug therapy ; *Hyperglycemia/complications/drug therapy ; },
abstract = {The pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis. This detrimental impact of tPA on the neurovascular unit in patients with hyperglycemia has been ascribed to its capacity to induce endothelial N-methyl-D-aspartate receptor (NMDAR) signaling, contributing to compromised blood-brain barrier integrity and neuroinflammatory processes. In a mouse model of thromboembolic stroke with chronic hyperglycemia, we assessed the effectiveness of rtPA and N-acetylcysteine (NAC) as thrombolytic agents. We also tested the effect of blocking tPA/NMDAR signaling using a monoclonal antibody, Glunomab. Magnetic resonance imaging, speckle contrast imaging, flow cytometry, and behavioral tasks were used to evaluate stroke outcomes. In hyperglycemic animals, treatment with rtPA resulted in lower recanalization rates and increased HTs. Conversely, NAC treatment reduced lesion sizes while mitigating HTs. After a single administration, either in standalone or combined with rtPA-induced thrombolysis, Glunomab reduced brain lesion volumes, HTs, and neuroinflammation after stroke, translating into improved neurological outcomes. Additionally, we demonstrated the therapeutic efficacy of Glunomab in combination with NAC or as a standalone strategy in chronic hyperglycemic animals. Counteracting tPA-dependent endothelial NMDAR signaling limits ischemic damages induced by both endogenous and exogenous tPA, including HTs and inflammatory processes after ischemic stroke in hyperglycemic animals.},
}
@article {pmid38188454,
year = {2024},
author = {El-Sobky, H and El-Shanawany, SM and Ghanem, M and Atef, M},
title = {Role of N-acetylcysteine and vitamin B complex in improving outcomes of corrosive ingestion.},
journal = {Toxicology research},
volume = {13},
number = {1},
pages = {tfad125},
pmid = {38188454},
issn = {2045-452X},
abstract = {BACKGROUND: Corrosive ingestion remains a worldwide public health problem. To date, there are no specific medications with approved efficacy in reducing gastrointestinal injury progression following corrosive ingestion.<br><br>AIM: The current study assessed the efficacy of N-acetylcysteine (NAC) and vitamin B complex as adjuvant therapy in improving the outcome of patients with corrosive ingestion.<br><br>SUBJECTS AND METHODS: The study included 92 patients with acute corrosive ingestion admitted to Alexandria Poison Center. Patients were distributed into four equal-sized groups and managed as such; Group I received the standard treatment protocol. The other three groups received IV antioxidants in addition to the standard treatment; Group II received NAC, Group III received vitamin B complex, and Group IV received both NAC and vitamin B complex. To assess occurrence of delayed complications, barium swallow and meal were done 21&#xa0;days after acute corrosive ingestion, and every patient was followed up for one year.<br><br>RESULTS: Start of oral intake was earliest among patients in Group II, and as a result, the need for parenteral nutrition decreased significantly with a subsequent decrease in duration of hospitalization. The highest percentage of patients showing normal findings of barium swallow and meal was among the two groups that received NAC (72.7% in Group II and 77.8% in Group IV). Group IV patients who received NAC and vitamin B complex had no esophageal strictures with improved outcomes.<br><br>CONCLUSION: NAC and vitamin B complex enhanced recovery in the acute stage, in addition to prevention of delayed complications, especially esophageal strictures.<br><br>HIGHLIGHTS: Acute corrosive ingestion is associated with high morbidity because of its catastrophic presentation and lifelong complications.This study was conducted on 92 patients admitted to Alexandria Poison Center (APC).IV NAC significantly decreased the time needed for starting oral intake after acute corrosive ingestion and consequently, the need for parenteral nutrition and duration of hospitalization.No patients suffered from esophageal strictures in the group which received both IV NAC and vitamin B complex.Both NAC and vitamin B complex improved the outcome of patients after ingestion of corrosives whether acids or alkalis.},
}
@article {pmid38187538,
year = {2023},
author = {Dobariya, P and Xie, W and Rao, SP and Xie, J and Seelig, DM and Vince, R and Lee, MK and More, SS},
title = {Deletion of Glyoxalase 1 exacerbates acetaminophen-induced hepatotoxicity in mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38187538},
issn = {2692-8205},
support = {R01 AG062469/AG/NIA NIH HHS/United States ; },
abstract = {Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC) has a narrow therapeutic window and early treatment is essential for satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late-presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end-products (AGEs) and consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase-1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in APAP mediated activation of RAGE and downstream cell-death cascades. Constitutive Glo-1 knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were employed as tools. Our findings show elevated oxidative stress, activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild type controls. A unique feature of the hepatic necrosis in GKO mice is the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than inflammation seen in wild type. The GSH surrogate and general antioxidant, ψ-GSH alleviated APAP toxicity irrespective of Glo-1 status, suggesting that oxidative stress being the primary driver of APAP toxicity. Overall, exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against initial stages of APAP overdose.},
}
@article {pmid38184979,
year = {2024},
author = {Zhou, J and Zhang, Y and Zeng, L and Wang, X and Xiang, W and Su, P},
title = {Cadmium exposure induces pyroptosis of TM4 cells through oxidative stress damage and inflammasome activation.},
journal = {Ecotoxicology and environmental safety},
volume = {270},
number = {},
pages = {115930},
doi = {10.1016/j.ecoenv.2024.115930},
pmid = {38184979},
issn = {1090-2414},
mesh = {Male ; Humans ; *Inflammasomes/metabolism ; *Cadmium/toxicity ; Reactive Oxygen Species ; Pyroptosis ; Signal Transduction ; Oxidative Stress ; Acetylcysteine/pharmacology ; },
abstract = {Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1β (IL-1β) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11-7082 (BAY) alleviate the release of IL-1β and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.},
}
@article {pmid38169912,
year = {2023},
author = {Abdo, M and Kohaf, N and Hammad, MA and Ping, CC},
title = {The Role of Oral Ascorbic Acid Administration in Combination With IV N-acetylcysteine in Delaying Inflammatory Cascade in Sepsis: A Case Report.},
journal = {Cureus},
volume = {15},
number = {12},
pages = {e49868},
pmid = {38169912},
issn = {2168-8184},
abstract = {Sepsis is a life-threatening emergency that arises owing to a dysregulated host response to infection, leading to existence organ dysfunction. Vitamin C administration has led to a lower mortality rate in sepsis. N-acetylcysteine (NAC) treatment during sepsis improves hepatic function and enhances tissue oxygenation. The objective of this case report is to investigate the synergistic effect of the combination of vitamin C, thiamine, and NAC in delaying sepsis cascade and prolongation of survival time. In this case report, an oral dose of vitamin C 500 mg three times daily in combination with IV thiamine 100 mg three times daily, IV NAC, and hydrocortisone stress dose resulted in 12 days of survival of an immunocompromised patient with ventilator-associated pneumonia on single anti-pseudomonas beta-lactam antibiotic. The patient was a 60-year-old Malay female with previous bone marrow transplantation surgery and a medical history of ischemic stroke on phenytoin and valproate therapy. The patient was transferred to a medical ward in Penang General Hospital, Malaysia, due to community-acquired pneumonia. She was on ceftriaxone for five days, then sedated and ventilated in the ICU, with a shift to cefepime for three days, which was then changed to meropenem for nine days until the last day of life. Total anti-pseudomonas coverage was 12 days. The patient had multiple comorbidities from phenytoin-induced hepatic encephalopathy, acute kidney injury, and three sessions of hemodialysis. IV vitamin C was not available, so an oral dose was administered with potential efficacy in delaying the sepsis inflammatory cascade, leading to the use of a single (not double) anti-pseudomonas antibiotic for 12 days. Prolonged survival duration may be expected in the case of normal bone marrow patients with ventilator-associated pneumonia sepsis. In conclusion, Vitamin C, thiamine, and NAC combination resulted in delayed sepsis progression for 12 days and the survival of the immunocompromised patient on a single anti-pseudomonas beta-lactam antibiotic.},
}
@article {pmid38169324,
year = {2024},
author = {Bildik, G and Gray, JP and Mao, W and Yang, H and Ozyurt, R and Orellana, VR and De Wever, O and Carey, MS and Bast, RC and Lu, Z},
title = {DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.},
journal = {Autophagy},
volume = {20},
number = {3},
pages = {675-691},
pmid = {38169324},
issn = {1554-8635},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA083639/CA/NCI NIH HHS/United States ; P50 CA217685/CA/NCI NIH HHS/United States ; R01 CA266187/CA/NCI NIH HHS/United States ; },
mesh = {Female ; Humans ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Autophagy/physiology ; *Ovarian Neoplasms/drug therapy/genetics/metabolism ; *Pancreatic Neoplasms/drug therapy/genetics/pathology ; *Carcinoma, Pancreatic Ductal/pathology ; Chloroquine/pharmacology ; },
abstract = {Pancreatic ductal adenocarcinoma (PDAC) and low-grade ovarian cancer (LGSOC) are characterized by the prevalence of KRAS oncogene mutations. DIRAS3 is the first endogenous non-RAS protein that heterodimerizes with RAS, disrupts RAS clustering, blocks RAS signaling, and inhibits cancer cell growth. Here, we found that DIRAS3-mediated KRAS inhibition induces ROS-mediated apoptosis in PDAC and LGSOC cells with KRAS mutations, but not in cells with wild-type KRAS, by downregulating NFE2L2/Nrf2 transcription, reducing antioxidants, and inducing oxidative stress. DIRAS3 also induces cytoprotective macroautophagy/autophagy that may protect mutant KRAS cancer cells from oxidative stress, by inhibiting mutant KRAS, activating the STK11/LKB1-PRKAA/AMPK pathway, increasing lysosomal CDKN1B/p27 localization, and inducing autophagic gene expression. Treatment with chloroquine or the novel dimeric chloroquine analog DC661 significantly enhances DIRAS3-mediated inhibition of mutant KRAS tumor cell growth in vitro and in vivo. Taken together, our study demonstrates that DIRAS3 plays a critical role in regulating mutant KRAS-driven oncogenesis in PDAC and LGSOC.Abbreviations: AFR: autophagic flux reporter; ATG: autophagy related; CQ: chloroquine; DCFDA: 2'-7'-dichlorodihydrofluorescein diacetate; DIRAS3: DIRAS family GTPase 3; DOX: doxycycline; KRAS: KRAS proto-oncogene, LGSOC: low-grade serous ovarian cancer; MiT/TFE: microphthalmia family of transcription factors; NAC: N-acetylcysteine; PDAC: pancreatic ductal adenocarcinoma; ROS: reactive oxygen species; TFEB: transcription factor EB.},
}
@article {pmid38165196,
year = {2023},
author = {Cole, JB and Oakland, CL and Lee, SC and Considine, KA and Rudis, MI and Swanson, AL and Olives, TD},
title = {Is Two Better Than Three? A Systematic Review of Two-bag Intravenous N-acetylcysteine Regimens for Acetaminophen Poisoning.},
journal = {The western journal of emergency medicine},
volume = {24},
number = {6},
pages = {1131-1145},
pmid = {38165196},
issn = {1936-9018},
mesh = {Child ; Humans ; *Acetaminophen/poisoning ; *Acetylcysteine/therapeutic use/adverse effects ; Analgesics, Non-Narcotic/therapeutic use ; Antidotes/therapeutic use ; *Drug Overdose/drug therapy ; *Drug-Related Side Effects and Adverse Reactions ; Infusions, Intravenous ; },
abstract = {INTRODUCTION: Acetaminophen poisoning is commonly treated by emergency physicians. First-line therapy is N-acetylcysteine (NAC), traditionally administered intravenously via a US Food and Drug Administration (FDA)-approved three-bag protocol in which each bag has a unique concentration and infusion duration. Recently, simplified, off-label two-bag NAC infusion protocols have become more common. The purpose of this review is to summarize the effectiveness and safety of two-bag NAC.<br><br>METHODS: We undertook a comprehensive search of PubMed, EMBASE, and MEDLINE from inception to December 13, 2022, for articles describing human acetaminophen poisonings treated with two-bag NAC, defined as any regimen involving two discrete infusions in two separate bags. Outcomes included effectiveness (measured by incidence of liver injury); incidence of non-allergic anaphylactoid reactions (NAAR); gastrointestinal, cutaneous, and systemic reactions; treatments for NAARs; incidence of NAC-related medication errors; and delays or interruptions in NAC administration.<br><br>RESULTS: Twelve articles met final inclusion, 10 of which compared two-bag NAC to the three-bag regimen. Nine articles evaluated the two-bag/20-hour regimen, a simplified version of the FDA-approved three-bag regimen in which the traditional first and second bags are combined into a single four-hour infusion. Nine articles assessed comparative effectiveness of two-bag NAC in terms of liver injury, most commonly assessed for by incidence of hepatotoxicity (aspartate aminotransferase or alanine aminotransferase&#x2009;>1,000 international units per liter). No difference in liver injury was observed between two-bag and three-bag regimens. Of nine articles comparing incidence of NAARs, eight demonstrated statistically fewer NAARs with two-bag regimens, and one showed no difference. In seven articles evaluating treatment for NAARs (antihistamines, corticosteroids, epinephrine), all showed that patients received fewer medications for NAARs with two-bag NAC. Three articles evaluated NAC-related medication errors; two demonstrated no difference, while one study evaluating only children showed fewer errors with two-bag NAC. Two studies evaluated delays and/or interruptions in NAC infusions; both favored two-bag NAC.<br><br>CONCLUSION: For patients with acetaminophen poisoning, two-bag NAC regimens appear to have similar outcomes to the traditional three-bag regimen in terms of liver injury. Two-bag NAC regimens are associated with fewer adverse events and fewer treatments for those events than the three-bag regimen and fewer interruptions in antidotal therapy.},
}
@article {pmid38164872,
year = {2023},
author = {Sun, J and Zhang, X and Wang, L and Di Stefano, AFD and Zanin, V and Magrone, P and Yuan, Y},
title = {Phase I study of the pharmacokinetics and safety of single and multiple doses of intravenous N-acetylcysteine in healthy Chinese subjects.},
journal = {European review for medical and pharmacological sciences},
volume = {27},
number = {24},
pages = {12103-12111},
doi = {10.26355/eurrev_202312_34808},
pmid = {38164872},
issn = {2284-0729},
mesh = {Female ; Humans ; Male ; *Acetylcysteine/administration &amp; dosage/pharmacokinetics ; Administration, Intravenous ; Administration, Oral ; Area Under Curve ; China ; Dose-Response Relationship, Drug ; Healthy Volunteers ; East Asian People ; },
abstract = {OBJECTIVE: The aim of the study was to determine the pharmacokinetics (PK) and safety of single and repeat doses of intravenous (IV) N-acetylcysteine (NAC) in Chinese subjects.<br><br>PATIENTS AND METHODS: A total of 24 healthy male and female Chinese subjects aged 19-40 years were enrolled in this open-label phase I study. All subjects received a single dose of NAC 600&#xa0;mg IV on day 1 and, after a 3-day washout, received repeat doses of NAC 600&#xa0;mg IV (twice daily on days 4 and 5 and once on day 6).<br><br>RESULTS: Following a single dose, plasma NAC concentrations peaked rapidly, starting to fall at the end of the 5-minute infusion in a multiphasic manner. Mean Cmax was 83.30 &#x3bc;g/mL (CV% 30.7%), median Tmax was 0.083&#xa0;h (range 0.08-0.25 h), and mean AUC(0-12 h) was 81.87 h*&#x3bc;g/mL (CV 14.0%). Following repeat dosing, Cmax was approximately 20% higher than after a single dose, with similar Tmax. Total exposure AUC(0-12) was 13% higher at steady state than after single dosing. The accumulation ratio was approximately 1.13, indicating only a slight accumulation with multiple dosing. NAC was eliminated with T1/2 of approximately 8 hours. Around 15% of the total NAC dose was excreted in the urine in the 32 hours post-dose, keeping with extensive NAC metabolism and transformation. Renal clearance of NAC was 995.2 mL/h (CV 50.2%). IV NAC was well tolerated after both single and multiple dosing.<br><br>CONCLUSIONS: This is the first robust study evaluating the PK and safety of IV NAC 600 mg in Chinese subjects and provides important data if this agent is to be used IV as a mucolytic in this population.},
}
@article {pmid38159349,
year = {2024},
author = {Erkovich, AV and Korotkova, EI and Dorozhko, EV and Plotnikov, EV and Semin, VO and Chernova, AP and Barek, J and Solomonenko, AN and Aseeva, NV},
title = {A novel impedimetric sensor based on N-acetyl-L-cysteine for the determination of hydroxyl radicals in cell cultures in vitro.},
journal = {Talanta},
volume = {270},
number = {},
pages = {125600},
doi = {10.1016/j.talanta.2023.125600},
pmid = {38159349},
issn = {1873-3573},
mesh = {*Hydroxyl Radical ; Acetylcysteine ; Electrochemical Techniques/methods ; Gold/chemistry ; Electrodes ; Cell Culture Techniques ; Immunoglobulin E ; *Biosensing Techniques/methods ; Limit of Detection ; },
abstract = {We report a novel impedimetric sensor based on a graphite electrode impregnated with polyethylene and paraffin under vacuum (IGE) modified with electrochemically deposited gold and a self-assembled monolayer of N-acetyl-L-cysteine (NAC/Au/IGE) for selective and sensitive determination of extracellular hydroxyl radicals (OH[•]) generated by living cells. The application of a sulphur-containing molecule oxidized by OH[•] predicts the high selectivity of the sensor, and the utilization of the non-faradaic impedance spectroscopy for recording an analytical response makes it possible to achieve superior sensitivity with a detection limit of 0.01 nM and a linear dynamic range of 0.08-8 nM. Meanwhile, NAC/Au/IGE demonstrated a strong potential of detecting OH[•] generated by biological objects via successful determination of extracellular hydroxyl radicals generated by normal fibroblast cells and prostate carcinoma cells.},
}
@article {pmid38157955,
year = {2024},
author = {Asuku, AO and Ayinla, MT and Ajibare, AJ and Olajide, TS},
title = {Mercury chloride causes cognitive impairment, oxidative stress and neuroinflammation in male Wistar rats: The potential protective effect of 6-gingerol-rich fraction of Zingiber officinale via regulation of antioxidant defence system and reversal of pro-inflammatory markers increase.},
journal = {Brain research},
volume = {1826},
number = {},
pages = {148741},
doi = {10.1016/j.brainres.2023.148741},
pmid = {38157955},
issn = {1872-6240},
mesh = {Rats ; Male ; Animals ; Antioxidants/pharmacology/metabolism ; Rats, Wistar ; *Zingiber officinale ; Chlorides ; Neuroinflammatory Diseases ; Mercuric Chloride/toxicity ; Tumor Necrosis Factor-alpha/metabolism ; NF-kappa B/metabolism ; Interleukin-6 ; Acetylcholinesterase ; Oxidative Stress ; Glutathione/metabolism ; Acetylcysteine/pharmacology ; Superoxide Dismutase/metabolism ; *Mercury/pharmacology ; *Cognitive Dysfunction ; *Catechols ; *Fatty Alcohols ; },
abstract = {This study investigated the effects of 6-gingerol-rich fraction of Zingiber officinale (6-GIRIFZO) on mercury chloride (HgCl2)-induced neurotoxicity in Wistar rats. Thirty -five male Wistar rats weighing between (150-200 g) were divided randomly into five groups (n = 7): group 1: control, received 0.5 mL of normal saline, group 2: received HgCl2 (5 mg/kg), group 3: received N-acetylcysteine (NAC) (50 mg/kg) as well as HgCl2 (5 mg/kg), group 4: received 6-GIRIFZO (100 mg/kg) and HgCl2 (5 mg/kg), group 5: had 6-GIRIFZO (200 mg/kg) and HgCl2 (5 mg/kg), consecutively for 14 days. On the day14, the rats were subjected to behavioural tests using a Morris water maze and novel object recognition tests. The rats were then euthanized to obtain brain samples for the determination of biochemical parameters (acetylcholinesterase (AchE), nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione (GSH), tumor necrosis factor- alpha (TNF-α), nuclear factor kappa-B (NF-κB), interleukin-1β (IL-1β) and interleukin-6 (IL-6)) using standard methods. The result revealed a significant increase in escape latency and a significant decrease in recognition ratio in the rats that were exposed to HgCl2 only. However, 6-GIRIFZO produced a significant reduction in the escape latency and (p < 0.05) increase in the recognition ratio. Similarly, HgCl2 exposure caused a significant (p < 0.05) decrease in the brain SOD, GPx, CAT, GSH with increased brain levels of MDA, NO, AchE, TNF-α, NF-κB, IL-1β and IL-6. Similarly to the standard drug, NAC, 6-GIRIFZO (100 and 200 mg/kg) significantly (p < 0.05) increased brain SOD, GPx, CAT, and GSH levels with decreased concentrations of MDA, NO, AchE, TNF-α, NF-κB, IL-1β and IL-6. Also, pre-treatment with 6-GIRIFZO prevented the HgCl2-induced morphological aberrations in the rats. This study concludes that 6-GIRIFZO prevents HgCl2-induced cognitive deficit via reduction of brain inflammation as well as oxidative stress in rats.},
}
@article {pmid38157913,
year = {2024},
author = {Wang, Y and Xing, C and Cai, B and Qiu, W and Zhai, J and Zeng, Y and Zhang, A and Shi, S and Zhang, Y and Yang, X and Fu, TM and Shen, H and Wang, C and Zhu, L and Ye, J},
title = {Impact of antioxidants on PM2.5 oxidative potential, radical level, and cytotoxicity.},
journal = {The Science of the total environment},
volume = {912},
number = {},
pages = {169555},
doi = {10.1016/j.scitotenv.2023.169555},
pmid = {38157913},
issn = {1879-1026},
mesh = {Cricetinae ; Animals ; *Antioxidants/metabolism ; beta Carotene ; *Air Pollutants/toxicity/analysis ; CHO Cells ; Vitamin A ; Cricetulus ; Particulate Matter/toxicity/analysis ; Vitamin E ; Glutathione ; Oxidative Stress ; *Hydroquinones ; },
abstract = {Antioxidants are typically seen as agents that mitigate environmental health risks due to their ability to scavenge free radicals. However, our research presents a paradox where these molecules, particularly those within lung fluid, act as prooxidants in the presence of airborne particulate matter (PM2.5), thus enhancing PM2.5 oxidative potential (OP). In our study, we examined a range of antioxidants found in the respiratory system (e.g., vitamin C, glutathione (GSH), and N-acetylcysteine (NAC)), in plasma (vitamin A, vitamin E, and β-carotene), and in food (tert-butylhydroquinone (TBHQ)). We aimed to explore antioxidants' prooxidant and antioxidant interactions with PM2.5 and the resulting OP and cytotoxicity. We employed OH generation assays and electron paramagnetic resonance assays to assess the pro-oxidative and anti-oxidative effects of antioxidants. Additionally, we assessed cytotoxicity interaction using a Chinese hamster ovary cell cytotoxicity assay. Our findings revealed that, in the presence of PM2.5, all antioxidants except vitamin E significantly increased the PM2.5 OP by generating more OH radicals (OH generation rate: 0.16-24.67 pmol·min[-1]·m[-3]). However, it's noteworthy that these generated OH radicals were at least partially neutralized by the antioxidants themselves. Among the pro-oxidative antioxidants, vitamin A, β-carotene, and TBHQ showed the least ability to quench these radicals, consistent with their observed impact in enhancing PM2.5 cytotoxicity (PM2.5 LC50 reduced to 91.2 %, 88.8 %, and 75.1 % of PM2.5's original level, respectively). Notably, vitamin A and TBHQ-enhanced PM2.5 OP were strongly associated with the presence of metals and organic compounds, particularly with copper (Cu) contributing significantly (35 %) to TBHQ's pro-oxidative effect. Our study underscores the potential health risks associated with the interaction between antioxidants and ambient pollutants.},
}
@article {pmid38154185,
year = {2024},
author = {Dong, B and Jiang, Y and Shi, B and Zhang, Z and Zhang, Z},
title = {Selenomethionine alleviates decabromodiphenyl ether-induced oxidative stress and ferroptosis via the NRF2/GPX4 pathway in the chicken brain.},
journal = {Journal of hazardous materials},
volume = {465},
number = {},
pages = {133307},
doi = {10.1016/j.jhazmat.2023.133307},
pmid = {38154185},
issn = {1873-3336},
mesh = {Chick Embryo ; Animals ; *Selenomethionine ; Chickens ; NF-E2-Related Factor 2 ; Antioxidants ; *Ferroptosis ; Oxidative Stress ; Brain ; *Halogenated Diphenyl Ethers ; },
abstract = {Decabromodiphenyl ether (BDE209) is a toxic environmental pollutant that can cause neurotoxicity, behavioral abnormalities, and cognitive impairment in animals. However, the specific mechanisms of BDE209-induced neurological injury and effective preventative and therapeutic interventions are lacking. Even though selenomethionine (Se-Met) has a significant detoxification effect and protects the nervous system, it remains unclear whether Se-Met can counteract the toxic effects of BDE209. For the in vivo test, we randomly divided 60 1-week-old hy-line white variety chicks into the Con, BDE209, Se-Met, and BDE209 +Se-Met groups. In vitro experiments were performed, exposing chick embryo brain neurons to BDE209, Se-Met, N-Acetylcysteine (NAC, a ROS inhibitor), and RSL3 (a GPX4 inhibitor). We demonstrated that BDE209 induced oxidative stress and ferroptosis in the chicken brain, which mainly manifested as mitochondrial atrophy, cristae breakage, increased Fe[2+] and MDA content, decreased antioxidant enzyme activity, and the inhibition of the NRF2/GPX4 signaling pathway in the brain neurons. However, Se-Met supplementation reversed these changes by activating the NRF2/GPX4 pathway, reducing mitochondrial damage, enhancing antioxidant enzyme activity, and alleviating ferroptosis. This study provides insight into the mechanism of BDE209-related neurotoxicity and suggests Se-Met as an effective preventative and control measure against BDE209 poisoning.},
}
@article {pmid38150719,
year = {2024},
author = {Liu, J and Yan, P and Liu, X and Long, Z and Bing, T and Zhang, N and Shangguan, D},
title = {Heptamethine Cyanine-Based Molecule Release Triggered by Mitochondrial ROS.},
journal = {ACS applied bio materials},
volume = {7},
number = {1},
pages = {362-368},
doi = {10.1021/acsabm.3c00955},
pmid = {38150719},
issn = {2576-6422},
mesh = {Reactive Oxygen Species ; *Hydrogen Peroxide ; *Mitochondria ; Fluorescent Dyes ; Acetylcysteine/pharmacology ; },
abstract = {Conditionally activated molecule release in live cells would provide spatiotemporal control for the study and intervention of biological processes, e.g., bioactive molecule monitoring and controlled drug release. Mitochondria are the main sites of reactive oxygen species (ROS) production in cells. Here, we report an ROS-triggered molecule release strategy in mitochondria. A molecule IRTO with dual targeting groups was designed by covalently linking IR-780 (a mitochondrial targeted heptamethine cyanine) and 4-aminobutyl-thiazole orange (NH2-TO, a nuclear dye). IRTO diffused into live cells and first accumulated in mitochondria. As the cyanine moiety reacted with mitochondrial ROS directly or with the help of mitochondrial cytochromes, NH2-TO was released, escaped from mitochondria, and finally located in the nucleus. This process could be visualized by fluorescent imaging, i.e., red fluorescence (from the cyanine moiety of IRTO) first located in mitochondria, and green fluorescence (from NH2-TO) appeared and gradually enhanced in the nucleus with the increase of incubation time. The addition of H2O2 or lipopolysaccharide (LPS, an ROS accelerator) could accelerate the release of NH2-TO, whereas N-acetyl-l-cysteine (NAC, an ROS inhibitor) and mitoquinone mesylate (MitoQ, a mitochondrial ROS scavenger) could obviously decrease the release of NH2-TO. These results suggest that IRTO could serve as a fluorescent probe for monitoring ROS in mitochondria and that IR-780 might be a promising endogenous ROS-triggered molecule release platform.},
}
@article {pmid38145809,
year = {2024},
author = {Shore, R and Behlen, J and McBee, D and Prayaga, K and Haugen, F and Craig, L and Shields, M and Mustapha, T and Harvey, N and Johnson, N},
title = {Lactational transfer of sulforaphane-N-acetylcysteine in vivo and in human breast milk.},
journal = {Toxicology and applied pharmacology},
volume = {482},
number = {},
pages = {116796},
pmid = {38145809},
issn = {1096-0333},
support = {P30 ES029067/ES/NIEHS NIH HHS/United States ; R01 ES028866/ES/NIEHS NIH HHS/United States ; T32 ES026568/ES/NIEHS NIH HHS/United States ; },
mesh = {Mice ; Animals ; Child ; Infant, Newborn ; Humans ; Female ; *Acetylcysteine/pharmacology ; *Lactation ; Breast Feeding ; NF-E2-Related Factor 2/genetics/metabolism ; Milk, Human/metabolism ; Isothiocyanates/pharmacology ; *Sulfoxides ; },
abstract = {Sulforaphane (SFN) is a bioactive phytonutrient found in cruciferous vegetables. There is a lack of detailed information on the lactational transfer of SFN and SFN metabolites, and potential pharmacological effects on breastfeeding infants. We carried out two maternal supplementation studies in a mouse model, wherein lactating dams received either vehicle, 300 or 600 ppm SFN from postnatal day (PND) 1 to 5, or in a second experiment, vehicle or 600 ppm SFN from PND 1 to 14. The parent compound was only detectable in milk and plasma from dams receiving 600 ppm SFN for five days. The predominant metabolite SFN-N-acetylcysteine (SFN-NAC) was readily detected in milk from dams receiving 300 and 600 ppm SFN for five days or 600 ppm for 14 days. Maternal SFN-NAC plasma levels were elevated in both 600 ppm groups. Maternal hepatic and pulmonary expression of NRF2-related genes, Nqo1, Gsta2, Gstm1, and Gstp1, were significantly increased, generally following a dose-response; however, offspring induction varied. PND5 neonates in the 600-ppm group exhibited significantly elevated expression of Nqo1, Gsta2, and Gstp1 in liver, and Gstm1 and Gstp1 in lung. Findings support maternal dietary supplementation with SFN induces NRF2-related gene expression in neonates via lactational transfer of SFN-NAC. However, NQO1 enzyme activity was not significantly elevated, highlighting the need to optimize dosing strategy. Additionally, in a pilot investigation of lactating women consuming a typical diet, without any purified SFN supplementation, 7 out of 8 breast milk samples showed SFN-NAC above the limit of quantification (LOQ). Notably, the one sample below the LOQ was collected from the only participant who reported no consumption of cruciferous vegetables in the past 24 h. The parent compound was not detected in any of the human breast milk samples. Overall, these data indicate lactational transfer of SFN-NAC at dietary relevant levels. Future studies are needed to evaluate pharmacokinetics and pharmacodynamics of lactational transfer for potential preventive or therapeutic effects in breastfeeding children.},
}
@article {pmid38142783,
year = {2024},
author = {Singh, B and Patwardhan, RS and Pal, D and Maurya, DK and Singh, BG and Checker, R and Sharma, D and Sandur, SK},
title = {Repurposing of FDA approved kinase inhibitor bosutinib for mitigation of radiation induced damage via inhibition of JNK pathway.},
journal = {Toxicology and applied pharmacology},
volume = {482},
number = {},
pages = {116792},
doi = {10.1016/j.taap.2023.116792},
pmid = {38142783},
issn = {1096-0333},
mesh = {Animals ; Humans ; Mice ; *Aniline Compounds/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/therapeutic use ; DNA Damage ; *Drug Repositioning ; MAP Kinase Signaling System ; *Nitriles/pharmacology/therapeutic use ; *Quinolines/pharmacology/therapeutic use ; *Radiation Injuries/prevention &amp; control ; *Radiation-Protective Agents/pharmacology/therapeutic use ; },
abstract = {Radiotherapy is a common modality for cancer treatment. However, it is often associated with normal tissue toxicity in 20-80% of the patients. Radioprotectors can improve the outcome of radiotherapy by selectively protecting normal cells against radiation toxicity. In the present study, compound libraries containing 54 kinase inhibitors and 80 FDA-approved drugs were screened for radioprotection of lymphocytes using high throughput cell analysis. A second-generation FDA-approved kinase inhibitor, bosutinib, was identified as a potential radioprotector for normal cells. The radioprotective efficacy of bosutinib was evinced from a reduction in radiation induced DNA damage, caspase-3 activation, DNA fragmentation and apoptosis. Oral administration of bosutinib protected mice against whole body irradiation (WBI) induced morbidity and mortality. Bosutinib also reduced radiation induced bone-marrow aplasia and hematopoietic damage in mice exposed to 4 Gy and 6 Gy dose of WBI. Mechanistic studies revealed that the radioprotective action of bosutinib involved interaction with cellular thiols and modulation of JNK pathway. The addition of glutathione and N-acetyl cysteine significantly reduced the radioprotective efficacy of bosutinib. Moreover, bosutinib did not protect cancer cells against radiation induced toxicity. On the contrary, bosutinib per se exhibited anticancer activity against human cancer cell lines. The results highlight possible use of bosutinib as a repurposable radioprotective agent for mitigation of radiation toxicity in cancer patients undergoing radiotherapy.},
}
@article {pmid38141851,
year = {2024},
author = {Jayaram, L and King, PT and Hunt, J and Lim, M and Park, C and Hu, E and Dousha, L and Ha, P and Bartlett, JB and Southcott, AM and Muruganandan, S and Vogrin, S and Rees, MA and Dean, OM and Wong, CA},
title = {Evaluation of high dose N- Acetylcysteine on airway inflammation and quality of life outcomes in adults with bronchiectasis: A randomised placebo-controlled pilot study.},
journal = {Pulmonary pharmacology &amp; therapeutics},
volume = {84},
number = {},
pages = {102283},
doi = {10.1016/j.pupt.2023.102283},
pmid = {38141851},
issn = {1522-9629},
mesh = {Adult ; Humans ; Male ; Aged ; *Acetylcysteine/adverse effects ; Quality of Life ; Pilot Projects ; *Bronchiectasis/drug therapy ; Inflammation/drug therapy ; Anti-Inflammatory Agents/adverse effects ; Double-Blind Method ; },
abstract = {BACKGROUND: High dose N acetylcysteine (NAC), a mucolytic, anti-inflammatory and antioxidant agent has been shown to significantly reduce exacerbations, and improve quality of life in placebo controlled, double blind randomised (RCT) studies in patients with COPD, and in an open, randomised study in bronchiectasis. In this pilot, randomised, double-blind, placebo-controlled study, we wished to investigate the feasibility of a larger clinical trial, and the anti-inflammatory and clinical benefits of high dose NAC in bronchiectasis.<br><br>AIMS: Primary outcome: to assess the efficacy of NAC 2400&#xa0;mg/day at 6 weeks on sputum neutrophil elastase (NE), a surrogate marker for exacerbations. Secondary aims included assessing the efficacy of NAC on sputum MUC5B, IL-8, lung function, quality of life, and adverse effects.<br><br>METHODS: Participants were randomised to receive 2400&#xa0;mg or placebo for 6 weeks. They underwent 3 visits: at baseline, week 3 and week 6 where clinical and sputum measurements were assessed.<br><br>RESULTS: The study was stopped early due to the COVID pandemic. In total 24/30 patients were recruited, of which 17 completed all aspects of the study. Given this, a per protocol analysis was undertaken: NAC (n&#xa0;=&#xa0;9) vs placebo (n&#xa0;=&#xa0;8): mean age 72 vs 62 years; male gender: 44% vs 50%; baseline median FEV11.56&#xa0;L (mean 71.5 % predicted) vs 2.29L (mean 82.2% predicted). At 6 weeks, sputum NE fell by 47% in the NAC group relative to placebo (mean fold difference (95%CI: 0.53 (0.12,2.42); MUC5B increased by 48% with NAC compared with placebo. Lung function, FVC improved significantly with NAC compared with placebo at 6 weeks (mean fold difference (95%CI): 1.10 (1.00, 1.20), p&#xa0;=&#xa0;0.045. Bronchiectasis Quality of life measures within the respiratory and social functioning domains demonstrated clinically meaningful improvements, with social functioning reaching statistical significance. Adverse effects were similar in both groups.<br><br>CONCLUSION: High dose NAC exhibits anti-inflammatory benefits, and improvements in aspects of quality of life and lung function measures. It is safe and well tolerated. Further larger placebo controlled RCT's are now warranted examining its role in reducing exacerbations.},
}
@article {pmid38136214,
year = {2023},
author = {Yang, Y and Liu, Z and Wu, J and Bao, S and Wang, Y and Li, J and Song, T and Sun, Y and Pi, J},
title = {Nrf2 Mitigates RANKL and M-CSF Induced Osteoclast Differentiation via ROS-Dependent Mechanisms.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {12},
pages = {},
pmid = {38136214},
issn = {2076-3921},
support = {81830099 (J.P.), 82020108027 (J.P.), 82204090 (Z.L.)//National Natural Science Foundation of China/ ; 2018YFC1311600 (J.P.)//National Key R&amp;D Program of China of the Ministry of Science and Technology of the People's Republic of China/ ; 2022JH2/101300028 (Y.R.)//The Liaoning Applied Basic Research Program/ ; 2022-BS-131, (Z.L.)//Liaoning Provincial Department of Science and Technology Doctoral Launch/ ; 2023JH2/101300024 (Y.S.)//The Liaoning Applied Basic Research Program/ ; },
abstract = {Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been shown to be a negative regulator of osteoclast differentiation, but the precise mechanisms have not yet been established. We examined the precise roles of Nrf2 in regulating antioxidants and reactive oxygen species (ROS) levels, especially the cytoplasmic and mitochondrial ROS during osteoclastogenesis in vitro. In the current study, we found that the absence of Nrf2 promotes osteoclast differentiation in bone-marrow-derived macrophages (BMMs) and RAW 264.7 cells. The receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) significantly lowered the levels of Nrf2 and its downstream antioxidant enzymes at mRNA and/or protein levels during osteoclast differentiation in the BMMs of mice and RAW 264.7 mouse leukemic monocytes. Compared to the wild-type cells, Nrf2-deficient cells exhibited heightened sensitivity to both transient RANKL-induced cytoplasmic ROS and prolonged RANKL and M-CSF-induced cytoplasmic and mitochondrial ROS accumulation. Furthermore, exogenous antioxidant agents, including N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and mitoquinone mesylate (MitoQ), exhibited substantial capability to suppress the elevation of ROS levels during osteoclast differentiation induced by Nrf2 deficiency, and they consequently inhibited osteoclast differentiation augmented by the lack of Nrf2. The activation of phosphorylated c-FOS resulting from elevated ROS promoted osteoclast differentiation. The inhibition of c-FOS blocked osteoclast differentiation, which was elevated by Nrf2-deficiency. Taken together, these data reveal that Nrf2 effectively decreased the accumulation of intracellular ROS and the phosphorylation of c-FOS during osteoclastic differentiation by regulating antioxidant enzymes and subsequently inhibited RANKL-induced osteoclast differentiation.},
}
@article {pmid38136193,
year = {2023},
author = {Cui, Y and Zhu, Q and Hao, H and Flaker, GC and Liu, Z},
title = {N-Acetylcysteine and Atherosclerosis: Promises and Challenges.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {12},
pages = {},
pmid = {38136193},
issn = {2076-3921},
support = {R01 HL148196/HL/NHLBI NIH HHS/United States ; RF1 NS132279/NS/NINDS NIH HHS/United States ; },
abstract = {Atherosclerosis remains a leading cause of cardiovascular diseases. Although the mechanism for atherosclerosis is complex and has not been fully understood, inflammation and oxidative stress play a critical role in the development and progression of atherosclerosis. N-acetylcysteine (NAC) has been used as a mucolytic agent and an antidote for acetaminophen overdose with a well-established safety profile. NAC has antioxidant and anti-inflammatory effects through multiple mechanisms, including an increase in the intracellular glutathione level and an attenuation of the nuclear factor kappa-B mediated production of inflammatory cytokines like tumor necrosis factor-alpha and interleukins. Numerous animal studies have demonstrated that NAC significantly decreases the development and progression of atherosclerosis. However, the data on the outcomes of clinical studies in patients with atherosclerosis have been limited and inconsistent. The purpose of this review is to summarize the data on the effect of NAC on atherosclerosis from both pre-clinical and clinical studies and discuss the potential mechanisms of action of NAC on atherosclerosis, as well as challenges in the field.},
}
@article {pmid38136155,
year = {2023},
author = {Ovalle Rodríguez, P and Ramírez Ortega, D and Blanco Ayala, T and Roldán Roldán, G and Pérez de la Cruz, G and González Esquivel, DF and Gómez-Manzo, S and Sánchez Chapul, L and Salazar, A and Pineda, B and Pérez de la Cruz, V},
title = {Modulation of Kynurenic Acid Production by N-acetylcysteine Prevents Cognitive Impairment in Adulthood Induced by Lead Exposure during Lactation in Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {12},
pages = {},
pmid = {38136155},
issn = {2076-3921},
support = {286885//Consejo Nacional de Humanidades, Ciencias y Tecnolog&#xed;as/ ; },
abstract = {Lead (Pb[2+]) exposure during early life induces cognitive impairment, which was recently associated with an increase in brain kynurenic acid (KYNA), an antagonist of NMDA and alpha-7 nicotinic receptors. It has been described that N-acetylcysteine (NAC) favors an antioxidant environment and inhibits kynurenine aminotransferase II activity (KAT II, the main enzyme of KYNA production), leading to brain KYNA levels decrease and cognitive improvement. This study aimed to investigate whether the NAC modulation of the brain KYNA levels in mice ameliorated Pb[2+]-induced cognitive impairment. The dams were divided into four groups: Control, Pb[2+], NAC, and Pb[2+]+NAC, which were given drinking water or 500 ppm lead acetate in the drinking water ad libitum, from 0 to 23 postnatal days (PNDs). The NAC and Pb[2+]+NAC groups were simultaneously fed NAC (350 mg/day) in their chow from 0 to 23 PNDs. At PND 60, the effect of the treatment with Pb[2+] and in combination with NAC on learning and memory performance was evaluated. Immediately after behavioral evaluation, brain tissues were collected to assess the redox environment; KYNA and glutamate levels; and KAT II activity. The NAC treatment prevented the long-term memory deficit exhibited in the Pb[2+] group. As expected, Pb[2+] group showed redox environment alterations, fluctuations in glutamate levels, and an increase in KYNA levels, which were partially avoided by NAC co-administration. These results confirmed that the excessive KYNA levels induced by Pb[2+] were involved in the onset of cognitive impairment and could be successfully prevented by NAC treatment. NAC could be a tool for testing in scenarios in which KYNA levels are associated with the induction of cognitive impairment.},
}
@article {pmid38126172,
year = {2024},
author = {Bresette, CA and Ashworth, KJ and Di Paola, J and Ku, DN},
title = {N-Acetyl Cysteine Prevents Arterial Thrombosis in a Dose-Dependent Manner In Vitro and in Mice.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {44},
number = {2},
pages = {e39-e53},
doi = {10.1161/ATVBAHA.123.319044},
pmid = {38126172},
issn = {1524-4636},
mesh = {Mice ; Humans ; Animals ; Platelet Aggregation Inhibitors/pharmacology ; Acetylcysteine/pharmacology ; *Thrombosis/chemically induced/prevention &amp; control/drug therapy ; Platelet Aggregation ; Blood Platelets/metabolism ; *Thromboembolism ; Hemorrhage/metabolism ; von Willebrand Factor/metabolism ; },
abstract = {BACKGROUND: Platelet-rich thrombi occlude arteries causing fatal infarcts like heart attacks and strokes. Prevention of thrombi by current antiplatelet agents can cause major bleeding. Instead, we propose using N-acetyl cysteine (NAC) to act against the protein VWF (von Willebrand factor), and not platelets, to prevent arterial thrombi from forming.<br><br>METHODS: NAC was assessed for its ability to prevent arterial thrombosis by measuring platelet accumulation rate and occlusion time using a microfluidic model of arterial thrombosis with human blood. Acute clot formation, clot stability, and tail bleeding were measured in vivo with the murine modified Folts model. The effect of NAC in the murine model after 6 hours was also measured to determine any persistent effects of NAC after it has been cleared from the blood.<br><br>RESULTS: We demonstrate reduction of thrombi formation following treatment with NAC in vitro and in vivo. Human whole blood treated with 3 or 5 mmol/L NAC showed delayed thrombus formation 2.0&#xd7; and 3.7&#xd7; longer than control, respectively (P<0.001). Blood treated with 10 mmol/L NAC did not form an occlusive clot, and no macroscopic platelet aggregation was visible (P<0.001). In vivo, a 400-mg/kg dose of NAC prevented occlusive clots from forming in mice without significantly affecting tail bleeding times. A lower dose of NAC significantly reduced clot stability. Mice given multiple injections showed that NAC has a lasting and cumulative effect on clot stability, even after being cleared from the blood (P<0.001).<br><br>CONCLUSIONS: Both preclinical models demonstrate that NAC prevents thrombus formation in a dose-dependent manner without significantly affecting bleeding time. This work highlights a new pathway for preventing arterial thrombosis, different from antiplatelet agents, using an amino acid derivative as an antithrombotic therapeutic.},
}
@article {pmid38118330,
year = {2024},
author = {Fu, X and Song, L and Chen, L and Jin, S and Duan, Z and Zhang, B and Xing, Y and Wang, Y},
title = {Mechanistic insights into aniline-induced liver injury: Role of the mmu_circ_26984/Myh9/NLRP3 axis and modulation by N-acetylcysteine.},
journal = {Ecotoxicology and environmental safety},
volume = {270},
number = {},
pages = {115826},
doi = {10.1016/j.ecoenv.2023.115826},
pmid = {38118330},
issn = {1090-2414},
mesh = {Animals ; Mice ; *Acetylcysteine/pharmacology ; *Chemical and Drug Induced Liver Injury, Chronic ; In Situ Hybridization, Fluorescence ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; RNA, Circular ; Aniline Compounds/toxicity ; Cytoskeletal Proteins ; Myosin Heavy Chains ; },
abstract = {Aniline is a widely used chemical. Chronic or high-dose exposure to aniline can lead to hepatocellular damage. Although the hepatic pathogenicity of aniline has been established in previous studies, studies involving pathogenic genes during aniline-induced liver injury are limited. Our study first discovered and identified the role and mechanism underlying a new circRNA mmu_circ_26984 in aniline-induced chemical liver injury. Further, we discuss the protective effect of N-acetylcysteine (NAC) in this pathway. After constructing in vitro and in vivo models of aniline treatment, we screened the circRNA with significant differences in expression in AML12 cells from control and aniline-treated groups by circRNA microarray analysis. Next, using RNA pulldown, liquid chromatography-mass spectrometry (LC-MS), and RNA immunoprecipitation, we analyzed the relationship between mmu_circ_26984 and myosin heavy chain 9 (Myh9). Subsequently, we determined the specific mechanism of action of mmu_circ_26984 and Myh9 in aniline-induced liver injury and the protective effect of NAC against aniline-induced liver injury process using Cell Counting Kit-8, Western blot, RNA extraction, a reverse transcription quantitative polymerase chain reaction (RT-qPCR), fluorescence in situ hybridization, immunohistochemistry, and immunofluorescence. The expression of mmu_circ_26984 was significantly increased in liver tissues and AML12 cells of aniline-treated mice compared with the control group. This high expression of mmu_circ_26984 increased the expression of injury-related inflammatory factors, such as NLRP3, Caspase-1, IL-18, and IL-1β in vivo and ex vivo, which exacerbated the level of liver injury. The interaction of mmu_circ_26984 with Myh9 also affected the course of liver injury. Mmu_circ_26984 overexpression and reduced treatment affected the levels of Myh9 expression in AML12 cells, as well as downstream inflammatory factors associated with injury, such as NLRP3. In addition, NAC reduced the process of liver injury mediated by the mmu_circ_26984/Myh9/NLRP3 axis. In conclusion, mmu_circ_26984 is a potential molecular marker and therapeutic target in the process of aniline-induced liver injury that can mediate aniline-exposure-induced liver injury via modulation of the mmu_circ_26984/Myh9/NLRP3 axis, and NAC can effectively attenuate the effect of this liver injury.},
}
@article {pmid38115863,
year = {2023},
author = {Gugsa, E and Molla, TS and Bekele, T and Dejenie, TA},
title = {Hepatoprotective effect of hydromethanol extract of Otostegia integrifolia benth leaves in isoniazid and rifampicin induced Swiss albino mice.},
journal = {Metabolism open},
volume = {20},
number = {},
pages = {100255},
pmid = {38115863},
issn = {2589-9368},
abstract = {INTRODUCTION: Drug-induced liver injury is the most common cause of acute liver failure. Off-Target effect "hepatotoxicity "frequently detected during clinical examination of patients on anti-Tb medication particularly isoniazid (INH), and rifampin (RMP). However, there is no any treatment option against isoniazid and rifampicin induced hepatotoxicity. It is, therefore, necessary to search for effective affordable and safe drugs from medicinal plants for the prevention of liver toxicity caused by isoniazid and rifampicin. The aim the current study is to evaluate hepatoprotective effect of hydro methanol extract from Otostegia integrifolia leaves in isoniazid and rifampicin-induced hepatotoxicity in Swiss albino mice.<br><br>METHODS: O. integrifolia leaves powder was macerated in hydromethanol and thirty Swiss albino mice 29.0-40.6&#xa0;g were grouped in to five groups. Group I were given 20&#xa0;ml/kg distilled water, group II were given 100&#xa0;mg INH and 150&#xa0;mg RIF per kg body weight. Group III, group IV, and group V were given 200&#xa0;mg extract, 400&#xa0;mg extract, and 100&#xa0;mg of N-acetyl cysteine respectively per kg 1hr before induction with 100&#xa0;mg INH plus 150&#xa0;mg RIF per kg. The treatments were followed for 14 days. On the 15th day, all mice were anaesthetized with diethyl ether; blood samples were collected for the assessment liver enzyme and function test.<br><br>RESULTS: Group II mice's serum ALT, AST and total bilirubin levels were significantly increased and serum total protein and albumin levels were significantly decreased as compared with group I mice. The groups of mice treated with O. integrifolia at a dose of 400&#xa0;mg/kg and N-acetyl cysteine AST, ALT and total bilirubin level were significantly decreased; and total protein and albumin levels were significantly (P&#xa0;<&#xa0;0.05) increased as compared with group II. The liver index of the group IV showed decreased (P&#xa0;<&#xa0;0.05) as compared to the group II.<br><br>CONCLUSION: Evidence from our study revealed that the hydromethanol extract of O. integrifolia has a hepatoprotective effect against isoniazid and rifampicin-induced hepatotoxicity in Swiss Albino mice. This protective effect of O. integrifolia extract may be based on its metal ion reducing power, free radical scavenging activity, and anti-inflammatory activity and could be used as a potential therapeutic option.},
}
@article {pmid38115663,
year = {2023},
author = {Wang, L and Quan, C and Liu, S and Sun, Y and Liu, Y and Zhang, L},
title = {[KEAP1/PGAM5/AIFM1 mediated oxeiptosis pathway in TDCIPP-induced reduction of TM4 cell viability].},
journal = {Wei sheng yan jiu = Journal of hygiene research},
volume = {52},
number = {6},
pages = {979-992},
doi = {10.19813/j.cnki.weishengyanjiu.2023.06.019},
pmid = {38115663},
issn = {1000-8020},
mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Cell Survival ; *NF-E2-Related Factor 2/metabolism ; *Phosphoprotein Phosphatases/metabolism/pharmacology ; Organophosphates ; },
abstract = {OBJECTIVE: To investigate the toxic effects and potential mechanisms of tri(1, 3-dichloro-2-propyl) phosphate(TDCIPP) exposure on the mouse testicular supporting cell line(TM4 cells).<br><br>METHODS: TM4 cells were treated with different concentrations of TDCIPP(0, 12.5, 25 and 50 &#x3bc;mol/L), or 50 &#x3bc;mol/L TDCIPP combined with antioxidant N-acetylcysteine(NAC) for 24 h. Cell viability was assessed using the CCK8 assay, intracellular ROS levels were detected using the DCFH-DA probe, and the protein levels of oxeiptosis-related proteins, such as KEAP1, PGAM5, AIFM1 and phosphorylated AIFM1(p-AIFM1), were detected using Western blot.<br><br>RESULTS: TDCIPP dose-dependently reduced TM4 cell viability(P<0.05). ROS levels in TM4 cells treated with 12.5, 25 and 50 &#x3bc;mol/L TDCIPP were 9.44&#xb1;1.42, 17.25&#xb1;1.81 and 18.38&#xb1;2.66, respectively, significantly higher than the control group&apos;s 5.08&#xb1;0.90(P<0.05). ROS levels in the 5 mmol/L NAC+50 &#x3bc;mol/L TDCIPP group were 14.70&#xb1;0.50, significantly lower than the corresponding TDCIPP group&apos;s 26.44&#xb1;0.73(P<0.05). The activity of TM4 cells in KEAP1siRNA+TDCIPP group and PGAM5siRNA+TDCIPP group were 77.00&#xb1;1.73 and 76.67&#xb1;1.53, respectively, significantly higher than TDCIPP group 68.67&#xb1;1.53(P<0.05). The relative expression of KEAP1 protein in TM4 cells treated with 25 and 50 &#x3bc;mol/L TDCIPP were 0.77&#xb1;0.04 and 0.82&#xb1;0.02, respectively, significantly higher than the control group&apos;s 0.57&#xb1;0.01(P<0.05). The relative expression of PGAM5 protein in TDCIPP-treated TM4 cells were 1.17&#xb1;0.04, 1.38&#xb1;0.03 and 1.41&#xb1;0.03, respectively, significantly higher than the control group&apos;s 0.81&#xb1;0.02(P<0.05). The relative expression of AIFM1 protein were 0.42&#xb1;0.01, 0.63&#xb1;0.01 and 0.68&#xb1;0.02, respectively, significantly higher than the control group&apos;s 0.34&#xb1;0.02(P<0.05). The relative expression of p-AIFM1 protein were 1.73&#xb1;0.02, 1.52&#xb1;0.02 and 0.73&#xb1;0.01, respectively, significantly lower than the control group&apos;s 2.25&#xb1;0.02(P<0.05). In the 5 mmol/L NAC+50 &#x3bc;mol/L TDCIPP group, the relative expression of KEAP1, PGAM5 and AIFM1 proteins in TM4 cells were 0.61&#xb1;0.01, 0.58&#xb1;0.01 and 0.48&#xb1;0.03, respectively, significantly lower than the TDCIPP group&apos;s 0.86&#xb1;0.12(P<0.05), 0.74&#xb1;0.02(P<0.05) and 0.92&#xb1;0.01(P<0.05). The relative expression of p-AIFM1 protein in the 5 mmol/L NAC+50 &#x3bc;mol/L TDCIPP group was 0.45&#xb1;0.11, significantly higher than the TDCIPP group&apos;s 0.23&#xb1;0.01(P<0.05).<br><br>CONCLUSION: The reduction of TM4 cell viability induced by TDCIPP may be related to ROS-mediated regulation of the KEAP1/PGAM5/AIFM1 pathway, leading to oxeiptosis.},
}
@article {pmid38111943,
year = {2023},
author = {Jing, RH and Hu, CH and Qi, TT and Ma, B},
title = {Role of reactive oxygen species in epithelial-mesenchymal transition and apoptosis of human lens epithelial cells.},
journal = {International journal of ophthalmology},
volume = {16},
number = {12},
pages = {1935-1941},
pmid = {38111943},
issn = {2222-3959},
abstract = {AIM: To investigate the role of reactive oxygen species (ROS) in epithelial-mesenchymal transition (EMT) and apoptosis of human lens epithelial cells (HLECs).<br><br>METHODS: Flow cytometry was used to assess ROS production after transforming growth factor &#x3b2;2 (TGF-&#x3b2;2) induction. Apoptosis of HLECs after H2O2 and TGF-&#x3b2;2 interference with or without ROS scavenger N-acetylcysteine (NAC) were assessed by flow cytometry. The corresponding protein expression levels of the EMT marker &#x3b1;-smooth muscle actin (&#x3b1;-SMA), the extracellular matrix (ECM), marker fibronectin (Fn), and apoptosis-associated proteins were detected by using Western blotting in the presence of an ROS scavenger (NAC). Wound-healing and Transwell assays were used to assess the migration capability of HLECs.<br><br>RESULTS: TGF-&#x3b2;2 stimulates ROS production within 8h in HLECs. Additionally, TGF-&#x3b2;2 induced HLECs cell apoptosis, EMT/ECM synthesis protein markers expression, and pro-apoptotic proteins production; nonetheless, NAC treatment prevented these responses. Similarly, TGF-&#x3b2;2 promoted HLECs cell migration, whereas NAC inhibited cell migration. We further determined that although ROS initiated apoptosis, it only induced the accumulation of the EMT marker &#x3b1;-SMA protein, but not COL-1 or Fn.<br><br>CONCLUSION: ROS contribute to TGF-&#x3b2;2-induced EMT/ECM synthesis and cell apoptosis of HLECs; however, ROS alone are not sufficient for EMT/ECM synthesis.},
}
@article {pmid38111454,
year = {2023},
author = {Hakobyan, N and Yadav, R and Pokhrel, A and Wasifuddin, M and John, MJ and Yadav, S and Boris, A},
title = {Miller-Fisher Syndrome Unveiled in the Presence of Cholangiocarcinoma.},
journal = {Cureus},
volume = {15},
number = {11},
pages = {e49016},
pmid = {38111454},
issn = {2168-8184},
abstract = {Miller-Fisher syndrome (MFS) is a rare variant of Guillain-Barré syndrome, characterized by ataxia, areflexia, ophthalmoplegia, and possible facial, swallowing and limb weakness alongside respiratory failure. Variations within MFS may include respiratory and limb weakness and Bickerstaff brainstem encephalitis (BBE), marked by altered consciousness, ataxia, ophthalmoparesis, and paradoxical hyperreflexia. MFS can emerge in both children and adults, often following bacterial or viral illness. While autoimmune-driven nerve damage occurs, most MFS patients recover within six months without specific treatment, with a low risk of lasting neurological deficits or relapses. Rarely fatal, MFS's co-occurrence with cholangiocarcinoma (CCA) presents unique management challenges. CCA, primarily affecting bile ducts, has a bleak prognosis; surgical resection offers limited cure potential due to late-stage detection and high recurrence rates. Advances in CCA's molecular understanding have led to novel diagnostic and therapeutic approaches, requiring a comprehensive interdisciplinary care approach for optimal MFS and CCA management outcomes. Herein, we present a 50-year-old male with a complex medical history who was admitted to the hospital due to abdominal discomfort, nausea, vomiting, and ascites. Imaging revealed pneumonia and secondary bacterial peritonitis. Later, he developed neurological symptoms, including weakness, gait abnormalities, and brainstem symptoms, leading to the diagnosis of MFS. Despite treatment efforts, his condition deteriorated, leading to acute liver failure and unexplained anasarca. N-acetyl cysteine was initiated for liver issues. Neurologically, he showed quadriparesis and areflexia. Intravenous immunoglobulin (IVIG) treatment improved his neurological symptoms but worsened gastrointestinal issues, including ileus and elevated CA19-9 levels, suggesting a potential carcinoma. A liver biopsy was performed. After IVIG treatment, he experienced widespread discomfort, emotional unresponsiveness, swallowing difficulties, and aspiration risk, ultimately leading to his demise.},
}
@article {pmid38109166,
year = {2025},
author = {Sangeet, S and Khan, A},
title = {An in-silico approach to identify bioactive phytochemicals from Houttuynia cordata Thunb. As potential inhibitors of human glutathione reductase.},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {43},
number = {5},
pages = {2300-2319},
doi = {10.1080/07391102.2023.2294181},
pmid = {38109166},
issn = {1538-0254},
mesh = {*Phytochemicals/chemistry/pharmacology ; Humans ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; *Houttuynia/chemistry ; *Glutathione Reductase/antagonists &amp; inhibitors/chemistry ; *Enzyme Inhibitors/chemistry/pharmacology ; Protein Binding ; Antioxidants/chemistry/pharmacology ; },
abstract = {Cellular infections are central to the etiology of various diseases, notably cancer and malaria. Counteracting cellular oxidative stress via the inhibition of glutathione reductase (GR) has emerged as a promising therapeutic strategy. Houttuynia cordata, a medicinal plant known for its potent antioxidant properties, has been the focus of our investigation. In this study, we conducted comprehensive in silico analyses involving the phytochemical constituents of H. cordata to identify potential natural GR inhibitors. Our methodological approach encompassed multiple in silico techniques, including molecular docking, molecular dynamics simulations, MMPBSA analysis, and dynamic cross-correlation analysis. Out of 13 docked phytochemicals, Quercetin, Quercitrin, and Sesamin emerged as particularly noteworthy due to their exceptional binding affinities for GR. Notably, our investigation demonstrated that Quercetin and Sesamin exhibited promising outcomes compared to the well-established pharmaceutical agent N-acetylcysteine (NAC). Molecular dynamics analyses provided insights into the ability of these phytochemicals to induce structural compaction and stabilization of the GR protein, as evidenced by changes in radius of gyration and solvent-accessible surface area. Moreover, MMPBSA analysis highlighted the crucial roles of specific residues, namely Gly27, Gly28, Ser51, His52, and Val61, in mediating essential interactions with these phytochemicals. Furthermore, an assessment of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME-Tox) profiles underscored the favourable drug-like attributes of these phytochemicals. Thus, the current findings underscore the immense potential of Houttuynia cordata phytochemicals as potent antioxidants with the capacity to combat a spectrum of maladies, including malaria and cancer. This study not only unveils novel therapeutic avenues but also underscores the distinctive outcomes and paramount significance of harnessing H. cordata phytochemicals for their efficacious antioxidant properties.},
}
@article {pmid38107500,
year = {2023},
author = {Tang, C and Wang, L and Chen, Z and Yang, J and Gao, H and Guan, C and Gu, Q and He, S and Yang, F and Chen, S and Ma, L and Zhang, Z and Zhao, Y and Tang, L and Xu, Y and Hu, Y and Luo, X},
title = {Efficacy and Safety of Hydrogen Therapy in Patients with Early-Stage Interstitial Lung Disease: A Single-Center, Randomized, Parallel-Group Controlled Trial.},
journal = {Therapeutics and clinical risk management},
volume = {19},
number = {},
pages = {1051-1061},
pmid = {38107500},
issn = {1176-6336},
abstract = {PURPOSE: Several in vivo experiments have shown that molecular hydrogen is a promising therapeutic agent for interstitial lung diseases (ILD). In this study, hydrogen therapy was investigated to determine whether it is superior to N-Acetylcysteine (NAC) for the treatment of patients with early-stage ILD.<br><br>PATIENTS AND METHODS: A prospective, single-center, randomized, controlled clinical trial was conducted in 87 patients with early-stage ILD. Hydrogen or NAC therapy was randomly assigned (1:1 ratio) to the eligible patients. The primary endpoint was the change in the high-resolution computed tomography (HRCT) and composite physiologic index (CPI) scores from baseline to week 48. Pulmonary function was evaluated as a secondary endpoint, and adverse events were recorded for safety analysis.<br><br>RESULTS: The rate of HRCT image improvement from the baseline in the HW group (63.6%) was higher than that in the NAC group (39.5%). A significant decrease in CPI and improvement in DLCO-sb were observed in the hydrogen group compared with those in the control group. Changes in other pulmonary function parameters, including FVC, FEV1, FEV1/FVC%, and TLC, were not significantly different between the two groups. Adverse events were reported in 7 (15.9%) patients in the HW group and 10 (23.3%) patients in the NAC group, but the difference was not significant (P=0.706).<br><br>CONCLUSION: Hydrogen therapy exhibits superior efficacy and acceptable safety compared with NAC therapy in patients with early-stage ILD.},
}
@article {pmid38105264,
year = {2023},
author = {Musillo, C and Creutzberg, KC and Collacchi, B and Ajmone-Cat, MA and De Simone, R and Lepre, M and Amrein, I and Riva, MA and Berry, A and Cirulli, F},
title = {Bdnf-Nrf-2 crosstalk and emotional behavior are disrupted in a sex-dependent fashion in adolescent mice exposed to maternal stress or maternal obesity.},
journal = {Translational psychiatry},
volume = {13},
number = {1},
pages = {399},
pmid = {38105264},
issn = {2158-3188},
mesh = {Animals ; Female ; Male ; Mice ; Pregnancy ; Hippocampus/metabolism ; Hypothalamo-Hypophyseal System/metabolism ; *Pregnancy in Obesity/metabolism ; Pituitary-Adrenal System/metabolism ; *Prenatal Exposure Delayed Effects ; Stress, Psychological/metabolism ; Brain-Derived Neurotrophic Factor ; NF-E2-Related Factor 2 ; },
abstract = {Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic-pituitary-adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal. Prenatal administration of the antioxidant N-acetyl-cysteine (NAC) was used as a strategy to protect fetal neurodevelopment from the negative effects of PNS and mHFD. Our findings show that these two stressors produce overlapping effects, reducing brain anti-oxidant defenses (Nrf-2) and leading to sex-dependent impairments of hippocampal Bdnf expression and alterations of the emotional behavior and HPA axis functionality. Prenatal NAC administration, by restoring the redox balance, was able to exert long-term protective effects on brain development, suggesting that the modulation of redox pathways might be an effective strategy to target common shared mechanisms between different adverse prenatal conditions.},
}
@article {pmid38104651,
year = {2024},
author = {Wen, T and Xie, J and Ma, L and Hao, Z and Zhang, W and Wu, T and Li, L},
title = {Vitamin D Receptor Activation Reduces Hepatic Inflammation via Enhancing Macrophage Autophagy in Cholestatic Mice.},
journal = {The American journal of pathology},
volume = {194},
number = {3},
pages = {369-383},
doi = {10.1016/j.ajpath.2023.11.016},
pmid = {38104651},
issn = {1525-2191},
mesh = {Animals ; Mice ; Acetylcysteine ; Autophagy/physiology ; *Cholestasis/metabolism ; *Inflammasomes/metabolism ; Inflammation/metabolism ; Interleukin-1beta/metabolism ; Macrophages/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Calcitriol/metabolism ; },
abstract = {Macrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-1β to its active, secreted form. We investigated whether the vitamin D/vitamin D receptor (VDR) axis could up-regulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-1β during cholestasis. Paricalcitol (PAL; VDR agonist) was intraperitoneally injected into bile duct-ligated mice for 5 days. Up-regulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress-induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-1β generation. Mechanistically, the knockdown of VDR increased IL-1β generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide treatment. The inflammasome antagonist glyburide, the caspase-1-specific inhibitor YVAD, and the reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) blocked the increase in Vdr shRNA-induced IL-1β production. Interestingly, up-regulation of VDR also enhanced macrophage autophagy. Autophagy reduction impaired the up-regulation of VDR-inhibited macrophage inflammasome-generated IL-1β, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38 mitogen-activated protein kinase (MAPK) pathway. This result was confirmed by p38 MAPK inhibitor, MAPK activator, and ROS inhibitor NAC. Collectively, PAL triggered macrophage autophagy by suppressing activation of the ROS-p38 MAPK pathway, which, in turn, suppressed inflammasome-generated cleaved, active forms of IL-1β, eventually leading to reduced inflammation. Thus, triggering the VDR may be a potential target for the anti-inflammatory treatment of cholestatic liver disease.},
}
@article {pmid38101763,
year = {2024},
author = {Fu, C and Yang, C and Ni, C and Wang, L and Hou, J},
title = {Echinococcus granulosus cyst fluid inhibits the type I interferon response by promoting ROS in macrophages.},
journal = {Acta tropica},
volume = {250},
number = {},
pages = {107101},
doi = {10.1016/j.actatropica.2023.107101},
pmid = {38101763},
issn = {1873-6254},
mesh = {Animals ; *Interferon Type I ; *Echinococcus granulosus/metabolism ; Reactive Oxygen Species ; Cyst Fluid ; Macrophages/metabolism ; Nucleotidyltransferases/metabolism ; },
abstract = {In cystic echinococcosis (CE), Echinococcus granulosus cystic fluid (EgCF) could impede macrophage-mediated immunity. However, whether EgCF is implicated in the type I interferon response remains to be established. Here, we revealed that EgCF reduced 2'3'-cGAMP-induced IFN-β production in macrophages by inhibiting the cGAS-STING-IRF3 signaling. EgCF also increased the intracellular reactive oxygen species (ROS) levels. Administration of the ROS inhibitor N-acetylcysteine (NAC) restored the cGAS-STING-IRF3 signaling, which, in turn, upregulated IFN-β expression. The findings disclose that EgCF could increase macrophage ROS levels, thereby blocking cGAS-STING-IRF3 signaling and repressing the IFN-I response.},
}
@article {pmid38092096,
year = {2024},
author = {Zhu, R and Shang, GJ and Zhang, BY and Wang, HT and Li, L and Wei, XF and Li, DL and Yang, ZY and Qu, ZH and Quan, YN and Liu, SY and Wang, YT and Meng, ST and Wu, LF and Qin, GX},
title = {Unlocking the potential of N-acetylcysteine: Improving hepatopancreas inflammation, antioxidant capacity and health in common carp (Cyprinus carpio) via the MAPK/NF-κB/Nrf2 signalling pathway.},
journal = {Fish &amp; shellfish immunology},
volume = {144},
number = {},
pages = {109294},
doi = {10.1016/j.fsi.2023.109294},
pmid = {38092096},
issn = {1095-9947},
mesh = {Animals ; *Antioxidants/metabolism ; NF-kappa B/metabolism ; Acetylcysteine/pharmacology ; *Carps/metabolism ; NF-E2-Related Factor 2/metabolism ; Hepatopancreas/metabolism ; Signal Transduction ; Diet/veterinary ; Inflammation/veterinary ; Glutathione ; Dietary Supplements ; },
abstract = {N-acetylcysteine (NAC) positively contributes to enhancing animal health, regulating inflammation and reducing stress by participating in the synthesis of cysteine, glutathione, and taurine in the body. The present study aims to investigate the effects of dietary different levels of NAC on the morphology, function and physiological state of hepatopancreas in juvenile common carp (Cyprinus carpio). 450 common carps were randomly divided into 5 groups: N1 (basal diet), N2 (1.5 g/kg NAC diet), N3 (3.0 g/kg NAC diet), N4 (4.5 g/kg NAC diet) and N5 (6.0 g/kg NAC diet), and fed for 8 weeks. The results indicated that dietary 3.0-6.0 g/kg NAC reduced hepatopancreas lipid vacuoles and nuclear translocation, and inhibited apoptosis in common carp. Simultaneously, the activities of hepatopancreas alanine aminotransferase and aspartate aminotransferase progressively increased with rising dietary NAC levels. Dietary NAC enhanced the non-specific immune function of common carp, and exerted anti-inflammatory effects by inhibiting the MAPK/NF-κB signaling pathway. Additionally, dietary 3.0-6.0 g/kg NAC significantly improved the antioxidant capacity of common carp, which was associated with enhanced glutathione metabolism, clearance of ROS and the activation of Nrf2 signaling pathway. In summary, NAC has the potential to alleviate inflammation, mitigate oxidative stress and inhibit apoptosis via the MAPK/NF-κB/Nrf2 signaling pathway, thereby improving hepatopancreas function and health of common carp. The current findings provide a theoretical basis for promoting the application of NAC in aquaculture and ecological cultivation of aquatic animals.},
}
@article {pmid38091079,
year = {2024},
author = {Mohamad, EA and Ali, AA and Sharaky, M and El-Gebaly, RH},
title = {Niosomes loading N-acetyl-L-cysteine for cancer treatment in vivo study.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {397},
number = {6},
pages = {4339-4353},
pmid = {38091079},
issn = {1432-1912},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Male ; *Mice, Inbred BALB C ; *Liposomes ; Mice ; Oxidative Stress/drug effects ; Antineoplastic Agents/administration &amp; dosage/pharmacology ; Cell Line, Tumor ; Apoptosis/drug effects ; DNA Damage/drug effects ; Tumor Burden/drug effects ; Drug Carriers ; },
abstract = {Scientists are seeking to find an effective treatment for tumors that has no side effects. N-Acetyl-l-cysteine (NAC) is a thiol compound extracted from garlic. Current study explores the potential of NAC-loaded niosomes (NAC-NIO) for tumor treatment in mice. NAC-loaded niosomes' efficiency, morphology, UV absorption, size distribution, zeta potential, release, and FTIR analysis were evaluated. For vivo study, 25 male BALB/c mice were divided to five groups: gp1 negative control (receive saline), gp2 positive control (tumor group), gp3 treated with NAC, gp4 treated with NAC-NIO at the same time of tumor injection, and gp5 treated with NAC-NIO after tumor growth (day 14). The impact of NAC-NIO on the tumor treatment was evaluated by measuring tumor size progress, comet assay, oxidative stress parameters (GSH, nitric oxide, MDA), western blot analysis, and histopathological investigation of tissues. NAC-NIO showed 72 ± 3% encapsulation efficiency and zeta potential - 5.95 mV with spherical shape. It was found that oral administration of NAC-NIO in a dose of 50 mg/kg provided significant protection against tumor cells. Our formulation decreases DNA injury significantly (P < 0.05). It was noticed that NAC-NIO can increase oxidative stress levels in tumor tissue. On the other hand, the caspase 3 and caspase 9 gene expression were upregulated significantly (P < 0.001) in mice administrated NAC-NIO compared with all other groups. Histological studies confirmed the protective effect of NAC-NIO against tumor especially for treatment during tumor growth protocol. The results suggested that oral delivery of NAC-NIO formulation improved antioxidant effect.},
}
@article {pmid38088332,
year = {2024},
author = {Bahoush, G and Rahab, M and Ahmadvand, P},
title = {Can N-acetylcysteine reduce red blood cell transfusion burden in patients with transfusion-dependent β-thalassemia?.},
journal = {Pediatric hematology and oncology},
volume = {41},
number = {4},
pages = {251-259},
doi = {10.1080/08880018.2023.2292556},
pmid = {38088332},
issn = {1521-0669},
mesh = {Humans ; *beta-Thalassemia ; Erythrocyte Transfusion ; Acetylcysteine/therapeutic use ; Quality of Life ; *Iron Overload/drug therapy/etiology ; Hemoglobins/analysis ; },
abstract = {Patients with beta-thalassemia major require lifelong and frequent red blood cell transfusions for survival, impacting their quality of life and life expectancy. This treatment approach poses risks of organ damage, iron overload, and increased transfusion-transmitted diseases. N-acetylcysteine (NAC) has been studied for its potential antioxidant effects on hemoglobin stability, aiming to reduce the burden of red blood cell transfusions. To explore this possibility further, we conducted a quasi-experimental study involving 35 individuals with thalassemia major over six months All subjects were already receiving iron chelators and blood transfusions. They were given a daily oral dose of 10 mg/kg NAC for three months. After three months of treatment with NAC, the serum levels of ferritin and liver enzymes (SGOT and SGPT) did not show significant changes (p = 0.35, p = 0.352, and p = 0.686, respectively). However, the red blood cell transfusion burden was significantly reduced in all patients after NAC therapy (p = 0.029), with no corresponding decrease in serum hemoglobin levels (p = 0.931), indicating maintained hemoglobin concentration despite reduced transfusion volume. The study indicates that NAC can effectively decrease the burden of red blood cell transfusions without significant toxicity in these patients. This finding suggests the potential for NAC as a cost-effective and manageable treatment option for these patients. A larger clinical trial with more robust statistical methods could further confirm these results and pave the way for using NAC as a valuable therapeutic agent for managing beta-thalassemia major patients.},
}
@article {pmid38088264,
year = {2023},
author = {Kandhari, K and Kant, R and Mishra, N and Agarwal, C and Agarwal, R},
title = {Phenylarsine oxide induced corneal injury involves oxidative stress mediated unfolded protein response and ferroptotic cell death: Amelioration by NAC.},
journal = {Free radical biology &amp; medicine},
volume = {209},
number = {Pt 2},
pages = {265-281},
pmid = {38088264},
issn = {1873-4596},
support = {U01 EY030405/EY/NEI NIH HHS/United States ; },
mesh = {Animals ; Humans ; Rabbits ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Irritants ; *Arsenicals ; *Corneal Injuries/chemically induced ; Oxidative Stress ; Unfolded Protein Response ; Cell Death ; },
abstract = {Phenylarsine oxide (PAO), an analog of lewisite, is a highly toxic trivalent arsenical and a potential chemical warfare agent. PAO-induced toxicity has been studied in lung, liver, and skin tissues. Nevertheless, very few studies have been published to comprehend the impact of PAO-induced toxicity on ocular tissues, even though eyes are uniquely vulnerable to injury by vesicants. Notably, arsenical vesicants such as lewisite have been shown to cause edema of eyelids, inflammation, massive corneal necrosis, and blindness. Accordingly, human corneal epithelial cells were used to study the effects of PAO exposure. PAO (100 and 200 nM) induced significant oxidative stress in corneal epithelial cells. Simultaneous treatment with N-acetyl-l-cysteine (NAC), an FDA-approved antioxidant, reversed the PAO-induced toxicity in human corneal epithelial cells. Furthermore, oxidative stress induction by PAO was accompanied by unfolded protein response (UPR) signaling activation and ferroptotic cell death. Further, to validate the findings of our in vitro studies, we optimized injury biomarkers and developed an ex vivo rabbit corneal culture model of PAO exposure. Investigations using PAO in ex vivo rabbit corneas revealed similar results. PAO (5 or 10 μg) for 3, 5, and 10 min caused moderate to extensive corneal epithelial layer degradation and reduced the epithelial layer thickness in a concentration- and time-dependent manner. Similar to human corneal cells, injuries by PAO in ex vivo cultured rabbit corneas were also associated with elevated oxidative stress, UPR signaling, and ferroptosis induction. NAC mitigated PAO-induced corneal injuries in rabbit ex vivo cornea culture as well. The reversal of PAO toxicity upon NAC treatment observed in our studies could be attributed to its antioxidant properties. These findings suggest that PAO exposure can cause significant corneal injury and highlight the need for further mechanistic studies to better understand the pathobiology of different arsenical vesicants, including PAO and lewisite.},
}
@article {pmid38086481,
year = {2024},
author = {Wu, Q and Liu, C and Liu, D and Wang, Y and Qi, H and Liu, X and Zhang, Y and Chen, H and Zeng, Y and Li, J},
title = {Polystyrene nanoplastics-induced lung apoptosis and ferroptosis via ROS-dependent endoplasmic reticulum stress.},
journal = {The Science of the total environment},
volume = {912},
number = {},
pages = {169260},
doi = {10.1016/j.scitotenv.2023.169260},
pmid = {38086481},
issn = {1879-1026},
mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Microplastics ; Polystyrenes/toxicity ; Endoplasmic Reticulum Chaperone BiP ; Endoribonucleases/pharmacology ; *Ferroptosis ; Protein Serine-Threonine Kinases ; Lung/metabolism ; Acetylcysteine/pharmacology ; Apoptosis ; Endoplasmic Reticulum Stress ; },
abstract = {It has been shown that exposure to nanoplastics (MNPs) through inhalation can induce pulmonary toxicity, but the toxicological mechanism of MNPs on the respiratory system remains unclear. Therefore, we explored the toxicological mechanism of exposure to polystyrene nanoplastics (PS-NPs) (0.05, 0.15, 0.2 mg/mL) on BEAS-2B cells. Results revealed that PS-NPs induce oxidative stress, increased apoptosis rate measured by flow cytometry, the key ferroptosis protein (GPX4 and FTH1) reduction, increased iron content, mitochondrial alterations, and increased malondialdehyde (MDA) level. Besides, consistent results were observed in mice exposed to PS-NPs (5 mg/kg/2d, 10 mg/kg/2d). Thus, we proved that PS-NPs induced cell death and lung damage through apoptosis and ferroptosis. In terms of mechanism, the elevation of the endoplasmic reticulum (ER) stress protein expression (IRE1α, PERK, XBP1S, and CHOP) revealed that PS-NPs induce lung damage by activating the two main ER stress pathways. Furthermore, the toxicological effects of PS-NPs observed in this study are attenuated by the ROS inhibitor N-acetylcysteine (NAC). Collectively, NPs-induced apoptosis and ferroptosis are attenuated by NAC via inhibiting the ROS-dependent ER stress in vitro and in vivo. This improves our understanding of the mechanism by which PS-NPs exposure leads to pulmonary injury and the potential protective effects of NAC.},
}
@article {pmid38079440,
year = {2023},
author = {Graham, RE and Elliott, RJR and Munro, AF and Carragher, NO},
title = {A cautionary note on the use of N-acetylcysteine as a reactive oxygen species antagonist to assess copper mediated cell death.},
journal = {PloS one},
volume = {18},
number = {12},
pages = {e0294297},
pmid = {38079440},
issn = {1932-6203},
mesh = {Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology/chemistry ; *Copper/chemistry ; Disulfiram/pharmacology ; Cell Death ; Apoptosis ; Antioxidants/pharmacology ; Ionophores/pharmacology ; Hydrazines ; },
abstract = {A new form of cell death has recently been proposed involving copper-induced cell death, termed cuproptosis. This new form of cell death has been widely studied in relation to a novel class of copper ionophores, including elesclomol and disulfiram. However, the exact mechanism leading to cell death remains contentious. The oldest and most widely accepted biological mechanism is that the accumulated intracellular copper leads to excessive build-up of reactive oxygen species and that this is what ultimately leads to cell death. Most of this evidence is largely based on studies using N-acetylcysteine (NAC), an antioxidant, to relieve the oxidative stress and prevent cell death. However, here we have demonstrated using inductively coupled mass-spectrometry, that NAC pretreatment significantly reduces intracellular copper uptake triggered by the ionophores, elesclomol and disulfiram, suggesting that reduction in copper uptake, rather than the antioxidant activity of NAC, is responsible for the diminished cell death. We present further data showing that key mediators of reactive oxygen species are not upregulated in response to elesclomol treatment, and further that sensitivity of cancer cell lines to reactive oxygen species does not correlate with sensitivity to these copper ionophores. Our findings are in line with several recent studies proposing the mechanism of cuproptosis is instead via copper mediated aggregation of proteins, resulting in proteotoxic stress leading to cell death. Overall, it is vital to disseminate this key piece of information regarding NAC's activity on copper uptake since new research attributing the effect of NAC on copper ionophore activity to quenching of reactive oxygen species is being published regularly and our studies suggest their conclusions may be misleading.},
}
@article {pmid38079000,
year = {2023},
author = {AbdelRazek, M and Mohamed, O and Ashour, R and Alemam, M and El-Gelany, M and Abdel-Kader, MS},
title = {Effect of co-trimoxazole and N-acetylcysteine alone and in combination on bacterial adherence on ureteral stent surface.},
journal = {Urolithiasis},
volume = {52},
number = {1},
pages = {11},
pmid = {38079000},
issn = {2194-7236},
mesh = {Adult ; Child ; Humans ; *Acetylcysteine/therapeutic use/pharmacology ; Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use ; Prospective Studies ; Escherichia coli ; *Ureter/surgery/microbiology ; Stents/adverse effects/microbiology ; Bacteria ; },
abstract = {To assess the effect of co-trimoxazole and N-acetylcysteine (NAC), alone and in combination, on bacterial adherence to biofilm formed on ureteral stent surfaces. This prospective randomized study was conducted on 636 patients who underwent double J ureteral stent insertion after variable urological procedures. Patients were randomized into four groups: A (n = 165), no antibiotics or mucolytics during stent indwelling; B (n = 153), oral NAC (200 mg/day for children aged < 12 years old and 600 mg/day for adults) during stent indwelling; C (n = 162), oral co-trimoxazole (2 mg TMP/kg/day) during stent indwelling; and D (n = 156), both oral NAC and co-trimoxazole during stent indwelling. Two weeks following double J stent (JJ stent) insertion, urinalysis was performed on all patients and urine culture was done for all the patients at the day of double J stent removal. The stent was removed 2 weeks postoperatively, and a stent segment sized 3-5 cm from the bladder segment of the stent was sent for culture. Positive stent cultures were found in 63.6% (105/165), 43.1% (66/153), 37% (60/162), and 19.2% (30/156) patients of groups A, B, C, and D, respectively. E. coli was the organism most commonly isolated from the stent culture in all groups. The combination of co-trimoxazole and NAC was more effective in reducing bacterial adherence on ureteral stent surfaces than either alone.},
}
@article {pmid38076819,
year = {2023},
author = {Zou, H and Boboltz, A and Cheema, Y and Song, D and Duncan, GA},
title = {Synthetic mucus barrier arrays as a nanoparticle formulation screening platform.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38076819},
issn = {2692-8205},
support = {R21 AI142050/AI/NIAID NIH HHS/United States ; },
abstract = {A mucus gel layer lines the luminal surface of tissues throughout the body to protect them from infectious agents and particulates. As a result, nanoparticle drug delivery systems delivered to these sites may become trapped in mucus and subsequently cleared before they can reach target cells. As such, optimizing the properties of nanoparticle delivery vehicles, such as their surface chemistry and size, is essential to improving their penetration through the mucus barrier. In previous work, we developed a mucin-based hydrogel that has viscoelastic properties like that of native mucus which can be further tailored to mimic specific mucosal tissues and disease states. Using this biomimetic hydrogel system, a 3D-printed array containing synthetic mucus barriers was created that is compatible with a 96-well plate enabling its use as a high-throughput screening platform for nanoparticle drug delivery applications. To validate this system, we evaluated several established design parameters to determine their impact on nanoparticle penetration through synthetic mucus barriers. Consistent with the literature, we found nanoparticles of smaller size and coated with a protective PEG layer more efficiently penetrated through synthetic mucus barriers. In addition, we evaluated a mucolytic (tris (2-carboxyethyl) phosphine, TCEP) for use as a permeation enhancer for mucosal drug delivery. In comparison to N-acetyl cysteine (NAC), we found TCEP significantly improved nanoparticle penetration through a disease-like synthetic mucus barrier. Overall, our results establish a new high-throughput screening approach using synthetic mucus barrier arrays to identify promising nanoparticle formulation strategies for drug delivery to mucosal tissues.},
}
@article {pmid38072040,
year = {2024},
author = {Xiao, Y and Huang, Z and Wang, Y and Wang, Y and Yu, L and Yang, J and Zou, H and Wan, W and Yang, X},
title = {Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway.},
journal = {European journal of pharmacology},
volume = {963},
number = {},
pages = {176227},
doi = {10.1016/j.ejphar.2023.176227},
pmid = {38072040},
issn = {1879-0712},
mesh = {Humans ; Collagen/metabolism ; Fibroblasts ; Fibrosis ; *NF-E2-Related Factor 2/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; *Scleroderma, Systemic/drug therapy/metabolism/pathology ; Skin ; Transforming Growth Factor beta/drug effects/metabolism ; Smad3 Protein/drug effects/metabolism ; Flavonoids ; Propiophenones ; },
abstract = {Skin fibrosis, the most obvious clinical manifestation of systemic sclerosis (SSc), has a high unmet need for treatment. Xanthohumol (Xn) has been shown to have beneficial effects on fibrotic diseases, but its efficacy in SSc remains unreported. This study aims to elucidate the effects and mechanisms of Xn on collagen synthesis in SSc skin fibroblasts (SScF). We found increased collagen production in SScF cultured in vitro, accompanied by dysregulated levels of oxidative stress. Cell experiments showed that Xn inhibited cell proliferation and promoted apoptosis. In addition, Xn was shown for the first time to upregulate reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2)levels in SScF, and when combined with the ROS scavenger N-acetylcysteine (NAC), Nrf2 expression was decreased. Importantly, we demonstrated that Xn significantly attenuated collagen synthesis by blocking the fibrotic classical transforming growth factor beta 1 (TGFβ1)/Smad3 pathway, which interestingly was upregulated when combined with the Nrf2 inhibitor 385. Taken together, Xn suppressed the TGFβ1/Smad3 pathway to ameliorate collagen overproduction by promoting ROS-induced oxidative stress damage and activating Nrf2, suggesting that Xn administration may be an emerging therapeutic strategy for skin fibrosis in SSc.},
}
@article {pmid38071432,
year = {2024},
author = {Şehirli, A&#xd6; and Aksoy, U and Sibai, A and Orhan, K and Sayıner, S},
title = {Effects of N-acetyl-L-cysteine against apical periodontitis in rats with adriamycin-induced cardiomyopathy and nephropathy.},
journal = {International endodontic journal},
volume = {57},
number = {2},
pages = {195-207},
doi = {10.1111/iej.14010},
pmid = {38071432},
issn = {1365-2591},
mesh = {Rats ; Animals ; Rats, Wistar ; Acetylcysteine/pharmacology/therapeutic use ; Doxorubicin ; *Periapical Periodontitis/chemically induced/drug therapy ; *Cardiomyopathies/chemically induced/drug therapy ; Body Weight ; },
abstract = {AIM: This study aimed to investigate the potential protective effects of N-acetyl-L-cysteine (NAC) against apical periodontitis (AP) in rats with adriamycin (ADR)-induced kidney and heart diseases.<br><br>METHODOLOGY: Fourty-eight Wistar albino rats were divided into six groups: (1) Control group, (2) ADR group (1&#x2009;mg/kg/day ip for 10&#x2009;days), (3) AP Group (1st mandibular molar tooth), (4) AP&#x2009;+&#x2009;ADR Group, (5) AP&#x2009;+&#x2009;NAC group (150&#x2009;mg/kg/day ip), and (6) AP&#x2009;+&#x2009;ADR&#x2009;+&#x2009;NAC group. After 3&#x2009;weeks, the rats were decapitated and blood and tissue samples (heart, kidney, and jaw) were collected. Tissue samples were evaluated by biochemical (inflammatory cytokines and hemodynamic parameters) and radiological analyses. One-way anova with Tukey post hoc tests was used to compare data, considering p&#x2009;<&#x2009;.05 as statistically significant.<br><br>RESULTS: The serum levels of TNF-&#x3b1;, IL-1&#x3b2;, BUN, Creatinine, CK, and LDH were elevated in the test groups compared with the control group, and treatment with NAC reduced these levels (p&#x2009;<&#x2009;.05). Heart and kidney tissue analysis showed a higher heart-to-body weight ratio (HW/BW) and kidney-to-body weight ratio (KW/BW) in the test groups compared with the control group (p&#x2009;<&#x2009;.05). No significant differences in HW/BW and KW/BW were found between the control and AP&#x2009;+&#x2009;NAC groups. Volumetric apical bone resorption analysis showed an increase in periapical radiolucencies in AP-induced groups indicating apical periodontitis. NAC treatment reduced the total area and volume of resorption cavities (p&#x2009;<&#x2009;.05).<br><br>CONCLUSIONS: The results suggest that NAC's antioxidant and anti-inflammatory effects can reduce adriamycin-mediated heart and kidney damage and may have a positive effect on apical periodontitis in individuals with nephropathy and cardiomyopathy.},
}
@article {pmid38071049,
year = {2023},
author = {Lu, M and He, CL and Wu, ZT and Lyu, Y and Duan, XH and Wang, BX and Wang, SX and Wang, JH and Liang, R},
title = {[Effect of Baicalin on Pyroptosis of Diffuse Large B-Cell Lymphoma Cell Lines DB and Its Mechanism].},
journal = {Zhongguo shi yan xue ye xue za zhi},
volume = {31},
number = {6},
pages = {1706-1713},
doi = {10.19746/j.cnki.issn.1009-2137.2023.06.016},
pmid = {38071049},
issn = {1009-2137},
mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Reactive Oxygen Species/metabolism/pharmacology ; Pyroptosis ; Cell Line ; RNA, Messenger ; *Lymphoma, Large B-Cell, Diffuse ; Flavonoids ; },
abstract = {OBJECTIVE: To investigate the effect of Baicalin on the proliferation and pyroptosis of diffuse large B-cell lymphoma cell line DB and its mechanism.<br><br>METHODS: DB cells were treated with baicalin at different concentrations (0, 5, 10, 20, 40 &#x3bc;mol/L). Cell proliferation was detected by CCK-8 assay and half maximal inhibitory concentration (IC50) was calculated. The morphology of pyroptosis was observed under an inverted microscope, the integrity of the cell membrane was verified by LDH content release assay, and the expressions of pyroptosis-related mRNA and protein (NLRP3, GSDMD, GSDME, N-GSDMD, N-GSDME) were detected by real-time fluorescence quantitative PCR and Western blot. In order to further clarify the relationship between baicalin-induced pyroptosis and ROS production in DB cells, DB cells were divided into control group, baicalin group, NAC group and NAC combined with baicalin group. DB cells in the NAC group were pretreated with ROS inhibitor N-acetylcysteine (NAC) 2 mmol/L for 2 h. Baicalin was added to the combined treatment group after pretreatment, and the content of reactive oxygen species (ROS) in the cells was detected by DCFH-DA method after 48 hours of culture.<br><br>RESULTS: Baicalin inhibited the proliferation of DB cells in a dose-dependent manner (r=-0.99), and the IC50 was 20.56 &#x3bc;mol/L at 48 h. The morphological changes of pyroptosis in DB cells were observed under inverted microscope. Compared with the control group, the release of LDH in the baicalin group was significantly increased (P<0.01), indicating the loss of cell membrane integrity. Baicalin dose-dependently increased the expression levels of NLRP3, N-GSDMD, and N-GSDME mRNA and protein in the pyroptosis pathway (P<0.05). Compared with the control group, the level of ROS in the baicalin group was significantly increased (P<0.05), and the content of ROS in the NAC group was significantly decreased (P<0.05). Compared with the NAC group, the content of ROS in the NAC + baicalin group was increased. Baicalin significantly attenuated the inhibitory effect of NAC on ROS production (P<0.05). Similarly, Western blot results showed that compared with the control group, the expression levels of pyroptosis-related proteins was increased in the baicalin group (P<0.05). NAC inhibited the expression of NLRP3 and reduced the cleavage of N-GSDMD and N-GSDME (P<0.05). Compared with the NAC group, the NAC + baicalin group had significantly increased expression of pyroptosis-related proteins. These results indicate that baicalin can effectively induce pyroptosis in DB cells and reverse the inhibitory effect of NAC on ROS production.<br><br>CONCLUSION: Baicalin can inhibit the proliferation of DLBCL cell line DB, and its mechanism may be through regulating ROS production to affect the pyroptosis pathway.},
}
@article {pmid38069498,
year = {2024},
author = {Tiouririne, NA and Kalelioglu, T and Seneviratne, C and Wang, XQ},
title = {Safety and tolerability of topiramate and N-acetyl cysteine combination in individuals with alcohol use disorder: a 12 week, randomized, double-blind, pilot study.},
journal = {Alcohol and alcoholism (Oxford, Oxfordshire)},
volume = {59},
number = {2},
pages = {},
doi = {10.1093/alcalc/agad082},
pmid = {38069498},
issn = {1464-3502},
support = {//University of Virginia/ ; },
mesh = {Humans ; Alcohol Drinking ; *Alcoholism/drug therapy/psychology ; Cysteine ; Double-Blind Method ; Glutathione/metabolism ; Pilot Projects ; *Topiramate/adverse effects ; Treatment Outcome ; Drug Combinations ; },
abstract = {Topiramate (TPM), a GABA/glutamate modulator, has shown positive results for treating alcohol use disorder (AUD), but causes significant cognitive adverse effects. TPM causes cognitive side effects by reducing glutathione levels in the frontal lobe. N-acetyl cysteine (NAC) increases level of intracellular glutathione. We hypothesized that combining NAC with TPM may mitigate the possible cognitive side effects of TPM, as well as working synergistically in reducing alcohol consumption more efficaciously than using TPM alone. A 12-week, double-blind randomized trial assessing the effects of combining NAC (1200 mg/day) with TPM (200 mg/day) vs TPM alone (i) cognitive side effects caused by TPM, (ii) percentage of heavy drinking days (PHDD) and percentage of days abstinent (PDA) using weekly calendar, and (iii) craving outcomes using the obsessive-compulsive drinking scale. Seventeen participants were randomized into the study (nine received TPM + NAC and eight matching TPM + Placebo). Cognitive adverse events were not significantly different between the treatment arms (P = 0.581). There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892). However, both treatment groups at study end, compared with the baseline, significantly reduced their PHDD and increased their PDA. As for cravings: TPM + NAC group has shown higher level in automaticity of drinking (P = 0.029) and interference due to drinking (P = 0.014) subscales compared with the TPM + Placebo group. No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales. This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking. Furthermore, craving outcomes may become worse with the addition of NAC.},
}
@article {pmid38068931,
year = {2023},
author = {Pérez-Torres, I and Aisa-Álvarez, A and Casarez-Alvarado, S and Borrayo, G and Márquez-Velasco, R and Guarner-Lans, V and Manzano-Pech, L and Cruz-Soto, R and Gonzalez-Marcos, O and Fuentevilla-Álvarez, G and Gamboa, R and Saucedo-Orozco, H and Franco-Granillo, J and Soto, ME},
title = {Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects.},
journal = {International journal of molecular sciences},
volume = {24},
number = {23},
pages = {},
pmid = {38068931},
issn = {1422-0067},
mesh = {Humans ; Antioxidants/therapeutic use ; Interleukin-6 ; Cytokine Release Syndrome/drug therapy ; Interleukin-10 ; *Shock, Septic/drug therapy ; Reproducibility of Results ; Oxidative Stress ; Ascorbic Acid/therapeutic use ; Vitamin E/therapeutic use ; Acetylcysteine/therapeutic use ; *Melatonin/therapeutic use ; Adjuvants, Immunologic/therapeutic use ; },
abstract = {Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1β, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFβ), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO3[-] and NO2[-]), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls (p = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects.},
}
@article {pmid38067442,
year = {2023},
author = {Lee, BH and Song, E and Hong, J},
title = {Interaction of Thiol Antioxidants with α,β-Unsaturated Ketone Moiety: Its Implication for Stability and Bioactivity of Curcuminoids.},
journal = {Molecules (Basel, Switzerland)},
volume = {28},
number = {23},
pages = {},
pmid = {38067442},
issn = {1420-3049},
support = {2021R1F1A1051466//National Research Foundation of Korea/ ; IHS GNU-2022-04//Institute of Health Sciences of Gyeongsang National University/ ; 2022//The research grant of the Gyeongsang National University/ ; },
mesh = {*Antioxidants/pharmacology ; Diarylheptanoids ; *Curcumin/pharmacology ; Sulfhydryl Compounds/pharmacology ; Glutathione/pharmacology ; Acetylcysteine/pharmacology ; },
abstract = {Many biological functions of curcumin have been reported. As certain bioactivities of curcumin are eliminated by antioxidants, reactive oxygen species generated by curcumin have been suggested as a relevant mechanism. In the present study, the effects of different types of antioxidants on the stability and bioactivities of curcumin were analyzed. High concentrations (>4 mM) of thiol antioxidants, including N-acetylcysteine (NAC), glutathione (GSH), and β-mercaptoethanol, accelerated the decomposition of curcumin and other curcuminoids; the submillimolar levels (<0.5 mM) of GSH and NAC rather improved their stability. Ascorbic acid or superoxide dismutase also stabilized curcumin, regardless of their concentration. The cellular levels and bioactivities of curcumin, including its cytotoxicity and the induction of heme oxygenase-1, were significantly reduced in the presence of 8 mM of GSH and NAC. The effects were enhanced in the presence of submillilmolar GSH and NAC, or non-thiol antioxidants. The present results indicate that antioxidants with a reduced thiol group could directly interact with the α,β-unsaturated carbonyl moiety of curcuminoids and modulate their stability and bioactivity.},
}
@article {pmid38065397,
year = {2024},
author = {Li, F and Zhu, X and Xu, X and Zhou, J and Lu, R and Wang, S and Xing, G and Ye, Y},
title = {Dibromoacetonitrile induced autophagy by mediating the PERK signalling pathway and ROS interaction in HT22 cell.},
journal = {Toxicology},
volume = {501},
number = {},
pages = {153698},
doi = {10.1016/j.tox.2023.153698},
pmid = {38065397},
issn = {1879-3185},
mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Protein Kinases/metabolism ; *Signal Transduction ; Endoplasmic Reticulum/metabolism ; Autophagy ; Endoplasmic Reticulum Stress ; Apoptosis ; Mammals/metabolism ; Butylamines ; Acetonitriles ; },
abstract = {Dibromoacetonitrile (DBAN) is a high-risk haloacetonitrile (HAN) generated as a byproduct of chloramine disinfection in drinking water. DBAN-induced neurotoxicity in mouse hippocampal neuronal cells (HT22) and mammals was observed to be related to reactive oxygen species (ROS). ROS, endoplasmic reticulum stress (ERS) and autophagy play crucial roles in regulating a variety of cellular processes. However, whether ERS and autophagy are associated with HAN-responsive apoptosis remains unclear. This study indicated that DBAN (10 μM, 24 h) activated the ERS protein kinase like endoplasmic reticulum kinase (PERK) signaling pathway. The ERS inhibitor 4-phenylbutyric acid (4-PBA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, indicating that activation of the ERS PERK pathway mediates DBAN induced cytotoxicity. Moreover, DBAN activated autophagy. The autophagy inhibitor 3-methyladenine(3-MA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, suggesting that autophagy activation mediates DBAN-induced cell toxicity. Notably, the results showed that 4-PBA inhibited DBAN-activated autophagy, demonstrating that ERS-PERK promotes DBAN-induced cellular autophagy. Pretreatment with antioxidant N-acetylcysteine (NAC) inhibited the increase in ROS production and the activation of ERS, and protected cells from toxicity. Furthermore, 4-PBA pretreatment reduced the increase in ROS production, indicating that the ROS and PERK promote each other and form a positive feedback loop. ROS also promoted DBAN-induced autophagy. In summary, our findings indicate that DBAN induced autophagy by mediating the PERK signalling pathway and ROS interaction, leading to HT22 cell damage. Accordingly, targeting these pathogenic mechanisms may provide a potential target and theoretical basis for preventing and improving HAN-induced neurotoxicity.},
}
@article {pmid38062506,
year = {2023},
author = {Kuo, SH and Hsu, WL and Wu, CY and Lai, YC and Chen, TC},
title = {Dolutegravir-induced growth and lifespan effects in Caenorhabditis elegans.},
journal = {BMC pharmacology &amp; toxicology},
volume = {24},
number = {1},
pages = {74},
pmid = {38062506},
issn = {2050-6511},
support = {kmtth-104-019, kmtth-107-045, kmtth-109-001, kmtth-109-030, Kmtth-110-014//Kaohsiung Municipal Ta- Tung Hospital, Kaohsiung Medical University, Taiwan/ ; },
mesh = {Humans ; Animals ; *HIV Integrase Inhibitors/pharmacology/therapeutic use ; Caenorhabditis elegans ; Longevity ; *HIV Infections/drug therapy ; Reactive Oxygen Species ; *Drug-Related Side Effects and Adverse Reactions ; Dolutegravir ; },
abstract = {BACKGROUND: Integrase strand transfer inhibitor (INSTIs)-based combination antiretroviral treatment in people living with HIV (PLWH) has been reportedly correlated with several adverse effects, such as weight gain, fetal defects or psychiatric disorders.<br><br>METHODS: To comprehensively understand the adverse effect of INSTIs, our study utilized Caenorhabditis Elegans (C. elegans) as a model to investigate how dolutegravir (DTG) affected its life cycle, growth, reproduction and lifespan.<br><br>RESULTS: Our results indicated that DTG enhanced body growth at the early stage of treatment, but no change was detected for long-term treatment. The treatment also influenced the reproductive system, decreased egg-hatching but had no effect on egg-laying. Besides, DTG resulted in lifespan reduction, which is dependent on increased levels of reactive oxidative species (ROS) accumulation. Treatment with N-acetyl-cysteine (NAC) in worms restrained intracellular ROS accumulation and improved DTG-induced lifespan reduction.<br><br>CONCLUSIONS: Our study demonstrates for the first time the effect of DTG treatment on life cycle. DTG-induced adverse effects are potentially associated with intracellular ROS accumulation. Quenching ROS accumulation might provide a novel strategy for dealing with the adverse effects of INSTIs.},
}
@article {pmid38061079,
year = {2024},
author = {Zhang, B and Huang, C and Xu, D and Huang, K and Li, Y and Jiao, L and Fu, B and Li, S and Li, Y},
title = {Patulin induces ROS-dependent cardiac cell toxicity by inducing DNA damage and activating endoplasmic reticulum stress apoptotic pathway.},
journal = {Ecotoxicology and environmental safety},
volume = {269},
number = {},
pages = {115784},
doi = {10.1016/j.ecoenv.2023.115784},
pmid = {38061079},
issn = {1090-2414},
mesh = {Animals ; Humans ; *Patulin/toxicity/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; DNA Damage ; Apoptosis ; Endoplasmic Reticulum Stress ; },
abstract = {Patulin (PAT) is one of the mycotoxins commonly found in agricultural products and fruits, and has obvious toxic effects on animals and humans. PAT has been found to cause myocardial toxicity and oxidative damage, but the mechanism of myocardial toxicity remained to be elucidated. We investigated the toxic effects and potential mechanisms of PAT on human cardiomyocytes and explored the effects of reactive oxygen species (ROS) on them. The study showed that treatment with PAT for 24 h decreased cell viability and superoxide dismutase (SOD) activity, and increased ROS and lactate dehydrogenase (LDH) levels. Moreover, in addition to detecting increased γ-H2AX expression and observing nuclear damage, the comet assay also showed increased DNA tail distance in the PAT-treated group, followed by an increase in phosphorylation of the p53 protein and p21 protein expression, and a decrease in CDK1 and Cyclin B1 protein expression, and G2/M phase arrest. In addition, PAT induced endoplasmic reticulum stress (ERS) and induced apoptosis, as evidenced by Ca[2+] increase, ER enlargement and swelling, and upregulation of ERS-related genes and proteins expression, and increased expression of three apoptotic pathway proteins under ERS, including CHOP, JNK, and caspase-12. Meanwhile, N-acetylcysteine (NAC, a ROS scavenger) reversed the negative effects of PAT treatment on cells. These results clarify that excessive ROS production by PAT-treated AC16 cells not only causes DNA damage, leading to cell cycle arrest, but also causes ERS, which triggers apoptotic pathways to cause apoptosis.},
}
@article {pmid38060590,
year = {2025},
author = {Yoldaş, MA and Bekdaş, M and Danış, A and Çetinkaya, A and Düzcü, SE and Alışık, M and Kocabey, H and Türel, &#x130; and Dinçel, GK},
title = {Protective and therapeutic effects of okra seed in acute nontraumatic brain injury.},
journal = {The International journal of neuroscience},
volume = {135},
number = {2},
pages = {148-157},
doi = {10.1080/00207454.2023.2292948},
pmid = {38060590},
issn = {1563-5279},
mesh = {Animals ; Male ; Rats, Wistar ; *Plant Extracts/pharmacology/therapeutic use ; Acetaminophen/toxicity ; Rats ; *Abelmoschus ; *Seeds/chemistry ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Brain Injuries/drug therapy/pathology/chemically induced ; Antioxidants/pharmacology ; },
abstract = {AIM: The purpose of this study was to examine the protective and therapeutic effects of okra (Abelmoschus esculentus [AE]) seed extract, with its known antioxidant, immunomodulatory, and anti-inflammatory properties, in an acetaminophen (paracetamol, N-acetyl- para-aminophenol)-induced model of hepatotoxicity and subsequent acute non-traumatic brain damage.<br><br>MATERIAL AND METHOD: Forty male Wistar rats were randomly divided into five equal groups, control, paracetamol (P), okra seed extract (AE), okra seed extract&#x2009;+&#x2009;paracetamol (P&#x2009;+&#x2009;AE), and okra seed extract&#x2009;+&#x2009;paracetamol&#x2009;+&#x2009;N-acetyl cysteine (NAC) (P&#x2009;+&#x2009;AE&#x2009;+&#x2009;N). AE was administered by oral gavage through a gastric tube at 600&#x2009;mg/kg/day for seven days. On the eighth day of the procedure, a single 1&#x2009;g/kg dose of paracetamol and 300&#x2009;mg/kg NAC were injected via the intraperitoneal route 1.5&#x2009;h after AE administration. Rat tissue specimens were subsequently subjected to biochemical and histopathological analyses. Levels of markers such as S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), and matrix membrane metalloproteinase-9 (MMP-9) were investigated from rat serum specimens. Malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured to determine oxidant-antioxidant status.<br><br>RESULTS: S100B, NSE, MMP-9, MDA levels, and SOD enzyme activities were examined using biochemical methods. MDA levels were significantly lower in the P&#x2009;+&#x2009;AE group and MMP-9 levels in the AE, P&#x2009;+&#x2009;AE, and P&#x2009;+&#x2009;AE&#x2009;+&#x2009;N groups compared to the P group. Histopathological examination results supported the biochemical findings.<br><br>CONCLUSION: Okra seed extract exhibits a protective and therapeutic effect against non-traumatic brain damage resulting from acute paracetamol intoxication. We think that this benefit of AE derives from its antioxidant property.},
}
@article {pmid38043497,
year = {2024},
author = {Bai, W and Liu, D and Cheng, Q and Yang, X and Zhu, L and Qin, L and Fang, J},
title = {Tetraarsenic tetrasulfide triggers ROS-induced apoptosis and ferroptosis in B-cell acute lymphoblastic leukaemia by targeting HK2.},
journal = {Translational oncology},
volume = {40},
number = {},
pages = {101850},
pmid = {38043497},
issn = {1936-5233},
abstract = {PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. Despite cure rates of higher than 85 %, refractory or relapsed ALL still exhibits a bleak prognosis indicative of the dearth of treatment modalities specific for relapsed or refractory ALL. Prior research has implicated metabolic alterations in leukemia pathogenesis, and literature on the therapeutic efficacy of arsenic compounds targeting metabolic pathways in B-cell acute lymphoblastic leukemia (B-ALL) cells is scarce.<br><br>METHODS: A compound extracted from realgar, tetraarsenic tetrasulfide (As4S4), and its antitumor effects on B-ALL were experimentally examined in vitro and in vivo.<br><br>RESULTS: As4S4 apparently targets B-ALL cells by inducing specific cellular responses, including apoptosis, G2/M arrest, and ferroptosis. Interestingly, these effects are attributed to reactive oxygen species (ROS) accumulation, and increased ROS levels have been linked to both the mitochondria-dependent caspase cascade and the activation of p53 signaling. The ROS scavenger N-acetylcysteine (NAC) can counteract the effects of As4S4 treatment on Nalm-6 and RS4;11 cells. Specifically, by targeting Hexokinase-2 (HK2), As4S4 induces alterations in mitochondrial membrane potential and disrupts glucose metabolism, leading to ROS accumulation, and was shown to inhibit B-ALL cell proliferation in vitro and in vivo. Intriguingly, overexpression of HK2 can partially desensitize B-ALL cells to As4S4 treatment.<br><br>CONCLUSION: Tetraarsenic tetrasulfide can regulate the Warburg effect by controlling HK2 expression, a finding that provides both new mechanistic insight into metabolic alterations and pharmacological evidence for the clinical treatment of B-ALL.},
}
@article {pmid38043329,
year = {2024},
author = {Andrade, BF and Guimarães, AS and do Carmo, LR and Tanaka, MS and Fontes, PR and Ramos, ALS and Ramos, EM},
title = {S-nitrosothiols as nitrite alternatives: Effects on residual nitrite, lipid oxidation, volatile profile, and cured color of restructured cooked ham.},
journal = {Meat science},
volume = {209},
number = {},
pages = {109397},
doi = {10.1016/j.meatsci.2023.109397},
pmid = {38043329},
issn = {1873-4138},
mesh = {*Meat Products/analysis ; Sodium Nitrite ; *S-Nitrosothiols/chemistry ; Lipids ; Acetylcysteine/*analogs &amp; derivatives ; },
abstract = {This study evaluated the use of the S-nitrosothiols, S-nitroso-N-acetylcysteine (NAC-SNO) and S-nitroso-N-acetylcysteine ethyl ester (NACET-SNO), at different concentrations (25-300 mg nitrite equivalent - NEq/kg) as sodium nitrite substitutes in restructured cooked hams. The pH value and instrumental cured color were not affected by the type or amount of curing agent used. Products with 25 and 50 mg/kg ingoing nitrite had lower thiobarbituric acid-reactive substance values than those with equimolar amounts of S-nitrosothiols. Products with >150 mg NEq/kg of S-nitrosothiols had residual nitrite similar to 50 mg/kg nitrite, and this resulted in the same volatile compound profile as nitrite added in equimolar amounts. A 300 mg NEq/kg of S-nitrosothiols was required to obtain a similar and minimally stable cured pink color perception as sliced samples with 50-150 mg/kg added nitrite. The results obtained reinforce the great potential of both alternative curing agents in the complete replacement of nitrite by equimolar amounts in restructured cooked products; however, differences in cured color stability should be considered.},
}
@article {pmid38042493,
year = {2024},
author = {Richartz, N and Pietka, W and Yadav, A and Bostad, M and Bhagwat, S and Naderi, S and Naderi, EH and Stokke, T and Ruud, E and Blomhoff, HK},
title = {N-acetyl cysteine turns EPAC activators into potent killers of acute lymphoblastic leukemia cells.},
journal = {The Journal of biological chemistry},
volume = {300},
number = {1},
pages = {105509},
pmid = {38042493},
issn = {1083-351X},
mesh = {Animals ; Child ; Humans ; Mice ; *Acetylcysteine/pharmacology/therapeutic use ; *Cyclic AMP/analogs &amp; derivatives/pharmacology/therapeutic use ; DNA/drug effects ; *Guanine Nucleotide Exchange Factors/agonists ; Mice, Inbred NOD ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Male ; Female ; Child, Preschool ; *Thionucleotides/pharmacology/therapeutic use ; DNA Damage ; Drug Therapy, Combination ; },
abstract = {Today, the majority of patients with pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL, hereafter ALL) survive their disease, but many of the survivors suffer from life-limiting late effects of the treatment. ALL develops in the bone marrow, where the cells are exposed to cAMP-generating prostaglandin E2. We have previously identified the cAMP signaling pathway as a putative target for improved efficacy of ALL treatment, based on the ability of cAMP signaling to reduce apoptosis induced by DNA damaging agents. In the present study, we have identified the antioxidant N-acetyl cysteine (NAC) as a powerful modifier of critical events downstream of the cell-permeable cAMP analog 8-(4-chlorophenylthio) adenosine-3', 5'- cyclic monophosphate (8-CPT). Accordingly, we found NAC to turn 8-CPT into a potent killer of ALL cells in vitro both in the presence and absence of DNA damaging treatment. Furthermore, we revealed that NAC in combination with 8-CPT is able to delay the progression of ALL in a xenograft model in NOD-scid IL2Rγ[null] mice. NAC was shown to rely on the ability of 8-CPT to activate the guanine-nucleotide exchange factor EPAC, and we demonstrated that the ALL cells are killed by apoptosis involving sustained elevated levels of calcium imposed by the combination of the two drugs. Taken together, we propose that 8-CPT in the presence of NAC might be utilized as a novel strategy for treating pediatric ALL patients, and that this powerful combination might be exploited to enhance the therapeutic index of current ALL targeting therapies.},
}
@article {pmid38042273,
year = {2023},
author = {Akakpo, JY and Ramachandran, A and Rumack, BH and Wallace, DP and Jaeschke, H},
title = {Lack of mitochondrial Cyp2E1 drives acetaminophen-induced ER stress-mediated apoptosis in mouse and human kidneys: Inhibition by 4-methylpyrazole but not N-acetylcysteine.},
journal = {Toxicology},
volume = {500},
number = {},
pages = {153692},
pmid = {38042273},
issn = {1879-3185},
support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; R21 AG073892/AG/NIA NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; U54 DK126126/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Mice ; Animals ; *Acetaminophen/toxicity ; Acetylcysteine/pharmacology/metabolism ; Fomepizole/pharmacology/therapeutic use ; Antidotes/pharmacology ; Cytochrome P-450 CYP2E1/metabolism ; Mice, Inbred C57BL ; Liver ; Apoptosis ; Mitochondria/metabolism ; Kidney/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism ; },
abstract = {Acetaminophen (APAP) overdose causes liver injury and acute liver failure, as well as acute kidney injury, which is not prevented by the clinical antidote N-acetyl-L-cysteine (NAC). The absence of therapeutics targeting APAP-induced nephrotoxicity is due to gaps in understanding the mechanisms of renal injury. APAP metabolism through Cyp2E1 drives cell death in both the liver and kidney. We demonstrate that Cyp2E1 is localized to the proximal tubular cells in mouse and human kidneys. Virtually all the Cyp2E1 in kidney cells is in the endoplasmic reticulum (ER), not in mitochondria. By contrast, hepatic Cyp2E1 is in both the ER and mitochondria of hepatocytes. Consistent with this subcellular localization, a dose of 600 mg/kg APAP in fasted C57BL/6J mice induced the formation of APAP protein adducts predominantly in mitochondria of hepatocytes, but the ER of the proximal tubular cells of the kidney. We found that reactive metabolite formation triggered ER stress-mediated activation of caspase-12 and apoptotic cell death in the kidney. While co-treatment with 4-methylpyrazole (4MP; fomepizole) or the caspase inhibitor Ac-DEVD-CHO prevented APAP-induced cleavage of procaspase-12 and apoptosis in the kidney, treatment with NAC had no effect. These mechanisms are clinically relevant because 4MP but not NAC also significantly attenuated APAP-induced apoptotic cell death in primary human kidney cells. We conclude that reactive metabolite formation by Cyp2E1 in the ER results in sustained ER stress that causes activation of procaspase-12, triggering apoptosis of proximal tubular cells, and that 4MP but not NAC may be an effective antidote against APAP-induced kidney injury.},
}
@article {pmid38034812,
year = {2023},
author = {Wang, L and Xu, Y and Zhao, X and Zhu, X and He, X and Sun, A and Zhuang, G},
title = {Antagonistic effects of N-acetylcysteine on lead-induced apoptosis and oxidative stress in chicken embryo fibroblast cells.},
journal = {Heliyon},
volume = {9},
number = {11},
pages = {e21847},
pmid = {38034812},
issn = {2405-8440},
abstract = {Lead (Pb) is a heavy metal that can have harmful effects on the environment, which has severe cytotoxicity in many animal tissues. N-acetylcysteine (NAC) has antioxidant activity, reducing lead-induced oxidative stress and apoptosis, but its role in chicken cells is unknown. The current study explored the antagonistic effect of NAC on lead-induced apoptosis and oxidative stress in chicken embryo fibroblast (CEF). In this study, CEF was used as a model to measure the cytotoxic effects of lead nitrate at different concentrations, demonstrating a dose-dependent effect on CEF activity. Employing inverted microscopy, the investigation of morphological alterations in CEF cells was conducted. Fluorescence staining methodology enabled the assessment of reactive oxygen species (ROS) levels within CEF cells. Moreover, an enzyme-linked immunosorbent assay was utilized to detect the presence of oxidative damage indicators encompassing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) activity, malondialdehyde (MDA) content, and total antioxidant capacity (T-AOC) within CEF cells. Furthermore, the determination of the apoptosis rate of CEF cells was accomplished through the utilization of the Hoechst 33258 staining method in combination with the Annexin V-FITC dual staining method. By using RT-qPCR for detection, lead treatment increased expression of pro-apoptotic genes, caspase-3, and caspase-9, and reduced expression of anti-apoptotic genes, Bcl-2, and BI-1. Reduced antioxidant capacity was shown by increased ROS and MDA levels in CEF cells after lead treatment. The results showed that NAC inhibited the expression of caspase-3 and caspase-9 in lead-treated CEF cells, while NAC had a certain inhibitory effect on the relative expression of Bcl-2 and BI-1 mRNA in lead-induced CEF cells. NAC significantly reduced lead-induced oxidative damage and apoptosis. Overall, our results demonstrate a novel protective effect of NAC against lead-induced injury in chicken cells, providing a theoretical basis for future investigations of drugs that are effective in preventing lead poisoning in animals.},
}
@article {pmid38031002,
year = {2023},
author = {Zhang, XL and Cao, Y and Zheng, B},
title = {Efficacy of N-acetylcysteine plus pirfenidone in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.},
journal = {BMC pulmonary medicine},
volume = {23},
number = {1},
pages = {479},
pmid = {38031002},
issn = {1471-2466},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Pyridones/adverse effects ; Treatment Outcome ; *Idiopathic Pulmonary Fibrosis ; },
abstract = {BACKGROUND: Numerous studies have demonstrated the potential of pirfenidone to enhance the prognosis of patients afflicted with idiopathic pulmonary fibrosis (IPF). Although N-acetylcysteine (NAC) is utilized as an antioxidant in IPF treatment, the combination of NAC and pirfenidone has produced inconsistent outcomes in certain studies. To assess the clinical effectiveness and safety of NAC plus pirfenidone (designated as the treatment group) versus pirfenidone monotherapy (designated as the control group), we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs).<br><br>METHODS: RCTs of NAC plus pirfenidone were reviewed searching from databases and networks of unpublished and published studies in any language. Using pair-wise meta-analysis, changes in pulmonary function test (PFT) parameters and safety were evaluated.<br><br>RESULTS: Two independent reviewers selected and obtained data from 5 RCTs (n&#x2009;=&#x2009;398), comprising 1 study from Japan, 1 from Europe, and 3 from China. NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of skin effects(RR 1.26 [95%CI 0.64 to 2.45]) and mortality(RR 0.35 [95%CI 0.07 to 1.68])(both moderate certainty). NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of at least one side effects(RR 1.00 [95%CI 0.84 to 1.19]; low certainty),severe side effects(RR 0.67 [95%CI 0.30 to 1.47]; low certainty) and gastrointestinal effects(RR 0.67 [95%CI 0.41 to 1.09]; low certainty) with possibly no effect in &#x394;%DLco(SMD -0.17 [95%CI -0.15 to 0.48]; low certainty). Meanwhile, the effect of NAS plus pirfenidone as compared to pirfenidone monotherapy on &#x394;FVC(SMD 0.18 [95%CI -0.68 to 1.05]), &#x394;%FVC(SMD -2.62 [95%CI -5.82 to 0.59]) and &#x394;6MWT(SMD -0.35 [95%CI -0.98 to 0.28]) is uncertain(extremely low certainty).<br><br>CONCLUSION: Moderate certainty evidence suggests that NAS plus pirfenidone, compared to pirfenidone monotherapy for IPF, does not reduce the incidence of skin effects and mortality.},
}
@article {pmid38019375,
year = {2024},
author = {Roy, A and Goenka, MK},
title = {Simethicone and N-acetyl cysteine in improving mucosal visibility: Towards a "clearer view" during endoscopy.},
journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology},
volume = {43},
number = {5},
pages = {863-865},
pmid = {38019375},
issn = {0975-0711},
mesh = {Humans ; *Acetylcysteine ; *Simethicone/administration &amp; dosage ; Endoscopy, Gastrointestinal/methods ; },
}
@article {pmid38018602,
year = {2023},
author = {Atefi, N and Goodarzi, A and Riahi, T and Khodabandehloo, N and Talebi Taher, M and Najar Nobari, N and Seirafianpour, F and Mahdi, Z and Baghestani, A and Valizadeh, R},
title = {Evaluation of the efficacy and safety of oral N-acetylcysteine in patients with COVID-19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial.},
journal = {Immunity, inflammation and disease},
volume = {11},
number = {11},
pages = {e1083},
pmid = {38018602},
issn = {2050-4527},
mesh = {Humans ; *Ritonavir/therapeutic use ; *COVID-19 ; Antiviral Agents/adverse effects ; Hydroxychloroquine/adverse effects ; Atazanavir Sulfate/adverse effects ; Acetylcysteine/therapeutic use ; C-Reactive Protein ; SARS-CoV-2 ; COVID-19 Drug Treatment ; Inflammation/drug therapy ; Randomized Controlled Trials as Topic ; },
abstract = {BACKGROUND: The current absence of gold-standard or all-aspect favorable therapies for COVID-19 renders a focus on multipotential drugs proposed to prevent or treat this infection or ameliorate its signs and symptoms vitally important. The present well-designed randomized controlled trial (RCT) sought to evaluate the efficacy and safety of N-acetylcysteine (NAC) as adjuvant therapy for 60 hospitalized Iranian patients with COVID-19.<br><br>METHODS: Two 30-person diets, comprising 15 single diets of Kaletra (lopinavir/ritonavir) + hydroxychloroquine (HCQ) with/without NAC (600 mg TDS) and atazanavir/ritonavir + HCQ with/without NAC (600 mg TDS), were administered in the study.<br><br>RESULTS: At the end of the study, a further decrease in C-reactive protein was observed in the NAC group (P&#x2009;=&#x2009;0.008), and no death occurred in the atazanavir/ritonavir + HCQ + NAC group, showing that the combination of these drugs may reduce mortality. The atazanavir/ritonavir + HCQ and atazanavir/ritonavir + NAC groups exhibited the highest O2 saturation at the end of the study and a significant rise in O2 saturation following intervention commencement, including NAC (P&#x2009;>&#x2009;0.05). Accordingly, oral or intravenous NAC, if indicated, may enhance O2 saturation, blunt the inflammation trend (by reducing C-reactive protein), and lower mortality in hospitalized patients with COVID-19.<br><br>CONCLUSION: The NAC could be more effective as prophylactic or adjuvant therapy in stable non-severe cases of COVID-19 with a particularly positive role in the augmentation of O2 saturation and faster reduction of the CRP level and inflammation or could be effective for better controlling of COVID-19 or its therapy-related side effects.},
}
@article {pmid38016189,
year = {2023},
author = {Rosas-Gutiérrez, GDC and Fernández-Hernández, JP and Olea-González, AI},
title = {[Efficacy of intratympanic infiltration of N-acetyl cysteine in cisplatin ototoxicity].},
journal = {Revista medica del Instituto Mexicano del Seguro Social},
volume = {61},
number = {Suppl 2},
pages = {S318-S322},
pmid = {38016189},
issn = {2448-5667},
mesh = {Humans ; Middle Aged ; Cisplatin/adverse effects ; *Antineoplastic Agents/adverse effects ; Acetylcysteine/therapeutic use/pharmacology ; *Ototoxicity ; Prospective Studies ; },
abstract = {INTRODUCTION: Currently there is no approved preventive or therapeutic pharmacological treatment to treat ototoxicity caused by cisplatin. N-acetyl cysteine (NAC) is a safe and inexpensive antioxidant that has been studied as an otoprotective alternative.<br><br>OBJECTIVE: To describe the efficacy of intratympanic infiltration of NAC as prevention and treatment of ototoxicity induced in patients treated with cisplatin.<br><br>MATERIAL AND METHODS: Open, longitudinal, prospective, randomized clinical trial in cancer patients treated with cisplatin who met the inclusion criteria. Out of the sample of 22 patients, 11 underwent intratympanic NAC infiltration and 11 were taken as a control group. It was performed an audiometry at the beginning and one month after on all patients.<br><br>RESULTS: A sample of 22 patients with a mean age of 53 (&#xb1;13) was collected. In our sample of 11 patients with infiltration in both ears, 1 ear showed improvement; on the other hand, in the control group that was not infiltrated, 4 showed an increase in hearing loss from mild to moderate in all 4 cases, 2 in the left ear and 2 in the right ear (Spearman's Rho = 0.93, p &#x2264; 0.001). Relative risk was of 1.22.<br><br>CONCLUSIONS: An association can be observed that intratympanic NAC could become an alternative for the prevention and treatment of cisplatin-induced ototoxicity.},
}
@article {pmid38015959,
year = {2023},
author = {Bosman, M and Krüger, DN and Favere, K and De Meyer, GRY and Franssen, C and Van Craenenbroeck, EM and Guns, PJ},
title = {Dexrazoxane does not mitigate early vascular toxicity induced by doxorubicin in mice.},
journal = {PloS one},
volume = {18},
number = {11},
pages = {e0294848},
pmid = {38015959},
issn = {1932-6203},
mesh = {Mice ; Animals ; Male ; *Dexrazoxane/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Cardiotoxicity/drug therapy/prevention &amp; control/metabolism ; Acetylcholine/metabolism ; Doxorubicin/toxicity/metabolism ; Mice, Inbred C57BL ; Myocytes, Cardiac/metabolism ; Antibiotics, Antineoplastic/pharmacology ; },
abstract = {Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) provokes acute and long-term vascular toxicity. Dexrazoxane (DEXRA) is an effective drug for treatment of DOX-induced cardiotoxicity, yet it remains currently unknown whether DEXRA prevents vascular toxicity associated with DOX. Accordingly, the present study aimed to evaluate the protective potential of DEXRA against DOX-related vascular toxicity in a previously-established in vivo and ex vivo model of vascular dysfunction induced by 16 hour (h) DOX exposure. Vascular function was evaluated in the thoracic aorta in organ baths, 16h after administration of DOX (4 mg/kg) or DOX with DEXRA (40 mg/kg) to male C57BL6/J mice. In parallel, vascular reactivity was evaluated after ex vivo incubation (16h) of murine aortic segments with DOX (1 μM) or DOX with DEXRA (10 μM). In both in vivo and ex vivo experiments, DOX impaired acetylcholine-stimulated endothelium-dependent vasodilation. In the ex vivo setting, DOX additionally attenuated phenylephrine-elicited vascular smooth muscle cell (VSMC) contraction. Importantly, DEXRA failed to prevent DOX-induced endothelial dysfunction and hypocontraction. Furthermore, RT-qPCR and Western blotting showed that DOX decreased the protein levels of topoisomerase-IIβ (TOP-IIβ), a key target of DEXRA, in the heart, but not in the aorta. Additionally, the effect of N-acetylcysteine (NAC, 10 μM), a reactive oxygen species (ROS) scavenger, was evaluated ex vivo. NAC did not prevent DOX-induced impairment of acetylcholine-stimulated vasodilation. In conclusion, our results show that DEXRA fails to prevent vascular toxicity resulting from 16h DOX treatment. This may relate to DOX provoking vascular toxicity in a ROS- and TOP-IIβ-independent way, at least in the evaluated acute setting. However, it is important to mention that these findings only apply to the acute (16h) treatment period, and further research is warranted to delineate the therapeutic potential of DEXRA against vascular toxicity associated with longer-term repetitive DOX dosing.},
}
@article {pmid38013123,
year = {2024},
author = {Alhajj, N and Yahya, MFZR and O'Reilly, NJ and Cathcart, H},
title = {Development and characterization of a spray-dried inhalable ternary combination for the treatment of Pseudomonas aeruginosa biofilm infection in cystic fibrosis.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {192},
number = {},
pages = {106654},
doi = {10.1016/j.ejps.2023.106654},
pmid = {38013123},
issn = {1879-0720},
mesh = {Humans ; Pseudomonas aeruginosa ; *Cystic Fibrosis/drug therapy ; Powders ; Particle Size ; Respiratory Aerosols and Droplets ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Administration, Inhalation ; Acetylcysteine ; Drug Combinations ; Biofilms ; Dry Powder Inhalers/methods ; *Pseudomonas Infections/drug therapy ; },
abstract = {Cystic fibrosis (CF) is an inherited lung disease characterised by the accumulation of thick layers of dried mucus in the lungs which serve as a nidus for chronic infection. Pseudomonas aeruginosa is the predominant cause of chronic lung infection in cystic fibrosis. The dense mucus coupled with biofilm formation hinder antibiotic penetration and prevent them from reaching their target. Mucoactive agents are recommended in the treatment of CF in combination with antibiotics. In spite of the extensive research in developing novel drug combinations for the treatment of lung infection in CF, to our knowledge, there is no study that combines antibiotic, antibiofilm and mucoactive agent in a single inhaled dry powder formulation. In the present study, we investigate the possibility of adding a mucoactive agent to our previously developed ciprofloxacinquercetin (antibiotic-antibiofilm) dry powder for inhalation. Three mucoactive agents, namely mannitol (MAN), N-acetyl-L-cysteine (NAC) and ambroxol hydrochloride (AMB), were investigated for this purpose. The ternary combinations were prepared via spray drying without the addition of excipients. All ternary combinations conserved or improved the antibacterial and biofilm inhibition activities of ciprofloxacin against P. aeruginosa (ATCC 10145). The addition of AMB resulted in an amorphous ternary combination (SD-CQA) with superior physical stability as indicated by DSC and nonambient XRPD. Furthermore, SD-CQA displayed better in vitro aerosolization performance (ED ∼ 71 %; FPF ∼ 49 %) compared to formulations containing MAN and NAC (ED ∼ 64 % and 44 %; FPF ∼ 44 % and 29 %, respectively). In conclusion, a ternary drug combination powder with suitable aerosolization, physical stability and antibacterial/antibiofilm properties was prepared by a single spray drying step.},
}
@article {pmid38011683,
year = {2024},
author = {Duan, F and Liu, C and Chang, C and Song, S and Zhai, H and Cheng, J and Yang, S},
title = {Granulocyte colony-stimulating factor plus pentoxifylline increases short-term survival in patients with severe alcoholic hepatitis: a network meta-analysis.},
journal = {The American journal of drug and alcohol abuse},
volume = {50},
number = {2},
pages = {191-206},
doi = {10.1080/00952990.2023.2266117},
pmid = {38011683},
issn = {1097-9891},
mesh = {*Pentoxifylline/therapeutic use ; Humans ; *Hepatitis, Alcoholic/drug therapy/mortality ; *Granulocyte Colony-Stimulating Factor/therapeutic use ; *Drug Therapy, Combination ; Randomized Controlled Trials as Topic ; },
abstract = {Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results.Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH.Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls).Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92-45.10) and CS (OR 4.95, 95% Crls 1.11-25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome.Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.},
}
@article {pmid38004075,
year = {2023},
author = {Aydin, H and Bulmus, O and Korkut, O and Altun, E and Ulusal, AE},
title = {An Evaluation of the Effectiveness of Melatonin and n-Acetylcysteine in Cerebral Ischemia-Reperfusion Injury in Adult Rats.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {59},
number = {11},
pages = {},
pmid = {38004075},
issn = {1648-9144},
support = {2020/111//Bal&#x131;kesir University/ ; },
mesh = {Rats ; Male ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; *Melatonin/pharmacology/therapeutic use ; Rats, Wistar ; Antioxidants/pharmacology/therapeutic use ; *Reperfusion Injury/drug therapy ; },
abstract = {Background and Objectives: The purpose of this study was to apply histopathological and immunohistochemical methods to compare the protective efficacy of melatonin and N-acetylcysteine (NAC) application in rats with experimental brain ischemia/reperfusion (I/R) injury induced through occlusion of the middle cerebral artery (MCA), and to evaluate the protective effect of their combined use. Materials and Methods: Forty-one young adult male Wistar albino rats were divided into five groups-control (n = 8), I/R group (n = 8), melatonin (n = 8), NAC (n = 8), and melatonin + NAC (n = 9). Results: All scores differed between the groups, apart from vascular congestion (p < 0.05). At two-way comparisons, all histological scores were significantly higher in the I/R group than in the control group (p < 0.05). No change occurred in the vascular congestion scores with the administration of melatonin, although decreases were determined in all other scores. These decreases were statistically significant for cellular eosinophilic pyknotic degeneration, vacuolization, and edema (p < 0.05). All histopathological scores in the group administered NAC together with melatonin were significantly lower than in the I/R group (p < 0.05). Conclusions: The combined use of NAC and melatonin, the neuroprotective efficacy of which on histopathological parameters is shown in this study, now needs to be supported by further research.},
}
@article {pmid38004033,
year = {2023},
author = {Chiu, AH and Wang, CJ and Lin, YL and Wang, CL and Chiang, TI},
title = {N-Acetylcysteine Alleviates the Progression of Chronic Kidney Disease: A Three-Year Cohort Study.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {59},
number = {11},
pages = {},
pmid = {38004033},
issn = {1648-9144},
mesh = {Humans ; Cohort Studies ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Glomerular Filtration Rate ; Disease Progression ; Risk Factors ; *Renal Insufficiency, Chronic/complications/drug therapy/epidemiology ; *Kidney Failure, Chronic/epidemiology ; },
abstract = {Background and Objectives: The prevalence of chronic kidney disease (CKD) is approximately 10% of the population in many countries. CKD progresses to end-stage renal disease (ESRD), resulting in adverse outcomes, prolonged hospitalization, and increased healthcare costs. Therefore, reducing CKD progression to ESRD is recognized as an important health issue. Materials and Methods: Data from the study participants with stage 3 to stage 5 CKD (n = 7668) were collected from the National Health Insurance (NHI) program in Taiwan (1 November 2014 to 31 December 2020). CKD patients who had ingested or not ingested N-acetylcysteine (NAC) for three years were divided into the study group (NAC users; n = 165) and the control group (NAC non-users; n = 165) to explore whether NAC use could alleviate CKD progression and reduce the risks associated with hemodialysis in CKD patients. Results: The levels of serum creatinine (SCr) and estimated globular filtration rate (eGFR) were nearly unchanged and/or slightly changed in NAC users, but the SCr levels were slightly increased, and the eGFR levels were significantly decreased in NAC non-users at the six-month interval during the three years. A statistical difference was observed between the two groups for both levels from 12 months to 36 months. The incidence rate of hemodialysis was significantly lower in NAC users than in non-NAC users (4.8% vs. 12.7%, Wald test = 5.947, p = 0.015, OR = 34.9). These results indicated that NAC use may improve renal function of CKD patients by modulating SCr and eGFR and, in turn, reducing the risk of hemodialysis. Conclusions: We investigated whether NAC could be used to reduce CKD progression to ESRD. For the three-year retrospective study, the incidence rate of hemodialysis was significantly lower in NAC users than in non-NAC users via modulating SCr and eGRF levels. NAC use might be a useful clinical approach for reducing CKD progression to ESRD.},
}
@article {pmid38001773,
year = {2023},
author = {Banik, A and Eum, J and Hwang, BJ and Kee, Y},
title = {Differential Neuroprotective Effects of N-Acetylcysteine against Dithianon Toxicity in Glutamatergic, Dopaminergic, and GABAergic Neurons: Assessment Using Zebrafish.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {11},
pages = {},
pmid = {38001773},
issn = {2076-3921},
support = {NRF-2019M3C7A1031836//Ministry of Science and ICT/ ; NRF-2020R1I1A3063583//Ministry of Education/ ; },
abstract = {Despite the widespread agricultural use of dithianon as an antifungal agent, its neurotoxic implications for humans and wildlife have not been comprehensively explored. Using zebrafish embryonic development as our model, we found that dithianon treatment induced behavioral alterations in zebrafish larvae that appeared normal. Detailed quantitative analyses showed that dithianon at ≥0.0001 µgmL[-1] induced cytoplasmic and mitochondrial antioxidant responses sequentially, followed by the disruption of mitochondrial and cellular homeostasis. Additionally, dithianon at 0.01 and 0.1 µgmL[-1] downregulated the expressions of glutamatergic (slc17a6b), GABAergic (gad1b), and dopaminergic (th) neuronal markers. Contrarily, dithianon upregulated the expression of the oligodendrocyte marker (olig2) at concentrations of 0.001 and 0.01 µgmL[-1], concurrently suppressing the gene expression of the glucose transporter slc2a1a/glut1. Particularly, dithianon-induced increase in reactive oxygen species (ROS) production was reduced by both N-acetylcysteine (NAC) and betaine; however, only NAC prevented dithianon-induced mortality of zebrafish embryos. Moreover, NAC specifically prevented dithianon-induced alterations in glutamatergic and dopaminergic neurons while leaving GABAergic neurons unaffected, demonstrating that the major neurotransmission systems in the central nervous system differentially respond to the protective effects. Our findings contribute to a better understanding of the neurotoxic potential of dithianon and to developing preventive strategies.},
}
@article {pmid38000947,
year = {2024},
author = {Alvarez, R and Kurfis, J and Hendrickson, M and Sem, DS},
title = {Real-time thiol detection in iPSC-derived neuron cultures using SemKur-IM, a novel fluorescent dithio probe.},
journal = {SLAS discovery : advancing life sciences R &amp; D},
volume = {29},
number = {3},
pages = {100127},
doi = {10.1016/j.slasd.2023.11.003},
pmid = {38000947},
issn = {2472-5560},
mesh = {*Induced Pluripotent Stem Cells/drug effects/metabolism/cytology ; *Neurons/drug effects/metabolism ; *Sulfhydryl Compounds/pharmacology/chemistry ; Humans ; *Fluorescent Dyes/chemistry ; Oxidative Stress/drug effects ; Glutathione/metabolism ; Acetylcysteine/pharmacology ; Cells, Cultured ; Oxidation-Reduction/drug effects ; },
abstract = {Neurological disorders associated with inflammation and oxidative stress show reduced glutathione (GSH) levels in the human brain. Drug discovery efforts and pharmacological studies would benefit from tools (e.g. chemical probes) that detect changes to oxidative stress, from the perspective of physiologically-relevant reporters like cellular thiols, including GSH. To this end, we have developed a fluorescence visualization assay using iPSC-derived cortical glutamatergic neurons that were loaded with 25 μM of a novel thiol-detection fluorescent probe, SemKur-IM. This probe enables visualization of cellular thiol level changes in the neuronal somas and neurites, in response exposure to N-acetyl-cysteine (NAC). Cellular thiol redox state was observed to change, based on an increase in green fluorescence (485 nm excitation maximum; 525 nm emission maximum) due to changes in thiol levels, from 0 to 40 mM. Interestingly, prior to treatment with NAC, cells did not appear to have significant levels of reduced thiols. Our studies demonstrate the utility of SemKur-IM in the detection of thiol levels in live cells in response to chemical exposures, such as from drugs that return the cell to a healthier reduced state. An initial application to screening the effects of an Alzheimer's disease drug candidate, Posiphen, using fluorescence cell sorting is presented. Other potential applications include high throughput screening of central nervous system (CNS) drugs thought to work by affecting cellular redox state in neurons.},
}
@article {pmid38000302,
year = {2023},
author = {Liang, M and Deng, J and Gu, J and Yang, J and Ge, F and Huang, C and Wu, W},
title = {TMBPF-induced neurotoxicity and oxidative stress in zebrafish larvae: impacts on central nervous system development and dopamine neurons.},
journal = {Ecotoxicology and environmental safety},
volume = {268},
number = {},
pages = {115710},
doi = {10.1016/j.ecoenv.2023.115710},
pmid = {38000302},
issn = {1090-2414},
mesh = {Humans ; Animals ; *Zebrafish/metabolism ; *Dopaminergic Neurons/metabolism ; Larva ; Dopamine/metabolism ; Benzhydryl Compounds/metabolism ; Oxidative Stress ; Central Nervous System ; Acetylcysteine/pharmacology ; Bisphenol F Compounds ; Bisphenol A Compounds ; },
abstract = {Bisphenol A (BPA), a common bisphenol molecule, is well known in the environment as an endocrine disruptor. Furthermore, BPs (BPA, BPS, BPF, and BPAF) have been shown in recent years to be neurotoxic to zebrafish. Tetramethyl bisphenol F (TMBPF) has recently been introduced as a substitute for bisphenol A (BPA) in various industries, including plastics and food contact coatings. However, a growing number of studies have demonstrated that the toxicity of some BPA substitutes is similar to or even stronger than BPA, posing potential harm to human health and the environment. In this study, we used zebrafish larvae as a model to investigate the neurodevelopmental effects of TMBPF at different concentrations (0, 0.25, 0.5, 1, 2, 4 and 8 mg/L). Our results showed that exposure to TMBPF at concentrations higher than 4 mg/L for 72 h post-fertilization (hpf) resulted in zebrafish mortality, whereas exposure to 2 mg/L for 144 hpf caused deformities. Furthermore, TMBPF exposure inhibited the development of the central nervous system, motor nerves, and dopamine neurons in zebrafish. Real-time polymerase chain reaction (PCR) analysis revealed that TMBPF exposure significantly down-regulated the expression of oxidative stress-related genes (Cu/Zn-SOD, Mn-SOD, and CAT) and neurodevelopmental genes (mbp, gafp, and syn2a), while up-regulated the expression of dopamine-related genes (th1, th2, and dat). Notably, treatment with the antioxidant N-acetylcysteine (NAC) alleviated TMBPF-induced toxicity. NAC can regulate the expression of genes related to oxidative stress, neurodevelopment and dopamine development, and make the nerve development of zebrafish normal. Overall, our research suggested that TMBPF may disrupt the development of the early central nervous system and dopamine neurons, leading to abnormal motor behavior in zebrafish larvae. These results highlight the potential risks associated with the use of TMBPF in various industries and the importance to evaluate its potential risks to human health and the environment.},
}
@article {pmid37996048,
year = {2024},
author = {Cao, L and Shao, N and Du, J and Zhu, H and Gao, J and Li, Q and Sun, Y and Hu, J and Yin, G and Xu, G},
title = {Involvement of reactive oxygen species (ROS) in the hepatopancreatic cytotoxicity, oxidative stress, and apoptosis induced by microcystin-LR in Eriocheir sinensis.},
journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP},
volume = {276},
number = {},
pages = {109801},
doi = {10.1016/j.cbpc.2023.109801},
pmid = {37996048},
issn = {1532-0456},
mesh = {Animals ; Reactive Oxygen Species/metabolism ; *Brachyura/metabolism ; Oxidative Stress ; Microcystins/toxicity ; Apoptosis ; Marine Toxins ; },
abstract = {There is limited knowledge about the toxicity of Microcystin-LR (MC-LR) in crustaceans, despite its high toxicity to aquatic organisms. This research aimed to explore the effects of MC-LR on cytotoxicity, oxidative stress, and apoptosis in the hepatopancreas of Eriocheir sinensis, as well as elucidate the involvement of reactive oxygen species (ROS) and potential mechanisms of toxicity. In vivo and in vitro exposures of crabs to MC-LR and N-acetylcysteine (NAC) were performed, followed by assessments of cell morphology, viability, tissue pathology, biochemical indicators, gene expression, and hepatopancreatic transcriptome. Results revealed that MC-LR facilitated the entry of the MC-LR transporter oatp3a into hepatopancreatic cells, leading to upregulated expression of phase I detoxification enzyme genes (cyp4c, cyp2e1, and cyp3) and downregulated the phase II enzyme genes (gst1, gpx, gsr2, gclc, and nqo1), resulting in increased ROS levels and cytotoxic effects. MC-LR exhibited cytotoxicity, reducing cell viability and inducing abnormal nuclear morphology with a 48 h-IC50 value of approximately 120 μm. MC-LR exposure caused biochemical changes indicative of oxidative stress damage and evident hepatopancreatic lesions. Additionally, MC-LR exposure regulated the levels of bax and bcl-2 expression, activating caspase 3 and 6 to induce cell apoptosis. Intervention with NAC attenuated MC-LR-induced ROS production and associated toxic effects. Transcriptome analysis revealed enrichment of differentially expressed genes in pathways related to cytochrome P450-mediated xenobiotic metabolism and the FoxO signaling pathway. These findings shed light on the potential mechanisms underlying MC-LR toxicity and provide valuable references for further research and conservation efforts regarding the health of aquatic animals.},
}
@article {pmid37992493,
year = {2024},
author = {Deng, YQ and Gao, M and Lu, D and Liu, QP and Zhang, RJ and Ye, J and Zhao, J and Feng, ZH and Li, QZ and Zhang, H},
title = {Compound-composed Chinese medicine of Huachansu triggers apoptosis of gastric cancer cells through increase of reactive oxygen species levels and suppression of proteasome activities.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {123},
number = {},
pages = {155169},
doi = {10.1016/j.phymed.2023.155169},
pmid = {37992493},
issn = {1618-095X},
mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Stomach Neoplasms/drug therapy/metabolism ; Proteasome Endopeptidase Complex ; Proto-Oncogene Proteins c-akt/metabolism ; Medicine, Chinese Traditional ; Phosphatidylinositol 3-Kinases/metabolism ; Proteomics ; Cell Line, Tumor ; Apoptosis ; *Amphibian Venoms ; },
abstract = {BACKGROUND: Huachansu (HCS), a known Chinese patent drug extracted from the Chinese toad skin, is frequently used for the treatment of various advanced cancers, especially gastric cancer, due to the good therapeutic effect. However, it is rather difficult to clarify the active substances and molecular mechanisms involved owing to the lack of appropriate research strategies. We recently proposed the concept and research ideas of compound-composed Chinese medicine formula.<br><br>PURPOSE: To discover compound-composed Chinese medicine from Huachansu and to explore its mechanism of action in inducing apoptosis of gastric cancer cells.<br><br>METHOD: Network pharmacology combined with serum pharmacochemistry was utilized to screen the predominant active constituents from HCS against gastric cancer. Then, the compound-composed Chinese medicine of HCS (CCMH) was prepared according to their relative contents in serum. The pharmacological effects and potential mechanisms for CCMH were investigated by assays for cell viability, cell cycle, apoptosis, mitochondrial membrane potential (MMP), proteomics, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, proteasome activity, and western blot.<br><br>RESULTS: CCMH was comprised of arenobufagin (11.14%), bufalin (18.67%), bufotalin (7.33%), cinobufagin (16.67%), cinobufotalin (16.74%), gamabufotalin (8.45%), resibufogenin (12.03%), and telocinobufagin (8.97%). CCMH evidently induced proliferation inhibition, cell cycle arrest, apoptosis, and MMP collapse in gastric cancer cells, possessing the better activities than HCS. Proteomic analysis showed that CCMH influenced ROS pathway, ubiquitin proteasome system, and PI3K/Akt and MAPK signaling pathways. CCMH markedly enhanced intracellular ROS levels in gastric cancer cells, which was reversed by NAC. Accordingly, NAC antagonized the apoptosis-inducing effect of CCMH. Significantly decreased proteasome 20S activity by CCMH was observed in gastric cancer cells. CCMH also regulated the expression of key proteins in PI3K/Akt and MAPK signaling pathways.<br><br>CONCLUSION: CCMH possesses more significant apoptotic induction effects on gastric cancer cells than HCS, which is achieved primarily through suppression of proteasome activities and increase of ROS levels, followed by regulating PI3K/Akt and MAPK signaling pathways. Network pharmacology combined with serum pharmacochemistry is an effective strategy for discovering compound-composed Chinese medicine from traditional Chinese medicine, which can help clarify the pharmacological substances and mechanisms of action for traditional Chinese medicine.},
}
@article {pmid37987619,
year = {2023},
author = {Marcano-Gómez, EC and de Souza, ABF and Machado-Junior, PA and Rodríguez-Herrera, AJ and Castro, TF and da Silva, SPG and Vieira, RG and Talvani, A and Nogueira, KOPC and de Oliveira, LAM and Bezerra, FS},
title = {N-acetylcysteine modulates redox imbalance and inflammation in macrophages and mice exposed to formaldehyde.},
journal = {Free radical research},
volume = {57},
number = {6-12},
pages = {444-459},
doi = {10.1080/10715762.2023.2284636},
pmid = {37987619},
issn = {1029-2470},
mesh = {Reactive Oxygen Species/metabolism ; *Lung ; Macrophages/metabolism ; Formaldehyde/toxicity/metabolism/adverse effects ; Mice ; Animals ; Mice, Inbred C57BL ; Inflammation/chemically induced/drug therapy/metabolism ; Oxidation-Reduction ; *Acetylcysteine/pharmacology ; Antioxidants/metabolism ; Oxidative Stress ; Respiratory Hypersensitivity ; },
abstract = {This study aimed to evaluate the protective role of N-acetylcysteine (NAC) in cells and mice exposed to formaldehyde. For the in vitro study, J774A.1 macrophages cells were incubated for 8, 16 and 24 h with formaldehyde or NAC to assess cell viability and reactive oxygen species (ROS). In the in vivo study, C57BL/6 mice (n = 48) were divided into 6 groups: control (CG), vehicle (VG) that received saline by orogastric gavage, a group exposed to formaldehyde 1% (FG) and formaldehyde exposed groups that received NAC at doses of 100, 150 and 200 mg/Kg (FN100, FN150 and FN200) for a period of 5 days. In vitro, formaldehyde promoted a decrease in cell viability and increased ROS, while NAC reduced formaldehyde-induced ROS production. Animals exposed to formaldehyde presented higher leukocyte counts in the blood and in the bronchoalveolar lavage fluid, and promoted secretion of inflammatory markers IL-6, IL-15, and IL-10. The exposure to formaldehyde also promoted redox imbalance and oxidative damage characterized by increased activities of superoxide dismutase, catalase, decreased GSH/GSSG ratio, as well as it increased levels of protein carbonyls and lipid peroxidation. NAC administration after formaldehyde exposure attenuated oxidative stress markers, secretion of inflammatory mediators and lung inflammation. In conclusion, both in in vitro and in vivo models, NAC administration exerted protective effects, which modulated the inflammatory response and redox imbalance, thus preventing the development airway injury induced by formaldehyde exposure.},
}
@article {pmid37984752,
year = {2024},
author = {Zhang, WY and Zhao, CM and Wang, CS and Xie, X and Li, YQ and Chen, BB and Feng, L and Jiang, P},
title = {Methylglyoxal accumulation contributes to accelerated brain aging in spontaneously hypertensive rats.},
journal = {Free radical biology &amp; medicine},
volume = {210},
number = {},
pages = {108-119},
doi = {10.1016/j.freeradbiomed.2023.11.012},
pmid = {37984752},
issn = {1873-4596},
mesh = {Rats ; Animals ; Rats, Inbred SHR ; *Pyruvaldehyde ; *Hypertension/metabolism ; Aging ; Acetylcysteine ; Brain/metabolism ; },
abstract = {While it is well-acknowledged that neurovascular dysfunction in hypertension is tightly associated with accelerated brain aging, we contend that the deleterious effects of hypertension may extend beyond affecting only the arteries. Methylglyoxal (MG) derived from glycolysis, is involved in the accumulation of advanced glycated end products (AGEs), which are the hallmarks of neurodegenerative disorders. Therefore, the present study aims to firstly investigate the role of MG metabolism in the hypertension-accelerated brain aging process. The results of our study indicate that the levels of MG increase with age in both the plasma and hippocampus of SHRs at 12, 16, and 30 weeks old. AGE methylglyoxal-hydro imidazoline-1 (MG-H1) is primarily localized in astrocytes, while its presence was not observed in neurons and microglia within the hypertensive hippocampus. Our observations also suggest that angiotensin II (Ang II) enhances glucose uptake and glycolysis while reducing the expression of Glo1 in cultured astrocytes. N-acetylcysteine (NAC) was found to counteract the increase in escape latency and inhibit the activation of the AGEs-RAGE axis in 30-week-old SHRs. NAC decreased Iba-1 immunofluorescence intensity, inhibited the levels of pro-inflammatory markers, and enhanced the abundance of anti-inflammatory markers in the hippocampus of SHRs. Moreover, NAC reduced the immunofluorescence signal of 4HNE and increased the content of GSH and SOD in SHRs. Finally, NAC was observed to inhibit apoptosis in the hippocampus of SHRs. Collectively, we firstly showed the enhanced accumulation of MG in the hypertensive brain, whereas the clearance of MG by NAC treatment mitigated the aging process and attenuated AGEs generation, neuroinflammation, and oxidative damage.},
}
@article {pmid37982208,
year = {2024},
author = {Allam, A and Ali, AA and Abdel Baky, NA and Balah, A},
title = {Omeprazole induces profibrotic gene expression in rat kidney: implication of TGF-β/Smad signaling pathway.},
journal = {Drug and chemical toxicology},
volume = {47},
number = {5},
pages = {748-755},
doi = {10.1080/01480545.2023.2282377},
pmid = {37982208},
issn = {1525-6014},
mesh = {Animals ; *Signal Transduction/drug effects ; *Omeprazole/pharmacology ; Male ; *Proton Pump Inhibitors/pharmacology ; *Kidney/drug effects/metabolism ; *Transforming Growth Factor beta/metabolism/genetics ; *Connective Tissue Growth Factor/genetics/metabolism ; Rats ; *Tissue Inhibitor of Metalloproteinase-1/metabolism/genetics ; Fibrosis ; Reactive Oxygen Species/metabolism ; Smad Proteins/metabolism/genetics ; Gene Expression Regulation/drug effects ; Rats, Wistar ; },
abstract = {Proton pump inhibitors (PPIs) are one of the most commonly prescribed medications. However, PPI usage is linked to a higher risk of both acute and chronic renal damage by mechanisms not entirely known. The present study demonstrates that omeprazole (10 mg/kg body weight, i.p.) causes TGF-β/Smad signaling activation and subsequent expression of the profibrotic genes CTGF and TIMP-1 in rat kidney. Increased production of CTGF and TIMP-1 accompany activation of the TGF-β/Smad signaling cascade. However, simultaneous treatment of omeprazole and the TGF-β inhibitor, disitertide (P144) (1 mg/kg body weight i.p.) suppresses the TGF-β/Smad signaling pathway and subsequent production of CTGF and TIMP-1. Additionally, TGF-β level in rat kidney was highly reduced in animals treated with the ROS (reactive oxygen species) scavenger, N-acetyl cysteine (NAC) (100 mg/kg body weight i.p.) before omeprazole administration. Furthermore, the reduction in SOD activity brought by omeprazole was returned to the normal level in those animals. However, MDA level increased by omeprazole was highly reduced in the presence of NAC. Collectively, the current findings demonstrate that omeprazole has the ability to promote the expression of the profibrotic genes CTGF and TIMP-1 in a ROS and TGF-β dependent manner. The present study suggests the co-use of ROS scavenger to improve the therapeutic use of the PPI omeprazole.},
}
@article {pmid37971568,
year = {2023},
author = {Sırrı Akosman, M and Türkmen, R and Demirel, HH},
title = {The protective effect of N-acetylcysteine against MK-801-induced neurodegeneration in mice.},
journal = {Molecular biology reports},
volume = {50},
number = {12},
pages = {10287-10299},
pmid = {37971568},
issn = {1573-4978},
support = {17.Kariyer.45//Afyon Kocatepe &#xdc;niversitesi/ ; },
mesh = {Humans ; Mice ; Animals ; Male ; *Acetylcysteine/pharmacology ; *Dizocilpine Maleate/pharmacology ; Quality of Life ; Antioxidants/pharmacology ; Excitatory Amino Acid Antagonists ; Protective Agents ; },
abstract = {BACKGROUND: Neurological disorders result in not only a decline in the quality of life of patients but also a global economic burden. Therefore, protective medicine becomes more important for society. MK-801 is a chemical agent used to understand the etiology of behavioral disorders and brain degeneration in animal models. This study aims to determine whether N-acetylcysteine (NAC) is useful to treat brain degeneration caused by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist.<br><br>METHODS AND RESULTS: Four groups were formed by dividing 24 male BALB/c mice into groups of six. The control group was given a saline solution (10 ml/kg-i.p.). MK-801 (1&#xa0;mg/kg-i.p.) was given alone to one group, and it was given with NAC (100&#xa0;mg/kg-i.p.) to another group, while the last group was given only NAC (100&#xa0;mg/kg-i.p.). The administration of drugs lasted for fourteen days. After the behavioral tests (open field and elevated plus-maze), all animals were euthanised, and brain tissues were collected for real-time PCR, TAS-TOS analysis, hematoxylin-eosin, Kluver-Barrera, and TUNEL staining. In the MK-801 group, besides nuclear shrinkage in neurons, glial cell infiltration, vacuolization in cortical neurons, white matter damage, and apoptosis were observed.<br><br>CONCLUSION: In the mice given NAC as a protective agent, it was observed that behavioral problems improved, antioxidant levels increased, and nuclear shrinkage, glial cell infiltration, vacuolization in neurons, and white matter degeneration were prevented. Moreover, MBP expression increased, and the number of TUNEL-positive cells significantly decreased. As a result, it was observed that NAC may have a protective effect against brain degeneration.},
}
@article {pmid37969394,
year = {2023},
author = {Wang, ZQ and Li, YQ and Wang, DY and Shen, YQ},
title = {Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity.},
journal = {Translational cancer research},
volume = {12},
number = {10},
pages = {2911-2922},
pmid = {37969394},
issn = {2219-6803},
abstract = {BACKGROUND: As a new form of cell death, ferroptosis has been shown to have inhibitory effects on a variety of tumor cells except oral squamous cell carcinoma (OSCC). There were few investigations on the effects and molecular mechanisms of piperlongumine (PL, a ferroptosis inducer) and CB-839 (a GLS1 inhibitor which promotes ferroptosis) on OSCC cells. This article assesses the anticancer effect and mechanism of PL as well as combined with CB-839.<br><br>METHODS: OSCC cells were treated with specified concentration of PL alone or with ferroptosis inhibitor Ferrostatin-1 (Fer-1) and antioxidant N-Acetylcysteine (NAC) to assess their effects on biological characteristics such as cell proliferation, cell death and intracellular ferroptosis related pathways. Also, cells were treated with PL combined with CB-839 to evaluate the synergistic effect of CB-839 on PL's anticancer effects.<br><br>RESULTS: The results showed that the proliferation rate of PL-treated OSCC cells were decreased in a dose- and time-dependent manner. PL can induce OSCC cells apoptosis. Lipid peroxidation (LPO) and intracellular reactive oxygen species (ROS) were accumulated after PL treatment. We found some protein changes significantly such as the expression of DMT1 increased, and the expression of FTH1, SLC7A11 and GPX4 decreased. In addition, the anti-proliferation effect of PL can be reversed by Fer-1 and NAC and the level of LPO and ROS was decreased accordingly. Importantly, we found that PL and CB-839 in combination could decrease the cell viability and the LPO level synergistically, accompanied by a large consumption of glutathione (GSH). These evidences prove that PL can induce ferroptosis of OSCC cells, which can be enhanced by CB-839.<br><br>CONCLUSIONS: Our study suggested that the nature product PL can induce the ferroptotic death of OSCC cells, which is further enhanced when combined with CB-839. The synergistic anticancer effect of these two may prove new strategy for OSCC treatment.},
}
@article {pmid37965267,
year = {2023},
author = {Manoharan, A and Farrell, J and Aldilla, VR and Whiteley, G and Kriel, E and Glasbey, T and Kumar, N and Moore, KH and Manos, J and Das, T},
title = {N-acetylcysteine prevents catheter occlusion and inflammation in catheter associated-urinary tract infections by suppressing urease activity.},
journal = {Frontiers in cellular and infection microbiology},
volume = {13},
number = {},
pages = {1216798},
pmid = {37965267},
issn = {2235-2988},
mesh = {Humans ; Urinary Catheterization ; Acetylcysteine/pharmacology ; Urease ; *Proteus Infections/drug therapy/prevention &amp; control/microbiology ; Proteus mirabilis ; *Urinary Tract Infections/prevention &amp; control/microbiology ; Catheters ; Inflammation/prevention &amp; control ; Anti-Inflammatory Agents/pharmacology ; Biofilms ; },
abstract = {INTRODUCTION: Proteus mirabilis is a key pathobiont in catheter-associated urinary tract infections (CA-UTIs), which is well known to form crystalline biofilms that occlude catheters. Urease activity alkylates urine through the release of ammonia, consequentially resulting in higher levels of Mg[2+] and Ca[2+] and formation of crystals. In this study, we showed that N-acetyl cysteine (NAC), a thiol antioxidant, is a potent urease inhibitor that prevents crystalline biofilm formation.<br><br>METHODS: To quantify urease activity, Berthelot's method was done on bacterial extracts treated with NAC. We also used an in vitro catheterised glass bladder model to study the effect of NAC treatment on catheter occlusion and biofilm encrustation in P. mirabilis infections. Inductively-coupled plasma mass spectrometry (ICP-MS) was performed on catheter samples to decipher elemental profiles.<br><br>RESULTS: NAC inhibits urease activity of clinical P. mirabilis isolates at concentrations as low as 1 mM, independent of bacterial killing. The study also showed that NAC is bacteriostatic on P. mirabilis, and inhibited biofilm formation and catheter occlusion in an in vitro. A significant 4-8log10 reduction in viable bacteria was observed in catheters infected in this model. Additionally, biofilms in NAC treated catheters displayed a depletion of calcium, magnesium, or phosphates (>10 fold reduction), thus confirming the absence of any urease activity in the presence of NAC. Interestingly, we also showed that not only is NAC anti-inflammatory in bladder epithelial cells (BECs), but that it mutes its inflammatory response to urease and P. mirabilis infection by reducing the production of IL-6, IL-8 and IL-1b.<br><br>DISCUSSION: Using biochemical, microbiological and immunological techniques, this study displays the functionality of NAC in preventing catheter occlusion by inhibiting urease activity. The study also highlights NAC as a strong anti-inflammatory antibiofilm agent that can target both bacterial and host factors in the treatment of CA-UTIs.},
}
@article {pmid37965065,
year = {2023},
author = {Wei, H and Liu, R and Zhao, M and Ma, Y and He, Y and Sun, X},
title = {Ischemia‒Reperfusion accelerates neointimal hyperplasia via IL-1β-mediated pyroptosis after balloon injury in the rat carotid artery.},
journal = {Biochemistry and biophysics reports},
volume = {36},
number = {},
pages = {101567},
pmid = {37965065},
issn = {2405-5808},
abstract = {BACKGROUND: Ischemia‒reperfusion (IR) is a pathological process that causes secondary damage to blood vessels. However, whether IR can further worsen neointima formation after balloon injury and the detailed mechanism are unclear.<br><br>METHODS: An in vivo model of balloon injury to the rat carotid artery was established to study the effect of IR following balloon injury on neointima formation. Smooth muscle cells (SMCs) were isolated from rat aortas and exposed to hypoxia-reoxygenation to mimic the IR process in vitro. The in vitro cell model was used to investigate the mechanism of IR-mediated neointima formation after balloon injury, which was further confirmed in an in vivo rat model.<br><br>RESULTS: IR aggravated neointima formation in the rat carotid artery 2 weeks after balloon injury compared with that observed in the absence of balloon injury (P&#xa0;<&#xa0;0.001). Compared with that of normal SMCs in the rat carotid artery, the expression of IL-1&#x3b2;, a key proinflammatory cytokine associated with pyroptosis, was increased more than 3-fold in the IR-induced neointima (P&#xa0;<&#xa0;0.0001) and contributed to the proliferation and migration of rat primary aortic SMCs (P&#xa0;<&#xa0;0.0001). This process was alleviated by the antioxidant acetylcysteine (NAC), suggesting its partial dependence on intracellular ROS. In the rat model of IR following balloon injury in the carotid artery, the carotid artery that was locally transfected with AAV carrying sh-IL-1&#x3b2; or sh-caspase-1, which alleviated neointima formation, as indicated by a reduction in intima-media thickness in the rat carotid artery (P&#xa0;<&#xa0;0.0001).<br><br>CONCLUSION: Our results suggested that IR could promote IL-1&#x3b2; production in SMCs in the carotid artery after balloon injury and aggravate neointimal hyperplasia, which was alleviated by silencing caspase-1/IL-1&#x3b2; signaling in SMCs in the carotid artery. These results suggest that IL-1&#x3b2; may be an effective target to combat IR-related neointima formation.},
}
@article {pmid37963954,
year = {2023},
author = {Akkahadsee, P and Sawangjit, R and Phumart, P and Chaiyakunapruk, N and Sakloetsakun, D},
title = {Systematic review and network meta-analysis of efficacy and safety of interventions for preventing anti-tuberculosis drug induced liver injury.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {19880},
pmid = {37963954},
issn = {2045-2322},
mesh = {Humans ; *Antitubercular Agents/adverse effects ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology/prevention &amp; control ; },
abstract = {Anti-tuberculosis drug induced liver injury (Anti-TB DILI) is the most common adverse events (AEs) necessitating therapy interruption but there is no preventing regimen. This study aimed to examine the efficacy and safety of herbs/alternative medicines for preventing anti-TB DILI. Relevant articles were identified through a systematic search in 5 international databases from inception till March 2022. All randomized controlled trials (RCT) assessing the effects of herbal or alternative medicines against anti-TB DILI were included. The network meta-analysis (NMA) was used to synthesize the evidence for preventing hepatotoxicity using a random-effects model. A total of 3423 patients from 14 RCTs were included. The NMA indicated that supplementation of Turmeric plus Tinospora cordifolia (RR 0.07; 95% CI 0.02 to 0.28), and N-acetyl cysteine (NAC) (RR 0.09; 95% CI 0.01 to 0.75) significantly reduced the incidence of anti-TB DILI compared with placebo. In addition, poly herbal product significantly reduced alkaline phosphatase (ALP) (MD - 21.80; 95% CI - 33.80 to - 9.80) and total bilirubin (Tbil) compared with placebo (MD - 0.51; 95% CI - 0.76 to - 0.26). There was no statistically significant difference in the occurrence of AEs in any intervention. In conclusion, Turmeric plus Tinospora cordifolia, NAC and poly-herbal product may provide benefit for preventing anti-TB DILI in TB patients. However, these findings are based on a small number of studies. Additional studies are warranted to confirm the findings.},
}
@article {pmid37960276,
year = {2023},
author = {Diniz, MS and Magalhães, CC and Tocantins, C and Grilo, LF and Teixeira, J and Pereira, SP},
title = {Nurturing through Nutrition: Exploring the Role of Antioxidants in Maternal Diet during Pregnancy to Mitigate Developmental Programming of Chronic Diseases.},
journal = {Nutrients},
volume = {15},
number = {21},
pages = {},
pmid = {37960276},
issn = {2072-6643},
support = {SFRH/BPD/116061/2016; SFRH/BD/11934/2022; SFRH/BD/11924/2022; SFRH/BD/5539/2020//ERDF funds through the Operational Programme for Competitiveness/ ; HORIZON-HLTH-2022-STAYHLTH-101080329-2; PTDC/DTP-DES/1082/2014 (POCI-01-0145-FEDER-016657), CENTRO-01-0246-FEDER- 000010 (Multidisciplinary Institute of Ageing in Coimbra), strategic projects UIDB/04539/2020, UIDP/04539/2020, LA/P/0058/2020//ERDF funds through the Operational Programme for Competitiveness-COMPETE 2020/ ; },
mesh = {Pregnancy ; Female ; Humans ; Antioxidants/pharmacology ; *Prenatal Exposure Delayed Effects/prevention &amp; control/etiology ; Resveratrol/pharmacology ; *Diabetes, Gestational/prevention &amp; control ; *Pregnancy Complications/prevention &amp; control ; Diet ; *Pregnancy in Obesity/complications ; Fetal Growth Retardation/prevention &amp; control ; Chronic Disease ; },
abstract = {Chronic diseases represent one of the major causes of death worldwide. It has been suggested that pregnancy-related conditions, such as gestational diabetes mellitus (GDM), maternal obesity (MO), and intra-uterine growth restriction (IUGR) induce an adverse intrauterine environment, increasing the offspring's predisposition to chronic diseases later in life. Research has suggested that mitochondrial function and oxidative stress may play a role in the developmental programming of chronic diseases. Having this in mind, in this review, we include evidence that mitochondrial dysfunction and oxidative stress are mechanisms by which GDM, MO, and IUGR program the offspring to chronic diseases. In this specific context, we explore the promising advantages of maternal antioxidant supplementation using compounds such as resveratrol, curcumin, N-acetylcysteine (NAC), and Mitoquinone (MitoQ) in addressing the metabolic dysfunction and oxidative stress associated with GDM, MO, and IUGR in fetoplacental and offspring metabolic health. This approach holds potential to mitigate developmental programming-related risk of chronic diseases, serving as a probable intervention for disease prevention.},
}
@article {pmid37958311,
year = {2023},
author = {Abdalbari, FH and Martinez-Jaramillo, E and Forgie, BN and Tran, E and Zorychta, E and Goyeneche, AA and Sabri, S and Telleria, CM},
title = {Auranofin Induces Lethality Driven by Reactive Oxygen Species in High-Grade Serous Ovarian Cancer Cells.},
journal = {Cancers},
volume = {15},
number = {21},
pages = {},
pmid = {37958311},
issn = {2072-6694},
support = {2020//Ovarian Cancer Canada/ ; },
abstract = {High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term consolidation therapies. Clinical remission can be temporarily induced by platinum-based chemotherapy, but death subsequently results from the extensive growth of a platinum-resistant component of the tumor. This work explores a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and the various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrated that AF potently inhibited TrxR activity and reduced the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We showed that AF induces the accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage, effects that were also prevented by the presence of NAC. Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their sensitivity to platinum, suggesting that the depletion of antioxidants is an efficient strategy to mitigate the course of this disease.},
}
@article {pmid37950627,
year = {2023},
author = {Sultanli, S and Schneider, J and Burkart, SS and Binder, M and Kubatzky, KF},
title = {Cellular ROS tolerance determines the effect of plumbagin on osteoclast differentiation.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {37},
number = {12},
pages = {e23293},
doi = {10.1096/fj.202301415R},
pmid = {37950627},
issn = {1530-6860},
mesh = {*Osteoclasts/metabolism ; Reactive Oxygen Species/metabolism ; *Naphthoquinones/pharmacology ; Cell Differentiation ; RANK Ligand/pharmacology/metabolism ; },
abstract = {Plumbagin is used in traditional medicine because of its anti-inflammatory and anti-microbial properties. As a naphthoquinone, plumbagin triggers the production of reactive oxygen species (ROS). In vitro cancer studies showed that plumbagin triggers apoptosis in cancer cells through ROS production. As cancer-mediated chronic inflammation can affect bone density, it was hypothesized that plumbagin might directly inhibit the formation of bone-resorbing osteoclasts. We previously showed that the effect of plumbagin on osteoclastogenesis differed between bone marrow-derived macrophages and the macrophage cell line RAW 264.7. Although RAW 264.7 macrophages are able to initiate the gene program required for osteoclastogenesis, only primary macrophages successfully differentiate into osteoclasts. Here, we show that RAW 264.7 cells are more sensitive toward plumbagin-induced apoptosis. In the presence of plumbagin and the cytokine RANKL, which triggers ROS production to drive osteoclastogenesis, RAW 264.7 macrophages produce increased amounts of ROS and die. Addition of the ROS scavenger N-acetyl cysteine prevented cell death, linking the failure to differentiate to increased ROS levels. RAW 264.7 cells show reduced expression of genes protective against oxidative stress, while primary macrophages have a higher tolerance toward ROS. Our data suggest that it is indispensable to consider cell (line)-intrinsic properties when studying phytochemicals.},
}
@article {pmid37949132,
year = {2024},
author = {Ye, Y and Liu, B and Wang, Z and Liu, L and Zhang, Q and Zhang, Q and Jiang, W},
title = {Sodium p-perfluorous nonenoxybenzene sulfonate induces ROS-mediated necroptosis by directly targeting catalase in HepG2 cells.},
journal = {The Science of the total environment},
volume = {910},
number = {},
pages = {168446},
doi = {10.1016/j.scitotenv.2023.168446},
pmid = {37949132},
issn = {1879-1026},
mesh = {Humans ; Reactive Oxygen Species ; Catalase ; Hep G2 Cells ; Necroptosis ; Molecular Docking Simulation ; Necrosis/chemically induced ; *Alkanesulfonic Acids/toxicity ; Alkanesulfonates ; *Fluorocarbons/toxicity ; Fluorobenzenes ; },
abstract = {Sodium p-perfluorous nonenoxybenzene sulfonate (OBS) has been widely used as a substitute for perfluorooctane sulfonic acid (PFOS) because of its high surface activity and low cost, but the knowledge of its biological effects is still limited. In this study, we compared the toxic effects of OBS and PFOS on human hepatoma cells (HepG2). OBS resulted in lower cell viability, higher ROS levels, and more severe necrosis than PFOS, indicating that OBS caused higher cytotoxicity than PFOS. In this process, OBS induced a burst of ROS and downregulation of catalase (CAT). OBS-induced oxidative stress was recovered after the CAT overexpression, but the CAT levels were not reversed after N-acetylcysteine (NAC) pretreatment. This indicates that the downregulated CAT is an upstream signal of the ROS burst. Moreover, drug affinity targeting assay, spectroscopic analysis and molecular docking were conducted, showing that OBS directly targeted CAT and therefore downregulated CAT. In addition, we found that OBS-induced necrosis is RIP1/RIP3-dependent programmed necroptosis. In summary, OBS directly targets CAT to reduce CAT levels and induces oxidative stress and necroptosis. Our findings are helpful to understand the toxicity of OBS and to evaluate the safety of OBS as a substitute for PFOS.},
}
@article {pmid37945228,
year = {2023},
author = {Wang, Y and Wang, A and Zhao, G and Liu, S and Li, K and Li, W and Peng, Y and Zheng, J},
title = {Glutathione conjugation and protein modification resulting from metabolic activation of pesticide metalaxyl in vitro and in vivo.},
journal = {Pesticide biochemistry and physiology},
volume = {196},
number = {},
pages = {105606},
doi = {10.1016/j.pestbp.2023.105606},
pmid = {37945228},
issn = {1095-9939},
mesh = {Rats ; Humans ; Mice ; Animals ; Activation, Metabolic ; *Pesticides/toxicity/metabolism ; Cysteine/metabolism/pharmacology ; Microsomes, Liver/metabolism ; Glutathione/metabolism ; Alanine/analogs &amp; derivatives ; },
abstract = {Metalaxyl (MTL), a germicidal agent, is widely used in agriculture. Due to the biological amplification effect, MTL entering the ecological environment would result in a threat to human health through the food chain. MTL is reportedly accumulated in liver. The objectives of the study included investigating the metabolic activation of MTL in liver and defining the mechanisms participating in the hepatotoxicity of MTL. The corresponding glutathione (GSH), N-acetylcysteine (NAC) conjugate, and cysteine conjugates were observed in liver microsomes, prepared from liver tissues of mice, containing MTL and GSH, NAC or cysteine. These conjugates were also detected in urine and bile of rats receiving MTL. Apparently, MTL was biotransformed to a quinone imine intermediate dose-dependently attacking the thiols and cysteine residues of protein. The bioactivation of MTL required cytochrome P450 enzymes, and CYP3A dominated the bio-activation of MTL.},
}
@article {pmid37944606,
year = {2024},
author = {Sun, W and Xu, T and Lin, H and Yin, Y and Xu, S},
title = {BPA and low-Se exacerbate apoptosis and autophagy in the chicken bursa of Fabricius by regulating the ROS/AKT/FOXO1 pathway.},
journal = {The Science of the total environment},
volume = {908},
number = {},
pages = {168424},
doi = {10.1016/j.scitotenv.2023.168424},
pmid = {37944606},
issn = {1879-1026},
mesh = {Animals ; Humans ; *Chickens/metabolism ; Reactive Oxygen Species/metabolism ; *Bursa of Fabricius/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Apoptosis ; Oxidative Stress ; Autophagy ; Forkhead Box Protein O1/metabolism/pharmacology ; Bisphenol A Compounds ; },
abstract = {Bisphenol A (BPA) is a ubiquitous environmental pollutant that can have harmful effects on human and animal immune systems by inducing oxidative stress. Selenium (Se) deficiency damages immune organ tissues and exhibits synergistic effects on the toxicity of environmental pollutants. However, oxidative stress, cell apoptosis, and autophagy caused by the combination of BPA and low-Se, have not been studied in the bursa of Fabricius of the immune organ of poultry. Therefore, in this study, BPA and/or low-Se broiler models and chicken lymphoma cells (MDCC-MSB-1 cells) models were established to investigate the effects of BPA and/or low-Se on the bursa of Fabricius of poultry. The data showed that BPA and/or low-Se disrupted the normal structure of the bursa of Fabricius, BPA (60 μM) significantly reduced the activity of MDCC-MSB-1 cells and disrupted normal morphology (IC50 = 192.5 ± 1.026 μM). Compared with the Control group, apoptosis and autophagy were increased in the BPA or low-Se groups, and the generation of reactive oxygen species (ROS) was increased. This inhibited the AKT/FOXO1 pathway, leading to mitochondrial fusion/division imbalance (Mfn1, Mfn2, OPA1 were increased, DRP1 was decreased) and dysfunction (CI-NDUFB8, CII-SDHB, CIII-UQCRC2, CIV-MTCO1, CV-ATP5A1, ATP). Furthermore, combined exposure of BPA and low-Se aggravated the above-mentioned changes. Treatment with N-acetylcysteine (NAC) reduced ROS levels and activated the AKT/FOXO1 pathway to further alleviate BPA and low-Se-induced apoptosis and autophagy. Apoptosis induced by low-Se + BPA was exacerbated after 3-Methyladenine (3-MA, autophagy inhibitor) treatment. Together, these results indicated that BPA and low-Se aggravated apoptosis and autophagy of the bursa of Fabricius in chickens by regulating the ROS/AKT/FOXO1 pathway.},
}
@article {pmid37942159,
year = {2023},
author = {Zhang, H and Gong, J and Zhang, S and Luo, L and Luo, C and Bi, K and Wang, L and Kan, X and Tian, Z and Wang, X},
title = {N-acetylcysteine attenuates the incidence of phlebitis induced by carbomer/vinorelbine gel.},
journal = {Heliyon},
volume = {9},
number = {11},
pages = {e21235},
pmid = {37942159},
issn = {2405-8440},
abstract = {BACKGROUND: The high incidence and severe clinical manifestations of phlebitis pose a complex and urgent clinical challenge. The rapid and simple establishment of animal phlebitis models and the development of preventive strategies are crucial to resolving this problem.<br><br>METHODS: In this study, we established such models by mixing vinorelbine ditartrate (VNR) and carbomer to form a sustained-release gel carrier, and then injected it around the veins rather than inside the vessels. Furthermore, we analyzed the efficacy of the carbomer/VNR gel in inducing phlebitis by monitoring the morphology of the veins using HE staining, immunohistochemical and immunofluorescence staining, and western blotting. Reactive oxygen species (ROS) and lipid peroxidation levels were determined using flow cytometry. Finally, we evaluated the inhibitory effect of N-acetylcysteine (NAC) on VNR-induced phlebitis in rabbits and rats.<br><br>RESULTS: Our findings suggested that the carbomer/VNR gel rapidly and easily induced phlebitis due to by retention of the gel in situ, wrapping the veins, and the prolonged release of VNR. NAC alleviated the VNR-induced oxidative stress response and expression of inflammatory cytokines by attenuating mitochondrial damage in venous endothelial cells, thereby preventing the occurrence of phlebitis in rabbits and rats.<br><br>CONCLUSION: The in situ carbomer/VNR gel provides a rapid and simple method for establishing an animal model to study the pathogenesis of phlebitis. Furthermore, the observed therapeutic effect of NAC highlights its novel and efficacious role in preventing and treating phlebitis.},
}
@article {pmid37937383,
year = {2023},
author = {Fayed, MS and Brooks, J and Seaquist, ER and Kumar, A and Moheet, A and Eberly, L and Mishra, U and Coles, LD},
title = {Population Pharmacokinetic Model of N-Acetylcysteine During Periods of Recurrent Hypoglycemia in Healthy Volunteers.},
journal = {Clinical pharmacology in drug development},
volume = {12},
number = {12},
pages = {1234-1240},
pmid = {37937383},
issn = {2160-7648},
support = {P30 DK020593/DK/NIDDK NIH HHS/United States ; P60 DK020593/DK/NIDDK NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; 2-SRA-2014-272-M-R/JDRF/Breakthrough T1D/United States ; },
mesh = {Humans ; *Acetylcysteine/pharmacokinetics ; Cross-Over Studies ; Glutathione/metabolism ; Healthy Volunteers ; *Hypoglycemia ; },
abstract = {Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia-induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia-associated autonomic failure. Our group conducted a randomized, double-blinded, placebo-controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N-acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia. The work presented herein aimed to characterize the NAC pharmacokinetics and its effects on oxidative stress. Whole blood and plasma samples were collected at specified time points during separate NAC and placebo infusions from 10 healthy volunteers. Samples were analyzed for NAC, cysteine, and glutathione (GSH) concentrations. A 2-compartment population NAC pharmacokinetic model was developed. Estimates for central compartment clearance and volume of distribution were 19.8 L/h, and 12.2 L, respectively, for a 70-kg person. Peripheral compartment clearance and volume of distribution estimates were 34.9 L/h and 13.1 L, respectively, for a 70-kg person. The PK parameters estimated here were different from those reported in the literature, suggesting a higher NAC clearance during hypoglycemic episodes. NAC leads to a significant increase in circulating cysteine concentration in a NAC concentration-dependent manner, suggesting rapid biotransformation. A transient decrease in plasma GSH was observed, supporting the hypothesis that NAC can act as a reducing agent displacing glutathione from the disulfide bond allowing for increased clearance and/or distribution of GSH.},
}
@article {pmid37931470,
year = {2023},
author = {Bauzá-Thorbrügge, M and Peris, E and Zamani, S and Micallef, P and Paul, A and Bartesaghi, S and Benrick, A and Wernstedt Asterholm, I},
title = {NRF2 is essential for adaptative browning of white adipocytes.},
journal = {Redox biology},
volume = {68},
number = {},
pages = {102951},
pmid = {37931470},
issn = {2213-2317},
mesh = {Animals ; Mice ; Acetylcysteine/pharmacology ; Adaptation, Physiological ; Adipocytes, Brown/metabolism ; *Adipocytes, White/metabolism ; Adipose Tissue, Brown/metabolism ; Adipose Tissue, White/metabolism ; Antioxidants/pharmacology/metabolism ; Lactates/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.},
}
@article {pmid37926333,
year = {2024},
author = {Aslanlar, DA and Vişneci, EF and Oz, M and Nurullahoglu Atalik, KE},
title = {N-acetylcysteine ameliorates chemotherapy-induced impaired anxiety and depression-like behaviors by regulating inflammation, oxidative and cholinergic status, and BDNF release.},
journal = {Behavioural brain research},
volume = {458},
number = {},
pages = {114740},
doi = {10.1016/j.bbr.2023.114740},
pmid = {37926333},
issn = {1872-7549},
mesh = {Rats ; Humans ; Male ; Animals ; *Acetylcysteine/pharmacology ; Antioxidants/pharmacology/therapeutic use ; Brain-Derived Neurotrophic Factor ; Rats, Wistar ; Depression/chemically induced/drug therapy ; Acetylcholinesterase ; Methotrexate ; Oxidative Stress ; Inflammation/chemically induced/drug therapy ; Anxiety/chemically induced/drug therapy ; *Antineoplastic Agents/pharmacology ; Cholinergic Agents/pharmacology ; },
abstract = {Mood disorders caused by chemotherapy have become more important as the survival of cancer patients increases, and new studies in this field will contribute to the prevention of this disorder. For this purpose, we used methotrexate, a chemotherapeutic agent frequently preferred in oncological cases. Mtx was administered as a single dose of 100 mg/kg intraperitoneally to male Wistar albino rats. Since oxidative stress plays an important role in chemotherapy-induced emotional impairment, n-acetylcysteine (NAC), a potent antioxidant, was administered at 500 mg/kg in two doses before Mtx administration. We evaluated anxiety and depression-like behaviors 24 h after Mtx administration, as well as some oxidative and inflammatory markers in blood serum and hippocampal tissue, acetylcholinesterase activity (AChE), and brain-derived neurotrophic factor (BDNF) release in hippocampal tissue. In rats, Mtx induced anxiety and depression-like behaviors as well as abnormalities in oxidative and inflammatory markers in blood serum and hippocampal tissue, increased AChE activity in hippocampal tissue, and decreased BDNF release. NAC treatment was found to ameliorate Mtx-induced anxiety and depression-like behaviors, increase antioxidant capacity, reduce oxidative stress and inflammatory response, and regulate AChE activity and BDNF release. In conclusion, the fact that NAC treatment of Mtx was effective is important for revising the treatment strategies for individuals suffering from this disorder, and this effect is thought to be related to the antioxidant and anti-inflammatory power of NAC.},
}
@article {pmid37923393,
year = {2024},
author = {Wang, H and Chang, Y and Liu, X and Liu, L and Hua, M and Li, A},
title = {Protective effects of baicalin on diethyl nitrosamine-induced liver cirrhosis by suppressing oxidative stress and inflammation.},
journal = {Chemical biology &amp; drug design},
volume = {103},
number = {1},
pages = {e14386},
doi = {10.1111/cbdd.14386},
pmid = {37923393},
issn = {1747-0285},
support = {//National Natural Science Foundation of China/ ; },
mesh = {Rats ; Animals ; Reactive Oxygen Species/metabolism ; *Liver Cirrhosis/chemically induced/drug therapy ; Liver ; Oxidative Stress ; Inflammation/chemically induced/drug therapy/metabolism ; *Nitrosamines/adverse effects/metabolism ; *Flavonoids ; },
abstract = {Baicalin (BA) is a natural product extract with anti-inflammatory, antioxidant, and hepatoprotective properties. Given that the exact underlying mechanisms responsible for the impact of BA on liver cirrhosis remain ambiguous, a detailed investigation is sorely needed. Accordingly, a rat liver cirrhosis model was established via the intraperitoneal injection of diethyl nitrosamine (DEN, 100 mg/kg). Following the modeling, these rats were given BA (100 mg/kg) or N-acetylcysteine (NAC, 150 mg/kg) alone or in combination. The pathological morphology of rat liver tissues in each group was observed by hematoxylin and eosin staining and Masson's trichrome staining. The expression of fibrosis-related proteins was evaluated by Western blot, and the levels of liver function-related biochemical indexes, oxidative stress-related indexes, and inflammatory factors in the serum by enzyme-linked immunosorbent assays (ELISA). The level of mitochondrial reactive oxygen species was measured by flow cytometry. The results depicted that in the rat model of DEN-induced liver cirrhosis, BA reduced the expression of fibrosis-related proteins (collagen type I alpha 1, α-smooth muscle actin, and transforming growth factor-β1), thereby alleviating the structural fibrosis of liver tissue. Furthermore, BA could diminish the level of mitochondrial reactive oxygen species, and the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1), while promoting albumin, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels. Notably, all these effects of BA above were strengthened following the combined treatment of BA and NAC. On the whole, BA suppresses liver fibrosis by inhibiting oxidative stress and inflammation, thereby exerting a hepatoprotective effect.},
}
@article {pmid37923985,
year = {2023},
author = {Huang, Z and Han, Y and Zhang, X and Sun, Y and Lin, Y and Feng, L and Zhou, T and Wang, Z},
title = {Acetylcysteine increases sensitivity of ceftazidime-avibactam-resistant enterobacterales with different enzymatic resistance to ceftazidime-avibactam in vitro and in vivo.},
journal = {BMC microbiology},
volume = {23},
number = {1},
pages = {321},
pmid = {37923985},
issn = {1471-2180},
mesh = {Animals ; Mice ; *Anti-Bacterial Agents/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Ceftazidime/pharmacology ; Azabicyclo Compounds/pharmacology ; Drug Combinations ; *Gammaproteobacteria/metabolism ; Microbial Sensitivity Tests ; beta-Lactamases/metabolism ; },
abstract = {BACKGROUND: Ceftazidime-avibactam (CZA) improves treatment outcomes for infections caused by carbapenem-resistant organisms, but has led to serious bacterial resistance. Acetylcysteine (NAC) is an approved medication that protects the respiratory tract through antioxidant and anti-inflammatory effects.<br><br>RESULTS: This study found that NAC combined with CZA effectively inhibits the growth of CZA-resistant clinical Enterobacterales strains. The CZA/NAC combination inhibits biofilm formation in vitro and decreases bacterial burden in a mouse thigh infection model. The combination is biocompatible and primarily increases cell membrane permeability to cause bacterial death.<br><br>CONCLUSIONS: These findings prove that the CZA/NAC combination has potential as a treatment for CZA-resistant Enterobacterales infections.},
}
@article {pmid37923778,
year = {2023},
author = {Clarke, G and Mao, J and Fan, Y and Hann, A and Gupta, A and Nutu, A and Buckel, E and Kayani, K and Murphy, N and Bangash, MN and Casey, AL and Wootton, I and Lawson, AJ and Dasari, BVM and Perera, MTPR and Mergental, H and Afford, SC},
title = {N-acetylcysteine: a novel approach to methaemoglobinaemia in normothermic liver machine perfusion.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {19022},
pmid = {37923778},
issn = {2045-2322},
support = {/WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Liver Transplantation/methods ; *Methemoglobinemia ; Acetylcysteine/pharmacology ; Organ Preservation/methods ; Methemoglobin ; Liver ; Perfusion/methods ; },
abstract = {Extended duration of normothermic machine perfusion (NMP) provides opportunities to resuscitate suboptimal donor livers. This intervention requires adequate oxygen delivery typically provided by a blood-based perfusion solution. Methaemoglobin (MetHb) results from the oxidation of iron within haemoglobin and represents a serious problem in perfusions lasting > 24 h. We explored the effects of anti-oxidant, N-acetylcysteine (NAC) on the accumulation of methaemoglobin. NMP was performed on nine human donor livers declined for transplantation: three were perfused without NAC (no-NAC group), and six organs perfused with an initial NAC bolus, followed by continuous infusion (NAC group), with hourly methaemoglobin perfusate measurements. In-vitro experiments examined the impact of NAC (3 mg) on red cells (30 ml) in the absence of liver tissue. The no-NAC group sustained perfusions for an average of 96 (range 87-102) h, universally developing methaemoglobinaemia (≥ 2%) observed after an average of 45 h, with subsequent steep rise. The NAC group was perfused for an average of 148 (range 90-184) h. Only 2 livers developed methaemoglobinaemia (peak MetHb of 6%), with an average onset of 116.5 h. Addition of NAC efficiently limits formation and accumulation of methaemoglobin during NMP, and allows the significant extension of perfusion duration.},
}
@article {pmid37921125,
year = {2024},
author = {Zhao, J and Han, M and Tian, Y and Zhao, P and Liu, X and Dong, H and Feng, S and Li, J},
title = {N-acetylcysteine Attenuates Cigarette Smoke-induced Alveolar Epithelial Cell Apoptosis through Reactive Oxygen Species Depletion and Glutathione Replenish In vivo and In vitro.},
journal = {Current pharmaceutical biotechnology},
volume = {25},
number = {11},
pages = {1466-1477},
pmid = {37921125},
issn = {1873-4316},
support = {232102311215//Science and Technology Department of Henan Province/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; Mice ; *Glutathione/metabolism ; *Pulmonary Disease, Chronic Obstructive/drug therapy/metabolism/pathology ; *Alveolar Epithelial Cells/drug effects/metabolism ; Cell Line ; Smoke/adverse effects ; Male ; Endoplasmic Reticulum Stress/drug effects ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. N-acetylcysteine (NAC) is well known for its antioxidant properties, along with potential protective effects on COPD. However, the molecular mechanism of NAC against the apoptosis of alveolar epithelial cells (AECs) in COPD remains unclear.<br><br>OBJECTIVE: This study aimed to explore the anti-apoptosis effect of NAC in COPD mice and alveolar epithelial cells.<br><br>METHODS: In the present study, the mouse model of COPD was established by cigarette smoke (CS), and mouse alveolar epithelial (MLE-12) cells were treated with cigarette smoke extract (CSE). TdT-mediated dUTP nick-end labeling (TUNEL) assay, reverse transcription polymerase chain reaction (RT-PCR), and western blot were performed to evaluate the effects of NAC on apoptosis, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Meanwhile, Lbuthionine- sulfoximine (BSO), a glutathione (GSH) inhibitor, was used to uncover the mechanism of COPD treatment by NAC.<br><br>RESULTS: We found that NAC pretreatment could attenuate the protein levels of apoptosis, ER stress, and mitochondrial dysfunction-related genes caused by CS in vivo. Meanwhile, CSE could decrease MLE-12 cell viability, which was prevented by apoptosis inhibitor ZVAD-FMK but not necroptosis inhibitor necrostatin-1. Pretreatment of MLE-12 cells with NAC increased cellular GSH levels, inhibited cellular and mitochondrial reactive oxygen species (ROS) accumulation, and decreased protein level of apoptosis, ER stress, and mitochondrial dysfunction-related genes. Moreover, experiment results showed that BSO could completely reverse the beneficial effects of NAC.<br><br>CONCLUSION: Our study confirmed that NAC can attenuate CS-induced AEC apoptosis via alleviating ROS-mediated ER stress and mitochondrial dysfunction pathway, and the mechanism was found to be related to replenishing the cellular GSH content.},
}
@article {pmid37918853,
year = {2024},
author = {Bryan, A and Pingali, P and Faber, A and Landry, J and Akakpo, JY and Jaeschke, H and Li, H and Lee, WS and May, L and Patel, B and Neuwelt, A},
title = {High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {388},
number = {1},
pages = {209-217},
pmid = {37918853},
issn = {1521-0103},
support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; P30 CA016059/CA/NCI NIH HHS/United States ; IK2 BX004914/BX/BLRD VA/United States ; R21 AG073892/AG/NIA NIH HHS/United States ; },
mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; *Cytochrome P-450 CYP2E1/metabolism ; Fomepizole ; Mice, Inbred NOD ; Liver/metabolism ; Acetylcysteine/pharmacology ; },
abstract = {Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgamma[null] mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity. SIGNIFICANCE STATEMENT: High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.},
}
@article {pmid37918281,
year = {2024},
author = {Li, Y and Yang, X and Bao, T and Sun, X and Li, X and Zhu, H and Zhang, B and Ma, T},
title = {Radix Astragali decoction improves liver regeneration by upregulating hepatic expression of aquaporin-9.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {122},
number = {},
pages = {155166},
doi = {10.1016/j.phymed.2023.155166},
pmid = {37918281},
issn = {1618-095X},
mesh = {Mice ; Animals ; Liver Regeneration ; Hydrogen Peroxide/metabolism ; Liver ; *Drugs, Chinese Herbal/chemistry ; *Astragalus Plant/chemistry ; *Aquaporins/genetics/metabolism/pharmacology ; Astragalus propinquus ; },
abstract = {BACKGROUND: The therapeutic efficacy of liver injuries heavily relies on the liver's remarkable regenerative capacity, necessitating the maintenance of glycose/lipids homeostasis and oxidative eustasis during the recovery process. Astragali Radix, an herbal tonic widely used in China and many other countries, is believed to have many positive effects, including immune stimulation, nourishing, antioxidant, liver protection, diuresis, anti-diabetes, anti-cancer and expectorant. Astragali Radix is widely integrated into hepatoprotective formulas as it is believed to facilitate liver regeneration. Nevertheless, the precise molecular pharmacological mechanisms underlying this hepatoprotective effect remain elusive.<br><br>PURPOSE: To investigate the improving effects of Astragali Radix on liver regeneration and the underlying mechanisms.<br><br>METHODS: A mouse model of 70% partial hepatectomy (PHx) was employed to investigate the impact of Radix Astragali decoction (HQD) on liver regeneration. HQD was orally administered for 7 days before the PHx procedure and throughout the experiment. N-acetylcysteine (NAC) was used as a positive control for liver regeneration. Liver regeneration was assessed by evaluating the liver-to-body weight ratio (LW/BW) and the expression of representative cell proliferation marker proteins. Oxidative stress and glucose metabolism were analyzed using biochemical assays, Western blotting, dihydroethidium (DHE) fluorescence, and periodic acid-Schiff (PAS) staining methods. To understand the role of AQP9 as a potential molecular target of HQD in promoting liver regeneration, td-Tomato-tagged AQP9 transgenic mice (AQP9-RFP) were employed to determine the expression pattern of AQP9 protein. AQP9 knockout mice (AQP9[-/-]) were used to assess the specific targeting of AQP9 in the promotion of liver regeneration by HQD.<br><br>RESULTS: HQD significantly upregulated hepatic AQP9 expression, alleviated liver injury and promoted liver regeneration in wild-type (AQP9[+/+]) mice after 70% PHx. However, the beneficial impact of HQD on liver regeneration was absent in AQP9 gene knockout (AQP9[-/-]) mice. Moreover, HQD facilitated the uptake of glycerol by hepatocytes, enhanced gluconeogenesis, and concurrently reduced H2O2 content and oxidative stress levels in AQP9[+/+] but not AQP9[-/-] mouse livers. Additionally, main active substance of Radix Astragali, astragaloside IV (AS-IV) and cycloastragenol (CAG), demonstrated substantial upregulation of AQP9 expression and promoted liver regeneration in AQP9[+/+] but not AQP9[-/-] mice.<br><br>CONCLUSION: This study is the first to demonstrate that Radix Astragali and its main active constituents (AS-IV and CAG) improve liver regeneration by upregulating the expression of AQP9 in hepatocytes to increase gluconeogenesis and reduce oxidative stress. The study revealed novel molecular pharmacological mechanisms of Radix Astragali and provided a promising therapeutic target of liver diseases.},
}
@article {pmid37913693,
year = {2023},
author = {Yilmaz, H and Mercantepe, F and Tumkaya, L and Mercantepe, T and Yilmaz, A and Yilmaz Rakici, S},
title = {The potential antioxidant effect of N-acetylcysteine on X-ray ionizing radiation-induced pancreas islet cell toxicity.},
journal = {Biochemical and biophysical research communications},
volume = {685},
number = {},
pages = {149154},
doi = {10.1016/j.bbrc.2023.149154},
pmid = {37913693},
issn = {1090-2104},
mesh = {Humans ; Male ; Rats ; Animals ; Antioxidants/pharmacology ; Acetylcysteine/pharmacology ; X-Rays ; Caspase 3/metabolism ; Glucagon ; Saline Solution/pharmacology ; Sodium Chloride/pharmacology ; Oxidative Stress ; Glutathione/metabolism ; Radiation, Ionizing ; *Radiation Injuries/drug therapy/prevention &amp; control ; *Islets of Langerhans/metabolism ; *Insulins ; },
abstract = {PURPOSE: Previous research has highlighted the impact of X-ray irradiation-induced organ damage, on cancer patients after radiation therapy. The ionizing radiation-induced oxidative stress causes injury to the pancreatic islet cells of Langerhans. We used histopathological, immunohistochemical, and biochemical analyses to examine α- and β-cells in the islets of Langerhans in rats undergoing whole-body x-ray ionizing radiation, a group of which was treated with NAC.<br><br>MATERIAL AND METHODS: Twenty-four male rats were randomly divided into 3 groups, one control, and two experimental groups. Group I (Control) was administered only saline solution (0.09% NaCl) by oral gavage for 7 days. Group II (IR) was administrated whole body single dose 6 Gray ionizing radiation (IR) and saline solution (0.09% NaCl) by oral gavage for 7 days. Group III (IR&#xa0;+&#xa0;NAC) was administered 300&#xa0;mg/kg NAC (N-acetylcysteine) by oral gavage for 7 days, 5 days before, and 2 days after 6 Gray IR application.<br><br>RESULTS: In the X-ray irradiation group, we observed diffuse necrotic endocrine cells in the islets of Langerhans. In addition, we found that Caspase-3, malondialdehyde (MDA) levels increased, and insulin, glucagon, and glutathione (GSH) levels decreased in the IR group compared to the control group. In contrast, we observed a decrease in Caspase-3, and MDA levels in necrotic endocrine cells, and an increase in insulin, glucagon, and GSH levels in the IR&#xa0;+&#xa0;NAC group compared to the IR group.<br><br>CONCLUSION: This study provides evidence for the beneficial effects of N-acetyl cysteine on islets of Langerhans cells with X-ray ionizing-radiation-induced damage in a rat model.},
}
@article {pmid37913572,
year = {2023},
author = {Feng, Q and Hu, K and Hu, H and Lu, Y and Zhang, H and Wang, G and Zhang, Q and Xu, Z and Gao, X and Jia, X and Zhu, H and Song, D and Yi, H and Peng, Y and Wu, X and Li, B and Zhu, W and Shi, J},
title = {Berberine derivative DCZ0358 induce oxidative damage by ROS-mediated JNK signaling in DLBCL cells.},
journal = {International immunopharmacology},
volume = {125},
number = {Pt A},
pages = {111139},
doi = {10.1016/j.intimp.2023.111139},
pmid = {37913572},
issn = {1878-1705},
mesh = {Humans ; Apoptosis ; *Berberine/pharmacology ; Cell Line, Tumor ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/pathology ; MAP Kinase Signaling System ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Isoquinolines ; Oxazoles ; },
abstract = {The most common neoplasm among adult lymphomas is diffuse large B-cell lymphoma (DLBCL), typically characterized by pain-free and progressive lymph node enlargement. Due to high heterogeneity of DLBCL, 30-40 % of patients are resistant to R-CHOP standard chemoimmunotherapy. DCZ0358 is a new compound designed and synthesized from berberine by our group and the molecular mechanism by which it inhibited DLBCL growth has attracted our widespread attention. In this study, we employed the CCK8 assay to reveal that DCZ0358 inhibited proliferation in a dependent manner of time and dosage of DLBCL cells. Moreover, flowcytometry and western blot results showed that DCZ0358 downregulated the expression of CDK4, CDK6 and CyclinD1 to block cell cycle progression in G0/G1 phase. Furthermore, DCZ0358 enhanced mitochondrial membrane potential depolarization, promoted mitochondrial permeability transport pore openness, increased cytoplastic Ca2+ levels and decreased intracellular adenosine triphosphate production, which led to mitochondrial dysfunction. In particular, DCZ0358 treatment triggered cell apoptosis and elevated intracellular reactive oxygen species (ROS) levels, which subsequently mediated JNK pathway activation. Further research indicated the pre-treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358. Most importantly, DCZ0358 exhibited synergistic anti-tumor effects when combined with etoposide, a common clinical anti-DLBCL drug, both in vitro and certainly in vivo. Above results demonstrated anti-tumor molecular mechanism of DCZ0358 in DLBCL cells and highlighted the ROS/JNK/DNA damage pathway as a potential target in therapies, which have implications for the development of more effective clinical treatments for DLBCL.},
}
@article {pmid37908648,
year = {2023},
author = {Li, H and Deng, X and Zhang, Z and Yang, Z and Huang, H and Ye, X and Zhong, L and Xu, G and Liu, R and Fang, Y},
title = {Nitric oxide/paclitaxel micelles enhance anti-liver cancer effects and paclitaxel sensitivity by inducing ferroptosis, endoplasmic reticulum stress and pyroptosis.},
journal = {RSC advances},
volume = {13},
number = {45},
pages = {31772-31784},
pmid = {37908648},
issn = {2046-2069},
abstract = {The objective of this study was to investigate the anticancer activities of biodegradable polymeric micelles composed of monomethoxy poly(ethylene glycol), polylactic acid, and nitric oxide (mPEG-PLA-NO) loaded with paclitaxel (PTX) as a nanomedicine delivery system. We aimed to compare the anticancer effects of these NO/PTX micelles with PTX alone and elucidate their mechanism of action. We evaluated the impact of NO/PTX and PTX on cell viability using Cell Counting Kit-8 (CCK8) assays conducted on the Bel-7402 liver cancer cell line. Additionally, we employed H22 xenografted mice to assess the in vivo tumor growth inhibitory activity of NO/PTX. To examine the cytotoxicity of NO/PTX, the intracellular levels of reactive oxygen species (ROS), and the expression of ferroptosis-related proteins, we conducted experiments in the presence of the ferroptosis inhibitor ferrostatin-1 (Fer-1) or the ROS inhibitor N-acetyl cysteine (NAC). Furthermore, we investigated the expression of endoplasmic reticulum stress (ERS) and apoptosis-associated proteins. Our results demonstrated that NO/PTX exhibited enhanced anticancer effects compared to PTX alone in both Bel-7402 cells and H22 xenografted mice. The addition of Fer-1 or NAC reduced the anticancer activity of NO/PTX, indicating the involvement of ferroptosis and ROS in its mechanism of action. Furthermore, NO/PTX modulated the expression of proteins related to ERS and apoptosis, indicating the activation of these cellular pathways. The anticancer effects of NO/PTX in liver cancer cells were mediated through the induction of ferroptosis, pyroptosis, ERS, and apoptosis-associated networks. Ferroptosis and pyroptosis were activated by treatment of NO/PTX at low concentration, whereas ERS was induced to trigger apoptosis at high concentration. The superior anti-tumor effect of NO/PTX may be attributed to the downregulation of a multidrug resistance transporter and the sensitization of cells to PTX chemotherapy. In summary, our study highlights the potential of mPEG-PLA-NO micelles loaded with PTX as a nanomedicine delivery system for liver cancer treatment. The observed enhancement in anticancer activity, combined with the modulation of key cellular pathways, provides valuable insights into the therapeutic potential of NO/PTX in overcoming resistance and improving treatment outcomes in liver cancer patients.},
}
@article {pmid37902021,
year = {2023},
author = {ALRashdi, BM and Mohamed, RA and Mohamed, AH and Samoul, FA and Mohamed, MI and Moussa, MM and Alrashidi, SM and Dawod, B and Habotta, OA and Abdel Moneim, AE and Ramadan, SS},
title = {Therapeutic activity of green synthesized selenium nanoparticles from turmeric against cisplatin-induced oxido-inflammatory stress and cell death in mice kidney.},
journal = {Bioscience reports},
volume = {43},
number = {11},
pages = {},
pmid = {37902021},
issn = {1573-4935},
mesh = {Mice ; Animals ; *Cisplatin/adverse effects ; *Selenium/pharmacology/metabolism ; Curcuma ; Kidney/pathology ; Apoptosis ; Oxidative Stress ; },
abstract = {Cisplatin (CDDP) is a commonly prescribed chemotherapeutic agent; however, its associated nephrotoxicity limits its clinical efficacy and sometimes requires discontinuation of its use. The existing study was designed to explore the reno-therapeutic efficacy of turmeric (Tur) alone or conjugated with selenium nanoparticles (Tur-SeNPs) against CDDP-mediated renal impairment in mice and the mechanisms underlying this effect. Mice were orally treated with Tur extract (200 mg/kg) or Tur-SeNPs (0.5 mg/kg) for 7 days after administration of a single dose of CDDP (5 mg/kg, i.p.). N-acetyl cysteine NAC (100 mg/kg) was used as a standard antioxidant compound. The results revealed that Tur-SeNPs counteracted CDDP-mediated serious renal effects in treated mice. Compared with the controls, Tur or Tur-SeNPs therapy remarkably decreased the kidney index along with the serum levels of urea, creatinine, Kim-1, and NGAL of the CDDP-injected mice. Furthermore, Tur-SeNPs ameliorated the renal oxidant status of CDDP group demonstrated by decreased MDA and NO levels along with elevated levels of SOD, CAT, GPx, GR, GSH, and gene expression levels of HO-1. Noteworthy, lessening of renal inflammation was exerted by Tur-SeNPs via lessening of IL-6 and TNF-α besides down-regulation of NF-κB gene expression in mouse kidneys. Tur-SeNPs treatment also restored the renal histological features attained by CDDP challenge and hindered renal apoptosis through decreasing the Bax levels and increasing Bcl-2 levels. Altogether, these outcomes suggest that the administration of Tur conjugated with SeNPs is effective neoadjuvant chemotherapy to guard against the renal adverse effects that are associated with CDDP therapy.},
}
@article {pmid37899576,
year = {2024},
author = {Sozer Karadagli, S and Gursoy, P},
title = {Liver toxicity with ribociclib in a patient with metastatic hormone receptor positive postmenopausal breast cancer.},
journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners},
volume = {30},
number = {2},
pages = {404-407},
doi = {10.1177/10781552231208390},
pmid = {37899576},
issn = {1477-092X},
mesh = {Female ; Humans ; *Aminopyridines/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Breast Neoplasms/drug therapy/pathology ; Cysteine/therapeutic use ; *Drug-Related Side Effects and Adverse Reactions/drug therapy ; Liver ; Postmenopause ; *Purines/adverse effects ; Erb-b2 Receptor Tyrosine Kinases ; },
abstract = {INTRODUCTION: In recent years, highly selective reversible CDK4/6 inhibitors have been combined with aromatase inhibitors for their efficacy and ease of application in the treatment of advanced stage of hormone-responsive breast cancers. Oral use of these drugs facilitates patient compliance. However, adverse drug reactions are reported due to these drugs, in the literature. Diverse adverse reactions such as skin reactions, liver toxicity, and vitiligo with ribociclib have been reported.<br><br>CASE REPORT: In this study, we present of liver toxicity due to the use of ribociclib in a case of advanced breast cancer with metastases. It is noteworthy that the patient did not have any other concomitant disease and did not take any other medication.<br><br>MANAGEMENT AND OUTCOME: After the 600&#x2005;mg initial dose of ribociclib, neutropenia occurred at the beginning of the therapy, the dose was reduced to 400&#x2005;mg, and liver enzymes started to rise in the second month of the therapy. In the fifth month of the intermittent treatment period, liver toxicity was grade 3.<br><br>DISCUSSION: Liver adverse reaction occurred due to ribociclib use in the patient who had no history of any other disease. The Naranjo algorithm score was evaluated as 9. Considering the excretion of ribociclib by sulfation, cysteine conjugation, and glucuronidation, which are phase II reactions, n-acetyl cysteine (NAC) treatment (600&#x2005;mg/day) was started for the patient. NAC therapy is recommended to reduce elevated liver enzymes in the case. The patient's treatment has been continuing with palbociclib for 5 months. No increase in liver enzymes was observed.},
}
@article {pmid37895148,
year = {2023},
author = {Yang, YF and Singh, S},
title = {Pharmacogenomic Landscape of Ivermectin and Selective Antioxidants: Exploring Gene Interplay in the Context of Long COVID.},
journal = {International journal of molecular sciences},
volume = {24},
number = {20},
pages = {},
pmid = {37895148},
issn = {1422-0067},
mesh = {Humans ; *COVID-19/genetics ; Antioxidants/therapeutic use ; Post-Acute COVID-19 Syndrome ; Ivermectin/therapeutic use ; Pandemics ; Anthocyanins ; Pharmacogenetics ; *MicroRNAs/genetics ; },
abstract = {COVID-19 pandemic has caused widespread panic and fear among the global population. As such, repurposing drugs are being used as viable therapeutic options due to the limited effective treatments for Long COVID symptoms. Ivermectin is one of the emerging repurposed drugs that has been shown effective to have antiviral effects in clinical trials. In addition, antioxidant compounds are also gaining attention due to their capabilities of reducing inflammation and severity of symptoms. Due to the absence of knowledge in pharmacogenomics and modes of actions in the human body for these compounds, this study aims to provide a pharmacogenomic profile for the combination of ivermectin and six selected antioxidants (epigallocatechin gallate (EGCG), curcumin, sesamin, anthocyanins, quercetin, and N-acetylcysteine (NAC)) as potentially effective regimens for long COVID symptoms. Results showed that there were 12 interacting genes found among the ivermectin, 6 antioxidants, and COVID-19. For network pharmacology, the 12 common interacting genes/proteins had the highest associations with Pertussis pathway, AGE-RAGE signaling pathway in diabetic complications, and colorectal cancer in the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Disease analyses also revealed that the top three relevant diseases with COVID-19 infections were diabetes mellitus, ischemia, reperfusion injury. We also identified 6 potential target microRNAs (miRNAs) of the 12 commonly curated genes used as molecular biomarkers for COVID-19 treatments. The established pharmacogenomic network, disease analyses, and identified miRNAs could facilitate developments of effective regimens for chronic sequelae of COVID-19 especially in this post-pandemic era. However, further studies and clinical trials are needed to substantiate the effectiveness and dosages for COVID-19 treatments.},
}
@article {pmid37894999,
year = {2023},
author = {Li, R and Kato, H and Fumimoto, C and Nakamura, Y and Yoshimura, K and Minagawa, E and Omatsu, K and Ogata, C and Taguchi, Y and Umeda, M},
title = {Essential Amino Acid Starvation-Induced Oxidative Stress Causes DNA Damage and Apoptosis in Murine Osteoblast-like Cells.},
journal = {International journal of molecular sciences},
volume = {24},
number = {20},
pages = {},
pmid = {37894999},
issn = {1422-0067},
support = {No. 23K19761//Japan Society for the Promotion of Science/ ; No. 21K09946//Japan Society for the Promotion of Science/ ; No. 22K09993//Japan Society for the Promotion of Science/ ; },
mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Oxidative Stress ; *Apoptosis ; Acetylcysteine/pharmacology/metabolism ; DNA Damage ; Osteoblasts/metabolism ; Amino Acids, Essential/metabolism ; },
abstract = {Intracellular nutrient metabolism, particularly the metabolism of essential amino acids (EAAs), is crucial for cellular functions, including energy production and redox homeostasis. An EAA deficiency can lead to cellular dysfunction and oxidative stress. This study explores the mechanisms underlying cellular responses to EAA starvation, focusing on ROS-induced DNA damage and apoptosis. MC3T3-E1 cells were subjected to EAA starvation, and various assays were conducted to assess cell proliferation, survival, DNA damage, and apoptosis. The antioxidant N-acetylcysteine (NAC) was employed to block ROS formation and mitigate cellular damage. Gene expression and Western blot analyses were performed to elucidate molecular pathways. EAA starvation-induced ROS generation, DNA damage, and apoptosis in MC3T3-E1 cells. NAC administration effectively reduced DNA damage and apoptosis, highlighting the pivotal role of ROS in mediating these cellular responses during EAA deficiency. This study demonstrates that EAA starvation triggers ROS-mediated DNA damage and apoptosis, offering insights into the intricate interplay between nutrient deficiency, oxidative stress, and programmed cell death. NAC emerges as a potential therapeutic intervention to counteract these adverse effects.},
}
@article {pmid37894565,
year = {2023},
author = {Ntorkou, M and Tsanaktsidou, E and Chachlioutaki, K and Fatouros, DG and Markopoulou, CK},
title = {In Vitro Permeability Study of Homotaurine Using a High-Performance Liquid Chromatography with Fluorescence Detection Pre-Column Derivatization Method.},
journal = {Molecules (Basel, Switzerland)},
volume = {28},
number = {20},
pages = {},
pmid = {37894565},
issn = {1420-3049},
mesh = {*Acetylcysteine/chemistry ; Chromatography, High Pressure Liquid/methods ; *Memantine ; o-Phthalaldehyde/chemistry ; Indicators and Reagents ; Tiopronin ; Reproducibility of Results ; Taurine/analogs &amp; derivatives ; },
abstract = {Homotaurine (HOM) is considered a promising drug for the treatment of Alzheimer's and other neurodegenerative diseases. In the present work, a new high-performance liquid chromatography with fluorescence detection (HPLC-FLD) (λex. = 340 nm and λem. = 455 nm) method was developed and validated for the study of substance permeability in the central nervous system (CNS). Analysis was performed on a RP-C18 column with a binary gradient elution system consisting of methanol-potassium phosphate buffer solution (pH = 7.0, 0.02 M) as mobile phase. Samples of homotaurine and histidine (internal standard) were initially derivatized with ortho-phthalaldehyde (OPA) (0.01 M), N-acetylcysteine (0.01 M) and borate buffer (pH = 10.5; 0.05 M). To ensure the stability and efficiency of the reaction, the presence of different nucleophilic reagents, namely (a) 2-mercaptoethanol (2-ME), (b) N-acetylcysteine (NAC), (c) tiopronin (Thiola), (d) 3-mercaptopropionic acid (3-MPA) and (e) captopril, was investigated. The method was validated (R[2] = 0.9999, intra-day repeatability %RSD < 3.22%, inter-day precision %RSD = 1.83%, limits of detection 5.75 ng/mL and limits of quantification 17.43 ng/mL, recovery of five different concentrations 99.75-101.58%) and successfully applied to investigate the in vitro permeability of homotaurine using Franz diffusion cells. The apparent permeability (Papp) of HOM was compared with that of memantine, which is considered a potential therapeutic drug for various CNSs. Our study demonstrates that homotaurine exhibits superior permeability through the simulated blood-brain barrier compared to memantine, offering promising insights for enhanced drug delivery strategies targeting neurological conditions.},
}
@article {pmid37891946,
year = {2023},
author = {Tieu, S and Charchoglyan, A and Paulsen, L and Wagter-Lesperance, LC and Shandilya, UK and Bridle, BW and Mallard, BA and Karrow, NA},
title = {N-Acetylcysteine and Its Immunomodulatory Properties in Humans and Domesticated Animals.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {10},
pages = {},
pmid = {37891946},
issn = {2076-3921},
abstract = {N-acetylcysteine (NAC), an acetylated derivative of the amino acid L-cysteine, has been widely used as a mucolytic agent and antidote for acetaminophen overdose since the 1960s and the 1980s, respectively. NAC possesses antioxidant, cytoprotective, anti-inflammatory, antimicrobial, and mucolytic properties, making it a promising therapeutic agent for a wide range of diseases in both humans and domesticated animals. Oxidative stress and inflammation play a major role in the onset and progression of all these diseases. NAC's primary role is to replenish glutathione (GSH) stores, the master antioxidant in all tissues; however, it can also reduce levels of pro-inflammatory tumor necrosis factor-alpha (TNF-∝) and interleukins (IL-6 and IL-1β), inhibit the formation of microbial biofilms and destroy biofilms, and break down disulfide bonds between mucin molecules. Many experimental studies have been conducted on the use of NAC to address a wide range of pathological conditions; however, its effectiveness in clinical trials remains limited and studies often have conflicting results. The purpose of this review is to provide a concise overview of promising NAC usages for the treatment of different human and domestic animal disorders.},
}
@article {pmid37886069,
year = {2023},
author = {Pacios, O and Blasco, L and Ortiz Cartagena, C and Bleriot, I and Fernández-García, L and López, M and Barrio-Pujante, A and Cuenca, FF and Aracil, B and Oteo-Iglesias, J and Tomás, M},
title = {Molecular studies of phages-Klebsiella pneumoniae in mucoid environment: innovative use of mucolytic agents prior to the administration of lytic phages.},
journal = {Frontiers in microbiology},
volume = {14},
number = {},
pages = {1286046},
pmid = {37886069},
issn = {1664-302X},
abstract = {Mucins are important glycoproteins that form a protective layer throughout the gastrointestinal and respiratory tracts. There is scientific evidence of increase in phage-resistance in the presence of mucin for some bacterial pathogens. Manipulation in mucin composition may ultimately influence the effectiveness of phage therapy. In this work, two clinical strains of K. pneumoniae (K3574 and K3325), were exposed to the lytic bacteriophage vB_KpnS-VAC35 in the presence and absence of mucin on a long-term co-evolution assay, in an attempt to mimic in vitro the exposure to mucins that bacteria and their phages face in vivo. Enumerations of the bacterial and phage counts at regular time intervals were conducted, and extraction of the genomic DNA of co-evolved bacteria to the phage, the mucin and both was performed. We determined the frequency of phage-resistant mutants in the presence and absence of mucin and including a mucolytic agent (N-acetyl L-cysteine, NAC), and sequenced them using Nanopore. We phenotypically demonstrated that the presence of mucin induces the emergence of bacterial resistance against lytic phages, effectively decreased in the presence of NAC. In addition, the genomic analysis revealed some of the genes relevant to the development of phage resistance in long-term co-evolution, with a special focus on the mucoid environment. Genes involved in the metabolism of carbohydrates were mutated in the presence of mucin. In conclusion, the use of mucolytic agents prior to the administration of lytic phages could be an interesting therapeutic option when addressing K. pneumoniae infections in environments where mucin is overproduced.},
}
@article {pmid37885115,
year = {2024},
author = {Salehi, AM and Hasanzarrini, M and Salehi, H and Jenabi, E},
title = {Liraglutide and Liver Injury: Rare Case Report with Literature Review.},
journal = {Endocrine, metabolic &amp; immune disorders drug targets},
volume = {24},
number = {6},
pages = {725-729},
pmid = {37885115},
issn = {2212-3873},
mesh = {Humans ; Female ; Adult ; *Liraglutide/adverse effects ; *Diabetes Mellitus, Type 2/diagnosis/drug therapy/chemically induced ; Hypoglycemic Agents/adverse effects ; Glucagon-Like Peptide 1 ; Liver ; },
abstract = {BACKGROUND: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus (T2DM). So far, few severe side effects have been reported for it.<br><br>CASE PRESENTATION: A 41-year-old woman was admitted to the Emergency Room with diffuse abdominal pain. The patient had a known case of T2DM, fatty liver disease, and hypertension and was treated with Metformin, Liraglutide, and Losartan. Her liver functional test (LFT) was consistent with hepatocellular injury; however, laboratory tests and abdominal ultrasound were used to rule out autoimmune hepatitis. Due to concerns for drug-induced liver injury (DILL), liraglutide was discontinued and N-acetyl cysteine was prescribed. On the fifth day of hospitalization, the patient's symptoms resolved and his LFT started to decrease on the sixth day after 2 months, the patient's liver enzyme levels returned to normal.<br><br>CONCLUSION: Liraglutide is one of the most important drugs in the treatment of T2DM.The most common side effects of this drug are constipation, nausea, vomiting, diarrhea, indigestion, and loss of appetite. In rare cases, symptoms of thyroid cancer, pancreatitis, and hypoglycemia have been reported, however, DILL is one of the extremely rare side effect of Liraglutide. It is important to increase the awareness of physicians about the liver injury of Liraglutide.},
}
@article {pmid37884214,
year = {2023},
author = {Kshirsagar, S and Dandekar, A and Srivastava, RK and Khan, J and Muzaffar, S and Athar, M and Banga, AK},
title = {Microneedle-mediated transdermal delivery of N-acetyl cysteine as a potential antidote for lewisite injury.},
journal = {International journal of pharmaceutics},
volume = {647},
number = {},
pages = {123547},
pmid = {37884214},
issn = {1873-3476},
support = {U01 AR078544/AR/NIAMS NIH HHS/United States ; },
mesh = {Humans ; *Antidotes ; *Acetylcysteine ; Administration, Cutaneous ; Skin ; Drug Delivery Systems ; Needles ; Arsenicals ; },
abstract = {Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister formation. N-acetyl cysteine (NAC) is an FDA-approved drug for acetaminophen toxicity, identified as a potential antidote against lewisite. In the present study, we have explored the feasibility of rapid NAC delivery through transdermal route for potentially treating chemical warfare toxicity. NAC is a small, hydrophilic molecule with limited passive delivery through the skin. Using skin microporation with dissolving microneedles significantly enhanced the delivery of NAC into and across dermatomed human skin in our studies. Microporation followed by application of solution (poke-and-solution) resulted in the highest in vitro delivery (509.84 ± 155.04 µg/sq·cm) as compared to poke-and-gel approach (474.91 ± 70.09 µg/sq·cm) and drug-loaded microneedles (226.89 ± 33.41 µg/sq·cm). The lag time for NAC delivery through poke-and-solution approach (0.23 ± 0.04 h) was close to gel application (0.25 ± 0.02 h), with the highest for drug-loaded microneedles (1.27 ± 1.16 h). Thus, we successfully demonstrated the feasibility of rapid NAC delivery using various skin microporation approaches for potential treatment against lewisite-mediated skin toxicity.},
}
@article {pmid37877516,
year = {2023},
author = {Li, S and Yang, N and Ma, Q and Li, S and Tong, S and Luo, J and Song, X and Yang, H},
title = {Tailoring Oxidation Responsiveness of Gold Nanoclusters via Ligand Engineering for Imaging Acute Kidney Injury.},
journal = {Analytical chemistry},
volume = {95},
number = {44},
pages = {16153-16159},
doi = {10.1021/acs.analchem.3c02698},
pmid = {37877516},
issn = {1520-6882},
mesh = {Animals ; Mice ; Gold/chemistry ; Ligands ; Diagnostic Imaging ; *Acute Kidney Injury ; *Metal Nanoparticles/chemistry ; },
abstract = {Gold nanoclusters (AuNCs) have shown great promise for in vivo imaging because of their definable structure, tunable photoluminescence (PL), and desired renal clearance. However, current understanding of the responsiveness of AuNCs to biological substances is still limited, which may hamper their biomedical applications. Herein, we explore the oxidation responsiveness of near-infrared II (NIR-II) luminescent AuNCs capped with two different ligands, which can be optimized for high-efficiency NIR-II PL imaging of mice acute kidney injury (AKI) featuring high-level peroxynitrite anions (ONOO[-]). We found that in the presence of ONOO[-], N-acetylcysteine-capped AuNCs (NAC-AuNCs) tended to be oxidized more easily than that capped with the macromolecular mercapto-β-cyclodextrin (CDS-AuNCs), resulting in the aggregation of NAC-AuNCs into large-sized assemblies, which was not observed in CDS-AuNCs. The oxidation-triggered morphology, composition, and NIR-II PL changes in NAC-AuNCs were then systematically studied. We finally demonstrated that NAC-AuNCs can be implemented for sensitive NIR-II PL imaging of mice AKI, facilitated by the synergetic in situ AuNC aggregation and decreased glomerular filtration rate (GFR) in the injured kidney, which outperforms the methods solely based on the decreased GFR effect. Therefore, this work highlights the critical significance of ligand engineering in AuNCs and may motivate future design of AuNCs for diverse bioimaging applications.},
}
@article {pmid37877260,
year = {2023},
author = {Wilson, SH and Sirianni, JM and Bridges, KH and Wolf, BJ and Valente, IE and Scofield, MD},
title = {The impact of intraoperative N-acetylcysteine on opioid consumption following spine surgery: a randomized pilot trial.},
journal = {Pain management},
volume = {13},
number = {10},
pages = {593-602},
pmid = {37877260},
issn = {1758-1877},
support = {R01 DA054154/DA/NIDA NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; UL1TR001450/TR/NCATS NIH HHS/United States ; UL1TR001450/TR/NCATS NIH HHS/United States ; },
mesh = {Adult ; Humans ; *Acetylcysteine/therapeutic use ; *Analgesics, Opioid/therapeutic use ; Double-Blind Method ; Postoperative Pain/drug therapy ; Pilot Projects ; Prospective Studies ; },
abstract = {Aim: N-acetylcysteine (NAC) decreases inflammation and could augment perioperative analgesia. Materials &amp; methods: This prospective pilot trial examined postoperative opioid consumption at 12 h following intraoperative NAC. In phase I, 20 adults scheduled for posterior spine surgery were randomized to NAC (0, 50, 100 and 150 mg/kg) to determine the optimal dose. In phase II, 30 patients were randomized to placebo or NAC (150 mg/kg). Opioid consumption, pain ratings and time to opioid rescue were recorded. Results: Postoperative opioid consumption was reduced in the NAC group 19.3% at 12 h and 20% at 18 and 36 h. Opioid consumption was reduced 22-24% in the NAC group at all times after adjusting for intraoperative opioid administration. NAC subjects reported lower pain scores relative to placebo. Conclusion: Subjects randomized to NAC consumed less postoperative opioids and reported less pain versus placebo. Larger randomized controlled trials are needed to further evaluate NAC for analgesia. Clinical Trial Registration: NCT04562597 (ClinicalTrials.gov).},
}
@article {pmid37870740,
year = {2024},
author = {Agarwal, A and Jayashree, M and Angurana, SK and Sharma, R and Ghosh, A and Singh, MP and Nallasamy, K and Bansal, A},
title = {Clinical Profile, Intensive Care Needs and Predictors of Outcome Among Children Admitted with Non-COVID Severe Acute Respiratory Illness (SARI) During the Pandemic.},
journal = {Indian journal of pediatrics},
volume = {91},
number = {4},
pages = {329-336},
pmid = {37870740},
issn = {0973-7693},
mesh = {Child ; Humans ; SARS-CoV-2 ; Pandemics ; Retrospective Studies ; *COVID-19 ; Critical Care ; *Respiratory Insufficiency ; },
abstract = {OBJECTIVES: To study the epidemiology of non-coronavirus disease-2019 (non-COVID-19) respiratory viral infections with respect to their clinical profile, intensive care needs and predictors of outcome once the non-pharmacological interventions (NPI) during the coronavirus disease-2019 (COVID-19) pandemic were relaxed.<br><br>METHODS: Retrospective analysis of children with Severe Acute Respiratory Illness (SARI) who were SARS-CoV-2 negative, admitted to the Pediatric Emergency/Intensive Care Unit (PICU) from July 2021 through October 2021 was conducted.<br><br>RESULTS: One hundred and thirty nine children with median age of 11 (4-28.5) mo were included. Besides respiratory symptoms in all, diarrhea was reported in 90 (64.7%) children. Nearly half (n&#xa0;=&#xa0;66; 47%) presented in hypoxemic respiratory failure (SpO2 <88%). Fifty-two (37.4%) children had co-morbidities, commonest being congenital heart disease in 12 (23.1%). Baseline parameters revealed leukopenia (specifically lymphopenia) 39 (28%), elevated aspartate transaminase [Serum glutamic-oxaloacetic transaminase (SGOT)] in 108 (77.6%), elevated N-acetyl-cysteine-activated creatinine kinase (CK-NAC) 23 (79%) and lactate dehydrogenase (LDH) 15 (88%). Intensive care needs included mechanical ventilation 51 (36.6%), vasoactive support 34 (24.5%), and renal replacement therapy 10 (7.1%). Forty-two (30.2%) children developed multi-organ dysfunction syndrome (MODS). One hundred and three (74.1%) children were discharged, 31 (22.3%) died, and 5 (3.6%) left against medical advice. On multivariate regression analysis, elevated liver enzymes (>5 times normal), hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted mortality.<br><br>CONCLUSIONS: A surge in non-COVID SARI was observed once lockdown measures were relaxed. Nearly 1/3[rd] progressed to multi-organ failure and died. Elevated liver enzymes, hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted death.},
}
@article {pmid37869073,
year = {2023},
author = {Ye, R and Ma, S and Chen, Y and Shan, J and Tan, L and Su, L and Tong, Y and Zhao, Z and Chen, H and Fu, M and Guo, Z and Zuo, X and Yu, J and Zhong, W and Zeng, J and Liu, F and Chai, C and Guan, X and Wang, Z and Liu, T and Liang, J and Zhang, Y and Shi, H and Wen, Z and Xia, H and Zhang, R},
title = {Single cell RNA-sequencing analysis reveals that N-acetylcysteine partially reverses hepatic immune dysfunction in biliary atresia.},
journal = {JHEP reports : innovation in hepatology},
volume = {5},
number = {11},
pages = {100908},
pmid = {37869073},
issn = {2589-5559},
abstract = {BACKGROUND &amp; AIMS: Our previous study indicated that CD177[+] neutrophil activation has a vital role in the pathogenesis of biliary atresia (BA), which is partially ameliorated by N-acetylcysteine (NAC) treatment. Here, we evaluated the clinical efficacy of NAC treatment and profiled liver-resident immune cells via single cell RNA-sequencing (scRNA-seq) analysis to provide a comprehensive immune landscape of NAC-derived immune regulation.<br><br>METHODS: A pilot clinical study was conducted to evaluate the potential effects of intravenous NAC treatment on infants with BA, and a 3-month follow-up was carried out to assess treatment efficacy. scRNA-seq analysis of liver CD45[+] immune cells in the control (n&#xa0;= 4), BA (n&#xa0;= 6), and BA&#xa0;+ NAC (n&#xa0;= 6) groups was performed and the effects on innate cells, including neutrophil and monocyte-macrophage subsets, and lymphoid cells were evaluated.<br><br>RESULTS: Intravenous NAC treatment demonstrated beneficial efficacy for infants with BA by improving bilirubin metabolism and bile acid flow. Two hepatic neutrophil subsets of innate cells were identified by scRNA-seq analysis. NAC treatment suppressed oxidative phosphorylation and reactive oxygen species production in immature neutrophils, which were transcriptionally and functionally similar to CD177[+] neutrophils. We also observed the suppression of hepatic monocyte-mediated inflammation, decreased levels of oxidative phosphorylation, and M1 polarisation in Kupffer-like macrophages by NAC. In lymphoid cells, enhancement of humoral immune responses and attenuation of cellular immune responses were observed after NAC treatment. Moreover, cell-cell interaction analysis showed that innate/adaptive proinflammatory responses were downregulated by NAC.<br><br>CONCLUSIONS: Our clinical and scRNA-seq data demonstrated that intravenous NAC treatment partially reversed liver immune dysfunction, alleviated the proinflammatory responses in BA by targeting innate cells, and exhibited beneficial clinical efficacy.<br><br>IMPACT AND IMPLICATIONS: BA is a serious liver disease that affects newborns and has no effective drug treatment. In this study, scRNA-seq showed that NAC treatment can partially reverse the immune dysfunction of neutrophil extracellular trap-releasing CD177+ neutrophils and Kupffer cells, and lower the inflammatory responses of other innate immune cells in BA. In consequence, intravenous NAC treatment improved the clinical outcomes of patients with BA in term of bilirubin metabolism.},
}
@article {pmid37865270,
year = {2023},
author = {Lefèvre, CR and Le Divenah, F and Collet, N and Pelletier, R and Robert, E and Ropert, M and Pawlowski, M and Gicquel, T and Bendavid, C},
title = {Avoiding falsely low creatinine concentrations measured in patients treated with N-acetylcysteine for acetaminophen intoxication using enzymo-amperometric method - An in vitro and in vivo study.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {551},
number = {},
pages = {117611},
doi = {10.1016/j.cca.2023.117611},
pmid = {37865270},
issn = {1873-3492},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Acetaminophen ; Creatinine ; Retrospective Studies ; Peroxidase ; Peroxidases ; },
abstract = {BACKGROUND: Circulating creatinine is a biomarker of paramount importance in clinical practice. In cases of acetaminophen (APAP) intoxication, the antidote, N-acetylcysteine (NAC), interferes with commonly used creatininase-peroxidase methods. This study aimed to assess whether creatininase-amperometric methods were affected in this context.<br><br>METHODS: This study includes in vitro interference tests, involving four creatinine assays using NAC-spiked plasma pools and an in vivo retrospective study comparing creatininase-peroxidase and creatininase-amperometric measurements in patients presenting with NAC-treated APAP poisoning.<br><br>RESULTS: Creatininase-peroxidase method was impacted by NAC interference in a clinically-significant manner at therapeutic NAC levels (basal value recovery of 80&#xa0;% and 70&#xa0;% for 500 and 1000&#xa0;mg.L[-1] of NAC, respectively), surpassing the desirable Reference Change Value (RCV%). Enzymo-amperometric methods were not impacted. Among patients, a mean bias of -45.2&#xa0;&#xb1;&#xa0;28.0&#xa0;% was observed for the peroxidase detection method compared to the amperometric in those who received NAC prior plasma sampling and -2.7&#xa0;&#xb1;&#xa0;5.4&#xa0;% in those who did not.<br><br>CONCLUSIONS: Our findings indicate that enzymo-amperometric creatinine assays remain unaffected by NAC interference due to the absence of the peroxidase step in the analytical process. Therefore, these methods are suitable to prevent spurious hypocreatininemia in APAP intoxicated patients undergoing NAC therapy.},
}
@article {pmid37864839,
year = {2024},
author = {Chao, SP and Cheng, WL and Yi, W and Cai, HH and Deng, K and Cao, JL and Zeng, Z and Wang, H and Wu, X},
title = {N-Acetylcysteine Alleviates Phenylephrine-Induced Cardiomyocyte Dysfunction via Engaging PI3K/AKT Signaling Pathway.},
journal = {American journal of hypertension},
volume = {37},
number = {3},
pages = {230-238},
doi = {10.1093/ajh/hpad100},
pmid = {37864839},
issn = {1941-7225},
support = {HHYC2019003//yellow crane of excellence program/ ; ZNXKPY2021011//Zhongnan disciplinary platform/ ; },
mesh = {Rats ; Animals ; *Phosphatidylinositol 3-Kinase/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Myocytes, Cardiac/metabolism ; Reactive Oxygen Species/metabolism ; Antioxidants/pharmacology ; Phenylephrine/pharmacology ; Signal Transduction ; Oxidative Stress ; Apoptosis ; },
abstract = {BACKGROUND: Increased reactive oxygen species (ROS) and oxidative stress response lead to cardiomyocyte hypertrophy and apoptosis, which play crucial roles in the pathogenesis of heart failure. The purpose of current research was to explore the role of antioxidant N-acetylcysteine (NAC) on cardiomyocyte dysfunction and the underlying molecular mechanisms.<br><br>METHODS AND RESULTS: Compared with control group without NAC treatment, NAC dramatically inhibited the cell size of primary cultured neonatal rat cardiomyocytes (NRCMs) tested by immunofluorescence staining and reduced the expression of representative markers associated with hypertrophic, fibrosis and apoptosis subjected to phenylephrine administration examined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Moreover, enhanced ROS expression was attenuated, whereas activities of makers related to oxidative stress response examined by individual assay Kits, including total antioxidation capacity (T-AOC), glutathione peroxidase (GSH-Px), and primary antioxidant enzyme Superoxide dismutase (SOD) were induced by NAC treatment in NRCMs previously treated with phenylephrine. Mechanistically, we noticed that the protein expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) and AKT were increased by NAC stimulation. More importantly, we identified that the negative regulation of NAC in cardiomyocyte dysfunction was contributed by PI3K/AKT signaling pathway through further utilization of PI3K/AKT inhibitor (LY294002) or agonist (SC79).<br><br>CONCLUSIONS: Collected, NAC could attenuate cardiomyocyte dysfunction subjected to phenylephrine, partially by regulating the ROS-induced PI3K/AKT-dependent signaling pathway.},
}
@article {pmid37860953,
year = {2024},
author = {Dos Santos, AC and França, TCS and Venzon, L and Polli, V and Polleti, G and Trembulak, E and Pilati, SFM and da Silva, LM},
title = {Are silymarin and N-acetylcysteine able to prevent liver damage mediated by multiple factors? Findings against ethanol plus LPS-induced liver injury in mice.},
journal = {Journal of biochemical and molecular toxicology},
volume = {38},
number = {1},
pages = {e23560},
doi = {10.1002/jbt.23560},
pmid = {37860953},
issn = {1099-0461},
mesh = {Mice ; Animals ; Acetylcysteine/pharmacology ; *Silymarin/pharmacology ; Lipopolysaccharides/toxicity ; Interleukin-10 ; Ethanol/toxicity ; *Chemical and Drug Induced Liver Injury, Chronic/pathology ; Interleukin-6/pharmacology ; Liver/pathology ; Antioxidants/pharmacology ; Glutathione ; Transaminases/pharmacology ; },
abstract = {This study investigated the effect of N-acetylcysteine (NAC) and silymarin (SIL) in the liver of mice exposed to ethanol and lipopolysaccharides (LPS). Mice were divided into four groups (n = 6): naive, vehicle, NAC (200 mg/kg), and SIL (200 mg/kg). Treatments were given orally (po) once daily for 10 days. Liver injury was induced by administration of ethanol (30%, po) for 10 days, once daily, followed by a single administration of LPS (2 mg/kg, ip) 24 h before euthanasia. After the treatment period, animals were euthanized, and liver and blood samples were collected. NAC, but not SIL, prevented the increase in oxalacetic glutamic transaminase (OGT) and pyruvic glutamic transaminase (PGT) serum levels. NAC and SIL did not restore levels of reduced glutathione or hepatic malonaldehyde. The treatments with NAC or SIL showed no difference in the activity of glutathione S-transferase, superoxide dismutase, and catalase compared to vehicle group. Myeloperoxidase and N-acetylglucosaminidase activities are increased, as well as the IL-6 and IL-10 levels in the liver. The treatment with NAC, but not SIL, reduced the N-acetylglucosamines activity and the IL-6 and IL-10 amount in the liver. Histological findings revealed microsteatosis in the vehicle group, which was not prevented by SIL but was partially reduced in animals receiving NAC. Unlike other liver injury models, NAC (200 mg/kg) or SIL (200 mg/kg) did not positively affect antioxidant patterns in liver tissue of animals exposed to ethanol plus LPS, but NAC treatment displays anti-inflammatory properties in this model.},
}
@article {pmid37859626,
year = {2023},
author = {Wang, J and Zhang, C and Zhao, R and Wang, P and Jin, M and Xu, J},
title = {Antioxidant N-acetylcysteine removing ROS: an antifouling strategy inspired by mussels.},
journal = {Environmental science. Processes &amp; impacts},
volume = {25},
number = {12},
pages = {1962-1973},
doi = {10.1039/d3em00191a},
pmid = {37859626},
issn = {2050-7895},
mesh = {Animals ; *Biofouling/prevention &amp; control ; Antioxidants ; Acetylcysteine/pharmacology ; Reactive Oxygen Species ; Ecosystem ; *Bivalvia ; Dihydroxyphenylalanine ; },
abstract = {Marine biofouling is a thorny issue that causes serious economic losses and adverse ecological impacts on marine ecosystems. Effective and promising antifouling strategies such as surface hydration, flow shear force, and lubricant injection have been developed to address this challenge. However, for the complex marine environment, they still appear inadequate. Mussels are a common fouling organism with strong surface adhesion ability. However, when hypoxia and the oxidative cross-linking reaction of 3,4-dihydroxy phenyl-L-alanine (DOPA) in the structure of adhesion proteins are disrupted, their adhesion ability will be greatly reduced. Inspired by this, we developed an effective antifouling strategy based on reactive oxygen species (ROS) scavenging using N-acetylcysteine (NAC) and evaluated its performance. As a ROS scavenger interfered with the oxidative cross-linking reaction of DOPA in an aqueous solution, the adhesion of DOPA was also affected on the surface of NAC functionalized polyvinyl chloride (PVC) (PVC-NAC). In addition, the colonization level of mussels and the adhesion rate of marine bacteria and benthic diatoms on PVC-NAC were low. The antifouling strategy proposed in this paper was eco-friendly and broad-spectrum, and may provide a new idea for solving marine biofouling and reducing the environmental and economic impacts of fouling organisms.},
}
@article {pmid37858742,
year = {2023},
author = {Tüfekci, KK and Tatar, M and Terzi, F and Bakirhan, EG},
title = {An investigation of the endoplasmic reticulum stress in obesity exposure in the prenatal period.},
journal = {Journal of chemical neuroanatomy},
volume = {134},
number = {},
pages = {102348},
doi = {10.1016/j.jchemneu.2023.102348},
pmid = {37858742},
issn = {1873-6300},
mesh = {Humans ; Rats ; Female ; Animals ; Pregnancy ; Infant ; *Acetylcysteine ; *Endoplasmic Reticulum Stress ; Obesity ; Endoplasmic Reticulum Chaperone BiP ; Hippocampus/metabolism ; },
abstract = {OBJECTIVES: Exposure to maternal obesity has been shown to make offspring more prone to cognitive and metabolic disorders later in life. Although the underlying mechanisms are unclear, the role of endoplasmic reticulum (ER) stress in the fetal programming process is remarkable. ER stress can be activated by many chronic diseases, including obesity and diabetes. Therefore, our study aimed to investigate the role of ER stress caused by maternal diet-induced obesity in the offspring hippocampus. We also evaluated the protective effect of N-acetylcysteine (NAC) against ER stress.<br><br>METHODS: A rat obesity model was created by providing a high-fat (60 % kcal) diet. N-acetylcysteine (NAC) was administered at a dosage of 150&#xa0;mg/kg via the intragastric route. The animals were mated at the age of 12 weeks. The same diet was maintained during pregnancy and lactation. The experiment was terminated on the postnatal 28th day, and the offspring's brain tissues were examined. Immunohistochemical staining for ER stress markers was performed on sections taken from tissues after routine histological procedures.<br><br>RESULTS: The results revealed increased GRP78, PERK, and eIF2&#x3b1; immunoreactivities in the hippocampal dentate gyrus (DG) and cornu ammonis 1 (CA1) regions in the obese group offspring, while the expression of those markers in those regions normalized with NAC supplementation (p&#xa0;<&#xa0;0.01). Statistical analysis of XBP1 immunoreactivity H-scores revealed no difference between the study groups (p&#xa0;>&#xa0;0.05).<br><br>DISCUSSION: These results suggest that exposure to obesity during the prenatal period may cause increased ER stress in hippocampal neurons, which have an important role in the regulation of learning, memory and behavior, and this may contribute to decreased cognitive performance. On the other hand, NAC stands out as an effective agent that can counteract hippocampal ER stress.},
}
@article {pmid37858609,
year = {2024},
author = {Roy, P and Kandel, R and Sawant, N and Singh, KP},
title = {Estrogen-induced reactive oxygen species, through epigenetic reprogramming, causes increased growth in breast cancer cells.},
journal = {Molecular and cellular endocrinology},
volume = {579},
number = {},
pages = {112092},
doi = {10.1016/j.mce.2023.112092},
pmid = {37858609},
issn = {1872-8057},
mesh = {Humans ; Female ; Reactive Oxygen Species/metabolism ; *Breast Neoplasms/genetics/metabolism ; Estrogens/pharmacology ; Estradiol/pharmacology ; Epigenesis, Genetic ; },
abstract = {Despite the progress made in cancer diagnosis and treatment, breast cancer remains the second leading cause of cancer-related death among the women. Exposure to elevated levels of endogenous estrogen or environmental estrogenic chemicals is an important risk factor for breast cancer. Estrogen metabolites and ROS generated during estrogen metabolism are known to play a critical role in estrogen carcinogenesis. However, the molecular mechanisms through which estrogen-induced ROS regulate gene expression is not clear. Epigenetic changes of DNA methylation and histone modifications are known to regulate genes expression. Therefore, the objective of this study was to evaluate whether estrogen-induced ROS, through aberrant expression of epigenetic regulatory genes and epigenetic reprogramming, causes growth of breast cancer cells. Estrogen responsive MCF-7 and T47D human breast cancer cells were exposed to natural estrogen 17 beta-estradiol (E2) and synthetic estrogen Diethylstilbestrol (DES) both alone and in combination with antioxidant N-acetyl cysteine. Effects of NAC-mediated scavenging of estrogen-induced ROS on cell growth, gene expression, and histone modifications were measured. The result of MTT and cell cycle analysis revealed significant abrogation of E2 and DES-induced growth by scavenging ROS through NAC. E2 and DES caused significant changes in expression of epigenetic regulatory genes for DNA methylation and histone modifications as well as changes in both gene activating and repressive marks in the Histone H3. NAC restored the expression of epigenetic regulatory genes and changes in histone marks. Novel findings of this study suggest that estrogen can induce growth of breast cancer cells through ROS-dependent regulation of epigenetic regulatory genes and epigenetic reprogramming of histone marks.},
}
@article {pmid37853974,
year = {2023},
author = {Nalbant, K and Erden, S},
title = {Possible effects of N-acetylcysteine in autism spectrum disorders: major clinical aspects, eating behaviors, and sleeping habits.},
journal = {The Turkish journal of pediatrics},
volume = {65},
number = {5},
pages = {832-844},
doi = {10.24953/turkjped.2022.573},
pmid = {37853974},
issn = {2791-6421},
mesh = {Child, Preschool ; Humans ; Child ; *Autism Spectrum Disorder/drug therapy ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Sleep ; Feeding Behavior ; },
abstract = {BACKGROUND: N-acetylcysteine (NAC) is a promising agent for reducing irritability and hyperactivity and enhancing social responsiveness in children with autism spectrum disorders (ASD). This study aims to examine the effects of NAC on cardinal symptoms, eating, and sleeping habits in preschool children with autism.<br><br>METHODS: The medical records of ASD patients were investigated retrospectively. 37 children with ASD who regularly received oral NAC in two divided doses per day (400-600 mg/day) for 8 weeks were included as the study group. The control group consisted of 21 children with ASD who were recommended NAC but never used it. The initial and second assessment scores after 8 weeks of regular use of the NAC group and control group on the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Children Eating Behavior Questionnaire (CEBQ), and the Sleep Habits Questionnaire (CSHQ) were compared.<br><br>RESULTS: Our findings suggested that oral NAC alleviated the intensity of cardinal autistic symptoms in areas of social withdrawal, interpersonal relationships, body use, listening response, and verbal communication. Corresponding problem behaviors such as irritability, stereotypic behavior, and hyperactivity were reduced. It was determined that there was no difference between the two groups in terms of eating behaviors and sleeping habits.<br><br>CONCLUSIONS: According to the results, NAC alleviated the severity of cardinal symptoms and reduced problem behaviors in autism. Additional trials with more systematic planning, controlling for confounding effects, and long-term follow-up should be provided in future studies.},
}
@article {pmid37852631,
year = {2023},
author = {Fond, G and Mallet, J and Urbach, M and Benros, ME and Berk, M and Billeci, M and Boyer, L and Correll, CU and Fornaro, M and Kulkarni, J and Leboyer, M and Llorca, PM and Misdrahi, D and Rey, R and Schürhoff, F and Solmi, M and Sommer, IEC and Stahl, SM and Pignon, B and Berna, F},
title = {Adjunctive agents to antipsychotics in schizophrenia: a systematic umbrella review and recommendations for amino acids, hormonal therapies and anti-inflammatory drugs.},
journal = {BMJ mental health},
volume = {26},
number = {1},
pages = {},
pmid = {37852631},
issn = {2755-9734},
mesh = {Humans ; Acetylcysteine/therapeutic use ; Amino Acids/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; *Antipsychotic Agents/therapeutic use ; *Schizophrenia/drug therapy ; Meta-Analysis as Topic ; Randomized Controlled Trials as Topic ; },
abstract = {QUESTION: This umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia.<br><br>STUDY SELECTION AND ANALYSIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and World Federation of Societies of Biological Psychiatry (WFSBP)-grading recommendations, 63 randomised control trials (RCTs) (of which 4219 unique participants have completed the RCTs) and 29 meta-analyses were analysed.<br><br>FINDINGS: Provisional recommendations (WFSBP-grade 1) could be made for two molecules in augmentation to antipsychotics: (1) N-acetyl-cysteine (NAC, 1200-3600&#x2009;mg/day, for >12 consecutive weeks) in improving negative symptoms, general psychopathology (positive and negative syndrome scale for schizophrenia (PANSS) general psychopathology factor (G)-G subscale), with the RCTs with the longer duration showing the most robust findings; (2) polyunsaturated fatty acids (3000&#x2009;mg/day of eicosapentaenoic acid, for >12 weeks) in improving general psychopathology. Weaker recommendations (ie, WFSBP-grade 2) could be drawn for sarcosine (2&#x2009;g/day) and minocycline (200-300&#x2009;mg/day) for improving negative symptoms in chronic schizophrenia (not early schizophrenia), and NAC for improving positive symptoms and cognition. Weak recommendations are not ready for clinical practice. There is provisional evidence that oestrogens and raloxifene are effective in some patients, but further research is needed to determine their benefit/risk ratio.<br><br>CONCLUSIONS: The results of this umbrella review should be interpreted with caution as the number of RCTs included in the meta-analyses was generally small and the effect sizes were weak or medium. For NAC, two RCTs with low risk of bias have provided conflicting results and the WFSBP-grade recommendation included also the results of meta-analyses. These drugs could be provisionally prescribed for patients for whom no other treatments have been effective, but they should be discontinued if they prove ineffective.},
}
@article {pmid37851785,
year = {2023},
author = {Brasil, VP and Siqueira, RM and Campos, FG and Yoshitani, MM and Pereira, GP and Mendonça, RLDS and Kanno, DT and Pereira, JA and Martinez, CAR},
title = {Mucin levels in glands of the colonic mucosa of rats with diversion colitis subjected to enemas containing sucralfate and n-acetylcysteine alone or in combination.},
journal = {Acta cirurgica brasileira},
volume = {38},
number = {},
pages = {e384023},
pmid = {37851785},
issn = {1678-2674},
mesh = {Rats ; Animals ; *Sucralfate/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Rats, Wistar ; Colon ; *Colitis/drug therapy/prevention &amp; control ; Mucins ; Sialomucins ; Intestinal Mucosa ; Enema/methods ; },
abstract = {PURPOSE: To evaluate the tissue content of neutral and acidic mucins, sulfomucins and sialomucins in colonic glands devoid of intestinal transit after enemas containing sucralfate and n-acetylcysteine alone or in combination.<br><br>METHODS: Sixty-four rats underwent intestinal transit bypass. A colonic segment was collected to compose the white group (without intervention). After derivation, the animals were divided into two groups according to whether enemas were performed daily for two or four weeks. Each group was subdivided into four subgroups according to the substance used: control group: saline 0.9%; sucralfate group (SCF): SCF 2 g/kg/day; n-acetylcysteine group (NAC): NAC 100 mg/kg/day; and SCF+NAC group: SCF 2 g/kg/day + NAC 100 mg/kg/day.Neutral and acidic mucins were stained by periodic acid-Schiff and alcian-blue techniques, respectively. The distinction between sulfomucins and sialomucin was made by the high alcian-blue iron diamine technique. The content of mucins in the colonic glands was measured by computerized morphometry. The inflammatory score was assessed using a validated scale. The results between the groups were compared by the Mann-Whitney's test, while the variation according to time by the Kruskal-Wallis' test (Dunn's post-test). A significance level of 5% was adopted.<br><br>RESULTS: There was reduction in the inflammatory score regardless of the application of isolated or associated substances. Intervention with SCF+NAC increased the content of all mucin subtypes regardless of intervention time.<br><br>CONCLUSIONS: The application of SCF+NAC reduced the inflammatory process of the colonic mucosa and increased the content of different types of mucins in the colonic glands of segments excluded from fecal transit.},
}
@article {pmid37848768,
year = {2024},
author = {Nabi, Z and Vamsi, M and Goud, R and Sayyed, M and Basha, J and Reddy, PM and Reddy, R and Reddy, P and Manchu, C and Darisetty, S and Gupta, R and Tandan, M and Rao, GV and Reddy, DN},
title = {Pre-medication with simethicone and N-acetyl cysteine for improving mucosal visibility during upper gastrointestinal endoscopy: A randomized controlled trial.},
journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology},
volume = {43},
number = {5},
pages = {986-994},
pmid = {37848768},
issn = {0975-0711},
mesh = {Humans ; *Simethicone/administration &amp; dosage ; Male ; Female ; *Acetylcysteine/administration &amp; dosage ; Adult ; Double-Blind Method ; *Premedication/methods ; Middle Aged ; Endoscopy, Digestive System/methods ; Endoscopy, Gastrointestinal/methods ; },
abstract = {BACKGROUND AND AIM: Diagnostic performance of esophagogastroduodenoscopy (EGD) may be compromized due to adherent mucus and foam. In this study, we aimed at assessing the impact of premedication on mucosal visibility during endoscopy.<br><br>METHODS: This is a double-blinded (patient and investigator), randomized trial conducted at a tertiary care centre. Patients were randomized into four groups: A (water), B (simethicone [S]), C (N-acetyl cysteine [NAC]), D (S&#x2009;+&#x2009;NAC). Premedication solutions were administered 10-30&#xa0;minutes before endoscopy and mucosal visibility graded from 1&#xa0;(best) to 4&#xa0;(worst) (1 best, 4 worst). Total mucosal visibility scores (TMVS) from six sites ranged from 6 (best) to 24 (worst) points. The primary outcome of study was comparison of TMVS between simethicone and combination (S&#x2009;+&#x2009;NAC) premedication groups. Secondary outcomes were adverse events and impact of endoscopy timing on TMVS.<br><br>RESULTS: Total 800 patients (39&#xa0;years, 68.8% males) were randomized into four groups. Median TMVS were significantly lower in groups B (7 [6-8]) and D (8 [6-9]) as compared to A (11 [9-13]) and C (10 [8-12]). Proportion of cases with adequate gastric mucosal visibility (score&#x2009;<&#x2009;7) was 26% in group A, 71% in group B, 36% in group C and 79% in group D. There was no difference in TMVS in groups A and C (p&#x2009;=&#x2009;0.137). TMVS were significantly lower in late (>&#x2009;20-30&#xa0;minutes) vs. early (10-20&#xa0;minutes) endoscopy sub-group (8 [7-11] vs, 9 ([7-11], p&#x2009;=&#x2009;0.001). However, TMVS were similar between group B and group D in early endoscopy group (p&#x2009;=&#x2009;0.451). There was no significant difference in the lesion detection rate among the different premedication drugs (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSIONS: Premedication with simethicone or combination (simethicone and NAC) significantly improves mucosal visibility during EGD. If early endoscopy is indicated, simethicone provides similar mucosal visibility and may be an effective alternative to combined premedication.<br><br>TRIAL REGISTRATION: NCT05951712.},
}
@article {pmid37845590,
year = {2024},
author = {Dai, Y and Sang, XB and Bai, WP},
title = {N-acetylcysteine and Hydroxychloroquine Ameliorate ADMA-Induced Fetal Growth Restriction in Mice via Regulating Oxidative Stress and Autophagy.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {31},
number = {3},
pages = {779-790},
pmid = {37845590},
issn = {1933-7205},
support = {2021-q03//Youth Fund of Beijing Shijitan Hospital/ ; },
mesh = {Humans ; Pregnancy ; Mice ; Female ; Animals ; *Placenta/metabolism ; *Acetylcysteine/pharmacology/therapeutic use/metabolism ; Fetal Growth Retardation/chemically induced/drug therapy/metabolism ; Hydroxychloroquine/pharmacology/therapeutic use/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Oxidative Stress ; TOR Serine-Threonine Kinases/metabolism ; Autophagy ; Arginine/*analogs &amp; derivatives ; },
abstract = {Fetal growth restriction (FGR) seriously threatens perinatal health. The main cause of FGR is placental malperfusion, but the specific mechanism is still unclear, and there is no effective treatment for FGR. We constructed a FGR mouse model by adding exogenous asymmetric dimethylarginine (ADMA) through in vivo experiments and found that ADMA could cause placental dysplasia and induce the occurrence of FGR. Compared with the control group, reactive oxygen species (ROS) production in the placenta was increased in mice with FGR, and the expression of autophagy-related proteins p-AKT/AKT, p-mTOR/mTOR, and P62 was significantly decreased, while the expression of Beclin-1 and LC3-II was significantly increased in the FGR group. Furthermore, ADMA had a favorable effect in promoting the formation of autophagosomes. Hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) improved ADMA-induced disorders of placental development and alleviated ADMA-induced FGR. This study found that ADMA could cause excessive autophagy of trophoblasts by increasing the level of oxidative stress, ultimately leading to the occurrence of FGR, and HCQ and NAC had therapeutic effects on ADMA-induced FGR.},
}
@article {pmid37841396,
year = {2023},
author = {Liu, J and Su, H and Jin, X and Wang, L and Huang, J},
title = {The effects of N-acetylcysteine supplement on metabolic parameters in women with polycystic ovary syndrome: a systematic review and meta-analysis.},
journal = {Frontiers in nutrition},
volume = {10},
number = {},
pages = {1209614},
pmid = {37841396},
issn = {2296-861X},
abstract = {OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common endocrine disease, often accompanied by metabolic disorders. Metformin, as an insulin sensitizer, is widely used to improve the metabolic function of PCOS, but may have gastrointestinal side effects. Emerging evidence suggests that N-acetylcysteine (NAC) improves metabolic parameters in PCOS and may be a potential alternative to metformin.<br><br>METHODS: We searched four online databases, PubMed, Embase, Web of Science, and Cochrane Library, from inception to April 1, 2023. The I[2] statistic and Cochrane's Q test were employed to determine heterogeneity between studies, with an I[2] value >50% or p&#x2009;<&#x2009;0.1 considered significant. The data were expressed as standardized mean differences and corresponding 95% confidence intervals.<br><br>RESULTS: A total of 11 randomized controlled trials were included in the final analysis, including 869 women with PCOS. The results showed that NAC caused more changes in body mass index (SMD: -0.16, 95% CI: -0.40 to 0.08), body weight (SMD: -0.25, 95% CI: -0.50 to 0.00), fasting insulin (SMD: -0.24, 95% CI: -0.53 to 0.06), ratio of fasting blood glucose to fasting insulin (SMD: 0.38, 95% CI: -0.33 to 1.08), total cholesterol (SMD: -0.11, 95% CI: -0.39 to 0.17), triglycerides (SMD: -0.18, 95% CI: -0.63 to 0.28), and low-density lipoprotein (SMD: -0.09, 95% CI: -0.51 to 0.33) compared with metformin. Compared with metformin or placebo, NAC significantly reduced fasting blood-glucose levels (SMD: -0.23, 95% CI: -0.43 to -0.04; SMD: -0.54, 95% CI: -1.03 to -0.05, respectively). In addition, NAC significantly reduced total cholesterol (SMD: -0.74, 95% CI: -1.37 to -0.12), and this effect was observed when NAC was compared with placebo. However, NAC reduced HDL levels in women with PCOS compared with metformin (SMD: -0.14, 95% CI: -0.42 to 0.14).<br><br>CONCLUSION: This study suggests that NAC is effective in improving metabolic parameters in PCOS and may be a promising nutritional supplement for the treatment of PCOS.Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=415172, identifier CRD42022339171.},
}
@article {pmid37839787,
year = {2023},
author = {Zhu, S and Wu, H and Cui, H and Guo, H and Ouyang, Y and Ren, Z and Deng, Y and Geng, Y and Ouyang, P and Wu, A and Deng, J and Deng, H},
title = {Induction of mitophagy via ROS-dependent pathway protects copper-induced hypothalamic nerve cell injury.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {181},
number = {},
pages = {114097},
doi = {10.1016/j.fct.2023.114097},
pmid = {37839787},
issn = {1873-6351},
mesh = {Male ; Mice ; Animals ; *Mitophagy ; Copper/toxicity ; Reactive Oxygen Species/metabolism ; *Mitochondrial Diseases ; Neurons/metabolism ; Quinazolinones ; },
abstract = {Copper (Cu) is one of the essential trace elements in the body, but excessive amounts of Cu harm multiple organs and tissues such as liver, kidneys, testis, ovaries, and brain. However, the mechanism of hypothalamic neurotoxicity induced by Cu is still unknown. This study examined the relationship between reactive oxygen species (ROS) and mitophagy in mouse hypothalamus treated with high Cu. The results demonstrated that high levels of copper sulfate (CuSO4) could cause histopathological and neuronal changes in the mouse hypothalamus, produce a large amount of ROS, induce mitophagy, and lead to an imbalance of mitochondrial fusion/fission. The main manifestations are an increase in the expression levels of LC3-II/LC3-I, p62, DRP1, and FIS1, and a decrease in the expression levels of MFN1 and MFN2. Cu can induce mitophagy also was confirmed by LC3 co-localization with TOMM20 (mitochondrial marker). Next, the effect of oxidative stress on CuSO4-induced mitophagy was demonstrated. The results showed that ROS inhibitor N-acetylcysteine (NAC) diminished CuSO4-induced mitophagy and reversed the disturbance of mitochondrial dynamics. Additionally, a study was carried out to evaluate the role of mitophagy in CuSO4-induced hypothalamic injury. The inhibition of mitophagy using mitophagy inhibitor (Mdivi-1) decreased cell viability and promoted CuSO4-inhibited mitochondrial fusion. The aforementioned results suggested that CuSO4 induced mitophagy via oxidative stress in N38 cells and mouse hypothalamus, and that the activation of mitophagy might generate protective mechanisms by alleviating Cu-induced mitochondrial dynamics disorder. This study provided a novel approach and theoretical basis for studying and preventing Cu neurotoxicity.},
}
@article {pmid37836642,
year = {2023},
author = {Samide, A and Dobriţescu, A and Tigae, C and Spînu, CI and Oprea, B},
title = {Experimental and Computational Study on Inhibitory Effect and Adsorption Properties of N-Acetylcysteine Amino Acid in Acid Environment.},
journal = {Molecules (Basel, Switzerland)},
volume = {28},
number = {19},
pages = {},
pmid = {37836642},
issn = {1420-3049},
abstract = {Potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) were applied to study the inhibitory effect of N-acetylcysteine (NAC) on corrosion inhibition of carbon steel in hydrochloric acid solution. N-acetylcysteine influenced the iron dissolution to a greater extent than the hydrogen evolution reaction acting as a mixed inhibitor, predominantly anodic. The charge transfer resistance (Rct) gradually increased with the inhibitor concentration. From both methods, the inhibition efficiency (IE) reached a value of 89 ± 1% and NAC adsorption followed the Temkin isotherm. The value of adsorption Gibbs energy (ΔGadso), around -35 kJ mol[-1], indicated a spontaneous adsorption and mixed action mechanism, with NAC chemical adsorption prevailing over physical one. New data will be reported by the computational study, that was performed using the density functional theory (DFT) method in aqueous phase. Quantum chemical descriptors were determined by B3LYP theory level with 6-31G+(d) basis set. Metropolis Monte Carlo atomistic simulation was used to reveal the adsorption configuration and interactions between acetylcysteine molecules and the carbon steel surface. Theoretical results were consistent with the experimental data, showing that the inhibitor action mechanism consisted of mainly chemisorption of its molecules on the carbon steel surface accompanied by van der Waals forces and electrostatic interactions.},
}
@article {pmid37836605,
year = {2023},
author = {Doroudian, M and Thibault, ME and Gailer, J},
title = {N-Acetylcysteine Displaces Glutathionyl-Moieties from Hg[2+] and MeHg[+] to Form More Hydrophobic Complexes at Near-Physiological Conditions.},
journal = {Molecules (Basel, Switzerland)},
volume = {28},
number = {19},
pages = {},
pmid = {37836605},
issn = {1420-3049},
mesh = {Animals ; Humans ; Acetylcysteine ; *Methylmercury Compounds/chemistry ; *Mercury/analysis ; Glutathione/analysis ; Sulfhydryl Compounds ; Mammals ; },
abstract = {The anthropogenic release of Hg is associated with an increased human exposure risk. Since Hg[2+] and MeHg[+] have a high affinity for thiols, their interaction with L-glutathione (GSH) within mammalian cells is fundamentally involved in their toxicological chemistry and excretion. To gain insight into the interaction of these mercurials with multiple small molecular weight thiols, we have investigated their competitive interactions with GSH and N-acetylcysteine (NAC) at near-physiological conditions, using a liquid chromatographic approach. This approach involved the injection of each mercurial onto a reversed-phase (RP)-HPLC column (37 °C) using a PBS buffer mobile phase containing 5.0 mM GSH to simulate cytosolic conditions with Hg being detected in the column effluent by an inductively coupled plasma atomic emission spectrometer (ICP-AES). When the 5.0 mM GSH mobile phase was amended with up to 10 mM NAC, gradually increasing retention times of both mercurials were observed. To explain this behavior, the experiment with 5.0 mM NAC and 5.0 mM GSH was replicated using 50 mM Tris buffer (pH 7.4), and the Hg-containing fractions were analyzed by electrospray ionization mass spectrometry. The results revealed the presence of Hg(GS)(NAC) and Hg(NAC)2 for Hg[2+] and MeHg(GS) and MeHg(NAC) for MeHg[+], which suggests that the coordination/displacement of GS-moieties from each mercurial by the more hydrophobic NAC can explain their retention behavior. Since the biotransformations of both mercurials were observed at near-physiological conditions, they are of toxicological relevance as they provide a biomolecular explanation for some results that were obtained when animals were administered with each mercurial and NAC.},
}
@article {pmid37835464,
year = {2023},
author = {Bryan, A and Pingali, P and Joslyn, M and Li, H and Bernas, T and Koblinski, J and Landry, J and Lee, WS and Patel, B and Neuwelt, A},
title = {High-Dose Acetaminophen with N-acetylcysteine Rescue Inhibits M2 Polarization of Tumor-Associated Macrophages.},
journal = {Cancers},
volume = {15},
number = {19},
pages = {},
pmid = {37835464},
issn = {2072-6694},
support = {IK2 BX004914/BX/BLRD VA/United States ; P30 CA016059/CA/NCI NIH HHS/United States ; },
abstract = {High-dose acetaminophen (AAP) with N-acetylcysteine (NAC) rescue is among the few treatments that has shown activity in phase I trials without achieving dose-limiting toxicity that has not progressed to evaluation in later line studies. While the anti-tumor effects of AAP/NAC appear not to be mediated by glutathione depletion and free radical injury, the mechanism of anti-tumor effects of AAP/NAC has not been definitively characterized. In vitro, the effects of AAP/NAC were evaluated on bone marrow derived macrophages. Effects of AAP on IL-4/STAT6 (M2) or IFN/LPS/STAT1 (M1) signaling and downstream gene and protein expression were studied. NAC reversed the AAP toxicity in the normal liver but did not reverse AAP cytotoxicity against tumor cells in vitro. AAP/NAC selectively inhibited IL-4-induced STAT6 phosphorylation but not IFN/LPS-induced STAT1 phosphorylation. Downstream, AAP/NAC inhibited IL-4 induction of M2-associated genes and proteins but did not inhibit the IFN/LPS induction of M1-associated genes and proteins. In vivo, AAP/NAC inhibited tumor growth in EF43.fgf4 and 4T1 triple-negative breast tumors. Flow cytometry of tumor-associated macrophages revealed that AAP/NAC selectively inhibited M2 polarization. The anti-tumor activity of high-dose AAP/NAC is lost in macrophage-depleted mouse syngeneic tumor models, suggesting a macrophage-dependent mechanism of action. In conclusion, our study is the first to show that high-dose AAP/NAC has profound effects on the tumor immune microenvironment that facilitates immune-mediated inhibition of tumor growth.},
}
@article {pmid37834105,
year = {2023},
author = {Gan, P and Li, P and Zhang, X and Li, H and Ma, S and Zong, D and He, C},
title = {Comparative Transcriptomic and Metabolomic Analyses of Differences in Trunk Spiral Grain in Pinus yunnanensis.},
journal = {International journal of molecular sciences},
volume = {24},
number = {19},
pages = {},
pmid = {37834105},
issn = {1422-0067},
support = {YUWR-CYJS-2020-018//Yunnan Provincial "Ten-Thousand Program" for Leading Industry Innovation/ ; 202005AF150020//Applied Basic Research Programs of Yunnan Provincial Expert Workstation/ ; },
mesh = {*Transcriptome ; *Pinus/genetics ; Gene Expression Profiling ; Metabolomics ; Metabolome ; Edible Grain/genetics ; Deoxyuridine ; Gene Expression Regulation, Plant ; },
abstract = {Having a spiral grain is considered to be one of the most important wood properties influencing wood quality. Here, transcriptome profiles and metabolome data were analyzed in the straight grain and twist grain of Pinus yunnanensis. A total of 6644 differential expression genes were found between the straight type and the twist type. A total of 126 differentially accumulated metabolites were detected. There were 24 common differential pathways identified from the transcriptome and metabolome, and these pathways were mainly annotated in ABC transporters, arginine and proline metabolism, flavonoid biosynthesis, isoquinoline alkaloid biosynthesis, linoleic acid metabolism, phenylpropanoid, tryptophan metabolism, etc. A weighted gene coexpression network analysis showed that the lightblue4 module was significantly correlated with 2'-deoxyuridine and that transcription factors (basic leucine zipper (bZIP), homeodomain leucine zipper (HD-ZIP), basic helix-loop-helix (bHLH), p-coumarate 3-hydroxylase (C3H), and N-acetylcysteine (NAC)) play important roles in regulating 2'-deoxyuridine, which may be involved in the formation of spiral grains. Meanwhile, the signal transduction of hormones may be related to spiral grain, as previously reported. ARF7 and MKK4_5, as indoleacetic acid (IAA)- and ethylene (ET)-related receptors, may explain the contribution of plant hormones in spiral grain. This study provided useful information on spiral grain in P. yunnanensis by transcriptome and metabolome analyses and could lay the foundation for future molecular breeding.},
}
@article {pmid37827291,
year = {2023},
author = {Hu, TH and Wu, JC and Huang, ST and Chu, TH and Han, AJ and Shih, TW and Chang, YC and Yang, SM and Ko, CY and Lin, YW and Kung, ML and Tai, MH},
title = {HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria.},
journal = {The Journal of biological chemistry},
volume = {299},
number = {11},
pages = {105335},
pmid = {37827291},
issn = {1083-351X},
mesh = {Animals ; Mice ; *Carcinoma, Hepatocellular/genetics/pathology ; Reactive Oxygen Species ; Carcinogenesis/genetics ; Intercellular Signaling Peptides and Proteins ; },
abstract = {Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.},
}
@article {pmid37823177,
year = {2023},
author = {Haugsten Hansen, M and Sadredini, M and Hasic, A and Eriksen, M and Stokke, MK},
title = {Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs.},
journal = {Frontiers in cardiovascular medicine},
volume = {10},
number = {},
pages = {1223496},
pmid = {37823177},
issn = {2297-055X},
abstract = {BACKGROUND: Arrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious.<br><br>METHODS: MI was induced in 7 male and 7 female pigs (Norwegian landrace, 35-40&#x2005;kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery. Ischemia was maintained for 90&#x2005;min, before observation for 1&#x2005;h after reperfusion. Pigs were randomized 1:1 in an operator-blinded fashion to receive either i.v. N-acetylcysteine (NAC) from 70&#x2005;min of ischemia and onwards, or 0.9% NaCl as a control. Blood samples and tissue biopsies were collected at baseline, 60&#x2005;min of ischemia, and 5 and 60&#x2005;min of reperfusion. ECG and invasive blood pressure were monitored throughout.<br><br>RESULTS: The protocol was completed in 11 pigs. Oxidative stress, as indicated by immunoblotting for Malondialdehyde in myocardial biopsies, was increased at 5&#x2005;min of reperfusion compared to baseline, but not at 60&#x2005;min of reperfusion, and not reduced with NAC. We found no significant differences in circulating biomarkers of myocardial necrosis, nor in the incidence of idioventricular rhythm (IVR), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT) or ventricular fibrillation (VF) between NAC-treated and control pigs during reperfusion.<br><br>CONCLUSION: Myocardial oxidation was increased early after reperfusion in a porcine model of MI, but systemic antioxidative treatment did not protect against reperfusion arrhythmias.},
}
@article {pmid37820773,
year = {2023},
author = {Gustafson, &#xc5; and Elfsmark, L and Karlsson, T and Jonasson, S},
title = {N-acetyl cysteine mitigates lung damage and inflammation after chlorine exposure in vivo and ex vivo.},
journal = {Toxicology and applied pharmacology},
volume = {479},
number = {},
pages = {116714},
doi = {10.1016/j.taap.2023.116714},
pmid = {37820773},
issn = {1096-0333},
mesh = {Mice ; Animals ; Swine ; *Acetylcysteine/pharmacology/therapeutic use ; Chlorine/toxicity ; *Lung Injury/chemically induced/drug therapy/prevention &amp; control ; Antioxidants/pharmacology ; Lung ; Inflammation/chemically induced/drug therapy ; Inflammation Mediators ; },
abstract = {The objective of this study was to explore the effects of antioxidant treatments, specifically N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA), in a mouse model of chlorine (Cl2)-induced lung injury. Additionally, the study aimed to investigate the utility of pig precision-cut lung slices (PCLS) as an ex vivo alternative for studying the short-term effects of Cl2 exposure and evaluating antioxidant treatments. The toxicological responses were analyzed in Cl2-exposed mice (inflammation, airway hyperresponsiveness (AHR)) and PCLS (viability, cytotoxicity, inflammatory mediators). Airways contractions were assessed using a small ventilator for mice and electric-field stimulation (EFS) for PCLS. Antioxidant treatments were administered to evaluate their effects. In Cl2-exposed mice, NAC treatment did not alleviate AHR, but it did reduce the number of neutrophils in bronchoalveolar lavage fluid and inflammatory mediators in lung tissue. In PCLS, exposure to Cl2 resulted in concentration-dependent toxicity, impairing the lung tissue's ability to respond to EFS-stimulation. NAC treatment increased viability, mitigated the toxic responses caused by Cl2 exposure, and maintained contractility comparable to unexposed controls. Interestingly, NACA did not provide any additional treatment effect beyond NAC in both models. In conclusion, the establishment of a pig model for Cl2-induced lung damage supports further investigation of NAC as a potential treatment. However, the lack of protective effects on AHR after NAC treatment in mice suggests that NAC alone may not be sufficient as a complete treatment for Cl2 injuries. Optimization of existing medications with a polypharmacy approach may be more successful in addressing the complex sequelae of Cl2-induced lung injury.},
}
@article {pmid37817304,
year = {2024},
author = {Ezhilarasan, D and Shree Harini, K and Karthick, M and Selvaraj, C},
title = {Ethyl gallate concurrent administration protects against acetaminophen-induced acute liver injury in mice: An in vivo and in silico approach.},
journal = {Chemical biology &amp; drug design},
volume = {103},
number = {1},
pages = {e14369},
doi = {10.1111/cbdd.14369},
pmid = {37817304},
issn = {1747-0285},
mesh = {Mice ; Animals ; *Antioxidants/pharmacology/therapeutic use/metabolism ; Acetaminophen/toxicity ; Liver ; Gallic Acid/metabolism/pharmacology/analogs &amp; derivatives ; Anti-Inflammatory Agents/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology ; Oxidative Stress ; },
abstract = {Acetaminophen (APAP) in high doses causes acute liver injury and acute liver failure. Ethyl gallate (EG) is a natural polyphenol, possessing antioxidant, anti-inflammatory, and anti-microbial properties. Therefore, in this study, we evaluated the protective role of EG against APAP-induced acute liver injury in mice. Acute liver injury was induced by a single dose of APAP (400 mg/kg., i.p.). In separate groups, EG (10 mg/kg), EG (20 mg/kg), and N-acetylcysteine (NAC; 1200 mg/kg., i.p.) were administered concurrently with APAP. The mice were sacrificed after 24 h of treatment. Liver marker enzymes of hepatotoxicity, antioxidant markers, inflammatory markers, and histopathological studies were done. APAP administration caused a significant elevation of marker enzymes of hepatotoxicity and lipid peroxidation. APAP administration also decreased enzymic and nonenzymic antioxidants. Acute APAP intoxication induced nuclear factor κ B, tumor necrosis factor-α, interleukin-1, p65, and p52 and downregulated IκB gene expressions. Our histopathological studies have confirmed the presence of centrilobular necrosis, 24 h after APAP intoxication. All the above abnormalities were significantly inhibited in groups of mice that were concurrently administered with APAP + EG and APAP + NAC. Our in silico analysis further confirms that hydroxyl groups of EG interact with the above inflammatory proteins at the 3,4,5-trihydroxybenzoic acid region. These effects of EG against APAP-induced acute liver injury could be attributed to its antioxidative, free radical scavenging, and anti-inflammatory potentials. Therefore, this study suggests that EG can be an efficient therapeutic approach to protect the liver from APAP intoxication.},
}
@article {pmid37814098,
year = {2023},
author = {Chitolina, R and Reis, CG and Stahlhofer-Buss, T and Linazzi, A and Benvenutti, R and Marcon, M and Herrmann, AP and Piato, A},
title = {Effects of N-acetylcysteine and acetyl-L-carnitine on acute PTZ-induced seizures in larval and adult zebrafish.},
journal = {Pharmacological reports : PR},
volume = {75},
number = {6},
pages = {1544-1555},
pmid = {37814098},
issn = {2299-5684},
mesh = {Animals ; Humans ; Adult ; *Zebrafish ; Acetylcysteine/therapeutic use ; Acetylcarnitine/adverse effects ; Larva ; Pentylenetetrazole/toxicity ; Seizures/chemically induced/drug therapy ; *Epilepsy/drug therapy ; Anticonvulsants/therapeutic use ; Disease Models, Animal ; },
abstract = {BACKGROUND: Epilepsy is a prevalent neurological disease, affecting approximately 1-2% of the global population. The hallmark of epilepsy is the occurrence of epileptic seizures, which are characterized by predictable behavioral changes reflecting the underlying neural mechanisms of the disease. Unfortunately, around 30% of patients do not respond to current pharmacological treatments. Consequently, exploring alternative therapeutic options for managing this condition is crucial. Two potential candidates for attenuating seizures are N-acetylcysteine (NAC) and Acetyl-L-carnitine (ALC), as they have shown promising neuroprotective effects through the modulation of glutamatergic neurotransmission.<br><br>METHODS: This study aimed to assess the effects of varying concentrations (0.1, 1.0, and 10&#xa0;mg/L) of NAC and ALC on acute PTZ-induced seizures in zebrafish in both adult and larval stages. The evaluation of behavioral parameters such as seizure intensity and latency to the crisis can provide insights into the efficacy of these substances.<br><br>RESULTS: Our results indicate that both drugs at any of the tested concentrations were not able to reduce PTZ-induced epileptic seizures. On the other hand, the administration of diazepam demonstrated a notable reduction in seizure intensity and increased latencies to higher scores of epileptic seizures.<br><br>CONCLUSION: Consequently, we conclude that, under the conditions employed in this study, NAC and ALC do not exhibit any significant effects on acute seizures in zebrafish.},
}
@article {pmid37812881,
year = {2023},
author = {Zeng, Z and Li, T and Liu, X and Ma, Y and Luo, L and Wang, Z and Zhao, Z and Li, H and He, X and Zeng, H and Tao, Y and Chen, Y},
title = {DNA dioxygenases TET2 deficiency promotes cigarette smoke induced chronic obstructive pulmonary disease by inducing ferroptosis of lung epithelial cell.},
journal = {Redox biology},
volume = {67},
number = {},
pages = {102916},
pmid = {37812881},
issn = {2213-2317},
mesh = {Animals ; Humans ; Mice ; *Cigarette Smoking/adverse effects ; *Dioxygenases/metabolism/pharmacology ; DNA/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Epithelial Cells/metabolism ; *Ferroptosis/genetics ; Inflammation/metabolism ; Lung/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; *Pulmonary Disease, Chronic Obstructive/chemically induced/genetics ; },
abstract = {Chronic obstructive pulmonary disease (COPD) is a significant global cause of morbidity and mortality currently. Long-term exposure of cigarette smoke (CS) inducing persistent inflammation, small airway remodeling and emphysematous lung are the distinguishing features of COPD. Ferroptosis, occurred in lung epithelial cells has recently been reported to be associated with COPD pathogenesis. DNA dioxygenase ten-eleven translocation 2 (TET2) is an important demethylase and its genetic mutation is associated with low forced expiratory volume in 1 s (FEV1) of lung function. However, its role in COPD remains elusive. Here, we found that TET2 regulates CS induced lipid peroxidation through demethylating glutathione peroxidase 4 (GPx4), thus alleviating airway epithelial cell ferroptosis in COPD. TET2 protein levels were mainly reduced in the airway epithelia of COPD patients, mouse models, and CS extract-treated bronchial epithelial cells. The deletion of TET2 triggered ferroptosis and further exaggerated CS-induced airway remodeling, inflammation, and emphysema in vivo. Moreover, we demonstrated that TET2 silencing intensified ferroptosis, while TET2 overexpression inhibited ferroptosis in airway epithelial cell treated with CSE. Mechanically, TET2 protected airway epithelial cells from CS-induced lipid peroxidation and ferroptosis through demethylating the promoter of glutathione peroxidase 4 (GPx4). Finally, co-administration of methylation inhibitor 5'-aza-2'-deoxycytidine (5-AZA) and the antioxidant N-acetyl-cysteine (NAC) have more protective effects on CS-induced COPD than either administration alone. Overall, our study reveals that TET2 is an essential modulator in the lipid peroxidation and ferroptosis of airway epithelial cell, and could act as a potential therapeutic target for CS-induced COPD.},
}
@article {pmid37810545,
year = {2023},
author = {Brown, C and Wang, J and Jiang, H and Elias, MF},
title = {Homocysteine Reduction for Stroke Prevention: Regarding the Recent AHA/ASA 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.},
journal = {Pharmacogenomics and personalized medicine},
volume = {16},
number = {},
pages = {895-900},
pmid = {37810545},
issn = {1178-7066},
abstract = {Reduction of secondary ischemic stroke risk following an initial stroke is an important goal. The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack assembles opportunities for up to 80% secondary stroke reduction. Homocysteine reduction was not included in the recommendations. The reduction of homocysteine with low doses of folic acid has been shown to reduce ischemic stroke and all stroke. This has been obscured by studies using high doses of folic acid and cyanocobalamin in patients with renal failure and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. The confounding impacts of high dose folic acid and cyanocobalamin toxicity in renal failure and MTHFR C677T subgroups are discussed. New studies show that their toxicity is due to non-bioequivalence to the natural dietary forms, L-methylfolate and methylcobalamin. Low doses of folic acid and cyanocobalamin are safer than high doses for these subpopulations. Even lower toxicity with greater effectiveness for reducing homocysteine is seen with L-methylfolate and methylcobalamin, which are safe at high doses. Retinal vascular imaging is a noninvasive method for evaluating central nervous system (CNS) microangiopathy. A formulation containing l-methylfolate and methylcobalamin has been shown to reduce homocysteine and increase perfusion in diabetic retinopathy. This supports homocysteine intervention for CNS ischemia. Future ischemic stroke intervention studies could benefit from monitoring retinal perfusion to estimate the impact of risk reduction strategies. The omission of a recommendation for homocysteine and secondary stroke reduction through the use of B vitamins should be reconsidered in light of re-analysis of major B vitamin intervention studies and new technologies for monitoring CNS perfusion. We recommend revision of the 2021 Guideline to include homocysteine reduction with low doses of folic acid and cyanocobalamin, or better yet, L-methylfolate and methylcobalamin, making a good clinical guideline better.},
}
@article {pmid37804692,
year = {2023},
author = {Guo, Y and Huang, C and Xu, C and Qiu, L and Yang, F},
title = {Dysfunction of ZNF554 promotes ROS-induced apoptosis and autophagy in Fetal Growth Restriction via the p62-Keap1-Nrf2 pathway.},
journal = {Placenta},
volume = {143},
number = {},
pages = {34-44},
doi = {10.1016/j.placenta.2023.09.009},
pmid = {37804692},
issn = {1532-3102},
mesh = {Female ; Humans ; Pregnancy ; Antioxidants/metabolism ; *Apoptosis/genetics ; Autophagy ; Cell Line, Tumor ; *Fetal Growth Retardation/genetics/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; *Placenta/metabolism ; Reactive Oxygen Species/metabolism ; Trophoblasts/metabolism ; *Kruppel-Like Transcription Factors/genetics/metabolism ; },
abstract = {Fetal growth restriction (FGR) is one of the most common complications of an abnormal pregnancy. Placental dysplasia has been established as a significant contributing factor to FGR. Zinc finger protein 554 (ZNF554) is a member of the Krüppel-associated box domain zinc finger protein subfamily, primarily expressed in the placenta and essential for maintaining normal pregnancy outcomes. However, its precise role in FGR remains uncertain. In this study, we confirmed that ZNF554 was low expressed in the placenta of the FGR pregnancy. To further elucidate the impact of ZNF554 on trophoblasts, we conducted experiments using siRNA and overexpression plasmids on HTR8/SVneo and JEG3 cells. Our findings revealed that silencing ZNF554 increased apoptosis and inhibited migration and invasion, while overexpression reduced apoptosis and promoted migration and invasion. Notably, ZNF554 knockdown decreased cellular antioxidant capacity and elevated the production of reactive oxygen species (ROS). Conversely, ZNF554 activated the nuclear factor E2-related factor 2 (NRF2) signaling pathway, exerting its antioxidant effects. Additionally, ZNF554 knockdown promoted cellular autophagy by suppressing P62 and enhancing LC3-II/LC3-I expression. Importantly, the antioxidant N-acetylcysteine (NAC) partially mitigated the impact of ZNF554 knockdown on mitochondrial ROS in trophoblast cells and subsequent effects on cellular autophagy and apoptosis. In conclusion, our results suggest that ZNF554 plays a pivotal role in modulating trophoblast cell invasion and may serve as a prognostic marker and potential therapeutic target for FGR.},
}
@article {pmid37801672,
year = {2024},
author = {Orhan, &#xd6; and Talay, MN},
title = {Methemoglobinemia and acute ıntravascular hemolysis after naphthalene poisoning in a pediatric patient.},
journal = {Archivos argentinos de pediatria},
volume = {122},
number = {2},
pages = {e202310095},
doi = {10.5546/aap.2023-10095.eng},
pmid = {37801672},
issn = {1668-3501},
mesh = {Humans ; Male ; Child ; Infant ; Child, Preschool ; Hemolysis ; *Methemoglobinemia/chemically induced/diagnosis ; *Anemia, Hemolytic/diagnosis ; Ascorbic Acid ; Naphthalenes ; },
abstract = {Poisoning by naphthalene is uncommon in children. It is a type of poisoning brought on by ingesting, inhaling, or coming into touch with naphthalene-containing substances on the skin. Patients typically present with an initial onset of dark brown urine, watery diarrhea, and bile vomit. The signs include fever, tachycardia, hypotension, and low pulse oximetry readings even with oxygen support. Hemolytic anemia, methemoglobinemia, renal failure, and hyperbilirubinemia are all detected in blood tests. Erythrocyte transfusion, ascorbic acid, methylene blue, and N-acetylcysteine (NAC) therapies are provided to inpatients in addition to symptomatic treatment. We present a 23-month-old male patient who developed methemoglobinemia and acute ıntravascular hemolysis, who was followed up in the intensive care unit for five days due to naphthalene intoxication. Although naphthalene poisoning is very rare, it should be known that it has fatal consequences, and more care should be taken in its use and sale.},
}
@article {pmid37798944,
year = {2024},
author = {Vélez, EJ and Schnebert, S and Goguet, M and Balbuena-Pecino, S and Dias, K and Beauclair, L and Fontagné-Dicharry, S and Véron, V and Depincé, A and Beaumatin, F and Herpin, A and Seiliez, I},
title = {Chaperone-mediated autophagy protects against hyperglycemic stress.},
journal = {Autophagy},
volume = {20},
number = {4},
pages = {752-768},
pmid = {37798944},
issn = {1554-8635},
mesh = {Animals ; *Chaperone-Mediated Autophagy/drug effects/physiology/genetics ; *Lysosomes/metabolism/drug effects ; *Oncorhynchus mykiss/metabolism ; *Glucose/metabolism ; Hyperglycemia/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Lysosomal-Associated Membrane Protein 2/metabolism/genetics ; Autophagy/physiology/genetics/drug effects ; Molecular Chaperones/metabolism ; Humans ; },
abstract = {Chaperone-mediated autophagy (CMA) is a major pathway of lysosomal proteolysis critical for cellular homeostasis and metabolism, and whose defects have been associated with several human pathologies. While CMA has been well described in mammals, functional evidence has only recently been documented in fish, opening up new perspectives to tackle this function under a novel angle. Now we propose to explore CMA functions in the rainbow trout (RT, Oncorhynchus mykiss), a fish species recognized as a model organism of glucose intolerance and characterized by the presence of two paralogs of the CMA-limiting factor Lamp2A (lysosomal associated membrane protein 2A). To this end, we validated a fluorescent reporter (KFERQ-PA-mCherry1) previously used to track functional CMA in mammalian cells, in an RT hepatoma-derived cell line (RTH-149). We found that incubation of cells with high-glucose levels (HG, 25 mM) induced translocation of the CMA reporter to lysosomes and/or late endosomes in a KFERQ- and Lamp2A-dependent manner, as well as reduced its half-life compared to the control (5 mM), thus demonstrating increased CMA flux. Furthermore, we observed that activation of CMA upon HG exposure was mediated by generation of mitochondrial reactive oxygen species, and involving the antioxidant transcription factor Nfe2l2/Nrf2 (nfe2 like bZIP transcription factor 2). Finally, we demonstrated that CMA plays an important protective role against HG-induced stress, primarily mediated by one of the two RT Lamp2As. Together, our results provide unequivocal evidence for CMA activity existence in RT and highlight both the role and regulation of CMA during glucose-related metabolic disorders.Abbreviations: AREs: antioxidant response elements; CHC: α-cyano -4-hydroxycinnamic acid; Chr: chromosome; CMA: chaperone-mediated autophagy; CT: control; DMF: dimethyl fumarate; Emi: endosomal microautophagy; HG: high-glucose; HMOX1: heme oxygenase 1; H2O2: hydrogen peroxide; KFERQ: lysine-phenylalanine-glutamate-arginine-glutamine; LAMP1: lysosomal associated membrane protein 1; LAMP2A: lysosomal associated membrane protein 2A; MCC: Manders' correlation coefficient; Manders' correlation coefficient Mo: morpholino oligonucleotide; NAC: N-acetyl cysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; PA-mCherry: photoactivable mCherry; PCC: Pearson's correlation coefficient; ROS: reactive oxygen species; RT: rainbow trout; siRNAs: small interfering RNAs; SOD: superoxide dismutase; Tsg101: tumor susceptibility 101; TTFA: 2-thenoyltrifluoroacetone; WGD: whole-genome duplication.},
}
@article {pmid37797590,
year = {2023},
author = {Palkovits, S and Schlatter, A and Ruiss, M and Georgiev, S and Zeilinger, J and Pilwachs, C and Findl, O},
title = {Occurrence of Corneal Staining after Cataract Surgery with and without Chitosan-N-Acetylcysteine Eye Drops.},
journal = {Ophthalmic research},
volume = {66},
number = {1},
pages = {1293-1299},
pmid = {37797590},
issn = {1423-0259},
mesh = {Humans ; Ophthalmic Solutions ; Acetylcysteine/therapeutic use/pharmacology ; *Chitosan ; *Cataract Extraction/adverse effects ; *Cataract ; *Dry Eye Syndromes ; },
abstract = {INTRODUCTION: The objective of this study was to evaluate the prevalence of ocular surface damage assessed by corneal staining scores right after cataract surgery and whether it can be prevented using chitosan-N-acetylcysteine (C-NAC) eye drops.<br><br>METHODS: We included patients scheduled for routine cataract surgery. Each patient was randomly assigned to one of three groups. Patients in group 1 underwent routine cataract surgery with no additional eye drops. In group 2, patients received C-NAC eye drops after cataract surgery, and in group 3, C-NAC was applied both before and after surgery. Both groups continued the treatment once daily for 4 days. Ocular surface alteration was assessed using the National Eye Institute (NEI) score, and the visual analog scale (VAS) was used to evaluate subjective complaints.<br><br>RESULTS: Thirty-six patients were included in the final analyses. One hour after cataract surgery, a statistically significant increase in corneal fluorescein staining was observed in all groups, which decreased again after 1 week. There was no significant difference between the groups 1 h after cataract surgery, though a tendency toward lower NEI scores was observed during this time point in group 3.<br><br>DISCUSSION: Cataract surgery induced ocular surface staining and subjective complaints after 1 h. However, the increase in VAS score was small and probably not clinically relevant. The application of perioperative C-NAC eye drops did reduce the rate of corneal staining after cataract surgery in a clinically relevant manner.},
}
@article {pmid37797457,
year = {2023},
author = {Liu, F and Li, Y and Zhu, J and Li, Y and Zhu, D and Luo, J and Kong, L},
title = {γ-Glutamyltranspeptidase-Activated Near-Infrared fluorescent probe for visualization of Drug-Induced liver injury.},
journal = {Bioorganic chemistry},
volume = {141},
number = {},
pages = {106899},
doi = {10.1016/j.bioorg.2023.106899},
pmid = {37797457},
issn = {1090-2120},
mesh = {Humans ; *Fluorescent Dyes ; Cell Line ; Hep G2 Cells ; *Chemical and Drug Induced Liver Injury/diagnosis ; gamma-Glutamyltransferase ; Glutathione ; },
abstract = {Drug-induced liver injury (DILI), induced by overdose or chronic administration of drugs, has become the leading cause of acute liver failure. Therefore, an accurate diagnostic method for DILI is critical to improve treatment efficiency. The production of γ-glutamyltranspeptidase (GGT) is closely related to the progression of drug-induced hepatotoxicity. KL-Glu exhibits a prominent GGT-activated NIR fluorescence (734 nm) with a large Stokes shift (137 nm) and good sensitivity/selectivity, making it favorable for real-time detection of endogenous GGT activity. Using this probe, we evaluated the GGT up-regulation under the acetaminophen-induced liver injury model. Moreover, KL-Glu was successfully used to assess liver injury induced by the natural active ingredient triptolide and the effective amelioration upon treatment with N-acetyl cysteine (NAC) or Glutathione (GSH) in cells and in vivo by fluorescent trapping the fluctuation of GGT for the first time. Therefore, the fluorescent probe KL-Glu can be used as a potential tool to explore the function of GGT in the progression of DILI and for the early diagnosis and prognostic evaluation of DILI.},
}
@article {pmid37795573,
year = {2023},
author = {Jung, IR and Ahima, RS and Kim, SF},
title = {Inositol polyphosphate multikinase modulates free fatty acids-induced insulin resistance in primary mouse hepatocytes.},
journal = {Journal of cellular biochemistry},
volume = {124},
number = {11},
pages = {1695-1704},
doi = {10.1002/jcb.30478},
pmid = {37795573},
issn = {1097-4644},
mesh = {Mice ; Animals ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Fatty Acids, Nonesterified/pharmacology ; *Insulin Resistance ; *Non-alcoholic Fatty Liver Disease ; Phosphotransferases (Alcohol Group Acceptor)/genetics/metabolism ; Insulin/pharmacology ; Hepatocytes/metabolism ; },
abstract = {Insulin resistance is a critical mediator of the development of nonalcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of NAFLD. Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of protein kinase B (Akt) phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-acetyl cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.},
}
@article {pmid37794966,
year = {2023},
author = {Sohouli, MH and Eslamian, G and Malekpour Alamdari, N and Abbasi, M and Fazeli Taherian, S and Behtaj, D and Zand, H},
title = {Effects of N-acetylcysteine on aging cell and obesity complications in obese adults: a randomized, double-blind clinical trial.},
journal = {Frontiers in nutrition},
volume = {10},
number = {},
pages = {1237869},
pmid = {37794966},
issn = {2296-861X},
abstract = {BACKGROUND: We decided to conduct this study with the aim of investigating the effects of N-Acetylcysteine (NAC) on obesity complications and senescence of visceral adipose tissue in obese adults.<br><br>METHODS AND ANALYSIS: The present study was conducted as a randomized clinical trial (RCT) (Clinical trial registry number: IRCT20220727055563N1) on 40 obese adults candidates for bariatric surgery, who were randomly assigned to receive 600&#x2009;mg of NAC (n&#x2009;=&#x2009;20) or placebo as a control (n&#x2009;=&#x2009;20) for 4&#x2009;weeks. During bariatric surgery, visceral adipose tissue was used to examine gene expression and senescence cells using SA-&#x3b2;-gal.<br><br>RESULTS: Our findings showed that intervention with NAC significantly reduces SA-&#x3b2;-gal activity (as a marker of senescence) and expression of p16 and interleukin 6 (IL-6) genes in the visceral adipose tissue compared to placebo in obese adults for 4&#x2009;weeks. In addition, our findings showed the potential and beneficial effect of NAC administration on reducing the levels of inflammatory factors including IL-6 and high-sensitivity C-reactive protein (hs-CRP), as well as the level of fasting blood sugar (FBS), homeostatic model assessment of insulin resistance (HOMA-IR), and insulin compared to placebo after adjusting for confounders. No significant effect was indicated on anthropometric factors and lipid profile.<br><br>CONCLUSION: Findings showed that NAC, in addition to having a potential beneficial effect on reducing some of the complications caused by obesity, seems to have synolytic/senomorphic potential as well.<br><br>CLINICAL TRIAL REGISTRATION: [https://clinicaltrials.gov/], identifier [IRCT20220727055563N1].},
}
@article {pmid37790388,
year = {2023},
author = {DeLouise, L and Piraino, L and Chen, CY and Mereness, J and Dunman, P and Benoit, D and Ovitt, C},
title = {Identifying novel radioprotective drugs via salivary gland tissue chip screening.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {37790388},
issn = {2693-5015},
support = {F31 DE029658/DE/NIDCR NIH HHS/United States ; P30 ES001247/ES/NIEHS NIH HHS/United States ; T32 ES007026/ES/NIEHS NIH HHS/United States ; UG3 DE027695/DE/NIDCR NIH HHS/United States ; },
abstract = {During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is FDA approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Other reported radioprotective drugs including Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin were also tested to validate the ability of the assays to detect cell damage and radioprotection. All of the drugs except NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified exhibiting mechanisms of action other than antioxidant activity. Hits were down-selected using EC50 values and pharmacokinetic and pharmacodynamic data from the PubChem database. This led us to test Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited radioprotection equivalent to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with non-antioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.},
}
@article {pmid37790125,
year = {2023},
author = {Zhu, R and Zheng, R and Deng, B and Liu, P and Wang, Y},
title = {Association of N-acetylcysteine use with contrast-induced nephropathy: an umbrella review of meta-analyses of randomized clinical trials.},
journal = {Frontiers in medicine},
volume = {10},
number = {},
pages = {1235023},
pmid = {37790125},
issn = {2296-858X},
abstract = {BACKGROUND: The effectiveness of N-acetylcysteine (NAC) in treating contrast-induced nephropathy (CIN) has been the subject of conflicting meta-analyses, but the strength of the evidence for these correlations between NAC use and CIN has not been measured overall.<br><br>OBJECTIVE: To evaluate the data from randomized clinical studies (RCTs) that examined the relationships between NAC use and CIN in meta-analyses.<br><br>METHODS: Between the creation of the database and April 2023, searches were made in PubMed, Cochrane Library, EMBASE, and Web of Science. N-acetylcysteine, contrast-induced nephropathy, or contrast-induced renal disease were among the search keywords used, along with terms including systematic review and meta-analysis. The Assessment of Multiple Systematic Reviews, version 2, which assigned grades of extremely low, low, moderate, or high quality to each meta-analysis's scientific quality, was used to evaluate each meta-analysis. The confidence of the evidence in meta-analyses of RCTs was evaluated using the Grading of Recommendation, Assessment, Development and Evaluations method, with evidence being rated as very low, low, moderate, or high.<br><br>RESULTS: In total, 493 records were screened; of those, 46 full-text articles were assessed for eligibility, and 12 articles were selected for evidence synthesis as a result of the screening process. Based on the pooled data, which was graded as moderate-quality evidence, it can be concluded that NAC can decrease CIN (OR 0.72, 95% CI 0.65-0.79, p&#x2009;<&#x2009;0.00001) and blood levels of serum creatinine (MD -0.09, 95% CI -0.17 to -0.01, p&#x2009;=&#x2009;0.03). In spite of this, there were no associations between NAC and dialysis requirement or mortality in these studies.<br><br>CONCLUSION: The results of this umbrella review supported that the renal results were enhanced by NAC. The association was supported by moderate-quality evidence.<br><br>[https://clinicaltrials.gov/], identifier [CRD42022367811].},
}
@article {pmid37782109,
year = {2023},
author = {Pertiwi, H and Majdeddin, M and Degroote, J and Zhang, H and Michiels, J},
title = {N-acetyl-L-cysteine improves the performance of chronic cyclic heat-stressed finisher broilers but has no effect on tissue glutathione levels.},
journal = {British poultry science},
volume = {64},
number = {6},
pages = {751-762},
doi = {10.1080/00071668.2023.2264234},
pmid = {37782109},
issn = {1466-1799},
mesh = {Animals ; *Acetylcysteine ; Antioxidants/metabolism ; Chickens ; Cystine ; Glutathione ; Diet/veterinary ; *Amino Acids, Sulfur ; Heat-Shock Response ; Butyrates ; Dietary Supplements ; Animal Feed/analysis ; },
abstract = {1. It was hypothesised that dietary N-acetyl-L-cysteine (NAC) in feed, as a source of cysteine, could improve the performance of heat-stressed finisher broilers by fostering glutathione (GSH) synthesis. GSH is the most abundant intracellular antioxidant for which the sulphur amino acid cysteine is rate limiting for its synthesis.2. In the first experiment, four levels of NAC: 0, 500, 1000 and 2000 mg/kg were added to a diet with a suboptimal level of sulphur amino acids in the finisher phase. In the second experiment, NAC was compared to other sulphur amino acid sources at equal molar amounts of digestible sulphur amino acids. Birds were allocated to four groups: control, 2000 mg/kg NAC, 1479 mg/kg L-cystine, and 2168 mg/kg Ca-salt of 2-hydroxy-4-(methylthio)butanoic acid. A chronic cyclic heat stress model (temperature was increased to 34°C for 7 h daily) was initiated at 28 d of age.3. In the first experiment, growth performance and feed efficiency in the finisher phase were significantly improved by graded NAC. ADG was 88.9, 92.2, 93.7 and 97.7 g/d, and the feed-to-gain ratio was 2.18, 1.91, 1.85 and 1.81 for the 0, 500, 1000 and 2000 mg/kg NAC treatments, respectively. However, liver and heart GSH levels were not affected by NAC. On d 29, liver gene transcript of cystathionine-beta-synthase like was reduced by NAC, which suggested reduced trans-sulphuration activity. The second experiment showed that L-cystine and Ca-salt of 2-hydroxy-4-(methylthio) butanoic acid were more effective in improving performance than NAC.4. In conclusion, N-acetyl-L-cysteine improved dose-dependently growth and feed efficiency in heat-stressed finishing broilers. However, this was not associated with changes in tissue GSH levels, but more likely worked by sparing methionine and/or NAC's and cysteine's direct antioxidant properties.},
}
@article {pmid37781647,
year = {2023},
author = {Miyashita, L and Foley, G and Semple, S and Gibbons, JM and Pade, C and McKnight, &#xc1; and Grigg, J},
title = {Curbside particulate matter and susceptibility to SARS-CoV-2 infection.},
journal = {The journal of allergy and clinical immunology. Global},
volume = {2},
number = {4},
pages = {100141},
pmid = {37781647},
issn = {2772-8293},
abstract = {BACKGROUND: Biologic plausibility for the association between exposure to particulate matter (PM) less than 10 μm in aerodynamic diameter (PM10) and coronavirus disease 2019 (COVID-19) morbidity in epidemiologic studies has not been determined. The upregulation of angiotensin-converting enzyme 2 (ACE2), the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) entry receptor on host cells, by PM10 is a putative mechanism.<br><br>OBJECTIVE: We sought to assess the effect of PM10 on SARS-CoV-2 infection of cells in&#xa0;vitro.<br><br>METHODS: PM10 from the curbside of London's Marylebone Road and from exhaust emissions was collected by cyclone. A549 cells, human primary nasal epithelial cells (HPNEpCs), SARS-CoV-2-susceptible Vero-E6 and Calu3 cells were cultured with PM10. ACE2 expression (as determined by median fluorescent intensity) was assessed by flow cytometry, and ACE2 mRNA transcript level was assessed by PCR. The role of oxidative stress was determined by N-acetyl cysteine. The cytopathic effect of SARS-CoV-2 (percentage of infection enhancement) and expression of SARS-CoV-2 genes' open reading frame (ORF) 1ab, S protein, and N protein (focus-forming units/mL) were assessed in Vero-E6 cells. Data were analyzed by either the Mann-Whitney U test or Kruskal-Wallis test with the Dunn multiple comparisons test.<br><br>RESULTS: Curbside PM10 at concentrations of 10 &#x3bc;g/mL or more increased ACE2 expression in A549 cells (P&#xa0;= .0021). Both diesel PM10 and curbside PM10 in a concentration of 10 &#x3bc;g/mL increased ACE2 expression in HPNEpCs (P&#xa0;= .0022 and P&#xa0;= .0072, respectively). ACE2 expression simulated by curbside PM10 was attenuated by N-acetyl cysteine in HPNEpCs (P&#xa0;= .0464). Curbside PM10 increased ACE2 expression in Calu3 cells (P&#xa0;= .0256). In Vero-E6 cells, curbside PM10 increased ACE2 expression (P&#xa0;= .0079), ACE2 transcript level (P&#xa0;= .0079), SARS-CoV-2 cytopathic effect (P&#xa0;= .0002), and expression of the SARS-CoV-2 genes' ORF1ab, S protein, and N protein (P&#xa0;= .0079).<br><br>CONCLUSIONS: Curbside PM10 increases susceptibility to SARS-COV-2 infection in&#xa0;vitro.},
}
@article {pmid37779397,
year = {2023},
author = {Heidari, B and Seyedian, ZA and Mehrpooya, M and Ahmadimoghaddam, D and Mirjalili, M and Ghiasian, M},
title = {N-Acetyl Cysteine as an Add-on Therapy is Useful in Treating Acute Lumbar Radiculopathy Caused by Disc Herniation: Results of a Randomized, Controlled Clinical Trial.},
journal = {Reviews on recent clinical trials},
volume = {18},
number = {4},
pages = {288-299},
doi = {10.2174/0115748871250545230919055109},
pmid = {37779397},
issn = {1876-1038},
support = {No: 140004293667//Hamadan University of Medical Sciences/ ; },
mesh = {Humans ; *Intervertebral Disc Displacement/complications/diagnosis/drug therapy ; *Radiculopathy/drug therapy/etiology/diagnosis ; Cysteine/therapeutic use ; Lumbar Vertebrae ; Treatment Outcome ; Pain/complications/drug therapy ; Anti-Inflammatory Agents, Non-Steroidal ; },
abstract = {BACKGROUND: Available experimental and clinical evidence indicates that N-Acetyl cysteine (NAC) may have an analgesic role in specific pain conditions, particularly neuropathic pain. Thus, we hypothesized that NAC supplementation might be also helpful in decreasing pain and improving pain-related disability in patients with acute radiculopathy. We designed this study to investigate the potential use of NAC-adjunctive treatment to Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) in patients with acute radiculopathy secondary to lumbar intervertebral disc herniation.<br><br>METHODS: Sixty-two patients diagnosed with acute lumbar radiculopathy associated with disc herniation were randomly allocated to the NAC or the placebo groups. Besides naproxen at a dose of 500 mg twice a day, participants based on their allocation group started with NAC or matched placebo at a dose of 600 mg twice a day for eight weeks. The pain severity, measured by the Visual Analog Scale (VAS), and pain-related disability measured by the Oswestry Disability Index (ODI) were measured at baseline and weeks 2, 4, and 8 of treatment. Global improvement of symptoms rated by Patient and Clinical Global Impressions of Change (PGIC and CGIC) was also recorded at the end of week 8. All analyses were conducted on an Intentionto- Treat (ITT) analysis data set.<br><br>RESULTS: A comparison of the VAS and ODI scores at weeks 2 and 4 of the treatment between the two groups did not show a significant difference. In contrast, from week 4 to week 8, we noticed a significantly greater reduction in the mean VAS and ODI scores in the NAC group compared to the placebo group (p-value <0.001 for both variables). In parallel with these results, also, more NAC-treated than placebo-treated patients achieved treatment success defined as ''very much'' or ''much improved'' on CGIC and PGIC scales, and these differences reached a significant level (p-value = .011 and p-value = .043).<br><br>CONCLUSIONS: This study suggested that NAC might be a relevant candidate for adjunct therapy in managing acute lumbar radiculopathy. Additional clinical trials are needed to validate these findings.},
}
@article {pmid37778984,
year = {2023},
author = {Kaji, T and Kuroishi, T and Bando, K and Takahashi, M and Sugawara, S},
title = {N-acetyl cysteine inhibits IL-1α release from murine keratinocytes induced by 2-hydroxyethyl methacrylate.},
journal = {The Journal of toxicological sciences},
volume = {48},
number = {10},
pages = {557-569},
doi = {10.2131/jts.48.557},
pmid = {37778984},
issn = {1880-3989},
mesh = {Mice ; Animals ; *Acetylcysteine/pharmacology ; Reactive Oxygen Species/metabolism ; *Calpain ; Methacrylates/toxicity/chemistry ; Keratinocytes/metabolism ; Inflammation ; },
abstract = {The hydrophilic compound 2-hydroxyethyl methacrylate (HEMA) is a major component of dental bonding materials, and it enhances the binding of resin-composites to biomolecules. However, HEMA is a well-known contact sensitizer. We reported previously that intradermal injection of HEMA induces the production of IL-1 locally in the skin. Keratinocytes are the first barrier against chemical insults and constitutively express IL-1α. In this study, we analyzed whether HEMA induces the production of inflammatory cytokines from murine keratinocyte cell line Pam212 cells. We demonstrated that HEMA induced the release of 17-kDa mature IL-1α and caused cytotoxicity. The activity of calpain, an IL-1α processing enzyme, was significantly higher in HEMA-treated cells. The thiol-containing antioxidant N-acetyl cysteine (NAC) inhibited HEMA-induced IL-1α release but not cytotoxicity. NAC inhibited intracellular calpain activity and reactive oxygen species (ROS) production induced by HEMA. NAC post-treatment also inhibited IL-1α release and intracellular ROS production induced by HEMA. Furthermore, HEMA-induced in vivo inflammation also inhibited by NAC. NAC inhibited polymerization of HEMA through adduct formation via sulfide bonds between the thiol group of NAC and the reactive double bond of HEMA. HEMA-induced IL-1α release and cytotoxicity were also inhibited if HEMA and NAC were pre-incubated before adding to the cells. These results suggested that NAC inhibited IL-1α release through decreases in intracellular ROS and the adduct formation with HEMA. We concluded that HEMA induces IL-1α release from skin keratinocytes, and NAC may be a promising candidate as a therapeutic agent against inflammation induced by HEMA.},
}
@article {pmid37777475,
year = {2024},
author = {Khoury, ES and Patel, RV and O'Ferrall, C and Fowler, A and Sah, N and Sharma, A and Gupta, S and Scafidi, S and Kurtz, JS and Olmstead, SJ and Kudchadkar, SR and Kannan, RM and Blue, ME and Kannan, S},
title = {Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.},
journal = {Journal of neurochemistry},
volume = {168},
number = {5},
pages = {841-854},
pmid = {37777475},
issn = {1471-4159},
support = {F32 NS010085/NS/NINDS NIH HHS/United States ; P50 HD103538/HD/NICHD NIH HHS/United States ; R01 NS113140/NS/NINDS NIH HHS/United States ; R21NS10085/NS/NINDS NIH HHS/United States ; P50 HD103538/HD/NICHD NIH HHS/United States ; //Hartwell Foundation/ ; R01 NS113140/NS/NINDS NIH HHS/United States ; R21NS10085/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; *Rett Syndrome/genetics/drug therapy ; Female ; *Methyl-CpG-Binding Protein 2/genetics ; Mice ; *Neuroglia/drug effects/metabolism ; *Disease Models, Animal ; *Dendrimers ; Phenotype ; Mice, Inbred C57BL ; Neuroinflammatory Diseases/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; Inflammation/drug therapy/metabolism ; Heterozygote ; Behavior, Animal/drug effects ; },
abstract = {Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.},
}
@article {pmid37774561,
year = {2023},
author = {Blum, K and Ashford, JW and Kateb, B and Sipple, D and Braverman, E and Dennen, CA and Baron, D and Badgaiyan, R and Elman, I and Cadet, JL and Thanos, PK and Hanna, C and Bowirrat, A and Modestino, EJ and Yamamoto, V and Gupta, A and McLaughlin, T and Makale, M and Gold, MS},
title = {Dopaminergic dysfunction: Role for genetic &amp; epigenetic testing in the new psychiatry.},
journal = {Journal of the neurological sciences},
volume = {453},
number = {},
pages = {120809},
doi = {10.1016/j.jns.2023.120809},
pmid = {37774561},
issn = {1878-5883},
abstract = {Reward Deficiency Syndrome (RDS), particularly linked to addictive disorders, costs billions of dollars globally and has resulted in over one million deaths in the United States (US). Illicit substance use has been steadily rising and in 2021 approximately 21.9% (61.2 million) of individuals living in the US aged 12 or older had used illicit drugs in the past year. However, only 1.5% (4.1 million) of these individuals had received any substance use treatment. This increase in use and failure to adequately treat or provide treatment to these individuals resulted in 106,699 overdose deaths in 2021 and increased in 2022. This article presents an alternative non-pharmaceutical treatment approach tied to gene-guided therapy, the subject of many decades of research. The cornerstone of this paradigm shift is the brain reward circuitry, brain stem physiology, and neurotransmitter deficits due to the effects of genetic and epigenetic insults on the interrelated cascade of neurotransmission and the net release of dopamine at the Ventral Tegmental Area -Nucleus Accumbens (VTA-NAc) reward site. The Genetic Addiction Risk Severity (GARS) test and pro-dopamine regulator nutraceutical KB220 were combined to induce "dopamine homeostasis" across the brain reward circuitry. This article aims to encourage four future actionable items: 1) the neurophysiologically accurate designation of, for example, "Hyperdopameism /Hyperdopameism" to replace the blaming nomenclature like alcoholism; 2) encouraging continued research into the nature of dysfunctional brainstem neurotransmitters across the brain reward circuitry; 3) early identification of people at risk for all RDS behaviors as a brain check (cognitive testing); 4) induction of dopamine homeostasis using "precision behavioral management" along with the coupling of GARS and precision Kb220 variants; 5) utilization of promising potential treatments include neuromodulating modalities such as Transmagnetic stimulation (TMS) and Deep Brain Stimulation(DBS), which target different areas of the neural circuitry involved in addiction and even neuroimmune agents like N-acetyl-cysteine.},
}
@article {pmid37773178,
year = {2023},
author = {Koning, T and Cordova, F and Aguilar, G and Sarmiento, J and Mardones, GA and Boric, M and Varas-Godoy, M and Lladser, A and Duran, WN and Ehrenfeld, P and Sanchez, FA},
title = {S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis.},
journal = {Biological research},
volume = {56},
number = {1},
pages = {51},
pmid = {37773178},
issn = {0717-6287},
support = {R01 GM122940/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Female ; *Breast Neoplasms/pathology ; Cell Adhesion ; Endothelial Cells ; Vascular Cell Adhesion Molecule-1/metabolism ; Nitric Oxide/metabolism ; Cutaneous Malignant Melanoma ; },
abstract = {BACKGROUND: Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown.<br><br>RESULTS: We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases.<br><br>CONCLUSIONS: S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.},
}
@article {pmid37771516,
year = {2023},
author = {Meziu, E and Shehu, K and Koch, M and Schneider, M and Kraegeloh, A},
title = {Impact of mucus modulation by N-acetylcysteine on nanoparticle toxicity.},
journal = {International journal of pharmaceutics: X},
volume = {6},
number = {},
pages = {100212},
pmid = {37771516},
issn = {2590-1567},
abstract = {Human respiratory mucus is a biological hydrogel that forms a protective barrier for the underlying epithelium. Modulation of the mucus layer has been employed as a strategy to enhance transmucosal drug carrier transport. However, a drawback of this strategy is a potential reduction of the mucus barrier properties, in particular in situations with an increased exposure to particles. In this study, we investigated the impact of mucus modulation on its protective role. In vitro mucus was produced by Calu-3 cells, cultivated at the air-liquid interface for 21 days and used for further testing as formed on top of the cells. Analysis of confocal 3D imaging data revealed that after 21 days Calu-3 cells secrete a mucus layer with a thickness of 24 ± 6 μm. Mucus appeared to restrict penetration of 500 nm carboxyl-modified polystyrene particles to the upper 5-10 μm of the layer. Furthermore, a mucus modulation protocol using aerosolized N-acetylcysteine (NAC) was developed. This treatment enhanced the penetration of particles through the mucus down to deeper layers by means of the mucolytic action of NAC. These findings were supported by cytotoxicity data, indicating that intact mucus protects the underlying epithelium from particle-induced effects on membrane integrity. The impact of NAC treatment on the protective properties of mucus was probed by using 50 and 100 nm amine-modified and 50 nm carboxyl-modified polystyrene nanoparticles, respectively. Cytotoxicity was only induced by the amine-modified particles in combination with NAC treatment, implying a reduced protective function of modulated mucus. Overall, our data emphasize the importance of integrating an assessment of the protective function of mucus into the development of therapy approaches involving mucus modulation.},
}
@article {pmid37769128,
year = {2023},
author = {Chakraborty, S and Bhattacharya, I and Mitra, RK},
title = {Solvation Plays a Key Role in Antioxidant-Mediated Attenuation of Elevated Creatinine Level: An In Vitro Spectroscopic Investigation.},
journal = {The journal of physical chemistry. B},
volume = {127},
number = {40},
pages = {8576-8585},
doi = {10.1021/acs.jpcb.3c05334},
pmid = {37769128},
issn = {1520-5207},
mesh = {Humans ; *Antioxidants ; Creatinine/urine ; Ascorbic Acid ; *Kidney Diseases ; Spectroscopy, Fourier Transform Infrared ; Acetylcysteine ; },
abstract = {An elevated level of creatinine (CRN) is a mark of kidney ailment, and prolonged retention of such condition could lead to renal failure, associated with severe ischemia. Antioxidants are clinically known to excrete CRN from the body through urine, thereby reducing its level in blood. The molecular mechanism of such an exclusion process is still illusive. As the excretion channel is urine, solvation of the solute is expected to play a pivotal role. Here, we report a detailed time-domain and frequency-domain terahertz (THz) spectroscopic investigation to understand the solvation of CRN in the presence of two model antioxidants, mostly used to treat elevated CRN level: N-Acetyl-l-cysteine (NAC) and ascorbic acid (ASC). FTIR spectroscopy in the mid-infrared region and UV absorption spectroscopy measurements coupled with quantum chemical calculations [at the B3LYP/6-311G++(d,p) level] reveal that both NAC and ASC form HBonded complexes with CRN and rapidly undergo a barrier-less proton transfer process to form creatinium ions. THz measurements provide explicit evidence of the formation of highly solvated complexes compared with bare CRN, which eventually enables its excretion through urine. These observations could provide a foundation for designing more beneficial drugs to resolve kidney diseases..},
}
@article {pmid37767143,
year = {2023},
author = {Alizadeh, N and Yaryari, AM and Behnoush, AH and Raoufinejad, K and Behnoush, B},
title = {Late N-acetylcysteine for successful recovery of acetaminophen-related acute liver failure: A case report.},
journal = {Clinical case reports},
volume = {11},
number = {9},
pages = {e7946},
pmid = {37767143},
issn = {2050-0904},
abstract = {Acetaminophen toxicity is one of the leading causes of liver failure. Although N-acetylcysteine (NAC) is generally successful in preventing acetaminophen hepatotoxicity when given in a timely manner, if not prescribed in the early golden time, the only practical way to save the patient might be liver transplantation. The case presented was a 20-year-old female with an acetaminophen overdose (30 g), for which more than 24 h had passed since the ingestion. Despite the critical clinical condition, loss of consciousness (Glasgow Coma Score of 4) of the patient, and passing the golden time of antidote administration, the decision was made by the healthcare team to administer NAC. After transferring the patient to the intensive care unit, the three-bag NAC regimen was initiated and appropriate monitoring was performed. After this, the regimen of 3 g q8h was continued for the patient. The patient's condition began to improve slowly on the second day and then she was extubated on the fourth day. Finally, she was discharged on the tenth day. Although the golden period of antidote administration had passed outwardly, there was no need for a liver transplant and the patient recovered successfully with late NAC administration. Hence, clinicians can benefit from the use of NAC even in the late phases of acetaminophen liver toxicity.},
}
@article {pmid37766400,
year = {2023},
author = {Benizio, E and Moreira-Espinoza, MJ and Triquell, MF and Mezzano, L and Díaz-Luján, CM and Fretes, RE},
title = {Pro-inflammatory cytokines are modified during the multiplication of Trypanosoma cruzi within the placental chorionic villi and are associated with the level of infection via the signaling pathway NF-κB.},
journal = {American journal of reproductive immunology (New York, N.Y. : 1989)},
volume = {90},
number = {4},
pages = {e13777},
doi = {10.1111/aji.13777},
pmid = {37766400},
issn = {1600-0897},
mesh = {Pregnancy ; Female ; Humans ; NF-kappa B ; Chorionic Villi ; Placenta ; Interleukin-10 ; *Trypanosoma cruzi ; Cytokines ; Tumor Necrosis Factor-alpha ; Signal Transduction ; *Chagas Disease ; },
abstract = {PROBLEM: Congenital Trypanosoma cruzi (T. cruzi) infection has been associated with changes in the levels of TNF-α and IFN-γ during the pregnancy. Therefore, we propose to study the participation and dynamics of proinflammatory cytokines in the infection process of placental explants infected by T. cruzi in vitro.<br><br>METHOD OF STUDY: Chorionic villous explants (CVE) obtained of human term placentas (n&#xa0;=&#xa0;8) from normal pregnancies were cultured with 10[5] trypomastigotes/mL of Tulahuen strain DTU VI for 0, 2, 4, 16, 24, 48 and 72&#xa0;h. Explants were treated with sulfasalazine (SULF) (5&#xa0;mM) and N-acetyl-cysteine (NAC) (15&#xa0;mM), as inhibitors molecules of NF-&#x3ba;B pathway, or LPS (1&#xa0;&#x3bc;g/mL) for 24 and 72&#xa0;h p.i. Motile trypomastigotes were counted in culture supernatants. Immunohistochemistry and ELISA for TNF-&#x3b1;, IFN-&#x3b3;, IL-1&#x3b2;, IL-4, and IL-10 were performed in CVE and culture supernatants respectively. The parasite load was measured by RT-qPCR.<br><br>RESULTS: T. cruzi invades the chorionic villi from 4&#xa0;h p.i. increasing significantly its DNA at 48 and 72&#xa0;h p.i. of culture (parasite multiplication phase). They were detected in stromal cells, which was related to elevation of TNF-&#x3b1;, IL-1&#x3b2;, IFN-&#x3b3;, and IL-10. The inhibition of NF-&#x3ba;B activity in the explants decreased the production of the analyzed cytokines, showing elevated levels of T. cruzi DNA during the multiplication phase of the parasite.<br><br>CONCLUSIONS: Placental tissue modifies the secretion of pro-inflammatory cytokines during the phase of parasite multiplication, but not during the invasion phase, which in turns modifies the level of infection via the signaling pathway NF-&#x3ba;B.},
}
@article {pmid37762548,
year = {2023},
author = {Chen, JS and Chiu, SC and Huang, SY and Chang, SF and Liao, KF},
title = {Isolinderalactone Induces Apoptosis, Autophagy, Cell Cycle Arrest and MAPK Activation through ROS-Mediated Signaling in Colorectal Cancer Cell Lines.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
pmid = {37762548},
issn = {1422-0067},
support = {TCMF-A 108-014//Buddhist Tzu Chi Medical Foundation/ ; TTCRD110-21//Buddhist Tzu Chi Medical Foundation/ ; TTCRD110-31//Buddhist Tzu Chi Medical Foundation/ ; TTCRD111-33//Buddhist Tzu Chi Medical Foundation/ ; },
mesh = {Humans ; Apoptosis ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; G2 Phase Cell Cycle Checkpoints ; Cell Cycle Checkpoints ; *Sesquiterpenes/pharmacology ; Autophagy ; *Colorectal Neoplasms/drug therapy ; Cell Proliferation ; },
abstract = {Colorectal cancer (CRC) is one of the most common malignancies worldwide. Isolinderalactone (ILL), a sesquiterpene isolated from the root extract of Lindera aggregata, has been reported to exhibit anti-proliferative and anti-metastatic activities in various cancer cell lines. However, the mechanisms associated with its antitumor effects on CRC cells remain unclear. ILL treatment significantly suppressed proliferation and induced cell cycle G2/M arrest in CRC cells by inhibiting the expression of cyclin B, p-cdc2, and p-cdc25c and up-regulating the expression of p21. In addition, ILL induced mitochondria-associated apoptosis through the up-regulation of cleaved -caspase-9 and -3 expression. ILL induced autophagy by increasing the levels of LC3B in CRC cells, which was partially rescued by treatment with an autophagy inhibitor (chloroquine). Furthermore, ILL increases the accumulation of reactive oxygen species (ROS) and activates the MAPK pathway. Application of the ROS scavenger, N-acetyl cysteine (NAC), effectively inhibited ILL toxicity and reversed ILL-induced apoptosis, cell cycle arrest, autophagy, and ERK activation. Taken together, these results suggest that ILL induces G2/M phase arrest, apoptosis, and autophagy and activates the MAPK pathway via ROS-mediated signaling in human CRC cells.},
}
@article {pmid37761021,
year = {2023},
author = {Ahmad, IM and Dafferner, AJ and Salloom, RJ and Abdalla, MY},
title = {Heme Oxygenase-1 Inhibition Modulates Autophagy and Augments Arsenic Trioxide Cytotoxicity in Pancreatic Cancer Cells.},
journal = {Biomedicines},
volume = {11},
number = {9},
pages = {},
pmid = {37761021},
issn = {2227-9059},
abstract = {Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form, accounting for more than 90% of all pancreatic malignancies. In a previous study, we found that hypoxia and chemotherapy induced expression of Heme Oxygenase-1 (HO-1) in PDAC cells and tissues. Arsenic trioxide (ATO) is the first-line chemotherapeutic drug for acute promyelocytic leukemia (APL). ATO increases the generation of reactive oxidative species (ROS) and induces apoptosis in treated cells. The clinical use of ATO for solid tumors is limited due to severe systemic toxicity. In order to reduce cytotoxic side effects and resistance and improve efficacy, it has become increasingly common to use combination therapies to treat cancers. In this study, we used ATO-sensitive and less sensitive PDAC cell lines to test the effect of combining HO-1 inhibitors (SnPP and ZnPP) with ATO on HO-1 expression, cell survival, and other parameters. Our results show that ATO significantly induced the expression of HO-1 in different PDAC cells through the p38 MAPK signaling pathway. ROS production was confirmed using the oxygen-sensitive probes DCFH and DHE, N-acetyl cysteine (NAC), an ROS scavenger, and oxidized glutathione levels (GSSG). Both ATO and HO-1 inhibitors reduced PDAC cell survival. In combined treatment, inhibiting HO-1 significantly increased ATO cytotoxicity, disrupted the GSH cycle, and induced apoptosis as measured using flow cytometry. ATO and HO-1 inhibition modulated autophagy as shown by increased expression of autophagy markers ATG5, p62, and LC3B in PDAC cells. This increase was attenuated by NAC treatment, indicating that autophagy modulation was through an ROS-dependent mechanism. In conclusion, our work explored new strategies that could lead to the development of less toxic and more effective therapies against PDAC by combining increased cellular stress and targeting autophagy.},
}
@article {pmid37760016,
year = {2023},
author = {Mokra, D and Mokry, J and Barosova, R and Hanusrichterova, J},
title = {Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {9},
pages = {},
pmid = {37760016},
issn = {2076-3921},
support = {APVV-15_0075//Slovak Research and Development Agency/ ; APVV-18-0084//Slovak Research and Development Agency/ ; APVV-22-0342//Slovak Research and Development Agency/ ; VEGA 1/0131/22//VEGA/ ; VEGA 1/0093/22//VEGA/ ; },
abstract = {N-acetylcysteine (NAC) is widely used because of its mucolytic effects, taking part in the therapeutic protocols of cystic fibrosis. NAC is also administered as an antidote in acetaminophen (paracetamol) overdosing. Thanks to its wide antioxidative and anti-inflammatory effects, NAC may also be of benefit in other chronic inflammatory and fibrotizing respiratory diseases, such as chronic obstructive pulmonary disease, bronchial asthma, idiopathic lung fibrosis, or lung silicosis. In addition, NAC exerts low toxicity and rare adverse effects even in combination with other treatments, and it is cheap and easily accessible. This article brings a review of information on the mechanisms of inflammation and oxidative stress in selected chronic respiratory diseases and discusses the use of NAC in these disorders.},
}
@article {pmid37746996,
year = {2023},
author = {Abushanab, D and Gasim, M and Devi, D and Elbdairy, M and Elqasass, H and Ahmed, N and Vincent, M and Abdul Rouf, PV and Mohammed, HR and Hail, MA and Thomas, B and Elkassem, W and Hanssens, Y and Elgassim, M and Elmoheen, A and Azad, A and Mohammed, S and Salem, W},
title = {Patterns and outcomes of paracetamol poisoning management in Hamad Medical Corporation, Qatar: A retrospective cohort study.},
journal = {Medicine},
volume = {102},
number = {38},
pages = {e34872},
pmid = {37746996},
issn = {1536-5964},
mesh = {Young Adult ; Humans ; Adolescent ; Adult ; Qatar/epidemiology ; Acetaminophen ; Retrospective Studies ; *Drug-Related Side Effects and Adverse Reactions ; *Drug Overdose/therapy ; Acetylcysteine/therapeutic use ; },
abstract = {We aimed to investigate the characteristics and clinical outcomes of paracetamol poisoning and paracetamol overdose in Qatar. This retrospective cohort study included patients admitted to the emergency department (ED). We included patients who presented with excessive paracetamol ingestion, between December 2018 and September 2019. The primary outcomes were describing the characteristics and outcomes of paracetamol overdose (from a suicidal overdose or accidental overdose, dose ≤ 150 mg/kg, when serum levels of <60 mmol/L) or dose ingested (≤75 mg/kg) with staggered ingestion poisoning due to suicidal attempt or accidental attempt, defined as the dose ingested (>150 mg/kg), acute ingestion, nomogram level more than the treatment line, or dose ingested (>75 mg/kg) with staggered ingestion, and assessing the management of excessive paracetamol ingestion. Secondary outcomes included evaluation of the time difference between ingestion and time of administration, hospitalization, and adverse drug events. Significant differences were detected between patients who presented with paracetamol overdose and those who presented with paracetamol toxicity. A total of 69 patients were analyzed, of whom 43 received paracetamol overdose (mean age 27.5 ± 11.1 years) and 26 had paracetamol poisoning (mean age 25 ± 6.22 years). Paracetamol poisoning was identified in 26% of the patients with a 24.3% history of psychiatric illness, compared to 18.6% with paracetamol overdose. More patients presented with paracetamol toxicity in the time between ingestion and obtaining serum levels compared to the overdose group. A significantly longer length of hospitalization was observed in the toxicity group. A significantly higher number of patients in the toxicity group received N-acetylcysteine (NAC). More hypotension and rashes were observed among those who received NAC in the toxicity group. Patients presenting to the ED due to paracetamol toxicity are not uncommon, and most cases occur in young adults, and few in patients with a history of psychiatric illness, suggesting that preventive approaches are highly required.},
}
@article {pmid37742933,
year = {2023},
author = {Zhuang, J and Yuan, Q and Chen, C and Liu, G and Zhong, Z and Zhu, K and Guo, J},
title = {Nanosecond pulsed cold atmospheric plasma jet suppresses proliferation and migration of human glioblastoma cells via apoptosis promotion and EMT inhibition.},
journal = {Archives of biochemistry and biophysics},
volume = {747},
number = {},
pages = {109757},
doi = {10.1016/j.abb.2023.109757},
pmid = {37742933},
issn = {1096-0384},
mesh = {Humans ; *Glioblastoma/metabolism ; Epithelial-Mesenchymal Transition ; Reactive Oxygen Species ; Apoptosis ; Cell Proliferation ; Cell Line, Tumor ; Cell Movement ; *Brain Neoplasms/metabolism ; },
abstract = {Glioblastoma (GBM) is one of the most aggressive and challenging cancers to treat. Despite extensive research on dozens of cancer cells, including GBM, the effect of cold atmospheric plasma (CAP) on the invasive migration of GBM cells has received limited attention, and the underlying mechanisms remain poorly understood. This study aims to investigate the potential molecular mechanism of ns-CAPJ in inhibiting the invasive migration of human GBM cells. The findings indicate that ns-CAPJ significantly reduces GBM cell invasion and migration, and induces apoptosis in GBM cells. Further mechanistic studies demonstrate a direct correlation between the suppression of the epithelial-mesenchymal transition (EMT) signaling pathway and ns-CAPJ's inhibitory effect on GBM cell invasion and migration. Additionally, combined with the N-acetyl cysteine (NAC, a ROS inhibitor) assay, we found that the ROS stimulated by the ns-CAPJ plays an important role in suppressing the EMT process. This work is expected to provide new insight into understanding the molecular mechanisms of how ns-CAPJ inhibits the proliferation and migration of human GBM cells.},
}
@article {pmid37742495,
year = {2023},
author = {Zeng, Y and Yang, Q and Ouyang, Y and Lou, Y and Cui, H and Deng, H and Zhu, Y and Geng, Y and Ouyang, P and Chen, L and Zuo, Z and Fang, J and Guo, H},
title = {Nickel induces blood-testis barrier damage through ROS-mediated p38 MAPK pathways in mice.},
journal = {Redox biology},
volume = {67},
number = {},
pages = {102886},
pmid = {37742495},
issn = {2213-2317},
mesh = {Mice ; Male ; Animals ; *p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; *Blood-Testis Barrier/metabolism ; Reactive Oxygen Species/metabolism ; Nickel/toxicity/metabolism ; Testis/metabolism ; },
abstract = {Nickel (Ni) is an essential common environmental contaminant, it is hazardous to male reproduction, but the precise mechanisms are still unknown. Blood-testis barrier (BTB), an important testicular structure consisting of connections between sertoli cells, is the target of reproductive toxicity caused by many environmental toxins. In this study, ultrastructure observation and BTB integrity assay results indicated that NiCl2 induced BTB damage. Meanwhile, BTB-related proteins including the tight junction (TJ), adhesion junction (AJ) and the gap junction (GJ) protein expression in mouse testes as well as in sertoli cells (TM4) were significantly decreased after NiCl2 treatment. Next, the antioxidant N-acetylcysteine (NAC) was co-treated with NiCl2 to study the function of oxidative stress in NiCl2-mediated BTB deterioration. The results showed that NAC attenuated testicular histopathological damage, and the expression of BTB-related proteins were markedly reversed by NAC co-treatment in vitro and vivo. Otherwise, NiCl2 activated the p38 MAPK signaling pathway. And, NAC co-treatment could significantly inhibit p38 activation induced by NiCl2 in TM4 cells. Furthermore, in order to confirm the role of the p38 MAPK signaling pathway in NiCl2-induced BTB impairment, a p38 inhibitor (SB203580) was co-treated with NiCl2 in TM4 cells, and p38 MAPK signaling inhibition significantly restored BTB damage induced by NiCl2 in TM4 cells. These results suggest that NiCl2 treatment destroys the BTB, in which the oxidative stress-mediated p38 MAPK signaling pathway plays a vital role.},
}
@article {pmid37741428,
year = {2023},
author = {Araujo, AM and Cerqueira, SVS and Menezes-Filho, JER and Heimfarth, L and Matos, KKOG and Mota, KO and Conceição, MRL and Marques, LP and Roman-Campos, D and Santos-Neto, AGD and Albuquerque-Júnior, RLC and Santos, VCO and Vasconcelos, CML},
title = {Naringin improves post-ischemic myocardial injury by activation of KATP channels.},
journal = {European journal of pharmacology},
volume = {958},
number = {},
pages = {176069},
doi = {10.1016/j.ejphar.2023.176069},
pmid = {37741428},
issn = {1879-0712},
abstract = {Naringin (NRG) is a flavonoid with recognized cardioprotective effects. Then, it was investigated the cardioprotective mechanisms of NRG against ischemia-reperfusion (I/R) injury. The rats were pretreated for 7 days (v.o.) with NRG (25 mg/kg) or n-acetylcysteine (NAC, 100 mg/kg) and their isolated hearts were subjected to global ischemia (30 min) and reperfusion (60 min). Furthermore, isolated hearts were perfused with 5 μM NRG in the presence of 10 μM glibenclamide (GLI) and subjected to I/R protocol. In healthy ventricular cardiomyocyte, it was evaluated the acute effect of 5 μM NRG on the GLI sensitive current. The results showed that NRG pretreatment restored the cardiac function and electrocardiogram (ECG) alterations induced by I/R injury, decreasing arrhythmia scores and the occurrence of severe arrhythmias. Lactate dehydrogenase and infarct area were decreased while superoxide dismutase (SOD), catalase and citrate synthase activities increased. Expression of SOD CuZn and SOD Mn not was altered. NRG treatment decreased reactive oxygen species (ROS) generation and lipid peroxidation without alter sulfhydryl groups and protein carbonylation. Also, NRG (5 μM) increased the glibenclamide sensitive current in isolated cardiomyocytes. In isolated heart, the cardioprotection of NRG was significantly reduced by GLI. Furthermore, NRG promoted downregulation of Bax expression and Bax/Bcl-2. Histopathological analysis showed that NRG decreased cell edema, cardiomyocytes and nucleus diameter. Thus, NRG has a cardioprotective effect against cardiac I/R injury which is mediated by its antioxidant and antiapoptotic actions and KATP channels activation.},
}
@article {pmid37741051,
year = {2023},
author = {Fayyazi, F and Ebrahimi, V and Mamaghani, MM and Abgharmi, BA and Zarrini, G and Mosarrezaii, A and Charkhian, H and Gholinejad, Z},
title = {N-Acetyl cysteine amide and cerium oxide nanoparticles as a drug delivery for ischemic stroke treatment: Inflammation and oxidative stress crosstalk.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {80},
number = {},
pages = {127300},
doi = {10.1016/j.jtemb.2023.127300},
pmid = {37741051},
issn = {1878-3252},
mesh = {Humans ; Rats ; Animals ; Antioxidants/pharmacology/metabolism ; Chitinase-3-Like Protein 1/pharmacology ; *Ischemic Stroke ; Olive Oil/pharmacology ; Oxidative Stress ; *Cerium/pharmacology ; Inflammation/drug therapy/pathology ; *Nanoparticles ; Acetylcysteine/pharmacology/analogs &amp; derivatives ; Drug Delivery Systems ; Anti-Bacterial Agents/pharmacology ; Urea ; Amides/pharmacology ; Copper ; Titanium ; },
abstract = {BACKGROUND: Inflammation and oxidative stress crosstalk is involved in the ischemic stroke(IS) pathogenesis and the new therapeutic options should be offered based on the targets that are critical in the golden hour of IS. YKL-40 and total antioxidant capacity(TAC), the inflammation and oxidative stress biomarkers, provide us with clues for proper intervention targets. N-acetyl cysteine amide (NACA), a lipophilic antioxidant, with a nanoparticle-based drug delivery system is permeable enough to penetrate blood-brain barrier (BBB) and was proposed as a new treatment option for IS. In this study, we evaluated the YKL-40 and TAC levels in the sera of IS patients to elucidate the best intervention target. A rat tissue model is used to assess the NACA efficiency. The microbiology tests performed to figure out the potential NACA and antibiotics interactions.<br><br>MATERIAL AND METHODS: The YKL-40 and TAC were measured in the serum of IS patients by ELISA and FRAP methods, respectively. The serum samples were obtained 12&#xa0;h after the patient's admission and meantime other laboratory findings and NIHSS-based prognosis were recorded. In the animal study, the brain cortex, liver, kidney, adipose, and the heart of healthy rats were dissected and then incubated in DMEM cell culture media containing 50 micrograms/milliliter of nanoparticles; the nanoparticles were titanium dioxide nanoparticles (TiO2 NPs), copper oxide nanoparticles (CuO NPs) and cerium dioxide nanoparticles (CeO2 NPs). Olive oil and human serum albumin solution were exposed to the nanoparticles with and without NACA. TAC was measured in the supernatant culture media. With similar concentrations and settings, we evaluated the NACA, nanoparticle, and antibiotics interactions on pseudomonas aeruginosa.<br><br>RESULTS: There was a nonparametric correlation between YKL-40 levels and post stroke serum TAC levels. Nonsmokers had higher YKL-40 and TAC levels than smokers. A new calculated variable, urea*lymphocyte/age, predicts a poor prognosis with an acceptable AUC (0.708). Exposing to the nanoparticles, the liver, kidney, and brain had a significantly higher TAC than adipose and cardiac tissue. The NACA had an ameliorative effect against TiO2 NPs in the brain. This effectiveness of NACA was also observed against CuO NPs treatment. However, the CeO2 NPs exert a strong antioxidant property by reducing the TAC in the brain tissue but not the others. Albumin showed antioxidant properties by itself, but olive oil had an inert behavior. NACA had no interaction with the action of routine antibiotics.<br><br>CONCLUSION: Oxidative stress but not inflammation is the best point for intervention in IS patients because YKL-40 has not a relationship with NIHSS score. The CeO2 NPs and NACA combination are eligible option to develop antioxidant-based drug for the treatment of IS. As a complementary finding, the urea*lymphocyte/age is proposed as a NIHSS-based prognosis biomarker.},
}
@article {pmid37739116,
year = {2023},
author = {Mushtaq, I and Mushtaq, I and Akhlaq, A and Usman, S and Ishtiaq, A and Khan, M and Mustafa, G and Khan, MS and Urooj, I and Bibi, S and Liaqat, F and Akhtar, Z and Murtaza, I},
title = {Cardioprotective effect of tetra(aniline) containing terpolymers through miR-15a-5p and MFN-2 regulation against hypertrophic responses.},
journal = {Archives of biochemistry and biophysics},
volume = {747},
number = {},
pages = {109763},
doi = {10.1016/j.abb.2023.109763},
pmid = {37739116},
issn = {1096-0384},
abstract = {OBJECTIVE: Cardiac hypertrophy is a condition of abnormal cardiomyocyte enlargement accompanied by ventricular wall thickening. The study aims to investigate the role of miR-15a-5p in the regulation of mitofusin-2 (MFN-2) and to explore the cardioprotective effect of terpolymers ES-37 and L-37.<br><br>METHODS: In this study, the Sprague Dawley rats' cardiac hypertrophic model was established by administering 5&#xa0;mg/kg Isoproterenol subcutaneously every other day for 14 days. As treatment rats received NAC (50&#xa0;mg/kg), NAC treatment (50&#xa0;mg/kg NAC&#xa0;+&#xa0;5&#xa0;mg/kg ISO), ES-37 (1&#xa0;mg/kg) and ES-37 treatment (1&#xa0;mg/kg ES-37+5&#xa0;mg/kg ISO), L-37 (1&#xa0;mg/kg) and L-37 treatment (1&#xa0;mg/kg L-37+5&#xa0;mg/kg ISO). subcutaneously every other day for 14 days. NAC, ES 37 and L-37 were given after 1&#xa0;h of Isoproterenol administration in treatment groups. Cardiac hypertrophy was confirmed through morphological and histological analysis. For estimation of oxidative stress profiling, ROS and TBARS and antioxidative profiling superoxide dismutase (SOD), Catalase, and Glutathione (GSH) levels were checked. Triglyceride, cholesterol, alanine transaminase (ALT), and aspartate transaminase (AST) were performed to evaluate levels of lipid profiling and liver profiling. Molecular expression analysis was checked through real-time PCR, and western blotting both at the transcriptional and translational levels. Molecular docking studies were performed to study the interactions and modes of binding between the synthetic polymers with three proteins (Mitofusin-2, DRP-1 and PUMA). All the studies were carried out using the AutoDock Vina software and the protein-ligand complexes were visualized in Biovia Discovery Studio. Cardiac hypertrophy was confirmed by the relative changes in the cellular structure of the heart by histopathological examination and physiological changes by estimating organ weights. Biochemical profiling results depict elevated oxidative and lipid profiles signify myocardial damage. N-acetyl cysteine (NAC), ES-37, and L-37 overcome the cardiac hypertrophic responses through attenuating oxidative stress and enhancing the antioxidative signaling mechanism. miR-15a-5p was identified as hypertrophic microRNA directly regulating the expression of Mitofusin-2 (MFN-2). Significantly increased expression of miR-15a-5p, Dynamin related protein 1 (Drp1), and P53 upregulated modulator of apoptosis (PUMA), was observed in the disease group, whereas MFN-2 expression was observed downregulated. N-acetyl cysteine (NAC), ES-37, and L-37 showed increased expression of antiapoptotic maker MFN-2 and decreased expression of miR-15a-5p, Drp1, and PUMA in treatment groups suggesting their cardioprotective role in attenuation of cardiac hypertrophy. An analysis of the docking results shows that ES-37 has greater binding affinity with the target proteins compared to L-37, with the highest binding values reported for MFN-2.<br><br>CONCLUSION: The physiochemical properties of ES-37 and L-37 predicted it as a good drug-like molecule and its mechanism of action is predictably through inhibition of ROS. Molecular docking results shows that the polymer ES-37 has greater binding affinity with the target proteins compared to L-37, with the highest binding values reported for MFN-2. Thus, the study validates the role and targeting of miR-15a-5p and MFN-2 in cardiac hypertrophy as well as the therapeutic potential of NAC, ES-37, and L-37 in overcoming oxidative stress and myocardial damage.},
}
@article {pmid37732506,
year = {2023},
author = {Sharma, S and Sharma, V and Taneja, S and Alka Bhatia, and Anand, A and Patil, AN and Banerjee, D},
title = {Scopoletin a potential phytochemical therapy for antitubercular treatment drug induced liver injury (ATT-DILI) model in Wistar rats.},
journal = {Journal of complementary &amp; integrative medicine},
volume = {20},
number = {4},
pages = {797-803},
pmid = {37732506},
issn = {1553-3840},
mesh = {Rats ; Animals ; Rats, Wistar ; *Scopoletin/pharmacology/therapeutic use/metabolism ; Plant Extracts/pharmacology/therapeutic use ; Antitubercular Agents/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy ; Liver ; Bilirubin/metabolism ; Alkaline Phosphatase/metabolism ; Carbon Tetrachloride/metabolism/pharmacology ; Alanine Transaminase/metabolism ; },
abstract = {OBJECTIVES: The hepatoprotective properties of scopoletin have been explored in carbon tetrachloride (CCl4) induced liver injury but not in drug-induced liver injury (DILI) scenarios. Only N-acetyl-cysteine (NAC) has proven efficacy in DILI treatment. Accordingly, we conducted a study to assess the hepatoprotective action of scopoletin in the anti-tubercular treatment (ATT)-DILI model in Wistar rats, if any.<br><br>METHODS: A total of 36 rats were evaluated, with six in each group. A 36-day ATT at 100&#x202f;mg/kg dose for isoniazid, 300&#x202f;mg/kg for rifampicin and 700&#x202f;mg/kg for pyrazinamide were fed to induce hepatotoxicity in rats. Group I and II-VI received normal saline and ATT, respectively. Oral scopoletin (1,5 and 10&#x202f;mg/kg) and NAC 150&#x202f;mg/kg were administered in groups III, IV, V and VI, respectively, once daily for the last&#xa0;15&#xa0;days of the experiment. LFT monitoring was performed at baseline, days 21, 28, and 36. Rats were sacrificed for the histopathology examination.<br><br>RESULTS: Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin levels were significantly increased in group II (receiving ATT) compared to normal control on day 28 and day 36 (p<0.05). All three doses of scopoletin and NAC groups led to the resolution of AST, ALT, ALP, and bilirubin changes induced by ATT medications effect beginning by day 28 and persisting on day 36 (p<0.01). An insignificant effect was observed on albumin and total protein levels. The effect was confirmed with antioxidants and histopathology analysis.<br><br>CONCLUSIONS: The study confirms the hepatoprotective efficacy of scopoletin in a more robust commonly encountered liver injury etiology.},
}
@article {pmid37730076,
year = {2023},
author = {Zhou, X and Chen, Q and Chen, L and Liao, X and Wang, Z and Zhu, F},
title = {The effect of reactive oxygen species (ROS) in immunity and WSSV infection of Scylla paramamosain.},
journal = {Fish &amp; shellfish immunology},
volume = {141},
number = {},
pages = {109075},
doi = {10.1016/j.fsi.2023.109075},
pmid = {37730076},
issn = {1095-9947},
mesh = {Animals ; Reactive Oxygen Species ; *Brachyura ; *White spot syndrome virus 1/physiology ; Arthropod Proteins ; Immunity, Innate/genetics ; *Virus Diseases ; Superoxide Dismutase ; Hemocytes ; },
abstract = {Reactive oxygen species (ROS) are typically regarded as being generated by the cellular respiratory chain or by cells under pathological damage, which play a crucial role as signaling molecules in promoting hemocytes circulation and normal cellular physiological functions. In this study, the antioxidant N-acetylcysteine (NAC) was used to reduce ROS in vivo and in vitro, which to analyze the effect of ROS on innate immunity and viral infection of mud crab. The total hemocyte count (THC), phenoloxidase (PO), superoxide dismutase (SOD) activity, immune-relative genes were analyzed, respectively. Moreover, the effect of ROS on WSSV infection was analyzed by THC and hemocytes apoptosis. The data showed that NAC could effectively remove and inhibit intracellular ROS. The THC of NAC group was reduced at 12 h and 24 h compared with that of control. And the inhibition of ROS by NAC could increase the SOD activity with control group, while increased the PO activity caused by early WSSV infection. And NAC could up-regulate the expression of MCM7, JAK, TLR and proPO significantly, while down-regulate the expression of Astakine, proPO, caspase and p53. Similarly, NAC could inhibit WSSV-induced apoptosis of S. paramamosain hemocytes. The data illustrated that ROS participates in the interaction between hemocytes and virus infection by regulating innate immunity. Especially, after NAC inhibited ROS, the expression of hemocytes proliferation gene Astakine was also inhibited, which may indicate that ROS is related to the process of hemocytes proliferation. The data will show a preliminary exploration on the regulatory role of ROS in crustacean immune system.},
}
@article {pmid37726091,
year = {2023},
author = {Sun, Z and Wu, K and Feng, C and Lei, XG},
title = {Selenium-dependent glutathione peroxidase 1 regulates transcription of elongase 3 in murine tissues.},
journal = {Free radical biology &amp; medicine},
volume = {208},
number = {},
pages = {708-717},
doi = {10.1016/j.freeradbiomed.2023.09.010},
pmid = {37726091},
issn = {1873-4596},
mesh = {Humans ; Male ; Mice ; Animals ; Infant ; *Glutathione Peroxidase GPX1 ; *Selenium/metabolism ; Glutathione Peroxidase/genetics/metabolism ; Fatty Acid Elongases/genetics/metabolism ; Diquat/metabolism ; HEK293 Cells ; Mice, Knockout ; RNA, Messenger/metabolism ; Liver/metabolism ; Organoselenium Compounds ; Isoindoles ; },
abstract = {We have previously shown dysregulated lipid metabolism in tissues of glutathione peroxidase 1 (GPX1) overexpressing (OE) or deficient (KO) mice. This study explored underlying mechanisms of GPX1 in regulating tissue fatty acid (FA) biosynthesis. GPX1 OE, KO, and wild-type (WT) mice (n = 5, male, 3-6 months old) were fed a Se-adequate diet (0.3 mg/kg) and assayed for liver and adipose tissue FA profiles and mRNA levels of key enzymes of FA biosynthesis and redox-responsive transcriptional factors (TFs). These three genotypes of mice (n = 5) were injected intraperitoneally with diquat, ebselen, and N-acetylcysteine (NAC) at 10, 50, and 50 mg/kg of body weight, respectively, and killed at 0 and 12 h after the injections to detect mRNA levels of FA elongases and desaturases and the TFs in the liver and adipose tissue. A luciferase reporter assay with targeted deletions of mouse Elovl3 promoter was performed to determine transcriptional regulations of the gene by GPX1 mimic ebselen in HEK293T cells. Compared with WT, GPX1 OE and KO mice had 9-42% lower (p < 0.05) and 36-161% higher (p < 0.05) concentrations of C20:0, C22:0, and C24:0 in these two tissues, respectively, along with reciprocal increases and decreases (p < 0.05) of Elovl3 transcripts. Ebselen and NAC decreased (p < 0.05), whereas diquat decreased (p < 0.05), Elovl3 transcripts in the two tissues. Overexpression and knockout of GPX1 decreased (p < 0.05) and increased (p < 0.05) ELOVL3 levels in the two tissues, respectively. Three TFs (GABP, SP1, and DBP) were identified to bind the Elovl3 promoter (-1164/+33 base pairs). Deletion of DBP (-98/-86 base pairs) binding domain in the promoter attenuated (13%, p < 0.05) inhibition of ebselen on Elovl3 promoter activation. In summary, GPX1 overexpression down-regulated very long-chain FA biosynthesis via transcriptional inhibition of the Elovl3 promoter activation.},
}
@article {pmid37716334,
year = {2023},
author = {Chung, TW and Cheng, CL and Liu, YH and Huang, YC and Chen, WP and Panda, AK and Chen, WL},
title = {Dopamine-dependent functions of hyaluronic acid/dopamine/silk fibroin hydrogels that highly enhance N-acetyl-L-cysteine (NAC) delivered from nasal cavity to brain tissue through a near-infrared photothermal effect on the NAC-loaded hydrogels.},
journal = {Biomaterials advances},
volume = {154},
number = {},
pages = {213615},
doi = {10.1016/j.bioadv.2023.213615},
pmid = {37716334},
issn = {2772-9508},
mesh = {Rats ; Animals ; *Fibroins ; Acetylcysteine/pharmacology ; Hyaluronic Acid/pharmacology ; Dopamine/pharmacology ; Hydrogels/pharmacology ; Nasal Cavity ; Brain ; },
abstract = {Hyaluronic acid/silk fibroin (HA/SF or HS) hydrogels with remarkable mechanical characteristics have been reported as tissue engineering biomaterials. Herein, the addition of dopamine/polydopamine (DA/PDA) to HS hydrogels to develop multifunctional HA/PDA/SF (or HDS) hydrogels for the delivery of drugs such as N-acetyl-L-cysteine (NAC) from nasal to brain tissue is examined. Herein, DA-dependent functions of HDS hydrogels with highly adhesive forces, photothermal response (PTR) effects generated by near infrared (NIR) irradiation, and anti-oxidative effects were demonstrated. An in-vitro study shows that the HDS/NAC hydrogels could open tight junctions in the RPMI 2650 cell line, a model cell of the nasal mucosa, as demonstrated by the decreased values of transepithelial electrical resistance (TEER) and more discrete ZO-1 staining than those for the control group. This effect was markedly enhanced by NIR irradiation of the HDS/NAC-NIR hydrogels. Compared to the results obtained using NAC solution, an in-vivo imaging study (IVIS) in rats showed an approximately nine-fold increase in the quantity of NAC delivered from the nasal cavity to the brain tissue in the span of 2 h through the PTR effect generated by the NIR irradiation of the nasal tissue and administration of the HDS/NAC hydrogels. Herein, dopamine-dependent multifunctional HDS hydrogels were studied, and the nasal administration of HDS/NAC-NIR hydrogels with PTR effects generated by NIR irradiation was found to have significantly enhanced NAC delivery to brain tissues.},
}
@article {pmid37715092,
year = {2024},
author = {Peng, HX and Chai, F and Chen, KH and Huang, YX and Wei, GJ and Yuan, H and Pang, YF and Luo, SH and Wang, CF and Chen, WC},
title = {Reactive Oxygen Species-Mediated Mitophagy and Cell Apoptosis are Involved in the Toxicity of Aluminum Chloride Exposure in GC-2spd.},
journal = {Biological trace element research},
volume = {202},
number = {6},
pages = {2616-2629},
pmid = {37715092},
issn = {1559-0720},
support = {2020KY13017//Guangxi University Young and Middle-aged Teachers' Basic Ability Improvement Project/ ; GZZC2020248//Guangxi Zhuang Autonomous Region Administration of Traditional Chinese Medicine Self-financing Scientific Research Project/ ; Z20201416//Guangxi Zhuang Autonomous Region Health and Health Commission Self-financing Scientific Research Course/ ; 81960303//National Natural Science Foundation of China/ ; 2020GXNSFAA297257)//Guangxi Natural Science Foundation Project/ ; },
mesh = {*Aluminum Chloride/toxicity ; Animals ; *Apoptosis/drug effects ; Male ; *Reactive Oxygen Species/metabolism ; *Mitophagy/drug effects ; Mice ; Membrane Potential, Mitochondrial/drug effects ; Testis/drug effects/metabolism/pathology ; Cell Survival/drug effects ; Spermatocytes/drug effects/metabolism ; Cell Line ; Chlorides/toxicity ; Aluminum Compounds/toxicity ; },
abstract = {Aluminum chloride is an inorganic polymeric coagulant commonly found in daily life and various materials. Although male reproductive toxicity has been associated with AlCl3 exposure, the underlying mechanism remains unclear. This study aimed to examine the impact of AlCl3 exposure on mitophagy and mitochondrial apoptosis in testicular tissue and mouse spermatocytes. Reactive oxygen species (ROS) and ATP levels were measured in GC-2spd after AlCl3 exposure using a multifunctional enzyme labeler. The changes in mitochondrial membrane potential (MMP) and TUNEL were observed through confocal laser microscopy, and the expression of proteins associated with mitophagy and apoptosis was analyzed using Western blot. Our results demonstrated that AlCl3 exposure disrupted mitophagy and increased apoptosis-related protein expression in testicular tissues. In the in vitro experiments, AlCl3 exposure induced ROS production, suppressed cell viability and ATP production, and caused a decrease in MMP, leading to mitophagy and cell apoptosis in GC-2spd cells. Intervention with N-acetylcysteine (NAC) reduced ROS production and partially restored mitochondrial function, thereby reversing the resulting mitophagy and cell apoptosis. Our findings provide evidence that ROS-mediated mitophagy and cell apoptosis play a crucial role in the toxicity of AlCl3 exposure in GC-2spd. These results contribute to the understanding of male reproductive toxicity caused by AlCl3 exposure and offer a foundation for future research in this area.},
}
@article {pmid37714033,
year = {2023},
author = {Ma, R and Sun, T and Wang, X and Ren, K and Min, T and Xie, X and Wang, D and Li, K and Zhang, Y and Zhu, K and Mo, C and Dang, C and Yang, Y and Zhang, H},
title = {Chronic exposure to low-dose deltamethrin can lead to colon tissue injury through PRDX1 inactivation-induced mitochondrial oxidative stress injury and gut microbial dysbiosis.},
journal = {Ecotoxicology and environmental safety},
volume = {264},
number = {},
pages = {115475},
doi = {10.1016/j.ecoenv.2023.115475},
pmid = {37714033},
issn = {1090-2414},
mesh = {Humans ; Animals ; Mice ; Dysbiosis/chemically induced ; *Gastrointestinal Microbiome ; Colon ; Oxidative Stress ; Acetylcysteine ; Peroxiredoxins/genetics ; Benzimidazoles ; Carbocyanines ; Nitriles ; Pyrethrins ; },
abstract = {OBJECTIVE: To date, it is unclear whether deltamethrin (DLM) intake causes damage to colon tissue. Hence, in this study, we aimed to clarify the effect of long-term exposure to low-dose DLM on colon tissues, and its potential mechanisms.<br><br>METHODS: Mice were treated with DLM (0.2&#xa0;mg/kg/day) or DLM combined with N-acetyl-l-cysteine (NAC) (50&#xa0;mg/kg/day) for 8 weeks. Human colon cancer cells (HCT-116) were treated with DLM (0, 25, 50, or 100&#xa0;&#xb5;M), NAC (2&#xa0;mM), or overexpression plasmids targeting peroxiredoxin 1 (PRDX1) for 48&#xa0;h. DLM was detected using a DLM rapid detection card. Colon injury was evaluated using haematoxylin and eosin staining and transmission electron microscopy. Apoptosis was determined using immunofluorescence staining (IF), western blotting (WB) and flow cytometry (FC) assays. MitoTracker, JC-1, and glutathione (GSH) detection were used to detect mitochondrial oxidative stress. Intestinal flora were identified by 16&#xa0;S rDNA sequencing.<br><br>RESULTS: DLM accumulation was detected in the colon tissue and faeces of mice following long-term intragastric administration. Interestingly, our results showed that, even at a low dose, long-term intake of DLM resulted in severe weight loss and decreased the disease activity index scores and colon length. The results of IF, WB, and FC showed that DLM induced apoptosis in the colon tissue and cells. MitoTracker, JC-1, and GSH assays showed that DLM increased mitochondrial stress in colonic epithelial cells. Mechanistic studies have shown that increased mitochondrial stress and apoptosis are mediated by PRDX1 inhibition. Further experiments showed that PRDX1 overexpression significantly reduced DLM-induced oxidative stress injury and apoptosis. In addition, we observed that chronic exposure to DLM altered the composition of the intestinal flora in mice, including an increase in Odoribacter and Bacteroides and a decrease in Lactobacillus. The gut microbial richness decreased after DLM exposure in mice. Supplementation with NAC both in vivo and in vitro alleviated DLM-induced oxidative stress injury, colonic epithelial cell apoptosis, and gut microbial dysbiosis.<br><br>CONCLUSION: Chronic exposure to DLM, even at small doses, can cause damage to the colon tissue, which cannot be ignored. The production and use of pesticides such as DLM should be strictly regulated during agricultural production.},
}
@article {pmid37712506,
year = {2024},
author = {Zhang, Q and Liu, Z and Wang, T and Yu, M and Li, X},
title = {Efficacy and acceptability of adjunctive n-acetylcysteine for psychotic disorders: Systematic review and meta-analysis.},
journal = {Human psychopharmacology},
volume = {39},
number = {2},
pages = {e2880},
doi = {10.1002/hup.2880},
pmid = {37712506},
issn = {1099-1077},
mesh = {Humans ; Acetylcysteine/therapeutic use ; *Antipsychotic Agents/therapeutic use ; *Schizophrenia/drug therapy ; *Psychotic Disorders/drug therapy ; Randomized Controlled Trials as Topic ; },
abstract = {INTRODUCTION: N-acetylcysteine (NAC) augmentation of antipsychotic medication has been studied in psychotic disorders but the results are inconsistent. This meta-analysis aimed to evaluate the efficacy and acceptability of NAC as an augmentation strategy for psychotic disorders.<br><br>METHODS: PubMed, Web of Science, EMBASE, PsycINFO, Cochrane Library, and ClinicalTrials.gov were searched until the date of November 28, 2022. The inclusion criteria were randomized controlled trials (RCTs) comparing NAC and placebo in patients with psychotic disorders. The outcomes were the psychotic symptoms measured by the Positive and Negative Syndrome Scale (PANSS) and drop-out rates.<br><br>RESULTS: A total of 594 patients from eight trials were included. The results showed that no difference was found in score changes of PANSS total, positive, negative, or general psychopathology scale scores between the NAC group and placebo group in both time points (&#x2264;24&#xa0;weeks and >24&#xa0;weeks). There was also no statistical difference in drop-out rates between the two groups.<br><br>CONCLUSION: For the moment, it is not appropriate to recommend NAC as an augmentation of antipsychotic medication to treat psychotic disorders in routine clinical practice.},
}
@article {pmid37711440,
year = {2023},
author = {Yamamoto, T and Tanji, M and Mitsunaga, F and Nakamura, S},
title = {SARS-CoV-2 sublingual vaccine with RBD antigen and poly(I:C) adjuvant: Preclinical study in cynomolgus macaques.},
journal = {Biology methods &amp; protocols},
volume = {8},
number = {1},
pages = {bpad017},
pmid = {37711440},
issn = {2396-8923},
abstract = {Mucosal vaccine for sublingual route was prepared with recombinant SARS-CoV-2 spike protein receptor binding domain (RBD) antigen and poly(I:C) adjuvant components. The efficacy of this sublingual vaccine was examined using Cynomolgus macaques. Nine of the macaque monkeys were divided into three groups of three animals: control [just 400 µg poly(I:C) per head], low dose [30 µg RBD and 400 µg poly(I:C) per head], and high dose [150 µg RBD and 400 µg poly(I:C) per head], respectively. N-acetylcysteine (NAC), a mild reducing agent losing mucin barrier, was used to enhance vaccine delivery to mucosal immune cells. RBD-specific IgA antibody secreted in pituita was detected in two of three monkeys of the high dose group and one of three animals of the low dose group. RBD-specific IgG and/or IgA antibodies in plasma were also detected in these monkeys. These indicated that the sublingual vaccine stimulated mucosal immune response to produce antigen-specific secretory IgA antibodies in pituita and/or saliva. This sublingual vaccine also affected systemic immune response to produce IgG (IgA) in plasma. Little RBD-specific IgE was detected in plasma, suggesting no allergic antigenicity of this sublingual vaccine. Thus, SARS-CoV-2 sublingual vaccine consisting of poly(I:C) adjuvant showed reasonable efficacy in a non-human primate model.},
}
@article {pmid37710183,
year = {2023},
author = {Du, YX and Zhao, YT and Sun, YX and Xu, AH},
title = {Acid sphingomyelinase mediates ferroptosis induced by high glucose via autophagic degradation of GPX4 in type 2 diabetic osteoporosis.},
journal = {Molecular medicine (Cambridge, Mass.)},
volume = {29},
number = {1},
pages = {125},
pmid = {37710183},
issn = {1528-3658},
mesh = {Animals ; Rats ; Autophagy ; Ceramides ; *Diabetes Mellitus, Type 2 ; *Ferroptosis ; Glucose ; *Osteoporosis/drug therapy/etiology ; Reactive Oxygen Species ; Sphingomyelin Phosphodiesterase/genetics ; X-Ray Microtomography ; Phospholipid Hydroperoxide Glutathione Peroxidase ; },
abstract = {BACKGROUND: Ferroptosis has been implicated in the pathological process of type 2 diabetic osteoporosis (T2DOP), although the specific underlying mechanisms remain largely unknown. This study aimed to clarify the role and possible mechanism of acid sphingomyelinase (ASM)-mediated osteoblast ferroptosis in T2DOP.<br><br>METHODS: We treated hFob1.19 cells with normal glucose (NG) and different concentrations of high glucose (HG, 26.25 mM, 35 mM, or 43.75 mM) for 48&#xa0;h. We then measured cell viability and osteogenic function, quantified ferroptosis and autophagy levels, and measured the levels of ASM and ceramide in the cells. To further investigate the specific mechanism, we examined these indicators by knocking down ASM expression, hydroxychloroquine (HCQ) treatment, or N-acetylcysteine (NAC) treatment. Moreover, a T2DOP rat model was induced and microcomputed tomography was used to observe the bone microstructure. We also evaluated the serum levels of iron metabolism-associated factors, ceramide and lipid peroxidation (LPO) and measured the expression of ASM, LC3 and GPX4 in bone tissues.<br><br>RESULTS: HG inhibited the viability and osteogenic function of osteoblasts by inducing ferroptosis in a concentration-dependent manner. Furthermore, the expression of ASM and ceramide and autophagy levels were increased by HG treatment, and these factors were required for the HG-induced reactive oxygen species (ROS) generation and LPO. Similarly, inhibiting intracellular ROS also reduced HG-induced ASM activation and autophagy. ASM-mediated activation of autophagy was crucial for HG-induced degradation of GPX4, and inhibiting ASM improved osteogenic function by decreasing HG-induced autophagy, GPX4 degradation, LPO and subsequent ferroptosis. We also found that inhibiting ASM could alleviated ferroptosis and autophagy and improved osteogenic function in a T2DOP rat model.<br><br>CONCLUSION: ASM-mediated autophagy activation induces osteoblast ferroptosis under HG conditions through the degradation of GPX4, providing a novel mechanistic insight into the treatment and prevention of T2DOP.},
}
@article {pmid37705917,
year = {2023},
author = {Granata, S and Bruschi, M and Verlato, A and Pontrelli, P and Gesualdo, L and Stallone, G and Zaza, G},
title = {Autophagy Activation in Peripheral Blood Mononuclear Cells of Peritoneal Dialysis Patients.},
journal = {Kidney international reports},
volume = {8},
number = {9},
pages = {1852-1863},
pmid = {37705917},
issn = {2468-0249},
abstract = {INTRODUCTION: The complete systemic deregulated biological network in patients on peritoneal dialysis (PD) is still only partially defined. High-throughput/omics techniques may offer the possibility to analyze the main biological fingerprints associated with this clinical condition.<br><br>METHODS: We applied an innovative bioinformatic analysis of gene expression microarray data (mainly based on support vector machine (SVM) learning) to compare the transcriptomic profile of peripheral blood mononuclear cells (PBMCs) of healthy subjects (HS), chronic kidney disease (CKD) patients, and patients on PD divided into a microarray group (5 HS, 9 CKD, and 10 PD) and a validation group (10 HS, 15 CKD, and 15 PD). Classical well-standardized biomolecular approaches (western blotting and flow cytometry) were used to validate the transcriptomic results.<br><br>RESULTS: Bioinformatics revealed a distinctive PBMC transcriptomic profiling for PD versus CKD and HS (n&#xa0;= 419 genes). Transcripts encoding for key elements of the autophagic pathway were significantly upregulated in PD, and the autophagy related 5 (ATG5) reached the top level of discrimination [-Log10 P-value&#xa0;= 11.3, variable importance in projection (VIP) score&#xa0;= 4.8, SVM rank:1]. Protein levels of ATG5 and microtubule associated protein 1 light chain 3 beta (LC3B), an important constituent of the autophagosome, validated microarray results. In addition, the incubation of PBMCs of HS with serum of patients on PD upregulated both proteins. Autophagy in PBMCs from patients on PD was attenuated by N-acetyl-cysteine or Resatorvid treatment.<br><br>CONCLUSIONS: Our data demonstrated, for the first time, that the autophagy pathway is activated in immune-cells of patients on PD, and this may represent a novel therapeutic target.},
}
@article {pmid37705749,
year = {2023},
author = {Wang, L and Huang, B and Zeng, Y and Yang, J and Li, Z and Ng, JPL and Xu, X and Su, L and Yun, X and Qu, L and Chen, R and Luo, W and Wang, Y and Chen, C and Yang, L and Qu, Y and Zhang, W and Chan, JTW and Wang, X and Law, BYK and Mok, SWF and Chung, SK and Wong, VKW},
title = {N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model.},
journal = {International journal of biological sciences},
volume = {19},
number = {13},
pages = {4082-4102},
pmid = {37705749},
issn = {1449-2288},
mesh = {Humans ; Animals ; Rats ; *Acetylcysteine/therapeutic use ; Leukocytes, Mononuclear ; Aldehydes ; *Arthritis, Rheumatoid/drug therapy ; Rhodanine/analogs &amp; derivatives ; Thiazolidines ; },
abstract = {Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA). The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1β, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition. Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.},
}
@article {pmid37705237,
year = {2024},
author = {Sheng, Y and Zhang, C and Cai, D and Xu, G and Chen, S and Li, W and Dong, J and Shen, B and Tang, J and Xu, L},
title = {2,2',4,4'-Tetrabromodiphenyl ether and cadmium co-exposure activates aryl hydrocarbon receptor pathway to induce ROS and GSDME-dependent pyroptosis in renal tubular epithelial cells.},
journal = {Environmental toxicology},
volume = {39},
number = {1},
pages = {289-298},
doi = {10.1002/tox.23957},
pmid = {37705237},
issn = {1522-7278},
support = {2023RC101//Medical Health Science and Technology Project of Zhejiang Provincial Health Commission/ ; 22206059//National Natural Science Foundation of China/ ; 2023R417A016//Zhejiang Provincial University Students Science and Technology Innovation Activity/ ; },
mesh = {*Receptors, Aryl Hydrocarbon/metabolism ; *Cadmium/toxicity ; Caspase 3/metabolism ; Reactive Oxygen Species/metabolism ; Pyroptosis ; Ether ; Epithelial Cells/metabolism ; Halogenated Diphenyl Ethers ; Azo Compounds ; Pyrazoles ; },
abstract = {We have previously found that a mixture exposure of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and cadmium (Cd) causes kidney damage; however, the mechanism was not fully understood. The aryl hydrocarbon receptor (AhR) is a ligand-receptor transcription factor that plays an important role in the adaptive response or metabolic detoxification of environmental toxins. Thus, this study aimed to examine the role of AhR in kidney toxicity. BDE-47 (50 μM) or Cd (5 μM) exposure reduced cell viability in renal tubular epithelial cells (HKC), with a larger effect observed in co-treatment. The cell morphology presented pyroptotic changes, including swollen cells, large bubbles, and plasma membrane pore formation. The gene expressions of AhR, heat shock protein 90 (Hsp90), AhR nuclear translocator (ARNT), and cytochrome P450 1B1 (CYP1B1) were increased, while CYP1A1 was decreased. Reactive oxygen species (ROS) were generated, which was reduced by the AhR antagonist CH223191. The apoptosis, necrosis, and intracellular lactated hydrogenase (LDH) release was elevated, and this was attenuated by N-acetylcysteine (NAC). Furthermore, the pyroptosis pathway was activated with increased protein levels of cleaved-caspase-3 and gasdermin E N-terminal (GSDME-NT), while caspase-8, caspase-3, and GSDME were decreased. These effects were alleviated by NAC and CH223191. Our data demonstrate a combined effect of BDE-47 and Cd on nephrotoxicity by activating AhR to induce ROS contributing to GSDME-dependent pyroptosis, and retardation of the AhR pathway could reduce this toxicity.},
}
@article {pmid37701655,
year = {2023},
author = {Eslami, G and Ghorbani, A and Akbari, J and Farmoudeh, A and Faghih, F and Moghimi, M},
title = {Efficacy of Oral Mucoadhesive N-Acetylcysteine Tablets in Treatment of Recurrent Aphthous Stomatitis: A Randomized Double-Blind, Placebo-Controlled Clinical Trial.},
journal = {Frontiers in dentistry},
volume = {20},
number = {},
pages = {18},
pmid = {37701655},
issn = {2676-296X},
abstract = {Objectives: This study aimed to assess the efficacy of oral mucoadhesive N-acetylcysteine (NAC) tablets for treatment of recurrent aphthous stomatitis (RAS). Materials and Methods: Forty-nine patients with RAS were randomized to receive mucoadhesive NAC tablets (n=25) or placebo (n=24). Tablets were prescribed three times a day for 7 days in each group. Pain intensity was evaluated with visual analog scale (VAS) three times a day from day 1 to day 7. Also, patients were clinically examined on days 0 (before entering the study), 3, 5, and 7 using a metal caliper to measure the diameter of the lesions. The data were statistically analyzed and P<0.05 was considered statistically significant. Results: Regarding the VAS score, all participants in the treatment group showed complete recovery on day 7 (P<0.01). Also, the diameter of the lesions was significantly smaller in the treatment group than the placebo group at the end of the study (P<0.001). Conclusion: The results of this clinical trial showed for the first time that mucoadhesive NAC tablets can significantly decrease pain and the diameter of RAS lesions without any systemic complications.},
}
@article {pmid37696227,
year = {2023},
author = {Chan, CY and Conley, SF and Salameh, S and Sayegh, J and Wurzba, SDS and Grenier, K and Linn, DT and Partain, MP and Daniel, SJ},
title = {Otologic safety of intratympanic N-acetylcysteine in an animal model.},
journal = {International journal of pediatric otorhinolaryngology},
volume = {173},
number = {},
pages = {111702},
doi = {10.1016/j.ijporl.2023.111702},
pmid = {37696227},
issn = {1872-8464},
mesh = {Humans ; Animals ; Guinea Pigs ; *Acetylcysteine/pharmacology ; *Ototoxicity ; Models, Animal ; Ciprofloxacin ; Dexamethasone ; },
abstract = {OBJECTIVE: N-acetylcysteine (NAC) is an anti-oxidant and mucolytic effective against bacterial biofilms, making it useful in the treatment of chronically discharging ears that are unresponsive to traditional treatment methods. The objective of this study was to evaluate the otologic safety of intratympanic NAC combined with Ciprodex® in an animal model.<br><br>METHODS: Baseline distortion product otoacoustic emissions (DPOAE) and auditory brainstem response (ABR) measurements were performed for both ears on thirteen guinea pigs from the animal care research facilities of the McGill University Health Center. This was followed by intratympanic administration of control solution (Ciprofloxacin 0.3%/Dexamethasone 0.1%) to the left ear and experimental solution (1.25% NAC/Ciprofloxacin 0.3%/Dexamethasone 0.1%) to the right ear. Three additional intratympanic injections were performed over the next fourteen days. DPOAE and ABR measurements were repeated 3-4 weeks after the initial procedure. Outcome measures included differences in DPOAE and ABR thresholds after intervention, clinical evidence of vestibular dysfunction and histological evidence of ototoxicity.<br><br>RESULTS: There were no significant differences in the ABR thresholds and DPOAE results of the control and experimental ears at baseline and after intervention. There was neither clinical manifestation of vestibular dysfunction nor histological evidence of ototoxicity.<br><br>CONCLUSION: Our study suggests that intratympanic 1.25% NAC with ciprofloxacin and dexamethasone is safe in guinea pigs and support its potential use in the treatment of chronically discharging ears. Further studies in humans are required to analyze its efficacy relative to conventional treatments.<br><br>LEVEL OF EVIDENCE: Animal Research.},
}
@article {pmid37692935,
year = {2023},
author = {Zhang, J and Xu, X and Liang, Y and Wu, X and Qian, Z and Zhang, L and Wang, T},
title = {Particulate matter promotes the epithelial to mesenchymal transition in human lung epithelial cells via the ROS pathway.},
journal = {American journal of translational research},
volume = {15},
number = {8},
pages = {5159-5167},
pmid = {37692935},
issn = {1943-8141},
abstract = {OBJECTS: Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased rates of chronic cardiopulmonary diseases, including asthma and idiopathic pulmonary fibrosis (IPF). Several investigations have suggested that the epithelial-to-mesenchymal transition (EMT) may contribute to the complex pathobiology of environmental exposure-mediated pulmonary fibrosis. The present study was designed to characterize the mechanisms of PM-mediated EMT in human lung epithelial cells (HBECs).<br><br>METHODS AND RESULTS: PM induced significant dose (0-100 &#x3bc;g/ml) and time (0-72 h)-dependent increases in transforming growth factor &#x3b2; (TGF&#x3b2;) and fibronectin (FN) protein levels in HBECs lysates. PM-activated TGF&#x3b2; and FN protein production in HBECs was prevented by the antioxidant N-acetyl-cysteine (NAC, 5 mM). Furthermore, the NF-&#x3ba;B inhibitor BAY11-7082 (5 &#x3bc;M) abolished PM-induced FN production in HBECs. Biomarkers of EMT (ACTA2, SNAIL1 and SNAIL2) in PM-treated HBECs were significantly increased at the mRNA level compared to control cells.<br><br>CONCLUSIONS: These results demonstrate that PM increases protein levels of TGF&#x3b2; and FN via reactive oxygen species (ROS)-dependent pathways. In addition, PM exposure induces EMT in human lung epithelial cells, supporting a novel mechanism for PM-induced pulmonary fibrosis.},
}
@article {pmid37692924,
year = {2023},
author = {Zhang, J and Wu, X and Liang, Y and Kelly, G and Burt, JM and Zhang, L and Wang, T},
title = {Particulate matter increases connexin 43 expression and exacerbates endothelial barrier disruption.},
journal = {American journal of translational research},
volume = {15},
number = {8},
pages = {5099-5109},
pmid = {37692924},
issn = {1943-8141},
abstract = {OBJECTIVES: Particulate Matter (PM) air pollution is known to exacerbate cardiopulmonary diseases. We previously demonstrated that PM mediates endothelial injury and barrier disruption by modulating the endothelial cytoskeleton and cell-cell junctions, but the effects of PM exposure on cell-cell communication and gap junction activity are still unknown.<br><br>METHODS: This study focused on the characterization of PM-regulated endothelial dysfunction through connexin 43 (Cx43), the most abundant gap junction protein expressed in lung endothelial cells (ECs), using cultured human lung endothelial cells and a well-characterized PM sample.<br><br>RESULTS: PM exposure induced a time-dependent increase of Cx43 in human lung ECs at both the mRNA and protein levels. N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, significantly suppressed PM-induced Cx43 expression. Cx43 proteins on the plasma membrane and ER/Golgi apparatus were elevated in response to a PM challenge. In addition, PM induced gap junction activity, which was indicated by green fluorescence dye transfer between two adjacent ECs. Moreover, GAP27, a selective Cx43 channel inhibitor, attenuated PM-induced human lung EC barrier disruption, which was reflected by rescued trans-endothelial electrical resistance (TER) with an electric cell-substrate impedance sensing system. Moreover, knocking down Cx43 alleviated PM-induced myosin light chain (MLC) phosphorylation.<br><br>CONCLUSIONS: These results strongly suggest that Cx43 plays a key role in PM-mediated endothelial barrier disruption and signal transduction. Cx43 may be a therapeutic target in PM-mediated cardiopulmonary disorders.},
}
@article {pmid37685966,
year = {2023},
author = {Muñoz-Sánchez, G and Godínez-Méndez, LA and Fafutis-Morris, M and Delgado-Rizo, V},
title = {Effect of Antioxidant Supplementation on NET Formation Induced by LPS In Vitro; the Roles of Vitamins E and C, Glutathione, and N-acetyl Cysteine.},
journal = {International journal of molecular sciences},
volume = {24},
number = {17},
pages = {},
pmid = {37685966},
issn = {1422-0067},
mesh = {Dietary Supplements ; Acetylcysteine/pharmacology ; Hyperaldosteronism ; Ascorbic Acid/pharmacology ; Glutathione Disulfide ; Horses ; Lipopolysaccharides/pharmacology ; Animals ; Glutathione ; Reactive Oxygen Species ; *Antioxidants/pharmacology ; Vitamins ; *Vitamin E/pharmacology ; },
abstract = {Neutrophil extracellular traps (NETs) require reactive oxygen species (ROS) to eliminate pathogens by inducing oxidative stress. However, this process can also cause tissue damage to the host. Neutrophils contain high concentrations of vitamin C (1.5 mM) compared to the bloodstream (0.1 mM), and this antioxidant can interact with vitamin E and glutathione (GSH) inside the cell to maintain the redox balance. Previous studies have investigated the effect of vitamins E or C and N-acetyl cysteine (NAC) on NET formation, but the interactions of these molecules in neutrophils remain unknown. In this study, we investigated the effect of antioxidants alone and two combinations on NET formation and oxidative stress. Neutrophils were pre-loaded with GSH + NAC or vitamin E + vitamin C + GSH + NAC (termed ALL), and LPS-induced NET formation was assessed using fluorometry and immunofluorescence. Antioxidant effects were evaluated by measuring the total antioxidant capacity (TAC), GSH/GSSG ratio, ROS production, nitrite + nitrate levels, and lipid peroxidation. Our results showed that even low doses of antioxidants are capable of decreasing NETs. Furthermore, the combinations augmented TAC and GSH/GSSG ratio and decreased ROS, nitrites + nitrates, and malondialdehyde (MDA) levels in supplemented neutrophils in vitro.},
}
@article {pmid37684590,
year = {2023},
author = {Liu, S and Guan, Y and Weng, Y and Liao, B and Tong, L and Hao, Z and Chen, J and Shi, J and Cheng, T},
title = {Genome-wide identification of the NAC gene family and its functional analysis in Liriodendron.},
journal = {BMC plant biology},
volume = {23},
number = {1},
pages = {415},
pmid = {37684590},
issn = {1471-2229},
support = {32101546//National Natural Science Foundation of China/ ; 32071784//National Natural Science Foundation of China/ ; 2021YFD2200103//National Key Research and Development Program of China during the 14th Five-year Plan Period/ ; PAPD//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; PAPD//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; },
mesh = {*Liriodendron ; Acetylcysteine/analogs &amp; derivatives ; Cell Nucleus ; Cytoplasm ; Lysine/analogs &amp; derivatives ; },
abstract = {As one of the largest plant specific transcription factor families, NAC family members play an important role in plant growth, development and stress resistance. To investigate the function of NAC transcription factors during abiotic stress, as well as during somatic embryogenesis, we identified and characterized the NAC gene family in Liriodendron chinense. We found that most LcNAC members contain more than three exons, with a relatively conserved gene and motif structure, especially at the N-terminus. Interspecies collinearity analysis revealed a closer relationship between the L. chinense NACs and the P. trichocarpa NACs. We analyzed the expression of LcNAC in different tissues and under three abiotic stresses. We found that 12 genes were highly expressed during the ES3 and ES4 stages of somatic embryos, suggesting that they are involved in the development of somatic embryos. 6 LcNAC genes are highly expressed in flower organs. The expression pattern analysis of LcNACs based on transcriptome data and RT-qPCR obtained from L. chinense leaves indicated differential expression responses to drought, cold, and heat stress. Genes in the NAM subfamily expressed differently during abiotic stress, and LcNAC6/18/41/65 might be the key genes in response to abiotic stress. LcNAC6/18/41/65 were cloned and transiently transformed into Liriodendron protoplasts, where LcNAC18/65 was localized in cytoplasm and nucleus, and LcNAC6/41 was localized only in nucleus. Overall, our findings suggest a role of the NAC gene family during environmental stresses in L. chinense. This research provides a basis for further study of NAC genes in Liriodendron chinense.},
}
@article {pmid37683986,
year = {2023},
author = {Lapenna, D},
title = {Glutathione and glutathione-dependent enzymes: From biochemistry to gerontology and successful aging.},
journal = {Ageing research reviews},
volume = {92},
number = {},
pages = {102066},
doi = {10.1016/j.arr.2023.102066},
pmid = {37683986},
issn = {1872-9649},
mesh = {Humans ; Aged ; *Antioxidants/metabolism ; Hydrogen Peroxide ; Glutathione/metabolism ; Glutamate-Cysteine Ligase/genetics/metabolism ; Acetylcysteine ; Glycine ; *Geriatrics ; },
abstract = {The tripeptide glutathione (GSH), namely γ-L-glutamyl-L-cysteinyl-glycine, is an ubiquitous low-molecular weight thiol nucleophile and reductant of utmost importance, representing the central redox agent of most aerobic organisms. GSH has vital functions involving also antioxidant protection, detoxification, redox homeostasis, cell signaling, iron metabolism/homeostasis, DNA synthesis, gene expression, cysteine/protein metabolism, and cell proliferation/differentiation or death including apoptosis and ferroptosis. Various functions of GSH are exerted in concert with GSH-dependent enzymes. Indeed, although GSH has direct scavenging antioxidant effects, its antioxidant function is substantially accomplished by glutathione peroxidase-catalyzed reactions with reductive removal of H2O2, organic peroxides such as lipid hydroperoxides, and peroxynitrite; to this antioxidant activity also contribute peroxiredoxins, enzymes further involved in redox signaling and chaperone activity. Moreover, the detoxifying function of GSH is basically exerted in conjunction with glutathione transferases, which have also antioxidant properties. GSH is synthesized in the cytosol by the ATP-dependent enzymes glutamate cysteine ligase (GCL), which catalyzes ligation of cysteine and glutamate forming γ-glutamylcysteine (γ-GC), and glutathione synthase, which adds glycine to γ-GC resulting in GSH formation; GCL is rate-limiting for GSH synthesis, as is the precursor amino acid cysteine, which may be supplemented as N-acetylcysteine (NAC), a therapeutically available compound. After its cell export, GSH is degraded extracellularly by the membrane-anchored ectoenzyme γ-glutamyl transferase, a process occurring, as GSH synthesis and export, in the γ-glutamyl cycle. GSH degradation occurs also intracellularly by the cytoplasmic enzymatic ChaC family of γ-glutamyl cyclotransferase. Synthesis and degradation of GSH, together with its export, translocation to cell organelles, utilization for multiple essential functions, and regeneration from glutathione disulfide by glutathione reductase, are relevant to GSH homeostasis and metabolism. Notably, GSH levels decline during aging, an alteration generally related to impaired GSH biosynthesis and leading to cell dysfunction. However, there is evidence of enhanced GSH levels in elderly subjects with excellent physical and mental health status, suggesting that heightened GSH may be a marker and even a causative factor of increased healthspan and lifespan. Such aspects, and much more including GSH-boosting substances administrable to humans, are considered in this state-of-the-art review, which deals with GSH and GSH-dependent enzymes from biochemistry to gerontology, focusing attention also on lifespan/healthspan extension and successful aging; the significance of GSH levels in aging is considered also in relation to therapeutic possibilities and supplementation strategies, based on the use of various compounds including NAC-glycine, aimed at increasing GSH and related defenses to improve health status and counteract aging processes in humans.},
}
@article {pmid37681263,
year = {2023},
author = {Pepin, L and Matsler, N and Fontes, A and Heard, K and Flaherty, BF and Monte, AA},
title = {Fomepizole Therapy for Acetaminophen-Induced Liver Failure in an Infant.},
journal = {Pediatrics},
volume = {152},
number = {4},
pages = {},
doi = {10.1542/peds.2022-061033},
pmid = {37681263},
issn = {1098-4275},
abstract = {Acetaminophen overdose is common in the pediatric population. N-acetylcysteine (NAC) is effective at preventing liver injury in most patients when started shortly after the overdose. Delays to therapy increase risk of hepatotoxicity and liver failure that may necessitate organ transplant. Animal studies have demonstrated fomepizole may provide added benefit in acetaminophen overdose because of its ability to block the metabolic pathway that produces the toxic acetaminophen metabolite and downstream inhibition of oxidative stress pathways that lead to cell death. Several adult case reports describe use of fomepizole in patients at higher risk for poor outcomes despite NAC. We describe a case of a 7-month-old female who presented in acute liver failure with persistently elevated acetaminophen concentration secondary to repeated supratherapeutic doses of acetaminophen to manage fever. Fomepizole and NAC antidotes were used in the management of the patient. She fully recovered despite demonstrating multiple markers of poor outcome on initial presentation. Although randomized trials are lacking, this case suggests that fomepizole may safely provide additional benefit in pediatric patients at risk for severe acetaminophen toxicity.},
}
@article {pmid37680754,
year = {2023},
author = {Alqahtani, QH and Fadda, LM and Alhusaini, AM and Hasan, IH and Ali, HM},
title = {Involvement of Nrf2, JAK and COX pathways in acetaminophen-induced nephropathy: Role of some antioxidants.},
journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society},
volume = {31},
number = {10},
pages = {101752},
pmid = {37680754},
issn = {1319-0164},
abstract = {OBJECTIVES: Acetaminophen (APAP)-induced nephrotoxicity is detrimental consequence for which there has not been a standardized therapeutic regimen. Although, N-acetylcysteine (NAC) is a well-known antidote used in APAP-induced hepatotoxicity, its benefit in nephrotoxicity caused by APAP is almost lacking. This study aimed to compare the possible protective effect of thymoquinone (TQ), curcumin (CR), and α-lipoic acid (α-LA), either in solo or in combination regimens with that of NAC against APAP-induced renal injury.<br><br>DESIGN AND METHOD: Rats were divided into nine groups; control group, APAP intoxicated group (1000&#x202f;mg/kg; orally), and the remaining seven groups received, in addition to APAP, oral doses of NAC, TQ, CR, &#x3b1;-LA, CR plus TQ, TQ plus &#x3b1;-LA, or CR plus &#x3b1;-LA. The first dose of the aforementioned antioxidants was given 24&#x202f;h before APAP, and then the second dose was given 2&#x202f;h after APAP, whereas the last dose was given 10&#x202f;h after administration of APAP.<br><br>RESULTS: Treatment with APAP elevated kidney markers like serum uric acid, urea, and creatinine. In addition, it increased the serum level of tumor necrosis factor alpha (TNF-&#x3b1;), interleukin-1beta (IL-1&#x3b2;) and thiobarbituric acid reactive species (TBARS). Also, the protein expression of renal janus kinase (JAK) and cyclooxygenase (COX)-2 were all upregulated by APAP. In contrast, the expression of Nrf2 and the renal levels of superoxide dismutase and glutathione were downregulated. Treatment with the indicated natural antioxidants resulted in amelioration of the aberrated parameters through exhibiting anti-inflammatory, antioxidant and free radical-scavenging effects with a variable degree.<br><br>CONCLUSION: The combined administration of CR and TQ exerted the most potent protection against APAP-induced nephrotoxicity through its anti-inflammatory and free radical-scavenging effects (antioxidant) which were comparable to that of NAC-treatment.},
}
@article {pmid37670970,
year = {2023},
author = {Zhang, Z and Luan, Q and Hao, W and Cui, Y and Li, Y and Li, X},
title = {NOX4-derived ROS Regulates Aerobic Glycolysis of Breast Cancer through YAP Pathway.},
journal = {Journal of Cancer},
volume = {14},
number = {13},
pages = {2562-2573},
pmid = {37670970},
issn = {1837-9664},
abstract = {Background: NOX4 is highly expressed in breast cancer and is closely associated with cell invasion and metastasis. The involvement of NOX4 in glycolysis in breast cancer remains unclear. The aim of this study was to investigate the role and mechanism of NOX4 in glycolysis in breast cancer. Methods: NOX4 expression in breast cancer cells was detected by qRT-PCR and western blotting. siRNAs and plasmids were used to silence or enhance the expression of NOX4. The mRNA and protein expression of HK2, GLUT1, PKM2, LDHA, and YAP was detected by qRT-PCR and western blotting, and the [18]F-FDG uptake rate was detected by γ-radiometer. Detection of reactive oxygen species (ROS) in cells was performed using a commercial ROS kit. After transfection, CCK8, EDU and Transwell experiments were conducted to detect cell proliferation and migration ability. MicroPET imaging was used to detect the effects of NOX4 on tumor metabolism. Immunohistochemistry was used to detect the expression of NOX4, glycolytic enzymes HK2, GLUT1, PKM2, LDHA, the proliferation index KI67, and the activation of YAP pathway molecule. Results: In this study, the expression of NOX4 in MDA-MB-231 and MDA-MB-453 was higher than in MCF10A. qRT-PCR and western blotting experiments showed that NOX4 downregulation decreased the expression of glycolytic enzymes HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Conversely, the overexpression of NOX4 enhanced the expression of HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Proliferation and migration experiments showed that after down-regulation of NOX4, cell proliferation and migration ability decreased, while NOX4 overexpression promoted cell proliferation and migration ability. Additionally, ROS content and YAP expression decreased after NOX4 down-regulation, while ROS content and YAP expression increased following NOX4 overexpression, which was reversed by N-acetyl cysteine (NAC), a ROS inhibitor. Furthermore, exposure to NAC and Peptide17, a YAP inhibitor, blocked the increase in glycolytic enzyme expression, and the enhancement of proliferation and migration caused by NOX4 overexpression. In addition, in animal experiments, the results of the MicroPET imaging showed that the glucose metabolism rate of the NOX4 inhibitor group was significantly lower than that of the control group. ROS levels in the NOX4 inhibitor group was lower than that in the control group. Immunohistochemistry showed that the expression of HK2, GLUT1, PKM2, LDHA, KI67, and YAP in the NOX4 knock-down group were decreased. Conclusions: NOX4 affects breast cancer glycolysis through ROS-induced activation of the YAP pathway, further promoting the proliferation and migration of breast cancer cells.},
}
@article {pmid37670199,
year = {2023},
author = {Kaya, S and Yalcın, T and Tektemur, A and Kuloğlu, T},
title = {N-Acetylcysteine may exert hepatoprotective effect by regulating Meteorin-Like levels in Adriamycin-induced liver injury.},
journal = {Cell stress &amp; chaperones},
volume = {28},
number = {6},
pages = {849-859},
pmid = {37670199},
issn = {1466-1268},
support = {TF.21.11//Firat University Scientific Research Projects Management Unit/ ; },
mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/metabolism/therapeutic use ; Doxorubicin/toxicity ; Caspase 3/metabolism ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy/metabolism/pathology ; Liver/metabolism ; Antioxidants/metabolism ; Oxidative Stress ; },
abstract = {Adriamycin (ADR) is an important chemotherapeutic drug, but it has serious side effects such as hepatotoxicity. This study aimed to evaluate whether N-acetylcysteine (NAC) has hepatoprotective effects against ADR-induced hepatotoxicity in rats. In addition, it was aimed to determine how Meteorin-Like (MtrnL), which has pleiotropic effects on immunology, inflammation, and metabolism, is affected by ADR and/or NAC applications in liver tissue. 28 rats were randomly assigned to one of four equal groups in the study: control (no treatment), NAC (150 mg/kg/day of NAC intraperitoneally (i.p), ADR (15 mg/kg only on the first day of the experiment), and ADR + NAC (ADR 15 mg/kg on the first day of the experiment + 150 mg/kg/day NAC i.p). After 15 days, liver enzyme levels in serum, oxidant/antioxidant parameters in liver tissue, histopathological changes, caspase 3 (Casp3) and heat shock protein 70 (HSP-70) immunoreactivities, and MtrnL levels were examined. Histopathological changes, liver enzyme levels, as well as HSP-70, and Casp3 immunoreactivities increased due to ADR application. Additionally, MtrnL levels in liver tissue were significantly increased as a result of ADR application. However, it was detected that the NAC application significantly regulated the ADR-induced changes. Furthermore, it was determined that NAC administration regulated the changes in ADR-induced oxidative stress parameters. We propose that NAC may exert a hepatoprotective effect by regulating ADR-induced altered oxidative stress parameters, MtrnL levels, Casp3, and HSP-70 immunoreactivities in the liver.},
}
@article {pmid37666440,
year = {2023},
author = {Wang, X and Zhou, P and Zhang, Z and Huang, Q and Chen, X and Ji, L and Cheng, X and Shi, Y and Yu, S and Tang, J and Sun, C and Zhao, X and Yu, J},
title = {A Drosophila model of gestational antimony exposure uncovers growth and developmental disorders caused by disrupting oxidative stress homeostasis.},
journal = {Free radical biology &amp; medicine},
volume = {208},
number = {},
pages = {418-429},
doi = {10.1016/j.freeradbiomed.2023.09.002},
pmid = {37666440},
issn = {1873-4596},
mesh = {Animals ; *Antimony/toxicity ; *Drosophila/metabolism ; Developmental Disabilities ; Oxidative Stress ; Antioxidants/pharmacology/metabolism ; Glutathione/metabolism ; Acetylcysteine/pharmacology/metabolism ; },
abstract = {The toxic heavy metal antimony (Sb) is ubiquitous in our daily lives. Various models have shown that Sb induces neuronal and reproductive toxicity. However, little is known about the developmental toxicity of Sb exposure during gestation and the underlying mechanisms. To study its effects on growth and development, Drosophila stages from eggs to pupae were exposed to different Sb concentrations (0, 0.3, 0.6 and 1.2 mg/mL Sb); RNA sequencing was used to identify the underlying mechanism. The model revealed that prenatal Sb exposure significantly reduced larval body size and weight, the pupation and eclosion rates, and the number of flies at all stages. With 1.2 mg/mL Sb exposure in 3rd instar larvae, 484 genes were upregulated and 694 downregulated compared to controls. Biological analysis showed that the disrupted transcripts were related to the oxidative stress pathway, as verified by reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and glutathione (GSH) intervention experiments. Sb exposure induced oxidative stress imbalance could be rectified by chelation and antioxidant effects of NAC/GSH. The Drosophila Schneider 2 (S2) model further demonstrated that NAC and GSH greatly ameliorated cell death induced by Sb exposure. In conclusion, gestational Sb exposure disrupted oxidative stress homeostasis, thereby impairing growth and development.},
}
@article {pmid37662796,
year = {2023},
author = {Çavuş, UY and Yılmaz, A and Tascanov, MB and Ocak, M},
title = {Efficacy of combination of N-acetylcysteine and primrose in spinal cord injury; an experimental study.},
journal = {Heliyon},
volume = {9},
number = {9},
pages = {e19350},
pmid = {37662796},
issn = {2405-8440},
abstract = {INTRODUCTION: Spinal cord trauma represents a major cause of emergency department admissions, with high morbidity and mortality rates. It requires early and urgent treatment. This experimental study assessed the effectiveness of a combination of primrose and N-acetylcysteine (NAC) in managing spinal cord injury (SCI).<br><br>METHODS: We divided 46 adult male Wistar albino rats (6-8 months old, weighing 300-350&#xa0;g) into five groups. Group 1 (n&#xa0;=&#xa0;10) received only primrose; group 2 (n&#xa0;=&#xa0;10) received only NAC; group 3 (n&#xa0;=&#xa0;10) received a combination of NAC and primrose; group 4 (n&#xa0;=&#xa0;10) received no intervention (first control group); group 5 (n&#xa0;=&#xa0;10) underwent laminectomy only (second control group). Intergroup neurological and motor function were evaluated on days 1, 7, and 14. Oxidative biochemical markers, such as superoxide dismutase (SOD), glutathione peroxidase (GPX), and malondialdehyde (MDA), were measured.<br><br>RESULTS: Significant differences were recorded in the GPX, SOD, and MDA values of groups 1, 2, 3, and 4 (p&#xa0;<&#xa0;0.001, p&#xa0;=&#xa0;0.005, and p&#xa0;=&#xa0;0.097, respectively). Groupwise comparisons were conducted to identify the clinical significance of these markers. GPX and SOD levels were significantly higher in group 1 than in group 2; MDA levels were lower in group 1. GPX and SOD levels were significantly higher than in group 3 than in group 1; MDA levels were lower in group 3. Compared with group 5, group 1 demonstrated significantly higher GPX and SOD levels and lower MDA levels. Results in group 2 were similar to results in group 5. In group 3, GPX and SOD levels were significantly higher than in groups 2 and 5; MDA levels were significantly lower. Comparisons according to inclined plane angle level and motor function values revealed significant results on day 14, in favor of group 3 rats that had received the combined treatment.<br><br>CONCLUSION: The combined administration of NAC and primrose for traumatic SCI was more effective than either treatment alone in terms of improving biochemical and neurological functions. These findings suggest that the combination of NAC and primrose can serve as an effective treatment option for traumatic SCI.},
}
@article {pmid37661403,
year = {2023},
author = {Kadota, Y and Yamanokuchi, R and Ohnishi, N and Matsuoka, M and Kawakami, T and Sato, M and Suzuki, S},
title = {Metallothionein Gene Deficiency Facilitates the Differentiation of C2C12 Myoblasts into Slow-Twitch Myotubes.},
journal = {Biological &amp; pharmaceutical bulletin},
volume = {46},
number = {9},
pages = {1240-1248},
doi = {10.1248/bpb.b23-00165},
pmid = {37661403},
issn = {1347-5215},
mesh = {Animals ; Mice ; *Muscle Fibers, Skeletal ; Cell Differentiation ; *Muscle, Skeletal ; Myoblasts ; Muscular Atrophy ; Acetylcysteine ; Antioxidants ; },
abstract = {Metallothionein (MT) 1 and 2 are ubiquitously expressed cysteine-rich, low molecular weight proteins. MT expression is upregulated in skeletal muscle during aging. MTs also play role in multiple types of skeletal muscle atrophy. Meanwhile, it has been reported that MT1 and MT2 gene deficiency increases myogenesis in MT knockout (MTKO) mice. However, little is known about the effect of MTs on muscle formation and atrophy. In this study, we investigated the effect of MT1 and MT2 gene knock-out using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (CRISPR-Cas9) system in an in vitro skeletal muscle differentiation model (C2C12 cell line). MT deficiency promoted myogenic differentiation and myotube formation in C2C12 cells. Muscle-specific transcription factors MyoD and myogenin were found to be upregulated at the late stage of myotube differentiation in MTKO cells. Furthermore, the fast-twitch myosin heavy chain (MyHC) protein expression was similar in MTKO and mock-transfected myotubes, but slow-MyHC expression was higher in MTKO cells than in mock cells. The MT gene deletion did not affect the number of fast MyHC-positive myotubes but increased the number of slow MyHC-positive myotubes. Treatment with the antioxidant N-acetylcysteine (NAC) inhibited the increase in the number of slow MyHC-positive myotubes as well as slow-MyHC expression in MTKO cells. In contrast, NAC treatment did not alter the number of fast MyHC-positive myotubes or the expression of fast-MyHC in MTKO cells. These results suggest that the antioxidant effects of MTs may be involved in slow-twitch myofiber formation in skeletal muscle.},
}
@article {pmid37659111,
year = {2023},
author = {Fraternale, A and Green, KA and Schiavano, GF and Bruschi, M and Retini, M and Magnani, M and Green, WR},
title = {Inhibition of myeloid-derived suppressor cell (MDSC) activity by redox-modulating agents restores T and B cell proliferative responses in murine AIDS.},
journal = {International immunopharmacology},
volume = {124},
number = {Pt A},
pages = {110882},
doi = {10.1016/j.intimp.2023.110882},
pmid = {37659111},
issn = {1878-1705},
abstract = {The mechanisms by which myeloid-derived suppressor cells (MDSCs) mediate inhibition prominently include the production of reactive nitrogen species, in particular those generated by inducible nitric oxide synthase (iNOS), and reactive oxygen species. LP-BM5 murine retroviral infection results in a profound immunodeficiency, known as murine AIDS, as well as in increased numbers and activity of monocytic-type MDSCs (M-MDSCs) that suppress both T and B cell responses. While M-MDSCs suppress T cells ex vivo in a fully iNOS/NO-dependent manner, M-MDSC suppression of B cell responses is only partially due to iNOS/NO. This study preliminarily explored the role of two redox-modulating compounds in inhibiting the M-MDSC suppressive activity in LP-BM5 infection. The tested molecules were: I-152 consisting in a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-cysteamine (SMEA) and C4-GSH that is the n-butanoyl glutathione (GSH) derivative. The results show that both molecules, tested in a concentration range between 3 and 20 mM, blocked the M-MDSC suppression of activated B and T cells ex vivo and restored their proliferative capacity in vivo. Ex vivo I-152 blockade of M-MDSC suppressiveness was more significant for T cell (about 70%) while M-MDSC blockade by C4-GSH was preferential for B cell responsiveness (about 60%), which was also confirmed by in vivo investigation. Beyond insights into redox-dependent suppressive effector mechanism(s) of M-MDSCs in LP-BM5 infection, these findings may ultimately be important to identify new immunotherapeutics against infectious diseases.},
}
@article {pmid37654348,
year = {2023},
author = {Veeraiyan, M and Kumar, YP and Chandhar, CY and Priyanka, Y and Jaiswal, M and Kemasaram, D},
title = {Evaluation of Smear Layer Removal and Micro Hardness Alteration of Radicular Dentin after Using Various Chelating Agents - An Atomic Force Microscopic Study.},
journal = {Journal of pharmacy &amp; bioallied sciences},
volume = {15},
number = {Suppl 1},
pages = {S582-S587},
pmid = {37654348},
issn = {0976-4879},
abstract = {BACKGROUND AND AIMS: For endodontic therapy to be successful, the smear layer produced by the root canal instruments must be removed. The study's objective is to evaluate the effectiveness of radicular dentin microhardness modification and smear layer removal utilizing various chelating agents.<br><br>MATERIALS AND METHODS: Extracted human mandibular single-rooted premolar teeth were selected for the study. The specimens were sectioned to obtain a standard root length and, working length determination was done. Cleaning and shaping were done in all the samples till the size F3 (Protaper universal). Based on the chelating agents using samples were randomly divided into four groups, Group-I: Saline (negative control), Group-II: 17% EDTA (DeSmear, Ahmedabad, Gujarat) (positive control), Group-III: 0.2% Chitosan (Everest-Biotech, Bengaluru), Group-IV: 20% N-Acetyl cysteine (NAC) (Sisco Research Laboratories, Mumbai), Group-V: 5% Pentetic acid (New Alliance Fine chem Pvt Ltd, Mumbai). All the samples were prepared for smear layer removal and surface roughness evaluation using an atomic force microscope.<br><br>RESULTS: It was observed that significantly (P = 0.000) the mean roughness average was higher among group II EDTA (148 &#xb1; 8.5) followed by group III 0.2% Chitosan (92.5 &#xb1; 3.42), group IV 20% NAC (85.2 &#xb1; 2.17), and group V 5% Pentetic acid (73.3 &#xb1; 3.39) and least by group I Saline (59.3 &#xb1; 3.31). The highest smear layer removal was seen with group II (EDTA) followed by group III (0.2% Chitosan), group IV (20% NAC), and group V (Pentetic acid).<br><br>CONCLUSION: All the chelating agents removed smear layer in coronal third, middle third whereas none of them were able to entirely eliminate from the apical third. Chitosan with smear layer removal capacity equal to EDTA with limited roughness can be considered as a valid alternative as final irrigant.},
}
@article {pmid37654090,
year = {2024},
author = {Frediani, JK and Lal, AA and Kim, E and Leslie, SL and Boorman, DW and Singh, V},
title = {The role of diet and non-pharmacologic supplements in the treatment of chronic neuropathic pain: A systematic review.},
journal = {Pain practice : the official journal of World Institute of Pain},
volume = {24},
number = {1},
pages = {186-210},
doi = {10.1111/papr.13291},
pmid = {37654090},
issn = {1533-2500},
mesh = {Humans ; Adult ; Acetylcarnitine/therapeutic use ; Magnesium/therapeutic use ; *Thioctic Acid/therapeutic use ; *Carnosine/therapeutic use ; Glutamine/therapeutic use ; Cysteine/therapeutic use ; Prospective Studies ; Dietary Supplements ; Vitamins/therapeutic use ; *Neuralgia/drug therapy ; Vitamin E/therapeutic use ; Ascorbic Acid/therapeutic use ; Diet ; Antioxidants/therapeutic use ; Vitamin B 12 ; *Complex Regional Pain Syndromes ; Vitamin D/therapeutic use ; Carotenoids ; },
abstract = {BACKGROUND/IMPORTANCE: Dietary interventions, vitamins, and nutritional supplementation are playing an increasingly important role in the management of neuropathic pain. Current pharmacological treatments are poorly tolerated and ineffective in many cases.<br><br>OBJECTIVE: This systematic review aims to study the efficacy of dietary interventions, vitamins, and nutritional supplementation in the management of chronic neuropathic pain in adults.<br><br>EVIDENCE REVIEW: The review followed PRISMA guidelines and was registered with PROSPERO (#CRD42022300312). Ten databases and gray literature, including Embase.com, MEDLINE and Web of Science, were systematically searched using a combination of keywords and controlled vocabulary related to chronic neuropathic pain and oral non-pharmacological supplements. Studies on adult humans published between 2000 and 2021 were considered for inclusion. The Cochrane Handbook was used to assess risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation was used to determine overall quality of evidence.<br><br>FINDINGS: Forty studies were included in the final review, and results were categorized according to pain type including pain related to chemotherapy-induced peripheral neuropathy (CIPN, 22 studies, including 3 prospective cohorts), diabetic peripheral neuropathy (DPN, 13 studies, including 2 prospective), complex regional pain syndrome (CRPS-I, 3 studies, including 1 prospective), and other (2 studies, both RCT). The CIPN studies used various interventions including goshajinkigan (4 studies), vitamin E (5), vitamin B12 (3), glutamine (3), N-acetyl-cysteine (2), acetyl-l-carnitine (2), guilongtonluofang (1), ninjin'yoeito (1), alpha-lipoic acid (1), l-carnosine (1), magnesium and calcium (1), crocin (1), and antioxidants (1), with some studies involving multiple interventions. All CIPN studies involved varying cancers and/or chemotherapies, advising caution for generalizability of results. Interventions for DPN included alpha-lipoic acid (5 studies), vitamin B12 (3), acetyl-l-carnitine (3), vitamin E (1), vitamin D (2), and a low-fat plant-based diet (1). Vitamin C was studied to treat CRPS-I (3 studies, including 1 prospective). Magnesium (1) and St. John's wort (1) were studied for other or mixed neuropathologies.<br><br>CONCLUSIONS: Based on the review, we cannot recommend any supplement use for the management of CIPN, although further research into N-acetyl-cysteine, l-carnosine, crocin, and magnesium is warranted. Acetyl-l-carnitine was found to be likely ineffective or harmful. Alpha-lipoic acid was not found effective. Studies with goshajinkigan, vitamin B12, vitamin E, and glutamine had conflicting results regarding efficacy, with one goshajinkigan study finding it harmful. Guilongtonluofang, ninjin'yoeito, and antioxidants showed various degrees of potential effectiveness. Regarding DPN, our review supports the use of alpha-lipoic acid, acetyl-l-carnitine, and vitamin D. The early use of vitamin C prophylaxis for the development of CRPS-I also seems promising. Further research is warranted to confirm these findings.},
}
@article {pmid37652392,
year = {2023},
author = {Xu, Y and Zhao, Z and Geng, Z and Zhou, H and Yang, C and Wang, Y and Kuerban, B and Xiao, Y and Luo, G},
title = {Enhancement of recombinant human interleukin-22 production by fusing with human serum albumin and supplementing N-acetylcysteine in Pichia Pastoris.},
journal = {Protein expression and purification},
volume = {212},
number = {},
pages = {106360},
doi = {10.1016/j.pep.2023.106360},
pmid = {37652392},
issn = {1096-0279},
mesh = {Saccharomycetales ; *Acetylcysteine/pharmacology ; Humans ; Interleukin-22 ; *Serum Albumin, Human/genetics ; Ascorbic Acid/pharmacology ; },
abstract = {Interleukin-22 (IL-22) plays an important role in the treatment of organ failure, which can induce anti-apoptotic and proliferative signaling pathways; Nevertheless, the practical utilization of IL-22 is hindered by the restricted efficacy of its production. Pichia pastoris presents a viable platform for both industrial and pharmaceutical applications. In this study, we successfully generated a fusion protein consisting of truncated human serum albumin and human IL-22 (HSA-hIL-22) using P. pastoris, and examined the impact of antioxidants on HSA-hIL-22 production. We have achieved the production of HSA-hIL-22 in the culture medium at a yield of approximately 2.25 mg/ml. Moreover, 0-40 mM ascorbic acid supplementation did not significantly affect HSA-hIL-22 production or the growth rate of the recombinant strain. However, 80 mM ascorbic acid treatment had a detrimental effect on the expression of HSA-hIL-22. In addition, 5-10 mM N-acetyl-l-cysteine (NAC) resulted in an increase of HSA-hIL-22 production, accompanied by a reduction in the growth rate of the recombinant strain. Conversely, 20-80 mM NAC supplementation inhibited the growth of the recombinant strains and reduced intact HSA-hIL-22 production. However, neither NAC nor ascorbic acid exhibited any effect on superoxide dismutase (SOD) and malondialdehyde (MDA) levels, except that NAC increased GSH content. Furthermore, our findings indicate that recombinant HSA-hIL-22, which demonstrated the ability to stimulate the proliferation of HepG2 cells, possesses bioactivity. In addition, NAC did not affect HSA-hIL-22 bioactivity. In conclusion, our study demonstrates that NAC supplementation can enhance the secretion of functional HSA-hIL-22 proteins produced in P. pastoris without compromising their activity.},
}
@article {pmid37647428,
year = {2023},
author = {Sun, X and Sun, Y and Cao, S and Liu, X},
title = {Effects of N-acetyl-L-cysteine polysulfides on periodontitis in a mouse model.},
journal = {Immunity, inflammation and disease},
volume = {11},
number = {8},
pages = {e959},
pmid = {37647428},
issn = {2050-4527},
mesh = {Animals ; Mice ; *Acetylcysteine/pharmacology ; Lipopolysaccharides/toxicity ; Toll-Like Receptor 4/genetics ; *Periodontitis/drug therapy ; Tumor Necrosis Factor-alpha ; Disease Models, Animal ; Sulfides ; },
abstract = {BACKGROUND: Polysulfides are reported to be involved in various important biological processes. N-acetyl-l-cysteine polysulfide with 2 sulfane sulfur atoms (NAC-S2) regulates diverse toll-like receptor (TLR) signaling pathways. Here, we aimed to determine the role of NAC-S2 in periodontitis and explore the potential mechanism.<br><br>METHODS: A periodontitis mouse model was established by ligating the subgingival between the first and second molars in wild-type, TLR4[-/-] , and Myd88[-/-] mice.<br><br>RESULTS: NAC-S2 did not affect the proportion of macrophages (CD11b[+] F4/80[+]) or neutrophils (CD11b[+] GR-1[+]) in the bone marrow. Mechanically, lipopolysaccharides (LPS), Zymosan A, or poly I: C induced tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1&#x3b2; expression in bone marrow-derived macrophages (BMDMs) could be inhibited by NAC-S2. On the other hand, NAC-S2 suppressed the phosphorylation levels of I&#x3ba;B-&#x3b1;, p65, and I&#x3ba;B kinase (IKK)-&#x3b2; induced by LPS in BMDMs, while LPS induced phosphorylation of ERK1/2, p38, and transforming growth factor &#x3b2;-activated kinase 1 (TAK1) could not be affected by NAC-S2. In wild-type periodontitis mice, NAC-S2 administration decreased the cemento-enamel-junction-alveolar bone crest (CEJ-ABC) distance and the relative mRNA expression of TNF, IL-6, and IL-1&#x3b2;, while such phenomena could not be observed in TLR4 deficiency or Myd88 deficiency mice.<br><br>CONCLUSIONS: All of these results indicate that NAC-S2 ameliorates TLR4/NF-&#x3ba;B pathway mediated inflammation in mouse periodontitis model.},
}
@article {pmid37645523,
year = {2023},
author = {Mi, K and Wu, S and Lv, C and Meng, Y and Yin, W and Li, H and Li, J and Yuan, H},
title = {Comparing the efficacy and safety of medications in adults with hypertrophic cardiomyopathy: a systematic review and network meta-analysis.},
journal = {Frontiers in cardiovascular medicine},
volume = {10},
number = {},
pages = {1190181},
pmid = {37645523},
issn = {2297-055X},
abstract = {BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. The purpose of this study was to evaluate the efficacy and safety of several medications and recommend better drug treatments for adults with HCM.<br><br>METHODS: A review of PubMed, Embase, the Cochrane Controlled Register of Trials (CENTRAL), ClinicalTrials.gov and CNKI databases was conducted for studies on the efficacy and safety of drugs for adults with HCM. A frequentist random effects model was used in this network analysis.<br><br>RESULTS: This network meta-analysis included 7 studies assessing seven medications, 6 studies evaluating monotherapy and 1 study evaluating combination therapy. Based on the network meta-analysis results, xiaoxinbi formula plus metoprolol (MD -56.50% [-72.43%, -40.57%]), metoprolol (MD -47.00% [-59.07%, -34.93%]) and mavacamten (MD -34.50% [-44.75%, -24.25%]) significantly reduced the resting left ventricular outflow tract gradient (LVOTG) in comparison with placebo. Resting LVOTG could also be reduced with N-acetylcysteine (NAC). The incidence of adverse drug reactions was not significantly different between the placebo group and the treatment group.<br><br>CONCLUSION: For adults with HCM, the top 4 treatments included xiaoxinbi formula plus metoprolol, metoprolol, mavacamten and NAC.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=374222], identifier [CRD42022374222].},
}
@article {pmid37635852,
year = {2023},
author = {Ng, WW and Tong, HF and Ng, WY and Yeung, JK and Young, JK and Woo, RK and Wong, MM},
title = {Pyroglutamic Acidosis - An Underrecognised Entity Associated with Acetaminophen Use.},
journal = {Romanian journal of anaesthesia and intensive care},
volume = {30},
number = {1},
pages = {26-30},
pmid = {37635852},
issn = {2392-7518},
abstract = {Pyroglutamic acidosis (PGA) is an underrecognized entity characterised by raised anion gap metabolic acidosis (RAGMA) and urinary hyper-excretion of pyroglutamic acid. It is frequently associated with chronic acetaminophen (APAP) ingestion. We report the case of a 73-year-old man with invasive pulmonary aspergillosis treated with voriconazole and APAP for analgesia with a cumulative dose of 160 g over 40 days. PGA was suspected as he developed severe RAGMA and common causes were excluded. Diagnosis was confirmed via urinary organic acid analysis which showed significant hyper-excretion of pyroglutamic acid. APAP was discontinued, and N-acetylcysteine (NAC) was administered. His RAGMA rapidly resolved following treatment.},
}
@article {pmid37634582,
year = {2023},
author = {Feng, C and Bai, H and Chang, X and Wu, Z and Dong, W and Ma, Q and Yang, J},
title = {Aflatoxin B1-induced early developmental hepatotoxicity in larvae zebrafish.},
journal = {Chemosphere},
volume = {340},
number = {},
pages = {139940},
doi = {10.1016/j.chemosphere.2023.139940},
pmid = {37634582},
issn = {1879-1298},
mesh = {Animals ; Aflatoxin B1/toxicity ; Zebrafish/genetics ; *Fatty Liver ; Acetylcysteine ; Larva/genetics ; *Chemical and Drug Induced Liver Injury ; },
abstract = {Aflatoxin B1 (AFB1) is a ubiquitous mycotoxin that causes oxidative damage in various organs. At present, the research studies on AFB1 are primarily focused on its effects on the terrestrial environment and animals. However, its toxicity mechanism in aquatic environments and aquatic animals has not been largely explored. Thus, in this study, zebrafish was used as a model to study the toxicity mechanism of AFB1 on the liver of developing larvae. The results showed that AFB1 exposure inhibited liver development and promoted fat accumulation in the liver. Transcriptome sequencing analysis showed that AFB1 affected liver redox metabolism and oxidoreductase activity. KEGG analysis showed that AFB1 inhibited the expression of gsto1, gpx4a, mgst3a, and idh1 in the glutathione metabolizing enzyme gene pathway, resulting in hepatic oxidative stress. At the same time, AFB1 also inhibited the expression of acox1, acsl1b, pparα, fabp2, and cpt1 genes in peroxidase and PPAR metabolic pathways, inducing hepatic steatosis and lipid droplet accumulation. Antioxidant N-Acetyl-l-cysteine (NAC) preconditioning up-regulated gsto1, gpx4a and idh1 genes, and improved the AFB1-induced lipid droplet accumulation in the liver. In summary, AFB1 induced hepatic oxidative stress and steatosis, resulting in abnormal liver fat metabolism and accumulation of cellular lipid droplets. NAC could be used as a potential preventative drug to improve AFB1-induced fat accumulation.},
}
@article {pmid37632646,
year = {2023},
author = {Chen, HY and Chen, RLC and Hsieh, BC and Cheng, TJ},
title = {Determination of o-phthalaldehyde for dose verification of the clinical disinfectant by fluorescent sequential injection analysis.},
journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry},
volume = {39},
number = {12},
pages = {2007-2017},
pmid = {37632646},
issn = {1348-2246},
support = {MOST-105-2313-B-002-022//Ministry of Science and Technology of Taiwan/ ; MOST-107-2313-B-002-015//Ministry of Science and Technology of Taiwan/ ; },
mesh = {*o-Phthalaldehyde/analysis ; *Disinfectants ; Reproducibility of Results ; Glutaral ; Coloring Agents ; },
abstract = {A new automated, generic analytical approach for determining the clinical disinfectant o-phthalaldehyde (OPA) is reported in this study. The proposed sequential injection analysis (SIA) is based on the online reaction of the OPA with glycine/N-acetylcysteine (NAC) in a neutral medium (pH = 7.0) to form a highly fluorescent isoindole derivative. All critical flow and reaction variables were investigated, while validation was carried out in the linearity detection range (0.0075-0.02%). As a result, excellent linearity (R[2] > 0.99) and precision (1.5-2.4% for repeatability and 0.7-2.2% for reproducibility) were achieved for the reference OPA solutions. Furthermore, reasonable concentration verification of OPA disinfection (0.2-0.6%) in healthcare institutes can be achieved using the developed fluorescent SIA due to its good sensitivity (0.111 V/%) and precision (1.0-2.3% for intermediate precision) around the minimum effective concentration (MEC) of 0.3% for Cidex-OPA disinfectant.},
}
@article {pmid37631065,
year = {2023},
author = {Blagov, AV and Orekhova, VA and Sukhorukov, VN and Melnichenko, AA and Orekhov, AN},
title = {Potential Use of Antioxidant Compounds for the Treatment of Inflammatory Bowel Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {16},
number = {8},
pages = {},
pmid = {37631065},
issn = {1424-8247},
support = {23-65-10014//Russian Science Foundation/ ; },
abstract = {Since inflammatory bowel diseases (IBDs) are chronic, the development of new effective therapeutics to combat them does not lose relevance. Oxidative stress is one of the main pathological processes that determines the progression of IBD. In this regard, antioxidant therapy seems to be a promising approach. The role of oxidative stress in the development and progression of IBD is considered in detail in this review. The main cause of oxidative stress in IBD is an inadequate response of leukocytes to dysbiosis and food components in the intestine. Passage of immune cells through the intestinal barrier leads to increased ROS concentration and the pathological consequences of exposure to oxidative stress based on the development of inflammation and impaired intestinal permeability. To combat oxidative stress in IBD, several promising natural (curcumin, resveratrol, quercetin, and melatonin) and artificial antioxidants (N-acetylcysteine (NAC) and artificial superoxide dismutase (aSOD)) that had been shown to be effective in a number of clinical trials have been proposed. Their mechanisms of action on pathological events in IBD and clinical manifestations from their impact have been determined. The prospects for the use of other antioxidants that have not yet been tested in the treatment of IBD, but have the properties of potential therapeutic candidates, have been also considered.},
}
@article {pmid37628913,
year = {2023},
author = {Alkandari, AF and Madhyastha, S and Rao, MS},
title = {N-Acetylcysteine Amide against Aβ-Induced Alzheimer's-like Pathology in Rats.},
journal = {International journal of molecular sciences},
volume = {24},
number = {16},
pages = {},
pmid = {37628913},
issn = {1422-0067},
support = {YM07/19//Kuwait University/ ; },
mesh = {Male ; Rats ; Animals ; Acetylcysteine/pharmacology/analogs &amp; derivatives ; Rats, Wistar ; *Alzheimer Disease/chemically induced/drug therapy ; Synaptophysin ; *Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides ; Gliosis/chemically induced/drug therapy ; Glutathione ; },
abstract = {Oxidative stress with a depletion of glutathione is a key factor in the initiation and progression of Alzheimer's disease (AD). N-Acetylcysteine (NAC), a glutathione precursor, provides neuroprotective effects in AD animal models. Its amide form, N-Acetylcysteine amide (NACA), has an extended bioavailability compared to NAC. This study evaluates the neuroprotective effects of NACA against Aβ1-42 peptide-induced AD-like pathology in rats. Male Wistar rats (2.5 months old) were divided into five groups: Normal Control (NC), Sham (SH), Aβ, Aβ + NACA and NACA + Aβ + NACA (n = 8 in all groups). AD-like pathology was induced by the intracerebroventricular infusion of Aβ1-42 peptide into the lateral ventricle. NACA (75 mg/kg) was administered either as a restorative (i.e., injection of NACA for 7 consecutive days after inducing AD-like pathology (Aβ + N group)), or as prophylactic (for 7 days before and 7 days after inducing the pathology (N + Aβ + N group)). Learning and memory, neurogenesis, expression of AD pathology markers, antioxidant parameters, neuroprotection, astrogliosis and microgliosis were studied in the hippocampus and the prefrontal cortex. All data were analyzed with a one-way ANOVA test followed by Bonferroni's multiple comparison test. NACA treatment reversed the cognitive deficits and reduced oxidative stress in the hippocampus and prefrontal cortex. Western blot analysis for Tau, Synaptophysin and Aβ, as well as a histopathological evaluation through immunostaining for neurogenesis, the expression of neurofibrillary tangles, β-amyloid peptide, synaptophysin, neuronal morphology and gliosis, showed a neuroprotective effect of NACA. In conclusion, this study demonstrates the neuroprotective effects of NACA against β-amyloid induced AD-like pathology.},
}
@article {pmid37628819,
year = {2023},
author = {Heiserman, JP and Minhas, Z and Nikpayam, E and Cheon, DJ},
title = {Targeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines.},
journal = {International journal of molecular sciences},
volume = {24},
number = {16},
pages = {},
pmid = {37628819},
issn = {1422-0067},
support = {1/CX/CSRD VA/United States ; },
mesh = {Humans ; Female ; *Cisplatin/pharmacology ; HSP27 Heat-Shock Proteins/genetics ; Reactive Oxygen Species ; Neoplasm Recurrence, Local ; *Ovarian Neoplasms/drug therapy ; Cell Line ; Fatty Acids ; },
abstract = {Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines to cisplatin and dual inhibition of both HSP27 and FAO induces substantial cell death in vitro. However, it is unclear how HSP27 and FAO promote cisplatin resistance, and if dual inhibition of both HSP27 and FAO would augment cisplatin treatment in vivo. Here we showed that HSP27 knockdown in two cisplatin-resistant ovarian cancer cell lines (A2780CIS and PEO4) resulted in more ROS production upon cisplatin treatment. HSP27-knockdown cancer cells exhibited decreased levels of reduced glutathione (GSH) and glucose6phosphate dehydrogenase (G6PD), a crucial pentose phosphate pathway enzyme. ROS depletion with the compound N-acetyl cysteine (NAC) attenuated cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis in cisplatin-resistant ovarian cancer cell lines. Finally, inhibition of HSP27 and FAO with ivermectin and perhexiline enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors in vivo. Our results suggest that two different cisplatin-resistant ovarian cancer cell lines upregulate HSP27 and FAO to deplete cisplatin-induced ROS to attenuate cisplatin's cytotoxic effect.},
}
@article {pmid37628771,
year = {2023},
author = {Staskiewicz, A and Wong, E and Tucker, M and Farhin, R and Park, J and Saade, R and Alkhazali, T and Dang, T and Wang, X},
title = {Cytotoxic and Apoptotic Effects of Pinostilbene and Bortezomib Combination Treatment on Human Multiple Myeloma Cells.},
journal = {International journal of molecular sciences},
volume = {24},
number = {16},
pages = {},
pmid = {37628771},
issn = {1422-0067},
mesh = {Humans ; Bortezomib/pharmacology ; Caspase 3 ; *Multiple Myeloma/drug therapy ; Antioxidants ; *Antineoplastic Agents ; Resveratrol/pharmacology ; Tumor Microenvironment ; Stilbenes ; },
abstract = {Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow characterized by bone lesions, hypercalcemia, anemia, and renal failure. Bortezomib (BTZ), a common treatment for MM, is a proteasome inhibitor that induces apoptosis in MM cells. However, high doses of BTZ can be very toxic, signifying a need for a synergistic drug combination to improve treatment efficacy. Resveratrol (RES), a phenolic compound found in grapes, has been shown to inhibit MM cell growth. We sought to identify a synergistic combination of BTZ with a RES derivative and analyze the effects on reducing viability and inducing apoptosis in human MM cells. BTZ as well as RES and its derivatives pinostilbene (PIN) and piceatannol (PIC) decreased MM cell viability in a dose- and time-dependent manner and increased expression of cleaved proapoptotic proteins poly(ADP-ribose) polymerase 1 (PARP1) and caspase-3 in a dose-dependent manner. The combination of 5 nM BTZ and 5 μM PIN was identified to have synergistic cytotoxic effects in MM RPMI 8226 cells. MM RPMI 8226 cells treated with this combination for 24 h showed increased cleaved PARP1 and caspase-3 expression and higher percentages of apoptotic cells versus cells treated with the individual compounds alone. The treatment also showed increased apoptosis induction in MM RPMI 8226 cells co-cultured with human bone marrow stromal HS-5 cells in a Transwell model used to mimic the bone marrow microenvironment. Expression of oxidative stress defense proteins (catalase, thioredoxin, and superoxide dismutase) in RPMI 8226 cells were reduced after 24 h treatment, and cytotoxic effects of the treatment were ameliorated by antioxidant N-acetylcysteine (NAC), suggesting the treatment impacts antioxidant levels in RPMI 8226 cells. Our results suggest that this combination of BTZ and PIN decreases MM cell viability synergistically by inducing apoptosis and oxidative stress in MM cells.},
}
@article {pmid37627587,
year = {2023},
author = {Cuevas-López, B and Romero-Ramirez, EI and García-Arroyo, FE and Tapia, E and León-Contreras, JC and Silva-Palacios, A and Roldán, FJ and Campos, ONM and Hernandez-Esquivel, L and Marín-Hernández, A and Gonzaga-Sánchez, JG and Hernández-Pando, R and Pedraza-Chaverri, J and Sánchez-Lozada, LG and Aparicio-Trejo, OE},
title = {NAC Pre-Administration Prevents Cardiac Mitochondrial Bioenergetics, Dynamics, Biogenesis, and Redox Alteration in Folic Acid-AKI-Induced Cardio-Renal Syndrome Type 3.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {8},
pages = {},
pmid = {37627587},
issn = {2076-3921},
support = {21-1252//Instituto Nacional de Cardiolog&#xed;a/ ; },
abstract = {The incidence of kidney disease is increasing worldwide. Acute kidney injury (AKI) can strongly favor cardio-renal syndrome (CRS) type 3 development. However, the mechanism involved in CRS development is not entirely understood. In this sense, mitochondrial impairment in both organs has become a central axis in CRS physiopathology. This study aimed to elucidate the molecular mechanisms associated with cardiac mitochondrial impairment and its role in CRS development in the folic acid-induced AKI (FA-AKI) model. Our results showed that 48 h after FA-AKI, the administration of N-acetyl-cysteine (NAC), a mitochondrial glutathione regulator, prevented the early increase in inflammatory and cell death markers and oxidative stress in the heart. This was associated with the ability of NAC to protect heart mitochondrial bioenergetics, principally oxidative phosphorylation (OXPHOS) and membrane potential, through complex I activity and the preservation of glutathione balance, thus preventing mitochondrial dynamics shifting to fission and the decreases in mitochondrial biogenesis and mass. Our data show, for the first time, that mitochondrial bioenergetics impairment plays a critical role in the mechanism that leads to heart damage. Furthermore, NAC heart mitochondrial preservation during an AKI event can be a valuable strategy to prevent CRS type 3 development.},
}
@article {pmid37625774,
year = {2023},
author = {Jhuo, JY and Tong, ZJ and Ku, PH and Cheng, HW and Wang, HT},
title = {Acrolein induces mitochondrial dysfunction and insulin resistance in muscle and adipose tissues in vitro and in vivo.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {336},
number = {},
pages = {122380},
doi = {10.1016/j.envpol.2023.122380},
pmid = {37625774},
issn = {1873-6424},
abstract = {Type 2 diabetes mellitus (DM) is a common chronic condition characterized by persistent hyperglycemia and is associated with insulin resistance (IR) in critical glucose-consuming tissues, including skeletal muscle and adipose tissue. Oxidative stress and mitochondrial dysfunction are known to play key roles in IR. Acrolein is a reactive aldehyde found in the diet and environment that is generated as a fatty acid product through the glucose autooxidation process under hyperglycemic conditions. Our previous studies have shown that acrolein impairs insulin sensitivity in normal and diabetic mice, and this effect can be reversed by scavenging acrolein. This study demonstrated that acrolein increased oxidative stress and inhibited mitochondrial respiration in differentiated C2C12 myotubes and differentiated 3T3-L1 adipocytes. As a result, insulin signaling pathways were inhibited, leading to reduced glucose uptake. Treatment with acrolein scavengers, N-acetylcysteine, or carnosine ameliorated mitochondrial dysfunction and inhibited insulin signaling. Additionally, an increase in acrolein expression correlated with mitochondrial dysfunction in the muscle and adipose tissues of diabetic mice. These findings suggest that acrolein-induced mitochondrial dysfunction contributes to IR, and scavenging acrolein is a potential therapeutic approach for treating IR.},
}
@article {pmid37625683,
year = {2023},
author = {Zhao, S and Li, Y and Li, G and Ye, J and Wang, R and Zhang, X and Li, F and Gao, C and Li, J and Jiang, J and Mi, Y},
title = {PI3K/mTOR inhibitor VS-5584 combined with PLK1 inhibitor exhibits synergistic anti-cancer effects on non-small cell lung cancer.},
journal = {European journal of pharmacology},
volume = {957},
number = {},
pages = {176004},
doi = {10.1016/j.ejphar.2023.176004},
pmid = {37625683},
issn = {1879-0712},
mesh = {Humans ; Animals ; Mice ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; Phosphatidylinositol 3-Kinases ; Reactive Oxygen Species ; *Lung Neoplasms/drug therapy ; TOR Serine-Threonine Kinases ; Polo-Like Kinase 1 ; Morpholines ; Purines ; },
abstract = {Small molecule drugs are of significant importance in the treatment of non-small cell lung cancer (NSCLC). Here, we explored biological effects of the PI3K/mTOR inhibitor VS-5584 on NSCLC. Our findings indicated that VS-5584 administration resulted in a dose-dependent inhibition of NSCLC cell proliferation, as well as the induction of apoptosis and cycle arrest. Additionally, we observed a significant increase in intracellular reactive oxygen species (ROS) levels following VS-5584 treatment. The use of the ROS inhibitor N-acetylcysteine (NAC) effectively reduced ROS levels and decreased the proportion of apoptotic cells. Treatment with VS-5584 led to an upregulation of genes associated with apoptosis and cell cycle, such as c-caspase 3 and P21. Conversely, a downregulation of cyclin-dependent kinase 1 (CDK1) expression was observed. Next, transcriptome analyses revealed that VS-5584 treatment altered the abundance of 1520 genes/transcripts in PC-9 cells, one of which was polo-like kinase 1 (PLK1). These differentially expressed genes were primarily enriched in biological processes such as cell cycle regulation and cell apoptosis, which are closely linked to the P53 and apoptosis pathways. Co-treatment with VS-5584 and PLK1 inhibitor NMS-P937 resulted in enhanced cancer cell death, exhibiting synergistic inhibitory activity. Notably, VS-5584 inhibited the growth of NSCLC in a patient-derived xenograft (PDX) mouse model without observable abnormalities in major organs. Overall, VS-5584 effectively suppressed the growth of NSCLC cells both in vitro and in vivo. VS-5584 combined with NMS-P937 exhibited a synergistic effect in inhibiting NSCLC cell growth. These findings suggest that VS-5584 has potential as a therapeutic strategy for treating NSCLC.},
}
@article {pmid37621062,
year = {2023},
author = {Chen, H and Zhou, H and Luo, C and Zong, K and Fu, Y and Li, W and Luo, C and Xue, G and Jiang, E and Duan, Y and Luo, T and Jiang, Y},
title = {Efficacy of treatment with N-acetylcysteine inhalation for AECOPD: A propensity-score-matched cohort study.},
journal = {The clinical respiratory journal},
volume = {17},
number = {10},
pages = {1038-1047},
pmid = {37621062},
issn = {1752-699X},
support = {2021-55//Social Undertakings and Livelihood Security Special Projects, the Science and Technology Bureau of Banan District, Chongqing/ ; },
mesh = {Humans ; *Acetylcysteine/adverse effects ; Cohort Studies ; Retrospective Studies ; Propensity Score ; *Pulmonary Disease, Chronic Obstructive ; Disease Progression ; },
abstract = {INTRODUCTION: N-acetylcysteine (NAC) prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, the value of NAC inhalation in the treatment of patients with AECOPD is still poorly understood. The study was conducted to evaluate the efficacy of NAC inhalation in AECOPD patients requiring hospitalization.<br><br>METHODS: In this single institutional, retrospective cohort study, all patients with AECOPD requiring hospitalization between January 2021 and January 2022 were included. Patients were divided into NAC group and Non-NAC group according to whether being treated with NAC inhalation and were matched using the propensity score. The primary outcome was a composite of progression to ventilation requirement, in-hospital mortality and readmission for AECOPD within 30&#x2009;days. The effect on the mean hospitalized days, blood gas indexes and the incidence rate of adverse drug events were compared between the two groups.<br><br>RESULTS: Ninety-six patients in the NAC group were matched with 96 patients in the Non-NAC group. The differences in the primary composite end point (NAC group vs Non-NAC group, 5.2% vs 16.7%; P&#x2009;=&#x2009;0.011) were significant. The median time to discharge was shorter in the NAC group (8.3 vs. 9.1&#x2009;days, P&#x2009;=&#x2009;0.030). The NAC group presented a larger increase in partial pressure of arterial oxygen (Pa O2) and a higher ratio of self-reported symptomatic improvement from admission to day 5. There was no definite difference between the two groups in the frequency of adverse event.<br><br>CONCLUSION: NAC inhalation is associated with an improved clinical outcome. A further study should be conducted to confirm the clinical usefulness of NAC inhalation in AECOPD patients.},
}
@article {pmid37611476,
year = {2023},
author = {Sun, S and Zhang, C and Zhang, Q and Li, C and Huang, D and Ding, R and Cao, J and Hao, J},
title = {Role of ROS-mediated PERK/ATF4 signaling activation in extracorporeal tube formation injury of human umbilical vein endothelial cells induced by cooking oil fume PM2.5 exposure.},
journal = {Ecotoxicology and environmental safety},
volume = {263},
number = {},
pages = {115332},
doi = {10.1016/j.ecoenv.2023.115332},
pmid = {37611476},
issn = {1090-2414},
mesh = {Humans ; Human Umbilical Vein Endothelial Cells ; Reactive Oxygen Species ; *Acetylcysteine/pharmacology ; *Cooking ; Gases ; Particulate Matter/toxicity ; Activating Transcription Factor 4/genetics ; },
abstract = {Cooking oil fume-derived PM2.5 (COF-PM2.5) is a major source of indoor air contamination in China, which has been demonstrated to be a hazard factor of cardiovascular and cerebrovascular diseases. This study aimed to investigate the role of ROS-mediated PERK/ATF4 signaling activation in COF-PM2.5-inhibited extracorporeal tube formation in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with 100 μg/mL COF-PM2.5 at different times, with or without 100 nM PERK activity inhibitor GSK2606414 (GSK) or 200 μM antioxidant N-acetylcysteine (NAC) pretreatment. Our results showed that COF-PM2.5 exposure can inhibit extracorporeal tube formation and down-regulate VEGFR2 expression in HUVECs. Furthermore, our data indicated that COF-PM2.5 exposure can activate the PERK/ATF4 signaling in HUVECs. Mechanistically, pretreatment with GSK interdicted PERK/ATF4 signaling, thereby reversing COF-PM2.5-downregulated VEGFR2 protein expression in HUVECs. Furthermore, NAC reversed VEGFR2 expression downregulated induced by COF-PM2.5 by inhibiting the upregulation of intracellular ROS levels and PERK/ATF4 signaling in HUVECs. As above, COF-PM2.5 exposure could induce ROS release from HUVECs, which in turn activate the endoplasmic reticulum PERK/ATF4 signaling and inhibit tube formation of HUVECs.},
}
@article {pmid37609158,
year = {2023},
author = {Gupta, K and Chen, D and Wells, RG},
title = {Microcystin-RR is a biliary toxin selective for neonatal cholangiocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {37609158},
issn = {2692-8205},
support = {P30 DK050306/DK/NIDDK NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 DK119290/DK/NIDDK NIH HHS/United States ; },
abstract = {BACKGROUND AND AIMS: Biliary atresia is a fibrosing cholangiopathy affecting neonates that is thought to be caused by a prenatal environmental insult to the bile duct. Biliatresone, a plant toxin with an α-methylene ketone group, was previously implicated in toxin-induced biliary atresia in Australian livestock, but is found in a limited location and is highly unlikely to be a significant human toxin. We hypothesized that other molecules with α-methylene ketone groups, some with the potential for significant human exposure, might also be biliary toxins.<br><br>APPROACH AND RESULTS: We focused on the family of microcystins, cyclic peptide toxins from blue-green algae that have an &#x3b1;-methylene ketone group and are found worldwide, particularly during harmful algal blooms. We found that microcystin-RR, but not 6 other microcystins, caused damage to cell spheroids made using cholangiocytes isolated from 2-3-day-old mice, but not from adult mice. We also found that microcystin-RR caused occlusion of extrahepatic bile duct explants from 2-day-old mice, but not 18-day-old mice. Microcystin-RR caused elevated reactive oxygen species in neonatal cholangiocytes, and treatment with N-acetyl cysteine partially prevented microcystin-RRinduced lumen closure, suggesting a role for redox homeostasis in its mechanism of action.<br><br>CONCLUSIONS: This study highlights the potential for environmental toxins to cause neonatal biliary disease and identifies microcystin-RR acting via increased redox stress as a possible neonatal bile duct toxin.},
}
@article {pmid37607187,
year = {2023},
author = {da Silva, RHS and de Moura, M and de Paula, L and Arantes, KC and da Silva, M and de Amorim, J and Miguel, MP and Martins, DB and de Melo E Silva, D and Melo, MM and Botelho, AFM},
title = {Effects of coenzyme Q10 and N-acetylcysteine on experimental poisoning by paracetamol in Wistar rats.},
journal = {PloS one},
volume = {18},
number = {8},
pages = {e0290268},
pmid = {37607187},
issn = {1932-6203},
mesh = {Adult ; Humans ; Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Acetaminophen ; Rats, Wistar ; Saline Solution ; Ubiquinone/analogs &amp; derivatives ; },
abstract = {Paracetamol (PAR) is a drug widely used in human and veterinary medicine as an analgesic and antipyretic, often involved in cases of intoxication. The most common clinical signs result from damage to red blood cells and hepatocytes, and this intoxication is considered a model for the induction of acute liver failure. In the present study, the hepatoprotective effects of coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC) against experimental paracetamol (PAR) poisoning were analysed. Thirty-five adult Wistar rats (Rattus novergicus albinus) were randomly assigned to five groups, and thirty-one of these survived the treatments. Negative control group (CON-) received 1mL of 0.9% NaCl orally (PO). Other groups received 1.2g/kg of PAR (PO). Positive control group (CON+) received only PAR. NAC group received 800 mg/kg intraperitoneally (IP) of NAC 1h after the administration of PAR and at 12 h received 1mL of 0.9% NaCl, IP. The fourth group (CoQ10) received 1h and 12 h after intoxication, CoQ10 (10mg/kg IP). And the fifth group (NAC+CoQ10) received NAC (800mg/kg, IP) and CoQ10 (10mg/kg, IP). After 12 hours, the rats were euthanized and necropsied to collect liver and kidney tissues for histopathological evaluation and electronic microscopy. A single dose of PAR caused severe acute hepatitis. NAC couldn't reverse the liver and kidney damages. The group that received CoQ10 and NAC had moderate liver damage, while the group that received only CoQ10 had lower values of liver enzymes and mild liver and kidney damage. Animals that received treatment with CoQ10 or NAC+CoQ10 presented normal hepatocyte mitochondria and nuclei. Although CoQ10 couldn't reverse PAR organ damage, results indicate promising hepatoprotection in Wistar rats.},
}
@article {pmid37604367,
year = {2023},
author = {Wang, X and Tian, X and Yan, H and Zhu, T and Ren, H and Zhou, Y and Zhao, D and Xu, D and Lian, X and Fang, L and Yu, Y and Liao, X and Liu, Y and Sun, J},
title = {Exposure to salinomycin dysregulates interplay between mitophagy and oxidative response to damage the porcine jejunal cells.},
journal = {The Science of the total environment},
volume = {900},
number = {},
pages = {166441},
doi = {10.1016/j.scitotenv.2023.166441},
pmid = {37604367},
issn = {1879-1026},
mesh = {Animals ; Swine ; *Mitophagy ; Kelch-Like ECH-Associated Protein 1 ; *Ecosystem ; Reactive Oxygen Species ; Chickens ; NF-E2-Related Factor 2 ; Antioxidants ; Oxidative Stress ; Protein Kinases ; Pyrans ; Polyether Polyketides ; },
abstract = {Salinomycin (SAL) has caused widespread pollution as a feed additive and growth promoter in livestock such as pigs, exerting a negative impact on public health. The toxicity mechanism of SAL has been widely studied in chickens, but the underlying mechanisms of SAL-induced toxicity to pigs and the ecosystem remain undefined. In this study, we explored the potential damage of SAL in IPEC-J2 cells to identify the effects of excessive SAL on the interplay between mitophagy and oxidative stress. The results showed that a concentration-dependent response was observed for SAL in altering cellular morphology and inducing cell death in IPEC-J2 cells, including the induction of cell cycle arrest and lactic dehydrogenase (LDH) release. Meanwhile, we found that excessive SAL led to oxidative damage by activating the Nrf2/Keap1/HO-1 pathway, accompanied by reactive oxygen species (ROS) elevation and the reduction of antioxidant enzyme activity. We also found that PINK1/Parkin-dependent mitophagy was activated by SAL exposure, particularly with mitochondrial membrane potential reduction. Interestingly, SAL-induced oxidative damages were prevented after the autophagy inhibitor 3-methyladenine (3-MA) treatment, and mitophagy was alleviated following ROS scavenger (N-acetylcysteine, NAC) treatment. Overall, our findings showed that SAL stimulated oxidative stress and mitophagy in IPEC-J2 cells resulting in cellular injury, and there was a strong connection between SAL-induced oxidative stress and mitophagy. Targeting ROS/PINK1/Parkin-dependent mitophagy and oxidative stress could be a novel protective mechanism in SAL-induced cell damage.},
}
@article {pmid37598316,
year = {2023},
author = {Etemadi, Y and Akakpo, JY and Ramachandran, A and Jaeschke, H},
title = {Nrf2 as a therapeutic target in acetaminophen hepatotoxicity: A case study with sulforaphane.},
journal = {Journal of biochemical and molecular toxicology},
volume = {37},
number = {12},
pages = {e23505},
pmid = {37598316},
issn = {1099-0461},
support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; },
mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; NF-E2-Related Factor 2/metabolism ; Antidotes/pharmacology/therapeutic use/metabolism ; Mice, Inbred C57BL ; Liver/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology/prevention &amp; control ; Sulfoxides ; Isothiocyanates ; },
abstract = {Acetaminophen (APAP) overdose can cause severe liver injury and acute liver failure. The only clinically approved antidote, N-acetylcysteine (NAC), is highly effective but has a narrow therapeutic window. In the last 2 decades, activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates acute phase proteins and antioxidant defense genes, has emerged as a putative new therapeutic target against APAP hepatotoxicity. However, virtually all studies that propose Nrf2 activation as mechanism of protection used prolonged pretreatment, which is not a clinically feasible approach to treat a drug overdose. Therefore, the objective of this study was to assess if therapeutic activation of Nrf2 is a viable approach to treat liver injury after APAP overdose. We used the water-soluble Nrf2 activator sulforaphane (SFN; 5 mg/kg) in a murine model of APAP hepatotoxicity (300 mg/kg). Our results indicate that short-term treatment (≤3 h) with SFN alone did not activate Nrf2 or its target genes. However, posttreatment with SFN after APAP partially protected at 6 h likely due to more rapid activation of the Nrf2-target gene heme oxygenase-1. A direct comparison of SFN with NAC given at 1 h after APAP showed a superior protection with NAC, which was maintained at 24 h unlike with SFN. Thus, Nrf2 activators have inherent problems like the need to create a cellular stress to activate Nrf2 and delayed adaptive responses which may hamper sustained protection against APAP hepatotoxicity. Thus, compared to the more direct acting antidote NAC, Nrf2 activators are less suitable for this indication.},
}
@article {pmid37596428,
year = {2023},
author = {Clark, RSB and Empey, PE and Kochanek, PM and Bell, MJ},
title = {N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {20},
number = {6},
pages = {1529-1537},
pmid = {37596428},
issn = {1878-7479},
support = {R01 NS069247/NS/NINDS NIH HHS/United States ; },
mesh = {Child ; Humans ; *Probenecid/therapeutic use/pharmacology ; Acetylcysteine/therapeutic use/pharmacology ; Pilot Projects ; *Brain Injuries, Traumatic/drug therapy ; Brain ; Blood-Brain Barrier ; },
abstract = {N-Acetylcysteine (NAC) has shown promise as a putative neurotherapeutic for traumatic brain injury (TBI). Yet, many such promising compounds have limited ability to cross the blood-brain barrier (BBB), achieve therapeutic concentrations in brain, demonstrate target engagement, among other things, that have hampered successful translation. A pharmacologic strategy for overcoming poor BBB permeability and/or efflux out of the brain of organic acid-based, small molecule therapeutics such as NAC is co-administration with a targeted or nonselective membrane transporter inhibitor. Probenecid is a classic ATP-binding cassette and solute carrier inhibitor that blocks transport of organic acids, including NAC. Accordingly, combination therapy using probenecid as an adjuvant with NAC represents a logical neurotherapeutic strategy for treatment of TBI (and other CNS diseases). We have completed a proof-of-concept pilot study using this drug combination in children with severe TBI-the Pro-NAC Trial (ClinicalTrials.gov NCT01322009). In this review, we will discuss the background and rationale for combination therapy with probenecid and NAC in TBI, providing justification for further clinical investigation.},
}
@article {pmid37595880,
year = {2023},
author = {Yang, L and Mei, G and Yang, Y and Cui, J and Peng, S and Peng, Z and Cheng, Y},
title = {Hexachlorocyclohexane impairs human sperm motility by affecting lysine glutarylation and mitochondrial functions.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {179},
number = {},
pages = {113991},
doi = {10.1016/j.fct.2023.113991},
pmid = {37595880},
issn = {1873-6351},
mesh = {Humans ; Male ; Acetylcysteine ; *Hexachlorocyclohexane ; *Lysine ; Mitochondria ; Reactive Oxygen Species ; Semen ; Sperm Motility ; Glutarates/chemistry/pharmacology ; },
abstract = {Decreased sperm motility is a leading cause of male infertility and persistent organic pollutants are known to contribute significantly to the development of this disease. The effects of organochlorine pesticides such as hexachlorocyclohexane (HCH) on human sperm function and their mechanisms of action have received much attention, but are still not fully understood. Herein, we discovered that HCH has a concentration- and time-dependent inhibitory effect on human sperm motility in vitro. Moreover, HCH could reduce the levels of lysine glutarylation (Kglu) and glucose-6-phosphate dehydrogenase activity in sperm. Meanwhile, HCH could increase reactive oxygen species and thereby lead to mitochondrial depolarization and the down-regulation of adenosine triphosphate levels. In particular, we observed that sodium glutarate (Na-glu), the precursor of glutaryl-CoA, could alleviate the inhibitory effect of HCH on sperm Kglu levels, whereas the ROS scavenger N-acetyl-L-cysteine (NAC) had no effect. Intriguingly, both Na-glu and NAC were able to partially inhibit the HCH-induced increase in sperm ROS levels and impaired sperm motility. In conclusion, we propose that HCH inhibits sperm Kglu, leading to the disruption of mitochondrial energy metabolism, which in turn adversely affects sperm motility.},
}
@article {pmid37595477,
year = {2023},
author = {Zhu, X and Song, Y and Wang, X and Zhou, Y and Chai, Y and Yuan, R},
title = {Copper nanoclusters electrochemiluminescence with tunable near-infrared emission wavelength for ultrasensitive detection of matrix metalloproteinase-2.},
journal = {Biosensors &amp; bioelectronics},
volume = {238},
number = {},
pages = {115580},
doi = {10.1016/j.bios.2023.115580},
pmid = {37595477},
issn = {1873-4235},
mesh = {Humans ; *Copper ; Matrix Metalloproteinase 2 ; *Biosensing Techniques ; Methionine ; Racemethionine ; Acetylcysteine ; },
abstract = {Herein, the methionine (Met)/N-acetyl-L-cysteine (NAC) templated copper nanoclusters (Met/NAC-Cu NCs) with tunable near-infrared region (NIR) electrochemiluminescence (ECL) emission wavelength was firstly synthesized as emitter for the ultrasensitive detection of matrix metalloproteinase-2 (MMP-2). Significantly, the NAC played the role of template and reductant of cupric to acquire Cu NCs, and the surface defect regulator Met was used to connect NAC through -S-S- bond, which could heighten the surface defect of Cu NCs to continuously regulate the maximum ECL emission by successively controlling the molar ratio of Met and NAC, leading to the ECL emission wavelength of Cu NCs ranged from 680 nm to 750 nm. In addition, a rapid target triggered catalyst hairpin assembly (CHA) recycling amplification strategy was constructed through orderly and equidistantly arranging hairpin to increase its local concentration, resulting in greatly accelerated signal amplification efficiency and reaction rate. As a proof of concept, based on Met/NAC-Cu NCs as NIR ECL emitter and effective signal amplification tactic, a super-sensitive ECL biosensor was fabricated to detect target MMP-2 with the detection limit (LOD) as low as 1.65 fg/mL and successfully utilized for detecting of MMP-2 that from Hela and MCF-7 cancer cells. This research provided a wonderful avenue for regulating the optical performance of metal nanoclusters-based ECL emitters, and the developed neoteric NIR ECL emitter with the merits of less photochemical damage and deeper tissue penetration exhibited great potential in ultrasensitive biosensing and high-definition ECL imaging.},
}
@article {pmid37594415,
year = {2023},
author = {Le-Vinh, B and Steinbring, C and Nguyen Le, NM and Matuszczak, B and Bernkop-Schnürch, A},
title = {S-Protected Thiolated Chitosan versus Thiolated Chitosan as Cell Adhesive Biomaterials for Tissue Engineering.},
journal = {ACS applied materials &amp; interfaces},
volume = {15},
number = {34},
pages = {40304-40316},
pmid = {37594415},
issn = {1944-8252},
mesh = {*Chitosan ; Biocompatible Materials/pharmacology ; Tissue Engineering ; Acetylcysteine ; Carbodiimides ; Cryogels ; },
abstract = {Chitosan (Ch) and different Ch derivatives have been applied in tissue engineering (TE) because of their biocompatibility, favored mechanical properties, and cost-effectiveness. Most of them, however, lack cell adhesive properties that are crucial for TE. In this study, we aimed to design an S-protected thiolated Ch derivative exhibiting high cell adhesive properties serving as a scaffold for TE. 3-((2-Acetamido-3-methoxy-3-oxopropyl)dithio) propanoic acid was covalently attached to Ch via a carbodiimide-mediated reaction. Low-, medium-, and high-modified Chs (Ch-SS-1, Ch-SS-2, and Ch-SS-3) with 54, 107 and 140 μmol of ligand per gram of polymer, respectively, were tested. In parallel, three thiolated Chs, namely Ch-SH-1, Ch-SH-2, and Ch-SH-3, were prepared by conjugating N-acetyl cysteine to Ch at the same degree of modification to compare the effectiveness of disulfide versus thiol modification on cell adhesion. Ch-SS-1 showed better cell adhesion capability than Ch-SS-2 and Ch-SS-3. This can be explained by the more lipophilic surfaces of Ch-SS as a higher modification was made. Although Ch-SH-1, Ch-SH-2, and Ch-SH-3 were shown to be good substrates for cell adhesion, growth, and proliferation, Ch-SS polymers were superior to Ch-SH polymers in the formation of 3D cell cultures. Cryogels structured by Ch-SS-1 (SSg) resulted in homogeneous scaffolds with tunable pore size and mechanical properties by changing the mass ratio between Ch-SS-1 and heparin used as a cross-linker. SSg scaffolds possessing interconnected microporous structures showed good cell migration, adhesion, and proliferation. Therefore, Ch-SS can be used to construct tunable cryogel scaffolds that are suitable for 3D cell culture and TE.},
}
@article {pmid37591474,
year = {2023},
author = {Singh, S and Wairkar, S},
title = {Long-circulating thiolated chitosan nanoparticles of nintedanib with N-acetyl cysteine for treating idiopathic pulmonary fibrosis: In vitro assessment of cytotoxicity, antioxidant, and antifibrotic potential.},
journal = {International journal of pharmaceutics},
volume = {644},
number = {},
pages = {123322},
doi = {10.1016/j.ijpharm.2023.123322},
pmid = {37591474},
issn = {1873-3476},
mesh = {Chitosan/chemistry ; Acetylcysteine/chemistry ; Sulfhydryl Compounds/chemistry ; *Idiopathic Pulmonary Fibrosis/drug therapy ; Antioxidants/chemistry/pharmacology ; Cell Line ; Particle Size ; Humans ; Cell Survival/drug effects ; *Nanoparticles/chemistry ; Indoles ; },
abstract = {Nintedanib (NIN) is one of the FDA-approved tyrosine kinase inhibitor drugs used to treat idiopathic pulmonary fibrosis (IPF). This study aimed to formulate a long-circulating injection of Nintedanib to treat bedridden patients with IPF. Nintedanib was incorporated into chitosan nanoparticles (NIN-NP) via the ionic gelation method, and N-acetyl cysteine (NAC), a known antioxidant and mucolytic agent, was added to the NIN-NP (NAC-NIN-NP). The lyophilized formulation had a particle size of 174 nm, a polydispersity index of 0.511, and a zeta potential of 18.6 mV. The spherical nanoparticles were observed in transmission electron microscopy, whereas field emission scanning electron microscopy showed irregular clusters of NP. The thiolation of the chitosan in NAC-NIN-NP was confirmed by ATR-FTIR and NMR, which improved drug release profiles showing >90 % drug release that was 2.42-folds greater than NIN-NP lasting for five days. The DPPH assay showed that adding NAC increased the % inhibition of oxidation in blank-NP (from 54.59 % to 87.17 %) and NIN-NP (58.65 %-89.19 %). The MTT assay on A549 cells showed 67.57 % cell viability by NAC-NIN-NP with an IC50 value of 28 μg/mL. The NAC formulation reduced hydroxyproline content (56.77 μg/mL) compared to NIN-NP (69.48 μg/mL) in WI-38 cell lines. Meanwhile, the healthy cells count with NAC-NIN-NP was higher (5.104 × 10[3]) than with NIN-NP (4.878 × 10[3]). In Hoechst staining, no significant damage to DNA was observed by the drug or formulation. Therefore, NAC-NIN-NP could be a promising treatment option for IPF patients and can be studied further clinically.},
}
@article {pmid37580920,
year = {2023},
author = {Niloufar Darbandi, - and Samira Moghadasi, - and Hamid Reza Momeni, - and Matin Ramezani, -},
title = {Comparing the acute and chronic effects of metformin and antioxidant protective effects of N-acetyl cysteine on memory retrieval and oxidative stress in rats with Alzheimer's disease.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {36},
number = {3},
pages = {731-739},
pmid = {37580920},
issn = {1011-601X},
mesh = {Rats ; Animals ; Antioxidants/pharmacology ; Acetylcysteine/pharmacology ; *Alzheimer Disease/chemically induced/drug therapy ; *Metformin/pharmacology ; Oxidative Stress ; Streptozocin/pharmacology ; Disease Models, Animal ; Maze Learning ; },
abstract = {It has been suggested that oxidative stress plays an important role in neural degeneration and Alzheimer's disease. Some studies have shown that metformin has some beneficial effects on the brain and reduces oxidative stress, while others reveal that metformin increases oxidative stress in diabetic patients. In this study acute and chronic effects of metformin and antioxidant protective effects of N-acetyl cysteine in Alzheimeric rats were investigated. Animals were divided into seven groups (n=8): Control, STZ, STZ + metformin (one, three and eleven weeks), STZ+ metformin (eleven weeks) +N-acetyl cysteine (eleven weeks) and N-acetyl cysteine (eleven weeks). ICV injections of saline (1μl/rat) or STZ (3mg/kg) and IP injections of Saline (1ml/kg), metformin (200mg/kg) and/or N-acetyl cysteine (100mg/kg) were done. Memory retrieval, CA1 neurons density and serums oxidative stress were investigated. STZ injections reduced memory retention, intact neurons and increased serum oxidative stress compared to the control (p<0/001). Metformin injection for one and three weeks (but not eleven weeks) improved the effects of STZ (p<0/001). Administration of N-acetylcysteine with metformin (eleven weeks) improved STZ bad effects (p<0/001). It seems that acute and chronic consumption of metformin have different effects on memory retrieval, CA1 neurons and serum oxidative stress factors in AD rats.},
}
@article {pmid37579929,
year = {2023},
author = {Kolomaznik, M and Hanusrichterova, J and Mikolka, P and Kosutova, P and Vatecha, M and Zila, I and Mokra, D and Calkovska, A},
title = {Efficiency of exogenous surfactant combined with intravenous N-acetylcysteine in two-hit rodent model of ARDS.},
journal = {Respiratory physiology &amp; neurobiology},
volume = {316},
number = {},
pages = {104138},
doi = {10.1016/j.resp.2023.104138},
pmid = {37579929},
issn = {1878-1519},
mesh = {Rats ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; *Lung Injury ; Antioxidants/pharmacology/therapeutic use ; Surface-Active Agents ; Rodentia ; *Hyperoxia ; Rats, Wistar ; Lung ; *Pulmonary Surfactants/pharmacology ; *Respiratory Distress Syndrome ; },
abstract = {Accumulation of reactive oxygen species during hyperoxia together with secondary bacteria-induced inflammation leads to lung damage in ventilated critically ill patients. Antioxidant N-acetylcysteine (NAC) in combination with surfactant may improve lung function. We compared the efficacy of NAC combined with surfactant in the double-hit model of lung injury. Bacterial lipopolysaccharide (LPS) instilled intratracheally and hyperoxia were used to induce lung injury in Wistar rats. Animals were mechanically ventilated and treated intravenously with NAC alone or in combination with intratracheal surfactant (poractant alfa; PSUR+NAC). Control received saline. Lung functions, inflammatory markers, oxidative damage, total white blood cell (WBC) count and lung oedema were evaluated during 4 hrs. Administration of NAC increased total antioxidant capacity (TAC) and decreased IL-6. This effect was potentiated by the combined administration of surfactant and NAC. In addition, PSUR+NAC reduced the levels of TNFα, IL-1ß, and TAC compared to NAC only and improved lung injury score. The combination of exogenous surfactant with NAC suppresses lung inflammation and oxidative stress in the experimental double-hit model of lung injury.},
}
@article {pmid37577725,
year = {2023},
author = {da Paz Martins, AS and de Andrade, KQ and de Araújo, ORP and da Conceição, GCM and da Silva Gomes, A and Goulart, MOF and Moura, FA},
title = {Extraintestinal Manifestations in Induced Colitis: Controversial Effects of N-Acetylcysteine on Colon, Liver, and Kidney.},
journal = {Oxidative medicine and cellular longevity},
volume = {2023},
number = {},
pages = {8811463},
pmid = {37577725},
issn = {1942-0994},
mesh = {Humans ; Male ; Mice ; Animals ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; Interleukin-10/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Hydrogen Peroxide/pharmacology ; Glutathione Disulfide/metabolism ; *Colitis/chemically induced/complications/drug therapy ; Colon ; *Colitis, Ulcerative/chemically induced/drug therapy/pathology ; Antioxidants/pharmacology ; Inflammation/pathology ; Oxidative Stress ; Liver/metabolism ; Glutathione/metabolism ; Superoxide Dismutase/metabolism ; Dextran Sulfate/toxicity ; },
abstract = {Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD) characterized by continuous inflammation in the colonic mucosa. Extraintestinal manifestations (EIM) occur due to the disruption of the intestinal barrier and increased permeability caused by redox imbalance, dysbiosis, and inflammation originating from the intestine and contribute to morbidity and mortality. The aim of this study is to investigate the effects of oral N-acetylcysteine (NAC) on colonic, hepatic, and renal tissues in mice with colitis induced by dextran sulfate sodium (DSS). Male Swiss mice received NAC (150 mg/kg/day) in the drinking water for 30 days before and during (DSS 5% v/v; for 7 days) colitis induction. On the 38[th] day, colon, liver, and kidney were collected and adequately prepared for the analysis of oxidative stress (superoxide dismutase (SOD), catalase (CAT), glutathione reduced (GSH), glutathione oxidized (GSSG), malondialdehyde (MDA), and hydrogen peroxide (H2O2)) and inflammatory biomarkers (myeloperoxidase (MPO) -, tumor necrosis factor alpha - (TNF-α, and interleukin-10 (IL-10)). In colon, NAC protected the histological architecture. However, NAC did not level up SOD, in contrast, it increased MDA and pro-inflammatory effect (increased of TNF-α and decreased of IL-10). In liver, colitis caused both oxidative (MDA, SOD, and GSH) and inflammatory damage (IL-10). NAC was able only to increase GSH and GSH/GSSG ratio. Kidney was not affected by colitis; however, NAC despite increasing CAT, GSH, and GSH/GSSG ratio promoted lipid peroxidation (increased MDA) and pro-inflammatory action (decreased IL-10). Despite some beneficial antioxidant effects of NAC, the negative outcomes concerning irreversible oxidative and inflammatory damage in the colon, liver, and kidney confirm the nonsafety of the prophylactic use of this antioxidant in models of induced colitis, suggesting that additional studies are needed, and its use in humans not yet recommended for the therapeutic routine of this disease.},
}
@article {pmid37575813,
year = {2023},
author = {Le, D and Hydro, BA and Jones, CL and Beauchamp, GA},
title = {Weight Loss or Liver Loss: A Case Report on Fulminant Hepatic Failure Secondary to Garcinia cambogia Supplementation.},
journal = {Cureus},
volume = {15},
number = {7},
pages = {e41778},
pmid = {37575813},
issn = {2168-8184},
abstract = {This case describes a 56-year-old man with a past medical history including sickle cell trait requiring blood transfusions, who presented to the emergency department (ED) with generalized weakness and fatigue following Garcinia cambogia supplementation. Initial laboratory abnormalities included: aspartate aminotransferase (AST) and alanine transaminase (ALT) 4,222 U/L and 4,664 U/L respectively, alkaline phosphatase 215 U/L, international normalized ratio (INR) 3.2, and his model for end-stage liver disease was 37. Creatinine, hemoglobin and hematocrit, and ferritin levels were all elevated. The differential diagnosis for his acute illness was broad ranging from hemochromatosis, anabolic steroid use, and portal venous thrombosis. The patient was started on N-acetylcysteine (NAC) and his liver function improved. He was discharged on hospital day 10 and instructed to discontinue his supplements and follow up for repeat blood work. This case explores the critical management of G. cambogia toxicity. The patient explored G. cambogia as an herbal supplementation resulting in weight loss, worsening generalized fatigue, and fulminant hepatic failure.},
}
@article {pmid37575276,
year = {2023},
author = {Tanomrat, R and Naktubtim, C and Aimvijarn, P and Suwannalert, P},
title = {N-acetylcysteine improves the inhibitory effect of Quercetin-rich onion extract on HT-29 and HCT-116 colorectal cancer migration and invasion through iNOS suppression.},
journal = {International journal of medical sciences},
volume = {20},
number = {9},
pages = {1123-1134},
pmid = {37575276},
issn = {1449-1907},
mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; *Colorectal Neoplasms/drug therapy/genetics/metabolism ; Glutathione/pharmacology ; Intercellular Adhesion Molecule-1 ; Matrix Metalloproteinase 2/genetics ; Onions ; Quercetin/pharmacology/therapeutic use ; Nitric Oxide Synthase Type II ; },
abstract = {As colorectal cancer (CRC) usually presents at an advanced stage, it responds poorly to traditional surgery and chemoradiotherapy. Reactive oxygen species (ROSs) are a critical factor in cancer progression. Quercetin, a bioflavonoid derived from onion peel extract, provides great anti-oxidant and anti-cancer potential. Therefore, quercetin in combination with N-Acetylcysteine (NAC), a well-known anti-oxidant and adjuvant agent in cancer-chemotherapeutic drugs, was considered as a way of increasing treatment efficacy. Thus, this study aimed to evaluate the improvement effect of quercetin in combination with NAC in human CRC (HT-29 and HCT-116) cell progression, migration and invasion. Firstly, the effects of quercetin, NAC, and the combination of quercetin and NAC on cellular oxidants and glutathione levels were evaluated. Cell viability, anti-migrative activity and invasive activity were determined by MTT, wound healing, and Matrigel invasion tests, respectively. Then, the proteins involved in cell migration, invasion, and cellular oxidants were investigated. Moreover, the gene expression and overall survival were further validated by the GEPIA2 database. The results reveal that the combination was most effective in decreasing cellular oxidants and increasing glutathione levels, while there was a significant decrease in cancer cell migration and invasion involved in the suppression of iNOS, ICAM-1, and MMP-2 proteins. Furthermore, bioinformatic analysis verified that iNOS, ICAM-1, and MMP-2 were highly expressed in CRC tissue and also associated with a poor prognosis. This study demonstrated that Quercetin has higher efficacy when used in combination with NAC, representing a potential combination agent for anti-cancer drug development.},
}
@article {pmid37573526,
year = {2023},
author = {Rasaeifar, K and Zavareh, S and Hajighasem-Kashani, M and Nasiri, M},
title = {Effects of pulsed electromagnetic fields and N-acetylcysteine on transplantation of vitrified mouse ovarian tissue.},
journal = {Electromagnetic biology and medicine},
volume = {42},
number = {2},
pages = {67-80},
doi = {10.1080/15368378.2023.2246503},
pmid = {37573526},
issn = {1536-8386},
mesh = {Mice ; Female ; Animals ; *Acetylcysteine/pharmacology ; *Tumor Necrosis Factor-alpha/genetics ; Electromagnetic Fields ; Fibroblast Growth Factor 2 ; Interleukin-6 ; Vascular Endothelial Growth Factor A/genetics ; Antioxidants/pharmacology/metabolism ; },
abstract = {In this experimental study, adult female NMRI mice were randomly assigned to five groups: control ;(fresh ovarian transplantation, OT); sham ;(vitrified OT); NAC ;(vitrified OT treated with N-acetyl cysteine, NAC); EMF ;(vitrified OT treated with pulsed electromagnetic fields, PEMF); and NAC+EMF ;(vitrified OT combined with NAC and PEMF). We conducted histological assessments to evaluate follicle reservation and vascularization. Furthermore, we examined the relative expression of Fgf-2, Vegf, Tnf-α, Il-6, Il-1, and Cd31 genes on days 2 and 7 after OT. Additionally, we measured total antioxidant capacity (TAC), malondialdehyde (MDA) levels, as well as the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Our results demonstrated that NAC, PEMF, and NAC+PEMF treatments significantly increased the number of follicles. Moreover, we observed a more pronounced development of vascularization in the NAC, PEMF, and PEMF+NAC groups. The relative expression levels of Fgf-2, Vegf, Tnf-α, Il-1β, and Il-6 were significantly elevated in the NAC, PEMF, and NAC+PEMF groups. Notably, TAC levels decreased significantly in the NAC group compared to the control group. Additionally, the MDA level showed a significant decrease in the PEMF+NAC group when compared to the other groups. Overall, the combination of NAC and PEMF exhibited a synergistic effect in promoting angiogenesis and protecting against oxidative stress and inflammation during OT.},
}
@article {pmid37572985,
year = {2023},
author = {Kim, D and Oh, E and Kim, H and Baek, SM and Cho, J and Kim, EH and Choi, S and Bian, Y and Kim, W and Bae, ON},
title = {Mono-(2-ethylhexyl)-phthalate potentiates methylglyoxal-induced blood-brain barrier damage via mitochondria-derived oxidative stress and bioenergetic perturbation.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {179},
number = {},
pages = {113985},
doi = {10.1016/j.fct.2023.113985},
pmid = {37572985},
issn = {1873-6351},
mesh = {Rats ; Animals ; *Diethylhexyl Phthalate/toxicity/analogs &amp; derivatives ; Pyruvaldehyde ; Blood-Brain Barrier/metabolism ; Endothelial Cells/metabolism ; Oxidative Stress ; Energy Metabolism ; Mitochondria/metabolism ; Phthalic Acids ; },
abstract = {Phthalates in contaminated foods and personal care products are one of the most frequently exposed chemicals with a public health concern. Phthalate exposure is related to cardiovascular diseases, including diabetic vascular complications and cerebrovascular diseases, yet the mechanism is still unclear. The blood-brain barrier (BBB) integrity disruption is strongly associated with cardiovascular and neurological disease exacerbation. We investigated BBB damage by di-(2-ethylhexyl) phthalate (DEHP) or its metabolite mono-(2-ethylhexyl) phthalate (MEHP) using brain endothelial cells and rat models. BBB damage by the subthreshold level of MEHP, but not a DEHP, significantly increased by the presence of methylglyoxal (MG), a reactive dicarbonyl compound whose levels increase in the blood in hyperglycemic conditions in diabetic patients. Significant potentiation in apoptosis and autophagy activation, mitochondria-derived reactive oxygen species (ROS) production, and mitochondrial metabolic disturbance were observed in brain ECs by co-exposure to MG and MEHP. N-acetyl cysteine (NAC) restored autophagy activation as well as tight junction protein impairment induced by co-exposure to MG and MEHP. Intraperitoneal administration of MG and MEHP significantly altered mitochondrial membrane potential and tight junction integrity in rat brain endothelium. This study may provide novel insights into enhancing phthalate toxicity in susceptible populations, such as diabetic patients.},
}
@article {pmid37569897,
year = {2023},
author = {Khashab, R and Gutman-Sharabi, N and Shabtai, Z and Landau, R and Halperin, R and Fay-Karmon, T and Leibowitz, A and Sharabi, Y},
title = {Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {24},
number = {15},
pages = {},
pmid = {37569897},
issn = {1422-0067},
mesh = {Rats ; Animals ; *Parkinson Disease/drug therapy/etiology/metabolism ; Rotenone/pharmacology ; Dopamine/metabolism ; Selegiline ; Aldehyde Dehydrogenase/metabolism ; Monoamine Oxidase Inhibitors/pharmacology ; Acetylcysteine/pharmacology ; },
abstract = {The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson's disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson's disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson's disease treatment.},
}
@article {pmid37569463,
year = {2023},
author = {Pieri, BLDS and Rodrigues, MS and Farias, HR and Silveira, GB and Ribeiro, VSGDC and Silveira, PCL and De Souza, CT},
title = {Role of Oxidative Stress on Insulin Resistance in Diet-Induced Obesity Mice.},
journal = {International journal of molecular sciences},
volume = {24},
number = {15},
pages = {},
pmid = {37569463},
issn = {1422-0067},
abstract = {Insulin resistance is the link between obesity and type 2 diabetes mellitus. The molecular mechanism by which obese individuals develop insulin resistance has not yet been fully elucidated; however, inconclusive and contradictory studies have shown that oxidative stress may be involved in the process. Thus, this study aimed to evaluate the effect of reactive species on the mechanism of insulin resistance in diet-induced obese mice. Obese insulin-resistant mice were treated with N-acetylcysteine (NAC; 50 mg/kg per day, for 15 days) by means of oral gavage. Twenty-four hours after the last NAC administration, the animals were euthanized and their tissues were extracted for biochemical and molecular analyses. NAC supplementation induced improved insulin resistance and fasting glycemia, without modifications in food intake, body weight, and adiposity. Obese mice showed increased dichlorofluorescein (DCF) oxidation, reduced catalase (CAT) activity, and reduced glutathione levels (GSH). However, treatment with NAC increased GSH and CAT activity and reduced DCF oxidation. The gastrocnemius muscle of obese mice showed an increase in nuclear factor kappa B (NFκB) and protein tyrosine phosphatase (PTP1B) levels, as well as c-Jun N-terminal kinase (JNK) phosphorylation compared to the control group; however, NAC treatment reversed these changes. Considering the molecules involved in insulin signaling, there was a reduction in insulin receptor substrate (IRS) and protein kinase B (Akt) phosphorylation. However, NAC administration increased IRS and Akt phosphorylation and IRS/PI3k (phosphoinositide 3-kinase) association. The results demonstrated that oxidative stress-associated obesity could be a mechanism involved in insulin resistance, at least in this animal model.},
}
@article {pmid37569345,
year = {2023},
author = {Kang, M and Kang, JH and Sim, IA and Seong, DY and Han, S and Jang, H and Lee, H and Kang, SW and Kim, SY},
title = {Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation.},
journal = {International journal of molecular sciences},
volume = {24},
number = {15},
pages = {},
pmid = {37569345},
issn = {1422-0067},
support = {NRF- 2019M3A9G1104345//National Research Foundation of Korea/ ; },
mesh = {*Glucose/deficiency ; *Adenosine Triphosphate/metabolism ; Pentose Phosphate Pathway ; *Reactive Oxygen Species/metabolism ; NADP/metabolism ; Glutathione/metabolism ; Acetylcysteine/metabolism/pharmacology ; PC-3 Cells ; Humans ; *Neoplasms/metabolism/pathology ; Cell Death ; },
abstract = {In previous work, we showed that cancer cells do not depend on glycolysis for ATP production, but they do on fatty acid oxidation. However, we found some cancer cells induced cell death after glucose deprivation along with a decrease of ATP production. We investigated the different response of glucose deprivation with two types of cancer cells including glucose insensitive cancer cells (GIC) which do not change ATP levels, and glucose sensitive cancer cells (GSC) which decrease ATP production in 24 h. Glucose deprivation-induced cell death in GSC by more than twofold after 12 h and by up to tenfold after 24 h accompanied by decreased ATP production to compare to the control (cultured in glucose). Glucose deprivation decreased the levels of metabolic intermediates of the pentose phosphate pathway (PPP) and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) in both GSC and GIC. However, glucose deprivation increased reactive oxygen species (ROS) only in GSC, suggesting that GIC have a higher tolerance for decreased NADPH than GSC. The twofold higher ratio of reduced/oxidized glutathione (GSH/GSSG) in GIS than in GSC correlates closely with the twofold lower ROS levels under glucose starvation conditions. Treatment with N-acetylcysteine (NAC) as a precursor to the biologic antioxidant glutathione restored ATP production by 70% and reversed cell death caused by glucose deprivation in GSC. The present findings suggest that glucose deprivation-induced cancer cell death is not caused by decreased ATP levels, but rather triggered by a failure of ROS regulation by the antioxidant system. Conclusion is clear that glucose deprivation-induced cell death is independent from ATP depletion-induced cell death.},
}
@article {pmid37567958,
year = {2023},
author = {Bhattacharya, R and Saini, S and Ghosh, S and Roy, P and Ali, N and Parvez, MK and Al-Dosari, MS and Mishra, AK and Singh, LR},
title = {Organosulfurs, S-allyl cysteine and N-acetyl cysteine sequester di-carbonyls and reduces carbonyl stress in HT22 cells.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {13071},
pmid = {37567958},
issn = {2045-2322},
mesh = {*Acetylcysteine/pharmacology ; *Cysteine/metabolism/analogs &amp; derivatives ; Glycation End Products, Advanced/metabolism ; Antioxidants/pharmacology ; Maillard Reaction ; },
abstract = {Diabetes, characterized by high blood glucose level, is a progressive metabolic disease that leads to serious health complications. One of the major pathological consequences associated with diabetes is the accumulation of highly reactive carbonyl compounds called advanced glycation end products (AGEs). Most of the AGEs are dicarbonyls and have the potential to covalently modify proteins especially at the lysine residues in a non-enzymatic fashion (a process termed as glycation) resulting in the functional impairment and/or toxic gain in function. Therefore, non-toxic small molecules that can inhibit glycation are of interest for the therapeutic intervention of diabetes. In the present communication, we have investigated the effect of organosulfurs (S-allyl cysteine, SAC and N-acetyl cysteine, NAC) that are major principal components of Allium sativa against the glycation of different proteins. We discovered that both SAC and NAC are potent anti-glycating agents. We also found that both SAC and NAC reduce ROS level and inhibit apoptosis caused by protein glycation.},
}
@article {pmid37567916,
year = {2023},
author = {Naushad, SM and Mandadapu, G and Ramaiah, MJ and Almajhdi, FN and Hussain, T},
title = {The role of TLR7 agonists in modulating COVID-19 severity in subjects with loss-of-function TLR7 variants.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {13078},
pmid = {37567916},
issn = {2045-2322},
mesh = {Humans ; Male ; Adaptor Proteins, Signal Transducing/metabolism ; Adjuvants, Immunologic ; *COVID-19/genetics ; Myeloid Differentiation Factor 88/genetics/metabolism ; RNA, Viral ; SARS-CoV-2/genetics ; *Toll-Like Receptor 7/agonists/genetics ; COVID-19 Drug Treatment ; },
abstract = {We investigate the mechanism associated with the severity of COVID-19 in men with TLR7 mutation. Men with loss-of-function (LOF) mutations in TLR7 had severe COVID-19. LOF mutations in TLR7 increased the risk of critical COVID by 16.00-fold (95% confidence interval 2.40-106.73). The deleterious mutations affect the binding of SARS-CoV2 RNA (- 328.66 ± 26.03 vs. - 354.08 ± 27.70, p = 0.03) and MYD88 (β: 40.279, p = 0.003) to TLR7 resulting in the disruption of TLR7-MyD88-TIRAP complex. In certain hypofunctional variants and all neutral/benign variants, there is no disruption of TLR7-MyD88-TIRAP complex and four TLR7 agonists showed binding affinity comparable to that of wild protein. N-acetylcysteine (NAC) also showed a higher binding affinity for the LOF variants (p = 0.03). To conclude, TLR7 LOF mutations increase the risk of critical COVID-19 due to loss of viral RNA sensing ability and disrupted MyD88 signaling. Majority of hypofunctional and neutral variants of TLR7 are capable of carrying MyD88 signaling by binding to different TLR7 agonists and NAC.},
}
@article {pmid37567457,
year = {2023},
author = {Zheng, X and Su, F and Lei, M and Li, J and Zhang, C and Zhang, Y and Wei, M and Li, W and Chen, S and Liu, Y and Gao, Q and Hao, L},
title = {The novel peptide athycaltide-1 attenuates Ang II-induced pathological myocardial hypertrophy by reducing ROS and inhibiting the activation of CaMKII and ERK1/2.},
journal = {European journal of pharmacology},
volume = {957},
number = {},
pages = {175969},
doi = {10.1016/j.ejphar.2023.175969},
pmid = {37567457},
issn = {1879-0712},
mesh = {Animals ; Mice ; Angiotensin II/adverse effects/metabolism/toxicity ; Calcium Signaling ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Cardiomegaly/chemically induced/drug therapy/metabolism ; Cells, Cultured ; *MAP Kinase Signaling System ; Myocytes, Cardiac ; Peptides/pharmacology ; Reactive Oxygen Species/metabolism ; },
abstract = {Pathological myocardial hypertrophy initially develops as an adaptive response to cardiac stress, which can be induced by many diseases. It is accompanied by adverse cardiovascular events, including heart failure, arrhythmias, and death. The purpose of this research was to explore the molecular mechanism of a novel peptide Athycaltide-1 (ATH-1) in the treatment of Ang II-induced pathological myocardial hypertrophy. In this study, the mRNA of Control group, Ang II group, ATH-1 group and Losartan group mice were sequenced by high-throughput sequencing technology. The results showed that the differentially expressed genes (DEGs) were significantly enriched in cell response to oxidative stress, regulation of reactive oxygen species metabolism and calmodulin binding. Then, the oxidation level of mouse hearts and H9c2 cardiomyocytes in each group and the expression of key proteins of CaMKII/HDAC/MEF2C and ERK1/2 signaling pathways were detected to preliminarily verify the positive effect of ATH-1. At the same time, the effect of ATH-1 was further determined by adding reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC) and CaMKII inhibitor AIP in vitro. The results showed that ATH-1 could significantly reduce the level of oxidative stress in hypertrophic cardiomyocytes and inhibiting the activation of CaMKII and ERK1/2.},
}
@article {pmid37562904,
year = {2023},
author = {Sukumaran, D and Usharani, P and Paramjyothi, GK and Subbalaxmi, MVS and Sireesha, K and Abid Ali, M},
title = {A study to evaluate the hepatoprotective effect of N- acetylcysteine on anti tuberculosis drug induced hepatotoxicity and quality of life.},
journal = {The Indian journal of tuberculosis},
volume = {70},
number = {3},
pages = {303-310},
doi = {10.1016/j.ijtb.2022.05.012},
pmid = {37562904},
issn = {0019-5707},
mesh = {Humans ; Acetylcysteine/therapeutic use/pharmacology ; Quality of Life ; Prospective Studies ; *Tuberculosis/drug therapy ; *Chemical and Drug Induced Liver Injury/etiology/prevention &amp; control ; Bilirubin ; Biomarkers ; },
abstract = {BACKGROUND: Drug induced liver injury (DILI) is a serious adverse effect caused by first-line anti-TB (ATT) drugs, limiting the TB-treatment. The tissue inflammation induced by free radical burst and poor dietary intake in TB induces oxidative stress, which was proposed as one of the mechanisms responsible for ATT induced DILI. N-acetylcysteine (NAC) exerts a hepato-protective effect by enhancing the cellular antioxidant defense mechanism. There are few studies evaluating the effect of NAC on ATT induced DILI in Indian-population.<br><br>METHODS: This is a prospective, randomized, double-blind, placebo-controlled, parallel-group study. Thirty-eight newly diagnosed TB patients on first-line ATT with normal liver function test (LFT) were recruited and randomized to receive either NAC 600 mg tablet or placebo twice daily for 4 weeks and followed-up for next 4 weeks. LFT [AST, ALT, ALP and Total bilirubin] was assessed at baseline, 2, 4 and 8 weeks. Oxidative-stress biomarkers [Malondialdehyde (MDA), Nitric Oxide (NO), Glutathione (GSH)] and quality of life (QOL) by SF-36 questionnaire were assessed at baseline, 4 and 8 weeks. Adverse Drug Reactions (ADRs) were monitored at every visit. Compliance was assessed by pill-count method.<br><br>RESULTS: Baseline characteristics were homogenous among both the groups. In the NAC group, there was significant reduction in ALT (p&#xa0;<&#xa0;0.01), ALP (p&#xa0;<&#xa0;0.01), total bilirubin (p&#xa0;<&#xa0;0.001) at 4 weeks compared to baseline. AST, MDA and NO showed a reduction of 19%, 21.6% and 5.5% respectively from baseline and GSH at showed an increase of 2.6% from baseline at 4 weeks in the NAC group, however these were not statistically significant. These effects in LFT and oxidative biomarkers persisted even at the end of 8 weeks. Significant improvement from baseline in QOL was observed in both the groups (p&#xa0;<&#xa0;0.05). Between group analysis showed, significant reduction in ALT (p&#xa0;<&#xa0;0.05) and AST (p&#xa0;<&#xa0;0.05) in NAC group at 4 weeks, whereas bilirubin, MDA, NO and GSH showed improvement at 4 weeks compared to placebo in NAC group, however it was not statistically significant. This improvement in the LFT and oxidative biomarkers continued even at the end of 8 weeks. Itching and rashes were the most common ADRs, with similar incidence in both the groups. Compliance to treatment was good in both the groups.<br><br>CONCLUSION: Significant improvement in liver function parameters is suggestive of hepatoprotective effect of NAC. This observed effect at 4 weeks was found to be persistent at 8 weeks, which signifies prolonged hepato-protective effect of NAC. Long duration studies with large sample size are required for further confirmation of hepato-protective action of NAC.},
}
@article {pmid37562091,
year = {2023},
author = {Geng, Y and Liu, P and Xie, Y and Liu, Y and Zhang, X and Hou, X and Zhang, L},
title = {Xanthatin suppresses pancreatic cancer cell growth via the ROS/RBL1 signaling pathway: In vitro and in vivo insights.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {119},
number = {},
pages = {155004},
doi = {10.1016/j.phymed.2023.155004},
pmid = {37562091},
issn = {1618-095X},
mesh = {Humans ; Mice ; Animals ; Reactive Oxygen Species/metabolism ; Mice, Nude ; Cell Line, Tumor ; *Signal Transduction ; Cell Proliferation ; Apoptosis ; Cell Transformation, Neoplastic ; *Pancreatic Neoplasms/drug therapy ; Furans ; },
abstract = {BACKGROUND: As a malignant digestive system tumor, pancreatic cancer has a high mortality rate. Xanthatin is a sesquiterpene lactone monomer compound purified from the traditional Chinese herb Xanthium strumarium L. It has been reported that Xanthatin exhibits inhibitory effects on various cancer cells in retinoblastoma, glioma, hepatoma, colon cancer, lung cancer, as well as breast cancer. However, in pancreatic cancer cells, only one report exists on the suppression of Prostaglandin E2 synthesis and the induction of caspase 3/7 activation in Xanthatin-treated MIA PaCa-2 cells, while systematic in vitro and in vivo investigations and related mechanisms have yet to be explored.<br><br>PURPOSE: This research aims to explore the in vitro and in vivo effects of Xanthatin on pancreatic cancer and its molecular mechanisms.<br><br>METHODS: The anticancer effects and mechanisms of Xanthatin on pancreatic cancer cells were assessed through employing cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, carboxyfluorescein diacetate succinimidyl ester (CFDA SE) cell proliferation assay, colony formation assay, wound healing assay, transwell assay, Annexin V-FITC/propidium iodide (PI) dual staining, Hoechst nuclear staining, Western blot analysis, phosphoproteomics, and reactive oxygen species (ROS) measurement. The in vivo anticancer effects of Xanthatin on pancreatic cancer cells were studied using a nude mouse model.<br><br>RESULTS: The present study showed that Xanthatin can prevent the proliferation and metastasis of pancreatic cancer cells and trigger the exposure of phosphatidylserine (PS), chromatin condensation, and caspase activation, thereby inducing apoptosis. Phosphoproteomic analysis indicated that Xanthatin inhibits the phosphorylation of the proliferation-associated protein RBL1, and oxidative stress can lead to RBL1 dephosphorylation. Further investigation revealed that Xanthatin significantly upregulates ROS levels in pancreatic cancer cells, and the antioxidant N-acetylcysteine (NAC) can reverse Xanthatin-induced cell proliferation inhibition and apoptosis. In addition, Xanthatin can suppress pancreatic cancer cell growth in a xenograft nude mouse model with low toxicity to the mice.<br><br>CONCLUSION: Xanthatin may inhibit the proliferation of pancreatic cancer cells and trigger apoptosis through the ROS/RBL1 signaling pathway.},
}
@article {pmid37561633,
year = {2023},
author = {Yao, H and Chen, X and Wang, T and Kashif, M and Qiao, X and Tüksammel, E and Larsson, LG and Okret, S and Sayin, VI and Qian, H and Bergo, MO},
title = {A MYC-controlled redox switch protects B lymphoma cells from EGR1-dependent apoptosis.},
journal = {Cell reports},
volume = {42},
number = {8},
pages = {112961},
doi = {10.1016/j.celrep.2023.112961},
pmid = {37561633},
issn = {2211-1247},
abstract = {Refractory and relapsed B cell lymphomas are often driven by the difficult-to-target oncogene MYC. Here, we report that high MYC expression stimulates proliferation and protects B lymphoma cells from apoptosis under normal oxidative stress levels and that compounds including N-acetylcysteine (NAC) and vitamin C (VitC) induce apoptosis by reducing oxidative stress. NAC and VitC injections effectively reduce tumor growth in lymphoma cells with high MYC expression but not in those with low MYC expression. MYC knockdown confers tumor resistance to NAC and VitC, while MYC activation renders B cells sensitive to these compounds. Mechanistically, NAC and VitC stimulate MYC binding to EGR1 through Cys117 of MYC, shifting its transcriptional output from cell cycle to apoptosis gene expression. These results identify a redox-controlled mechanism for MYC's role in maintaining proliferation and preventing apoptosis, offering a potential therapeutic rationale for evaluating NAC or VitC in patients with MYC-driven B cell lymphoma.},
}
@article {pmid37559860,
year = {2023},
author = {Mitchell, MC and Rogers, C},
title = {A Case of Cocaine-Induced Acute Liver Failure Reversed With N-Acetylcysteine.},
journal = {Cureus},
volume = {15},
number = {7},
pages = {e41579},
pmid = {37559860},
issn = {2168-8184},
abstract = {Acute liver failure (ALF) is a life-threatening injury that is most often caused by drug-induced injury, including acetaminophen overdose, in the United States. The hallmarks of ALF are hepatic encephalopathy and coagulopathy in a patient without an established history of liver disease. While acetaminophen overdose has an antidote, that is N-acetylcysteine (NAC), when given acutely, most other causes of hepatic failure require an urgent liver transplant. In this paper, we report a case of cocaine-induced acute liver failure that was reversed with the administration of NAC. Our case began when a middle-aged male presented to the emergency department complaining of nausea, vomiting, fatigue, and confusion for the past three days. His past medical history was pertinent for a history of opioid use disorder and his physical exam was remarkable for somnolence, asterixis, and periumbilical ecchymoses. His initial lab results showed markedly elevated liver function tests, prolonged coagulation studies, and a urine drug screen that was positive for cocaine. During the patient's interview, his vital signs became unstable. He was intubated for airway protection and transferred to a tertiary care facility for liver transplant evaluation with the diagnosis of cocaine-induced acute liver failure. There he received NAC, lactulose, rifaximin, and vasopressors. On day two of treatment, his clinical condition greatly improved, and he was extubated. He continued to receive NAC until day five when his liver function tests and coagulopathy improved enough to stop treatment. This case report highlights the clinical benefit of NAC in a case of cocaine-induced acute liver failure, improving the patient's survival and eliminating his need for a liver transplant.},
}
@article {pmid37558010,
year = {2023},
author = {Zhong, G and Guo, Y and Gong, X and Xu, M and Wang, Q and Wu, M and Zhang, X and Liang, Y and Zhao, W and Wang, H and Ye, J},
title = {Enhanced glycolysis by ATPIF1 gene inactivation increased the anti-bacterial activities of neutrophils through induction of ROS and lactic acid.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1869},
number = {8},
pages = {166820},
doi = {10.1016/j.bbadis.2023.166820},
pmid = {37558010},
issn = {1879-260X},
mesh = {Adenosine Triphosphate/metabolism ; Escherichia coli/metabolism ; Gene Silencing ; Glycolysis ; *Neutrophils/metabolism ; Nitric Oxide Synthase/metabolism ; *Peritonitis ; Reactive Oxygen Species/metabolism ; Animals ; Mice ; ATPase Inhibitory Protein ; },
abstract = {ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein that regulates the activity of FoF1-ATP synthase. Mice lacking ATPIF1 throughout their bodies (Atpif1[-/-]) exhibit a reduction in the number of neutrophils. However, it remains unclear whether the inactivation of ATPIF1 impairs the antibacterial function of mice, this study aimed to evaluate it using a mouse peritonitis model. Mice were intraperitoneally injected with E. coli to induce peritonitis, and after 24 h, the colonies of E. coli were counted in agarose plates containing mice peritoneal lavage fluids (PLF) or extract from the liver. Neutrophils were analyzed for glucose metabolism in glycolysis following LPS stimulation. Reactive oxygen species (ROS) and lactic acid (LA) levels in neutrophils were measured using flow cytometry and Seahorse analysis, respectively. N-Acetylcysteine (NAC) and 2-Deoxy-d-glucose (2-DG) were employed to assess the role of ROS and LA in neutrophil bactericidal activity. RNA-seq analysis was conducted in neutrophils to investigate potential mechanisms. In ATPIF1[-/-] neutrophils, bactericidal activity was enhanced, accompanied by increased levels of ROS and LA compared to wildtype neutrophils. The augmented bactericidal activity of ATPIF1[-/-] neutrophils was reversed by pretreatment with NAC or 2-DG. RNA-seq analysis revealed downregulation of multiple genes involved in glutathione metabolism, pyruvate oxidation, and heme synthesis, along with increased expression of inflammatory and apoptotic genes. This study suggests that the inactivation of the Atpif1 gene enhances glucose metabolism in neutrophils, resulting in increased bactericidal activity mediated by elevated levels of ROS and LA. Inhibiting ATPIF1 may be a potential approach to enhance antibacterial immunity.},
}
@article {pmid37556466,
year = {2023},
author = {Yu, H and Lv, M and Zhang, S and Zou, K and Qian, Y and Lv, S},
title = {Combination therapy with budesonide and acetylcysteine alleviates LPS-induced acute lung injury via the miR-381/NLRP3 molecular axis.},
journal = {PloS one},
volume = {18},
number = {8},
pages = {e0289818},
pmid = {37556466},
issn = {1932-6203},
mesh = {Animals ; Rats ; *Acetylcysteine/therapeutic use ; *Acute Lung Injury/chemically induced/drug therapy/metabolism ; *Budesonide/therapeutic use ; Lipopolysaccharides/adverse effects ; Lung/pathology ; *MicroRNAs/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; *Pulmonary Edema/pathology ; Signal Transduction ; },
abstract = {BACKGROUND: Acute lung injury (ALI) usually has a high morbidity and mortality rate, but the current treatment is relatively scarce. Both budesonide (Bud) and N-acetylcysteine (NAC) exhibit protective effects in ALI, so we further investigated whether they have a synergistic effect on ALI when used together.<br><br>METHODS: Establishment of a rat model of ALI with Lipopolysaccharide (LPS). Bud and NAC were administered by nebulized inhalation alone or in combination. Subsequently, HE staining was performed to observe the pathological changes in lungs of rat. Evans blue staining was implemented to assess alveolar permeability, and the pulmonary edema was assessed by measuring the ratio of wet to dry weight of the lung. Moreover, a TUNEL kit was served to test apoptosis in lung tissues. Western blot and immunohistochemistry were analyzed for expression of scorch-related proteins and NLRP3 in lung tissue, respectively. ELISA was implemented to detect inflammatory factor levels in BALF. and RT-qPCR was utilized to assess the expression level of miR-381. After stable transfection of miR-381 inhibitor or OE-NLRP3 in BEAS-2B treated with LPS, Bud and NAC, miR-381 expression was assessed by RT-qPCR, scorch death-related protein expression was measured by western blot, cell proliferation/viability was assayed by CCK-8, apoptosis was measured by flow cytometry, and ELISA was implemented to assess inflammatory factor levels. Furthermore, the Dual-luciferase assay was used to verify the targeting relationship.<br><br>RESULTS: Bud and NAC treatment alone or in combination with nebulized inhalation attenuated the increased alveolar permeability, pulmonary edema, inflammatory response and scorching in LPS-induced ALI rats, and combined treatment with Bud and NAC was the most effective. In addition, combined treatment with Bud and NAC upregulated miR-381 expression and inhibited NLRP3 expression in cellular models and LPS-induced ALI rats. Transfection of the miR-381 inhibitor and OE-NLRP3 partially reversed the protective effects of Bud and NAC combination treatment on BEAS-2B cell proliferation inhibition, apoptosis, focal death and the inflammatory response.<br><br>CONCLUSION: Combined Bud and NAC nebulization therapy alleviates LPS-induced ALI by modulating the miR-381/NLRP3 molecular axis.},
}
@article {pmid37555614,
year = {2024},
author = {Stannard, LM and Doherty, A and Chapman, KE and Doak, SH and Jenkins, GJ},
title = {Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations.},
journal = {Mutagenesis},
volume = {39},
number = {1},
pages = {13-23},
pmid = {37555614},
issn = {1464-3804},
support = {NC/R001375/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; },
mesh = {*Tumor Suppressor Protein p53/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Cadmium Chloride/toxicity/metabolism ; DNA Damage ; Cell Cycle ; Carcinogens/toxicity ; },
abstract = {Cadmium chloride (CdCl2) is a known genotoxic carcinogen, with a mechanism of action thought to partly involve the generation of reactive oxygen species (ROS). We applied here a multi-endpoint approach in vitro to explore the impact of CdCl2 on both the genome and on wider cell biology pathways relevant to cancer. Multi-endpoint approaches are believed to offer greater promise in terms of understanding the holistic effects of carcinogens in vitro. This richer understanding may help better classification of carcinogens as well as allowing detailed mechanisms of action to be identified. We found that CdCl2 caused DNA damage [micronuclei (MN)] in both TK6 and NH32 cells in a dose-dependent manner after 4 h exposure (plus 23 h recovery), with lowest observable effect levels (LOELs) for MN induction of 1 μM (TK6) and 1.6 μM (NH32). This DNA damage induction in TK6 cells was ROS dependent as pretreatment with the antioxidant N-Acetyl Cysteine (1 mM), abrogated this effect. However, 2',7'-dichlorofluorescin diacetate was not capable of detecting the ROS induced by CdCl2. The use of NH32 cells allowed an investigation of the role of p53 as they are a p53 null cell line derived from TK6. NH32 showed a 10-fold increase in MN in untreated cells and a similar dose-dependent effect after CdCl2 treatment. In TK6 cells, CdCl2 also caused activation of p53 (accumulation of total and phosphorylated p53), imposition of cell cycle checkpoints (G2/M) and intriguingly the production of smaller and more eccentric (elongated) cells. Overall, this multi-endpoint study suggests a carcinogenic mechanism of CdCl2 involving ROS generation, oxidative DNA damage and p53 activation, leading to cell cycle abnormalities and impacts of cell size and shape. This study shows how the integration of multiple cell biology endpoints studied in parallel in vitro can help mechanistic understanding of how carcinogens disrupt normal cell biology.},
}
@article {pmid37554797,
year = {2023},
author = {Zhou, Q and Zhou, Q and Xia, R and Zhang, P and Xie, Y and Yang, Z and Khan, A and Zhou, Z and Tan, W and Liu, L},
title = {Swertiamarin or heat-transformed products alleviated APAP-induced hepatotoxicity via modulation of apoptotic and Nrf-2/NF-κB pathways.},
journal = {Heliyon},
volume = {9},
number = {8},
pages = {e18746},
pmid = {37554797},
issn = {2405-8440},
abstract = {OBJECTIVE: Swertiamarin (STM) belongs to iridoid class of compounds, and the heat-transformed products (HTPS) are produced by STM in the process of drug processing. The purpose of this study was to explore the protective effect and mechanism of STM or HTPS on acetaminophen (APAP)-induced hepatotoxicity.<br><br>METHODS: Mice and L-O2 cells were given APAP to establish the hepatotoxicity model in vivo and in vitro. The effects of STM or HTPS on oxidative stress, inflammation, and apoptosis induced by APAP were evaluated, with N-acetylcysteine (NAC) as a positive control.<br><br>RESULTS: STM or HTPS reduced the APAP-induced apoptosis of L-O2 cells and significantly alleviated the liver injury index induced by APAP (p&#xa0;<&#xa0;0.01, 0.005) Interestingly, HTPS had better protective effect against APAP-induced hepatotoxicity than STM (p&#xa0;<&#xa0;0.05). In addition STM or HTPS improved the histological abnormalities; inhibited lipid peroxidation and reduced the level of inflammatory mediators. They also activated the defense system of nuclear factor erythroid 2 related factor 2 (Nrf-2) and inhibited nuclear factor-&#x3ba; B (NF-&#x3ba;B).},
}
@article {pmid37547958,
year = {2023},
author = {Wang, X and Liu, B and Liu, Y and Wang, Y and Wang, Z and Song, Y and Xu, J and Xue, C},
title = {Antioxidants ameliorate oxidative stress in alcoholic liver injury by modulating lipid metabolism and phospholipid homeostasis.},
journal = {Lipids},
volume = {58},
number = {5},
pages = {229-240},
doi = {10.1002/lipd.12377},
pmid = {37547958},
issn = {1558-9307},
mesh = {Mice ; Animals ; *Antioxidants/pharmacology/metabolism ; Lipid Metabolism ; Mice, Inbred C57BL ; Liver/metabolism ; Oxidative Stress ; *Liver Diseases, Alcoholic/drug therapy/metabolism ; Ethanol/metabolism/pharmacology ; Ascorbic Acid/metabolism/pharmacology ; Triglycerides/metabolism ; Homeostasis ; Phospholipids/metabolism ; },
abstract = {Alcoholic liver disease (ALD) is a significant risk factor in the global disease burden. The antioxidants vitamin C (Vc) and N-acetyl cysteine (NAC) have shown hepatoprotective effects in preventing and treating ALD. However, the correlation between the improved effect of antioxidants and lipid metabolism is still unclear. In this study, AML12 cells and C57BL/6 mice stimulated with alcohol were used to investigate the protective effects and potential mechanisms of two antioxidants (Vc and NAC) on alcoholic liver injury. Results showed that Vc and NAC attenuated intracellular lipid accumulation and oxidative damage induced by excessive alcohol exposure in hepatic AML12 cells. The in vivo results indicated that antioxidants ameliorated alcohol-induced changes in histopathology, reducing the levels of alcohol metabolizing factors and aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), and total cholesterol (TC) contents, which demonstrated that antioxidants effectively mitigated liver injury in ALD mice. Further studies showed that antioxidants reversed the disruption of fatty acid (FA) synthesis and lipid transport induced by alcohol exposure, and restored phospholipid levels. Especially, Vc and NAC increased the endogenous antioxidant plasmenyl phosphatidylethanolamine (PlsEtn). Additionally, antioxidants ameliorated the alcohol-impaired mitochondrial function and inhibited excessive oxidative stress. In conclusion, antioxidants can regulate lipid metabolism and phospholipid homeostasis, which in turn inhibit oxidative stress and thereby exert protective effects against ALD.},
}
@article {pmid37547194,
year = {2023},
author = {Summerlin, JA and Wang, KM and McMahon, AJ and Lund, JA},
title = {Effect of a pharmacist-based toxicology consult service on appropriate use of intravenous N-acetylcysteine for acetaminophen toxicity: A retrospective cohort study.},
journal = {International journal of critical illness and injury science},
volume = {13},
number = {2},
pages = {54-59},
pmid = {37547194},
issn = {2229-5151},
abstract = {BACKGROUND: Incorporating clinical pharmacists on the medical team has been associated with fewer medication errors and increased error interception. Due to the logistical complexities of the intravenous (IV) N-acetylcysteine (NAC) regimen for acetaminophen toxicity, many opportunities for medication errors exist. A pharmacist-based toxicology consultation service was implemented at our institution, allowing pharmacists to formally aid in the management of toxicology patients throughout their hospital admission, including those with acetaminophen toxicity. The purpose of this study was to evaluate the effect of a house-wide pharmacist-based toxicology consult service on errors associated with IV NAC treatment for patients admitted with acetaminophen toxicity.<br><br>METHODS: A retrospective, pre-post cohort study was conducted on patients who received IV NAC for acetaminophen toxicity. The intervention evaluated was the implementation of a pharmacist-based toxicology consult service, known as the pharmacy toxicology team. The primary end point was the incidence of an error associated with IV NAC. An error was defined as the composite of inappropriate dose, administration rate, initiation, continuation, or discontinuation.<br><br>RESULTS: Eighty-four patients were included; 30 patients in the pregroup, and 54 patients in the postgroup. Fewer patients experienced an error in the postgroup compared to the pregroup (30% vs 63%, P = 0.003).<br><br>CONCLUSION: The implementation of this unique pharmacist-based toxicology consult service was associated with fewer patients experiencing an error related to IV NAC therapy for acetaminophen toxicity. Application of this data may aid in the justification for development of clinical pharmacist-based toxicology consult services at other institutions.},
}
@article {pmid37545886,
year = {2023},
author = {Pimentel, BNADS and De Annunzio, SR and Assis, M and Barbugli, PA and Longo, E and Vergani, CE},
title = {Biocompatibility and inflammatory response of silver tungstate, silver molybdate, and silver vanadate microcrystals.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {11},
number = {},
pages = {1215438},
pmid = {37545886},
issn = {2296-4185},
abstract = {Silver tungstate (α-Ag2WO4), silver molybdate (β-Ag2MoO4), and silver vanadate (α-AgVO3) microcrystals have shown interesting antimicrobial properties. However, their biocompatibility is not yet fully understood. Cytotoxicity and the inflammatory response of silver-containing microcrystals were analyzed in THP-1 and THP-1 differentiated as macrophage-like cells, with the alamarBlue™ assay, flow cytometry, confocal microscopy, and ELISA. The present investigation also evaluated redox signaling and the production of cytokines (TNFα, IL-1β, IL-6, and IL-8) and matrix metalloproteinases (MMP-8 and -9). The results showed that α-AgVO3 (3.9 μg/mL) did not affect cell viability (p > 0.05). α-Ag2WO4 (7.81 μg/mL), β-Ag2MoO4 (15.62 μg/mL), and α-AgVO3 (15.62 μg/mL) slightly decreased cell viability (p ≤ 0.003). All silver-containing microcrystals induced the production of O2 [-] and this effect was mitigated by Reactive Oxygen Species (ROS) scavenger and N-acetylcysteine (NAC). TNFα, IL-6 and IL-1β were not detected in THP-1 cells, while their production was either lower (p ≤ 0.0321) or similar to the control group (p ≥ 0.1048) for macrophage-like cells. The production of IL-8 by both cellular phenotypes was similar to the control group (p ≥ 0.3570). The release of MMP-8 was not detected in any condition in THP-1 cells. Although MMP-9 was released by THP-1 cells exposed to α-AgVO3 (3.9 μg/mL), no significant difference was found with control (p = 0.7). Regarding macrophage-like cells, the release of MMP-8 and -9 decreased in the presence of all microcrystals (p ≤ 0.010). Overall, the present work shows a promising biocompatibility profile of, α-Ag2WO4, β-Ag2MoO4, and α-AgVO3 microcrystals.},
}
@article {pmid37545163,
year = {2024},
author = {Nayak, J and P, SV and Sahoo, SK and Kumar, M and Vashistha, VK and Kumar, R},
title = {Computational insight of antioxidant and doxorubicin combination for effective cancer therapy.},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {42},
number = {15},
pages = {7874-7882},
doi = {10.1080/07391102.2023.2242507},
pmid = {37545163},
issn = {1538-0254},
mesh = {*Molecular Docking Simulation ; *Doxorubicin/chemistry/pharmacology ; *Antioxidants/pharmacology/chemistry ; *Molecular Dynamics Simulation ; Humans ; Neoplasms/drug therapy ; DNA Topoisomerases, Type II/metabolism/chemistry ; Protein Binding ; Ligands ; Binding Sites ; Glutathione/metabolism/chemistry ; },
abstract = {Doxorubicin (DOX) is the most effective antineoplastic agent, destroys cancer cells by interrupting cellular function. However, the serious side effects on the heart limits its utility. To curb these unwanted side effects, nutritionist recommend antioxidants use along with DOX while chemotherapy. But it was not supported by various oncologists as it can alter the toxicity of DOX towards cancer cells. Therefore, here we explored the in silico pharmacokinetics and combination effect of DOX and antioxidants on topoisomerases-II (Top-II) and cyclophilin D (Cyp-D) therapeutic targets involved in cancer proliferation and post-myocardial infarction, respectively. The molecular docking study was conducted on target proteins and DOX including most prescribed antioxidants (melatonin, N-acetylcysteine (NAC), glutathione (GSH), β-carotene and vitamin C). GSH showed effective binding potential for Top-II and Cyp-D active sites, but other considered antioxidants possess low binding affinity. The highest docked conformations were subjected to molecular dynamics (MD) simulations to understand conformer stability of DOX and GSH with Cyp-D and Top-II for 100 ns. The results revealed that ligands pose at Top-II active sites where DOX showed strong binding affinity to DNA binding pocket and GSH to a buried site. The computational data summarised and proposed the GSH and DOX combination as antagonist effects on Top-II. Conversely, the binding compactness of GSH improved due to surface fit at the active pocket of Cyp-D and completely blocking DOX binding affinity, suppress adverse reactions of post-myocardial infarction.Communicated by Ramaswamy H. Sarma.},
}
@article {pmid37544576,
year = {2023},
author = {Su, AL and Lash, LH and Loch-Caruso, R},
title = {N-Acetyl-L-cysteine and aminooxyacetic acid differentially modulate toxicity of the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine in human placental villous trophoblast BeWo cells.},
journal = {Toxicology},
volume = {495},
number = {},
pages = {153611},
pmid = {37544576},
issn = {1879-3185},
support = {P42 ES017198/ES/NIEHS NIH HHS/United States ; T32 HD079342/HD/NICHD NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; T32 ES019851/ES/NIEHS NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; },
mesh = {Humans ; Female ; Pregnancy ; *Acetylcysteine/pharmacology/metabolism ; Cysteine ; *Trichloroethylene/toxicity/metabolism ; Placenta/metabolism ; Aminooxyacetic Acid/metabolism/pharmacology ; Trophoblasts/metabolism ; Cytochrome P-450 CYP3A/metabolism ; Hydrogen Peroxide/metabolism ; RNA, Messenger/metabolism ; },
abstract = {Trichloroethylene (TCE) is a known human carcinogen with toxicity attributed to its metabolism. S-(1,2-Dichlorovinyl)-L-cysteine (DCVC) is a metabolite of TCE formed downstream in TCE glutathione (GSH) conjugation and is upstream of several toxic metabolites. Despite knowledge that DCVC stimulates reactive oxygen species (ROS) generation and apoptosis in placental cells, the extent to which these outcomes are attributable to DCVC metabolism is unknown. The current study used N-acetyl-L-cysteine (NAC) at 5 mM and aminooxyacetic acid (AOAA) at 1 mM as pharmacological modifiers of DCVC metabolism to investigate DCVC toxicity at concentrations of 5-50 µM in the human placental trophoblast BeWo cell model capable of forskolin-stimulated syncytialization. Exposures of unsyncytialized BeWo cells, BeWo cells undergoing syncytialization, and syncytialized BeWo cells were studied. NAC pre/co-treatment with DCVC either failed to inhibit or exacerbated DCVC-induced H2O2 abundance, PRDX2 mRNA expression, and BCL2 mRNA expression. Although NAC increased mRNA expression of CYP3A4, which would be consistent with increased generation of the toxic metabolite N-acetyl-DCVC sulfoxide (NAcDCVCS), a CYP3A4 inhibitor ketoconazole did not significantly alter BeWo cell responses. Moreover, AOAA failed to inhibit cysteine conjugate β-lyase (CCBL), which bioactivates DCVC, and did not affect the percentage of nuclei condensed or fragmented, a measure of apoptosis, in all BeWo cell models. However, syncytialized cells had higher CCBL activity compared to unsyncytialized cells, suggesting that the former may be more sensitive to DCVC toxicity. Together, although neither NAC nor AOAA mitigated DCVC toxicity, differences in CCBL activity and potentially CYP3A4 expression dictated the differential toxicity derived from DCVC.},
}
@article {pmid37540942,
year = {2023},
author = {Kanaan, RA and Oliver, G and Dharan, A and Sendi, S and Maier, A and Mohebbi, M and Ng, C and Back, SE and Kalivas, P and Berk, M},
title = {A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial of adjunctive N-Acetylcysteine for treatment-resistant PTSD.},
journal = {Psychiatry research},
volume = {327},
number = {},
pages = {115398},
doi = {10.1016/j.psychres.2023.115398},
pmid = {37540942},
issn = {1872-7123},
mesh = {Adult ; Humans ; *Acetylcysteine/pharmacology/therapeutic use ; *Stress Disorders, Post-Traumatic/drug therapy ; Double-Blind Method ; Treatment Outcome ; },
abstract = {BACKGROUND: PTSD may involve oxidative stress, and N-acetylcysteine (NAC) may reduce the impact of oxidative stress in the brain. This study aims to investigate the efficacy of adjuvant NAC in people with treatment-resistant PTSD.<br><br>METHODS: A multicentre, randomised, double-blind, placebo-controlled trial for adults with PTSD unresponsive to first-line treatment. The intervention was either oral NAC 2.7&#xa0;g/day or placebo for 12 weeks. The primary outcome was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at 12 weeks compared with baseline. Secondary outcomes included depression and substance craving. Follow-up measures were obtained at 16 and 64-weeks.<br><br>RESULTS: 133 patients were assessed, with 105 randomised; 81 participants completed the 12-week trial, 79 completed week-16 follow-up, and 21 completed week-64 follow-up. There were no significant differences between those taking NAC and those taking placebo in CAPS-5 scores at week 12, nor in secondary outcomes. Significant between-group differences were observed at week 64 in craving duration (Cohen's d&#xa0;=&#xa0;1.61) and craving resistance (Cohen's d&#xa0;=&#xa0;1.03), both in favour of NAC.<br><br>CONCLUSION: This was the first multicentre, double-blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. No benefit of NAC was observed in this group beyond that provided by placebo at end of the trial.<br><br>TRIAL REGISTRATION: ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004.},
}
@article {pmid37540386,
year = {2023},
author = {Zhang, J and Sun, J and Zhang, Y and Zhang, M and Liu, X and Yang, L and Yin, Y},
title = {Dehydrocostus lactone inhibits Candida albicans growth and biofilm formation.},
journal = {AMB Express},
volume = {13},
number = {1},
pages = {82},
pmid = {37540386},
issn = {2191-0855},
support = {2019SCZT053//the Special Fund for Medical Professionals of Jilin Province/ ; },
abstract = {Candida albicans infections are threatening public health but there are only several antifungal drugs available. This study was to assess the effects of dehydrocostus lactone (DL) on the Candida albicans growth and biofilms Microdilution assays revealed that DL inhibits a panel of standard Candida species, including C. albicans, as well as 9 C. albicans clinical isolates. The morphological transition of C. albicans in RPMI-1640 medium and the adhesion to polystyrene surfaces can also be decreased by DL treatment, as evidenced by microscopic, metabolic activity and colony forming unit (CFU) counting assays. The XTT assay and microscopy inspection demonstrated that DL can inhibit the biofilms of C. albicans. Confocal microscopy following propidium iodide (PI) staining and DCFH-DA staining after DL treatment revealed that DL can increase the membrane permeability and intracellular reactive oxygen species (ROS) production. N-acetyl-cysteine could mitigate the inhibitory effects of DL on growth, morphological transition and biofilm formation, further confirming that ROS production induced by DL contributes to its antifungal and antibiofilm effects. This study showed that DL demonstrated antifungal and antibiofilm activity against C. albicans. The antifungal mechanisms may involve membrane damage and ROS overproduction. This study shows the potential of DL to fight Candida infections.},
}
@article {pmid37537647,
year = {2023},
author = {Refsnes, M and Skuland, T and Jørgensen, R and Sæter-Grytting, V and Snilsberg, B and Øvrevik, J and Holme, JA and Låg, M},
title = {Role of different mechanisms in pro-inflammatory responses triggered by traffic-derived particulate matter in human bronchiolar epithelial cells.},
journal = {Particle and fibre toxicology},
volume = {20},
number = {1},
pages = {31},
pmid = {37537647},
issn = {1743-8977},
mesh = {Humans ; *Particulate Matter/toxicity ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Cyclooxygenase 2 ; Cytochrome P-450 CYP1A1/genetics ; Plasminogen Activator Inhibitor 2/metabolism/pharmacology ; Cytokines/metabolism ; Epithelial Cells ; Vehicle Emissions/toxicity ; *Air Pollutants/toxicity/metabolism ; Azo Compounds ; Pyrazoles ; },
abstract = {BACKGROUND: Traffic-derived particles are important contributors to the adverse health effects of ambient particulate matter (PM). In Nordic countries, mineral particles from road pavement and diesel exhaust particles (DEP) are important constituents of traffic-derived PM. In the present study we compared the pro-inflammatory responses of mineral particles and DEP to PM from two road tunnels, and examined the mechanisms involved.<br><br>METHODS: The pro-inflammatory potential of 100&#xa0;&#xb5;g/mL coarse (PM10-2.5), fine (PM2.5-0.18) and ultrafine PM (PM0.18) sampled in two road tunnels paved with different stone materials was assessed in human bronchial epithelial cells (HBEC3-KT), and compared to DEP and particles derived from the respective stone materials. Release of pro-inflammatory cytokines (CXCL8, IL-1&#x3b1;, IL-1&#x3b2;) was measured by ELISA, while the expression of genes related to inflammation (COX2, CXCL8, IL-1&#x3b1;, IL-1&#x3b2;, TNF-&#x3b1;), redox responses (HO-1) and metabolism (CYP1A1, CYP1B1, PAI-2) was determined by qPCR. The roles of the aryl hydrocarbon receptor (AhR) and reactive oxygen species (ROS) were examined by treatment with the AhR-inhibitor CH223191 and the anti-oxidant N-acetyl cysteine (NAC).<br><br>RESULTS: Road tunnel PM caused time-dependent increases in expression of CXCL8, COX2, IL-1&#x3b1;, IL-1&#x3b2;, TNF-&#x3b1;, COX2, PAI-2, CYP1A1, CYP1B1 and HO-1, with fine PM as more potent than coarse PM at early time-points. The stone particle samples and DEP induced lower cytokine release than all size-fractionated PM samples for one tunnel, and versus fine PM for the other tunnel. CH223191 partially reduced release and expression of IL-1&#x3b1; and CXCL8, and expression of COX2, for fine and coarse PM, depending on tunnel, response and time-point. Whereas expression of CYP1A1 was markedly reduced by CH223191, HO-1 expression was not affected. NAC reduced the release and expression of IL-1&#x3b1; and CXCL8, and COX2 expression, but augmented expression of CYP1A1 and HO-1.<br><br>CONCLUSIONS: The results indicate that the pro-inflammatory responses of road tunnel PM in HBEC3-KT cells are not attributed to the mineral particles or DEP alone. The pro-inflammatory responses seem to involve AhR-dependent mechanisms, suggesting a role for organic constituents. ROS-mediated mechanisms were also involved, probably through AhR-independent pathways. DEP may be a contributor to the AhR-dependent responses, although other sources may be of importance.},
}
@article {pmid37537538,
year = {2023},
author = {Duan, Y and Wu, W and Cui, J and Matsubara, JA and Kazlauskas, A and Ma, G and Li, X and Lei, H},
title = {Ligand-independent activation of platelet-derived growth factor receptor β promotes vitreous-induced contraction of retinal pigment epithelial cells.},
journal = {BMC ophthalmology},
volume = {23},
number = {1},
pages = {344},
pmid = {37537538},
issn = {1471-2415},
support = {G2022026027L//Introduction plan of high-level foreign experts/ ; 2021JJ41030//Natural Science Foundation of&#xa0;Hunan Province/ ; 82171085//National Natural Science Foundation of China/ ; 202103021224345//Natural Science Foundation of Shanxi province/ ; R01 EY031350/EY/NEI NIH HHS/United States ; 82070989//National Natural Science Foundation of China/ ; 2022-203//Research Project Supported by Shanxi Scholarship Council of China/ ; 19JCZDJC64000//Natural Science Foundation of Tianjin City/ ; 2022Jx22//Shanxi Bethune Hospital Education and Teaching Reform Foundation/ ; 2020004//Health Commission of Shanxi Province/ ; 2021RC005//Shanxi Bethune Hospital Foundation/ ; },
mesh = {Humans ; *Receptor, Platelet-Derived Growth Factor beta/genetics/metabolism ; Retinal Pigment Epithelium/pathology ; Proto-Oncogene Proteins c-akt ; Ligands ; Reactive Oxygen Species/metabolism ; *Vitreoretinopathy, Proliferative/genetics/metabolism ; Platelet-Derived Growth Factor/metabolism ; Epithelial Cells/metabolism ; Retinal Pigments/metabolism ; Cell Movement ; },
abstract = {BACKGROUND: Epiretinal membranes in patients with proliferative vitreoretinopathy (PVR) consist of extracellular matrix and a number of cell types including retinal pigment epithelial (RPE) cells and fibroblasts, whose contraction causes retinal detachment. In RPE cells depletion of platelet-derived growth factor (PDGF) receptor (PDGFR)β suppresses vitreous-induced Akt activation, whereas in fibroblasts Akt activation through indirect activation of PDGFRα by growth factors outside the PDGF family (non-PDGFs) plays an essential role in experimental PVR. Whether non-PDGFs in the vitreous, however, were also able to activate PDGFRβ in RPE cells remained elusive.<br><br>METHODS: The CRISPR/Cas9 technology was utilized to edit a genomic PDGFRB locus in RPE cells derived from an epiretinal membrane (RPEM) from a patient with PVR, and a retroviral vector was used to express a truncated PDGFR&#x3b2; short of a PDGF-binding domain in the RPEM cells lacking PDGFR&#x3b2;. Western blot was employed to analyze expression of PDGFR&#x3b2; and &#x3b1;-smooth muscle actin, and signaling events (p-PDGFR&#x3b2; and p-Akt). Cellular assays (proliferation, migration and contraction) were also applied in this study.<br><br>RESULTS: Expression of a truncated PDGFR&#x3b2; lacking a PDGF-binding domain in the RPEM cells whose PDGFRB gene has been silent using the CRISPR/Cas9 technology restores vitreous-induced Akt activation as well as cell proliferation, epithelial-mesenchymal transition, migration and contraction. In addition, we show that scavenging reactive oxygen species (ROS) with N-acetyl-cysteine and inhibiting Src family kinases (SFKs) with their specific inhibitor SU6656 blunt the vitreous-induced activation of the truncated PDGFR&#x3b2; and Akt as well as the cellular events related to the PVR pathogenesis. These discoveries suggest that in RPE cells PDGFR&#x3b2; can be activated indirectly by non-PDGFs in the vitreous via an intracellular pathway of ROS/SFKs to facilitate the development of PVR, thereby providing novel opportunities for PVR therapeutics.<br><br>CONCLUSION: The data shown here will improve our understanding of the mechanism by which PDGFR&#x3b2; can be activated by non-PDGFs in the vitreous via an intracellular route of ROS/SFKs and provide a conceptual foundation for preventing PVR by inhibiting PDGFR&#x3b2; transactivation (ligand-independent activation).},
}
@article {pmid37536438,
year = {2023},
author = {Martis, RM and Grey, AC and Wu, H and Wall, GM and Donaldson, PJ and Lim, JC},
title = {N-Acetylcysteine amide (NACA) and diNACA inhibit H2O2-induced cataract formation ex vivo in pig and rat lenses.},
journal = {Experimental eye research},
volume = {234},
number = {},
pages = {109610},
doi = {10.1016/j.exer.2023.109610},
pmid = {37536438},
issn = {1096-0007},
support = {R21 EY033941/EY/NEI NIH HHS/United States ; },
mesh = {Rats ; Animals ; Swine ; Acetylcysteine/adverse effects/analogs &amp; derivatives ; Hydrogen Peroxide/pharmacology ; Cystine/adverse effects ; Chromatography, Liquid ; Rats, Wistar ; Tandem Mass Spectrometry ; *Lens, Crystalline/metabolism ; *Cataract/chemically induced ; Antioxidants ; Oxidative Stress ; Glutathione/metabolism ; Proteins ; Glutathione Disulfide ; },
abstract = {Oxidative stress plays a central role in cataract formation suggesting that antioxidants might slow cataract progression. The anticataract activity of N-acetylcysteine amide (NACA) and (2 R, 2 R')-3,3'-disulfanediyl bis(2-acetamidopropanamide) (diNACA) and/or N-acetylcysteine (NAC), were evaluated in porcine and rat lens models. Cataractogenesis via oxidation was induced with H2O2 and/or glucose oxidase (GO). Porcine lenses were incubated in 0.1 mM, 1 mM, or 10 mM NAC, NACA or diNACA for 24 h. Lenses were then transferred to media containing 0.75 mM H2O2 and 4.63U of GO in order to maintain a constant H2O2 level for an additional 8 h. At the end of incubation, lenses were imaged under darkfield microscopy. Separately, rat lenses were extracted from 3-week-old Wistar rats and incubated with either 10 mM NACA or 10 mM diNACA for 24 h prior to treatment with 0.2U GO to generate a steady source of ∼0.6 mM H2O2. Rat lenses were analyzed by LC-MS/MS to quantify changes in cysteine, cystine, glutathione (GSH) or oxidised glutathione (GSSG) levels in the lens epithelium, cortex or core. Pre-treatment with NACA or diNACA followed by oxidation with H2O2 and/or GO to stimulate cataract formation afforded rapid assessment in ex vivo porcine (32 h) and rat (48 h) lens models. Pre-treatment of isolated porcine lenses with 0.1 mM, 1 mM or 10 mM of either NAC, NACA or diNACA followed by H2O2/GO treatment resulted in reduced lens opacity relative to the lenses exposed to H2O2/GO, with NACA and diNACA reducing opacities to a greater extent than NAC. Rat lenses incubated with 10 mM NACA or 10 mM diNACA without exposure to H2O2 showed no signs of opacities. Pre-treatment of rat lenses with 10 mM NACA or 10 mM diNACA, followed by GO cataract induction resulted in reduced opacities compared to control (GO alone). LC-MS/MS analyses revealed that NACA, but not diNACA, increased cysteine, cystine and GSH levels in rat lens epithelium and cortex regions. Taken together, both NACA and diNACA inhibited cataract formation to a greater extent than NAC (all at 1-10 mM) in an ex vivo porcine lens model. Both NACA and diNACA (both at 10 mM) reduced cataract formation in rat lenses. Based on LC-MS/MS analyses, NACA-induced reduction in opacity observed in rat lenses was attributed to enhanced cysteine and GSH levels while the diNACA-induced reduction in opacity induced did not consistently increase cysteine, cystine and GSH levels and, therefore, appears to involve a different antioxidant mechanism. These screening studies warrant further testing of NACA and diNACA as anticataract agents.},
}
@article {pmid37536084,
year = {2023},
author = {Takeda, H and Murakami, S and Liu, Z and Sawa, T and Takahashi, M and Izumi, Y and Bamba, T and Sato, H and Akaike, T and Sekine, H and Motohashi, H},
title = {Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.},
journal = {Redox biology},
volume = {65},
number = {},
pages = {102834},
pmid = {37536084},
issn = {2213-2317},
mesh = {Mice ; Animals ; *Cystine ; Feedback ; *Lipopolysaccharides ; Macrophages/metabolism ; Acetylcysteine ; Sulfur/metabolism ; Amino Acid Transport System y+/genetics/metabolism ; },
abstract = {The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.},
}
@article {pmid37534881,
year = {2024},
author = {Ding, W and Fan, JH and Zhong, LR and Wang, NX and Liu, LH and Zhang, HB and Wang, L and Wang, MQ and He, BL and Wei, AY},
title = {N-acetylcysteine ameliorates erectile dysfunction in rats with hyperlipidemia by inhibiting oxidative stress and corpus cavernosum smooth muscle cells phenotypic modulation.},
journal = {Asian journal of andrology},
volume = {26},
number = {1},
pages = {99-106},
pmid = {37534881},
issn = {1745-7262},
mesh = {Male ; Animals ; *Hyperlipidemias/drug therapy/complications ; *Oxidative Stress/drug effects ; *Erectile Dysfunction/drug therapy/etiology ; *Acetylcysteine/pharmacology/therapeutic use ; *Rats, Sprague-Dawley ; Rats ; *Penis/drug effects/pathology ; *Myocytes, Smooth Muscle/drug effects ; Phenotype ; Penile Erection/drug effects ; },
abstract = {Hyperlipidemia is a major risk factor for erectile dysfunction (ED). Oxidative stress and phenotypic modulation of corpus cavernosum smooth muscle cells (CCSMCs) are the key pathological factors of ED. N-acetylcysteine (NAC) can inhibit oxidative stress; however, whether NAC can alleviate pathological variations in the corpus cavernosum and promote erectile function recovery in hyperlipidemic rats remains unclear. A hyperlipidemia model was established using 27 eight-week-old male Sprague-Dawley (SD) rats fed a high-fat and high-cholesterol diet (hyperlipidemic rats, HR). In addition, 9 male SD rats were fed a normal diet to serve as controls (NC). HR rats were divided into three groups: HR, HR+normal saline (NS), and HR+NAC (n = 9 for each group; NS or NAC intraperitoneal injections were administered daily for 16 weeks). Subsequently, the lipid profiles, erectile function, oxidative stress, phenotypic modulation markers of CCSMCs, and tissue histology were analyzed. The experimental results revealed that erectile function was significantly impaired in the HR and HR + NS groups, but enhanced in the HR + NAC group. Abnormal lipid levels, over-activated oxidative stress, and multi-organ lesions observed in the HR and HR + NS groups were improved in the HR + NAC group. Moreover, the HR group showed significant phenotypic modulation of CCSMCs, which was also inhibited by NAC treatment. This report focuses on the therapeutic effect of NAC in restoring erectile function using a hyperlipidemic rat model by preventing CCSMC phenotypic modulation and attenuating oxidative stress.},
}
@article {pmid37534078,
year = {2023},
author = {Alam, MS and Hasan, MN and Maowa, Z and Khatun, F and Nazir, KHMNH and Alam, MZ},
title = {N-acetylcysteine reduces severity and mortality in COVID-19 patients: A systematic review and meta-analysis.},
journal = {Journal of advanced veterinary and animal research},
volume = {10},
number = {2},
pages = {157-168},
pmid = {37534078},
issn = {2311-7710},
abstract = {OBJECTIVES: Recent clinical studies suggest that oxidative stress is one of the key players in the pathogenesis of coronavirus disease 2019 (COVID-19), and N-acetylcysteine (NAC), a potent antioxidant, has been shown to improve clinical outcomes in COVID-19 patients. We conducted a systematic review and meta-analysis of the literature published on the therapeutic intervention of NAC on COVID-19 infection.<br><br>METHODS: We searched PubMed, Google Scholar, and Science Direct. We identified and screened eight studies with 20,503 participants, including 2,852 in the NAC-treated group and 17,651 in the placebo group, which reported the effect of NAC on COVID-19 infection. A meta-analysis was performed using forest plots under fixed effect estimates based on the standardized mean difference (SMD) and risk ratio (RR).<br><br>RESULTS: Pooled analysis showed that NAC was associated with lower mortality in patients with COVID-19 compared with the placebo group [RR, 0.65; (95% CI: 0.56 to 0.75); p < 0.0001]. Similarly, C-reactive protein (CRP) [SMD, -0.32; (95% CI: -56 to -0.09); p = 0.0070] and D-dimer [SMD, -0.35, (95% CI: -0.59 to -0.10; p = 0.0062] levels were significantly decreased, and the oxygenation marker, PaO2/FiO2 ratio, was increased in the NAC-treated group compared with the placebo group [SMD, 0.76; (95% CI: 0.48 to 1.03); p < 0.0001].<br><br>CONCLUSION: Although the number of included studies was minimal, this meta-analysis suggests that NAC may have a positive effect on COVID-19 outcomes, specifically, a significant decrease in CRP and D-dimer levels and a significant increase in oxygen saturation, which decreased mortality. We have also presented a comprehensive review of the role and mechanisms of NAC in patients with COVID-19.},
}
@article {pmid37532734,
year = {2023},
author = {Chen, W and Yin, Y and Zhang, Z},
title = {Effects of N-acetylcysteine on CG8005 gene-mediated proliferation and apoptosis of Drosophila S2 embryonic cells.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {12502},
pmid = {37532734},
issn = {2045-2322},
mesh = {Animals ; Male ; *Acetylcysteine/pharmacology ; *Antioxidants/pharmacology ; Apoptosis ; Cell Proliferation ; *Drosophila/embryology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; *Drosophila Proteins/genetics/physiology ; },
abstract = {To investigate the effect of the antioxidant N-acetylcysteine (NAC) on the proliferation and apoptosis in CG8005 gene-interfering Drosophila S2 embryonic cells by scavenging intracellular reactive oxygen species (ROS). The interfering efficiency of CG8005 gene in Drosophila S2 embryonic cells was verified by real-time quantitative PCR (qRT-PCR). Different concentrations of NAC and phosphate buffered saline (PBS) were used to affect the Drosophila S2 embryonic cells. The growth state of Drosophila S2 embryonic cells was observed by light microscope. Two probes dihydroethidium (DHE) and 2,7-dichlorodihydrofluorescein-acetoacetate (DCFH-DA) were used to observe the ROS production in each group after immunofluorescence staining. TUNEL staining and flow cytometry were used to investigate the apoptosis level of Drosophila S2 embryos, and CCK-8 (Cell Counting Kit-8) was used to detect the cell viability of Drosophila S2 embryos. The knockdown efficiency of siCG8005-2 fragment was high and stable, which was verified by interference efficiency (P < 0.05). There was no significant change in the growth of Drosophila S2 embryonic cells after the treatment of NAC as compared to PBS group. Moreover, knockdowning CG8005 gene resulted in an increase in ROS and apoptosis in Drosophila S2 embryonic cells (P < 0.05) and a decrease in proliferation activity (P < 0.05). In addition, the pretreatment of antioxidant NAC could inhibit ROS production in Drosophila S2 embryonic cells (P < 0.05), reduce cell apoptosis (P < 0.05), and improve cell survival (P < 0.05). The CG8005 gene in Drosophila S2 embryonic cells could regulate the proliferation and apoptosis of S2 embryonic cells by disrupting the redox homeostasis, and antioxidant NAC could inhibit cell apoptosis and promotes cell proliferation by scavenging ROS in Drosophila S2 embryonic cells, which is expected to provide novel insights for the pathogenesis of male infertility and spermatogenesis.},
}
@article {pmid37531905,
year = {2023},
author = {Zhai, BW and Zhao, H and Zhu, HL and Huang, H and Zhang, MY and Fu, YJ},
title = {Triterpene acids from Rosa roxburghii Tratt fruits exert anti-hepatocellular carcinoma activity via ROS/JNK signaling pathway-mediated cell cycle arrest and mitochondrial apoptosis.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {119},
number = {},
pages = {154960},
doi = {10.1016/j.phymed.2023.154960},
pmid = {37531905},
issn = {1618-095X},
mesh = {Humans ; Reactive Oxygen Species/metabolism ; MAP Kinase Signaling System ; *Rosa ; Fruit ; *Carcinoma, Hepatocellular/pathology ; Cell Cycle Checkpoints ; Apoptosis ; Hep G2 Cells ; *Triterpenes/pharmacology ; *Liver Neoplasms/pathology ; Cell Line, Tumor ; },
abstract = {BACKGROUND: Rosa roxburghii Tratt (RRT) is a famous healthy and medicinal edible fruit in southwest China and has been shown to have some hepatoprotective properties. However, whether the active components, such as the triterpene acids from Rosa roxburghii Tratt fruits (TAR), have anti-hepatocellular carcinoma (HCC) effects and the potential molecular mechanisms are still unclear.<br><br>PURPOSE: This study aimed to investigate the anti-HCC effects and potential action mechanisms of triterpene components in RRT fruits.<br><br>METHODS: The triterpene acids in TAR were analyzed by using UPLC-Q-Exactive Orbitrap/MS, and the main components were virtual screening for targets based on pharmacophore and then performed enrichment analysis. HepG2 cells were used for in vitro experiments, including MTT assay, wound healing assay, and flow cytometry to detect cell cycle, reactive oxygen species (ROS) level, caspase-3 activity, and mitochondrial membrane potential (MMP) changes. Moreover, the western blot was used to detect mitochondrial apoptosis and ROS/ c-Jun N-terminal kinase (JNK) signaling pathway-related proteins.<br><br>RESULTS: The main components in TAR are pentacyclic triterpene acids (mainly euscaphic acid and roxburic acid). TAR could inhibit cell viability, cell migration ability and suppress the proliferation of HepG2 cells through G2/M cell cycle arrest. On the other hand, TAR could induce HepG2 cells apoptosis, which was achieved by causing the accumulation of ROS and activation of the JNK signaling pathway, and our research showed that this apoptosis was mediated through the mitochondrial pathway. In addition, the free radical scavenger N-acetyl cysteine (NAC) could attenuate TAR-induced ROS accumulation and JNK signaling pathway activation, which ultimately reversed mitochondrial apoptosis.<br><br>CONCLUSION: TAR could activate the ROS/JNK signaling pathway, which could inhibit the proliferation through G2/M cell cycle arrest and promote apoptosis through the mitochondrial pathway in HCC cells. This supports the anti-tumor potential in RRT fruits.},
}
@article {pmid37522842,
year = {2023},
author = {Pan, X and Giustarini, D and Lang, F and Rossi, R and Wieder, T and Köberle, M and Ghashghaeinia, M},
title = {Desipramine induces eryptosis in human erythrocytes, an effect blunted by nitric oxide donor sodium nitroprusside and N-acetyl-L-cysteine but enhanced by Calcium depletion.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {22},
number = {17},
pages = {1827-1853},
pmid = {37522842},
issn = {1551-4005},
mesh = {Humans ; *Nitric Oxide Donors/pharmacology/metabolism ; Nitroprusside/pharmacology/metabolism ; *Eryptosis ; Calcium/metabolism ; Acetylcysteine/pharmacology ; Desipramine/pharmacology/metabolism ; Erythrocytes/metabolism ; Glutathione/metabolism/pharmacology ; Annexins/metabolism/pharmacology ; Phosphatidylserines/metabolism ; Cell Size ; Ceramides/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; },
abstract = {Background: Desipramine a representative of tricyclic antidepressants (TCAs) promotes recovery of depressed patients by inhibition of reuptake of neurotransmitters serotonin (SER) and norepinephrine (NE) in the presynaptic membrane by directly blocking their respective transporters SERT and NET.Aims: To study the effect of desipramine on programmed erythrocyte death (eryptosis) and explore the underlying mechanisms.Methods: Phosphatidylserine (PS) exposure on the cell surface as marker of cell death was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry. Hemolysis was determined photometrically, and intracellular glutathione [GSH]i from high performance liquid chromatography.Results: Desipramine dose-dependently significantly enhanced the percentage of annexin-V-binding cells and didn´t impact glutathione (GSH) synthesis. Desipramine-induced eryptosis was significantly reversed by pre-treatment of erythrocytes with either nitric oxide (NO) donor sodium nitroprusside (SNP) or N-acetyl-L-cysteine (NAC). The highest inhibitory effect was obtained by using both inhibitors together. Calcium (Ca[2+]) depletion aggravated desipramine-induced eryptosis. Changing the order of treatment, i.e. desipramine first followed by inhibitors, could not influence the inhibitory effect of SNP or NAC.Conclusion: Antidepressants-caused intoxication can be treated by SNP and NAC, respectively. B) Patients with chronic hypocalcemia should not be treated with tricyclic anti-depressants or their dose should be noticeably reduced.},
}
@article {pmid37522559,
year = {2023},
author = {Kaur, K and Chen, PC and Ko, MW and Huerta-Yepez, S and Maharaj, D and Jewett, A},
title = {The Potential Role of Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis (ALS); A Longitudinal Case Study Comparing Patients with Genetically Identical Healthy Twin.},
journal = {Critical reviews in immunology},
volume = {43},
number = {1},
pages = {27-39},
doi = {10.1615/CritRevImmunol.2023047233},
pmid = {37522559},
issn = {2162-6472},
abstract = {Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neurons. The causes of ALS are heterogeneous, and are only partially understood to date. We studied percentage and function of immune cell subsets in particular natural killer (NK) and CD8+ T cells in an ALS patient and compared the results to those obtained from his genetically identical healthy twin in a longitudinal study. We found several basic mechanisms which were potentially involved in the disease induction and progression. Our findings demonstrate that ALS patient's peripheral blood contained higher NK and B cells and, lower T cell percentages compared with the healthy twin brother's peripheral blood. Significantly increased interferon-gamma secretion by anti-CD3/28 monoclonal antibody-treated peripheral blood mononuclear cells, and sorted CD8+ T cells were observed in the ALS patient, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism of ALS progression. Significant increase in NK cell function due to genetic mutations in ALS associated genes may partly be responsible for the increase expansion and function of CD8+ T cells with effector/memory phenotype, in addition to direct activation and expansion of antigen specific T cells by such mutations. Weekly N-acetyl cysteine infusion to block cell death in patient in addition to a number of other therapies listed in this paper were not effective, and even though the treatments might have extended the patient's life, it was not curative. Therefore, activated CD8+ T and NK cells are likely cells targeting motor neurons in the patient, and strategies should be designed to decrease the aggressive nature of these cells to achieve longer lasting therapeutic benefits.},
}
@article {pmid37522557,
year = {2023},
author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Huerta-Yepez, S and Maharaj, D and Malarkannan, S and Jewett, A},
title = {Successes and Challenges in Taming the Beast: Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis.},
journal = {Critical reviews in immunology},
volume = {43},
number = {1},
pages = {1-11},
doi = {10.1615/CritRevImmunol.2023047235},
pmid = {37522557},
issn = {2162-6472},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Cytokines/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.},
}
@article {pmid37522109,
year = {2023},
author = {Girone, N and Benatti, B and Molteni, L and Cassina, N and Giacovelli, L and Arici, C and Dell'Osso, B},
title = {Partial Response to Antidepressant Treatment: The Role of Nutraceutical Compounds.},
journal = {Clinical neuropsychiatry},
volume = {20},
number = {3},
pages = {183-192},
pmid = {37522109},
issn = {2385-0787},
abstract = {OBJECTIVE: Depression represents one of the most severe psychiatric disorders, characterized by low mood episodes, as well as loss of interest. Major Depressive Episodes (MDE) treatment relies primarily on monoaminergic prescriptions. However, although the presence of many antidepressant medications, their efficacy is still partial. A promising intervention to improve antidepressant treatment may be the use of adjunctive nutraceuticals. Aim of the present study was to assess the efficacy of a N-Acetyl-cysteine, S-Adenosyl-L-Methionine and Folic acid's combination for the treatment of depressive symptoms in a sample of MDE patients.<br><br>METHOD: Fifty outpatients with a MDE diagnosis in the context of different psychiatric disorders such as Major Depression, Bipolar Disorder, Anxiety disorders, and Personality disorders were recruited. The sample was divided into different groups based on the nutraceutical administration: a) concurrently with an AD (starter group); b) add-on to an already prescribed treatment; c) single treatment.<br><br>RESULTS: A significant reduction of CGI-Severity and Improvement scores from baseline to the end of treatment was found. Moreover, the starter group showed a significantly greater CGI-Improvement score compared to the other groups. Ninety-four percent of patients did not show any side effects.<br><br>CONCLUSIONS: The present study showed promising results for the use of nutraceuticals in the add-on treatment of MDE. Those compounds may be considered a versatile, tolerable, and effective add-on treatment for the reduction of depressive symptoms impact and for improving the functioning of patients affected by MDE.},
}
@article {pmid37521669,
year = {2023},
author = {Shalaby, AS and Eid, HH and El-Shiekh, RA and Mohamed, OG and Tripathi, A and Al-Karmalawy, AA and Sleem, AA and Morsy, FA and Ibrahim, KM and Tadros, SH and Youssef, FS},
title = {Taming Food-Drug Interaction Risk: Potential Inhibitory Effects of Citrus Juices on Cytochrome Liver Enzymes Can Safeguard the Liver from Overdose Paracetamol-Induced Hepatotoxicity.},
journal = {ACS omega},
volume = {8},
number = {29},
pages = {26444-26457},
pmid = {37521669},
issn = {2470-1343},
abstract = {Paracetamol overdose is the leading cause of drug-induced hepatotoxicity worldwide. Because of N-acetyl cysteine's limited therapeutic efficacy and safety, searching for alternative therapeutic substitutes is necessary. This study investigated four citrus juices: Citrus sinensis L. Osbeck var. Pineapple (pineapple sweet orange), Citrus reticulata Blanco × Citrus sinensis L. Osbeck (Murcott mandarin), Citrus paradisi Macfadyen var. Ruby Red (red grapefruit), and Fortunella margarita Swingle (oval kumquat) to improve the herbal therapy against paracetamol-induced liver toxicity. UHPLC-QTOF-MS/MS profiling of the investigated samples resulted in the identification of about 40 metabolites belonging to different phytochemical classes. Phenolic compounds were the most abundant, with the total content ranked from 609.18 to 1093.26 μg gallic acid equivalent (GAE)/mL juice. The multivariate data analysis revealed that phloretin 3',5'-di-C-glucoside, narirutin, naringin, hesperidin, 2-O-rhamnosyl-swertisin, fortunellin (acacetin-7-O-neohesperidoside), sinensetin, nobiletin, and tangeretin represented the crucial discriminatory metabolites that segregated the analyzed samples. Nevertheless, the antioxidant activity of the samples was 1135.91-2913.92 μM Trolox eq/mL juice, 718.95-3749.47 μM Trolox eq/mL juice, and 2304.74-4390.32 μM Trolox eq/mL juice, as revealed from 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid, ferric-reducing antioxidant power, and oxygen radical absorbance capacity, respectively. The in vivo paracetamol-induced hepatotoxicity model in rats was established and assessed by measuring the levels of hepatic enzymes and antioxidant biomarkers. Interestingly, the concomitant administration of citrus juices with a toxic dose of paracetamol effectively recovered the liver injury, as confirmed by normal sections of hepatocytes. This action could be due to the interactions between the major identified metabolites (hesperidin, hesperetin, phloretin 3',5'-di-C-glucoside, fortunellin, poncirin, nobiletin, apigenin-6,8-digalactoside, 6',7'-dihydroxybergamottin, naringenin, and naringin) and cytochrome P450 isoforms (CYP3A4, CYP2E1, and CYP1A2), as revealed from the molecular docking study. The most promising compounds in the three docking processes were hesperidin, fortunellin, poncirin, and naringin. Finally, a desirable food-drug interaction was achieved in our research to overcome paracetamol overdose-induced hepatotoxicity.},
}
@article {pmid37520878,
year = {2023},
author = {Afaghi, S and Moghimi, N and Malekpour Alamdari, N and Rahimi, FS and Irilouzadian, R and Esmaeili Tarki, F and Moghimi, M and Besharat, S and Salehi Omran, H and Karimi, A},
title = {N-acetylcysteine as adjuvant therapy for hospitalized Covid-19 patients: A single-center prospective cohort study.},
journal = {Caspian journal of internal medicine},
volume = {14},
number = {3},
pages = {543-552},
pmid = {37520878},
issn = {2008-6164},
abstract = {BACKGROUND: Whilst over two years have passed since the COVID-19 pandemic's emergence, the proper management of the disease remains challenging. N-acetylcysteine (NAC) as a potentially effective therapeutic option has been suggested by studies, while the exact clinical role of this agent is yet to be evaluated.<br><br>METHODS: This prospective case-control study was conducted in a major referral respiratory center in Tehran, Iran. We enrolled 217 patients treated with an intravenous daily dose of 1500 mg NAC as a case group; and 245 control patients who did not receive NAC. Two groups were matched based on other treatments, socio-demographics, medical history, and comorbidities.<br><br>RESULTS: After ten days of adjuvant therapy with NAC, patients in the NAC group and control group had median room-air SpO2 of 91% and 88%, respectively (P=0.02). Also, the SpO2 to FiO2 ratio had a median of 463 and 421 in the case and control groups, respectively (P=0.01). Furthermore, the case group's hospitalization period was three days shorter (P=0.002). Further, cough, dyspnea, and decreased appetite were reported to have a significantly lower incidence in the case group (P=0.03, 0.001, 0.008).<br><br>CONCLUSION: We showed that a daily intravenous dose of NAC in hospitalized COVID-19 patients could shorten the hospital stay and improve some clinical symptoms; however, it does not remarkably improve the risk of ICU admission and the 28 days in-hospital mortality rate.},
}
@article {pmid37519003,
year = {2023},
author = {Zhuo, Y and Chen, H and Liu, C and Zhang, Y and Fang, J and Li, M and Wang, Z and Jiang, Q and Yu, L and Pan, H and Wang, Q},
title = {Covalent Modification of Proteins by Osthole Reactive Metabolites using Proteomic Approaches.},
journal = {Current drug metabolism},
volume = {24},
number = {8},
pages = {611-620},
doi = {10.2174/1389200224666230727123006},
pmid = {37519003},
issn = {1875-5453},
abstract = {BACKGROUND: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,β- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites.<br><br>OBJECTIVE: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST.<br><br>METHODS: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer.<br><br>RESULTS: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor.<br><br>CONCLUSION: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).},
}
@article {pmid37517999,
year = {2023},
author = {Cazzola, M and Page, CP and Wedzicha, JA and Celli, BR and Anzueto, A and Matera, MG},
title = {Use of thiols and implications for the use of inhaled corticosteroids in the presence of oxidative stress in COPD.},
journal = {Respiratory research},
volume = {24},
number = {1},
pages = {194},
pmid = {37517999},
issn = {1465-993X},
mesh = {Humans ; *Antioxidants/therapeutic use/pharmacology ; Sulfhydryl Compounds/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/diagnosis/drug therapy/chemically induced ; Adrenal Cortex Hormones ; Oxidative Stress ; Acetylcysteine/therapeutic use ; Inflammation/drug therapy ; Expectorants/therapeutic use ; Thioglycolates ; Thiophenes ; },
abstract = {BACKGROUND: Oxidative stress and persistent airway inflammation are thought to be important contributors to the development of chronic obstructive pulmonary disease (COPD). This review summarizes the evidence for targeting oxidative stress and inflammation in patients with COPD with mucolytic/antioxidant thiols and inhaled corticosteroids (ICS), either alone or in combination.<br><br>MAIN BODY: Oxidative stress is increased in COPD, particularly during acute exacerbations. It can be triggered by oxidant air pollutants and cigarette smoke and/or by endogenous reactive oxygen species (ROS) released from mitochondria and activated inflammatory, immune and epithelial cells in the airways, together with a reduction in endogenous antioxidants such as glutathione (GSH). Oxidative stress also drives chronic inflammation and disease progression in the airways by activating intracellular signalling pathways and the release of further inflammatory mediators. ICS are anti-inflammatory agents currently recommended for use with long-acting bronchodilators to prevent exacerbations in patients with moderate-to-severe COPD, especially those with eosinophilic airway inflammation. However, corticosteroids can also increase oxidative stress, which may in turn reduce corticosteroid sensitivity in patients by several mechanisms. Thiol-based agents such as erdosteine, N-acetyl L-cysteine (NAC) and S-carboxymethylcysteine (S-CMC) are mucolytic agents that also act as antioxidants. These agents may reduce oxidative stress directly through the free sulfhydryl groups, serving as a source of reducing equivalents and indirectly though intracellular GSH replenishment. Few studies have compared the effects of corticosteroids and thiol agents on oxidative stress, but there is some evidence for greater antioxidant effects when they are administered together. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) report supports treatment with antioxidants (erdosteine, NAC, S-CMC) in addition to standard-of-care therapy as they have been demonstrated to reduce COPD exacerbations. However, such studies have demonstrated that NAC and S-CMC reduced the exacerbation risk only in patients not treated with ICS, whereas erdosteine reduced COPD exacerbations irrespective of concomitant ICS use suggesting that erdosteine has additional pharmacological actions to ICS.<br><br>CONCLUSIONS: Further clinical trials of antioxidant agents with and without ICS are needed to better understand the place of thiol-based drugs in the treatment of patients with COPD.},
}
@article {pmid37517847,
year = {2023},
author = {},
title = {Retraction notice to "Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial".},
journal = {Fertility and sterility},
volume = {120},
number = {2},
pages = {395},
doi = {10.1016/j.fertnstert.2023.06.016},
pmid = {37517847},
issn = {1556-5653},
}
@article {pmid37511170,
year = {2023},
author = {Kubovcikova, M and Sobotova, R and Zavisova, V and Antal, I and Khmara, I and Lisnichuk, M and Bednarikova, Z and Jurikova, A and Strbak, O and Vojtova, J and Mikolka, P and Gombos, J and Lokajova, A and Gazova, Z and Koneracka, M},
title = {N-Acetylcysteine-Loaded Magnetic Nanoparticles for Magnetic Resonance Imaging.},
journal = {International journal of molecular sciences},
volume = {24},
number = {14},
pages = {},
pmid = {37511170},
issn = {1422-0067},
support = {ITMS 313011AVG3//Operational Programme Integrated Infrastructure co-funded by ERDF/ ; APVV-18-0284, APVV SK-TW-21-0004//the Slovak Research and Development Agency/ ; EGA 02/0176/21, VEGA 02/0164/22, VEGA 02/0049/23//Slovak Grant Agency/ ; IMTS: 313011BWX6//The application of spectroscopic methods for early, non-invasive real-time identification of selected diseases using gasses released from lungs and skin/ ; ITMS: 313011AVG3 "BIOVID"//he Operational Program Integrated Infrastructure funded by the ERDF ITMS2014+ 313011T553 "DIAGNAD"/ ; },
mesh = {*Magnetite Nanoparticles/chemistry ; Contrast Media/chemistry ; Acetylcysteine/pharmacology ; Magnetic Resonance Imaging/methods ; *Nanoparticles/chemistry ; Adsorption ; },
abstract = {Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by the rapid onset of lung inflammation Therefore, monitoring the spatial distribution of the drug directly administered to heterogeneously damaged lungs is desirable. In this work, we focus on optimizing the drug N-acetylcysteine (NAC) adsorption on poly-l-lysine-modified magnetic nanoparticles (PLLMNPs) to monitor the drug spatial distribution in the lungs using magnetic resonance imaging (MRI) techniques. The physicochemical characterizations of the samples were conducted in terms of morphology, particle size distributions, surface charge, and magnetic properties followed by the thermogravimetric quantification of NAC coating and cytotoxicity experiments. The sample with the theoretical NAC loading concentration of 0.25 mg/mL was selected as an optimum due to the hydrodynamic nanoparticle size of 154 nm, the surface charge of +32 mV, good stability, and no cytotoxicity. Finally, MRI relaxometry confirmed the suitability of the sample to study the spatial distribution of the drug in vivo using MRI protocols. We showed the prevailing transverse relaxation with high transverse relaxivity values and a high r2[(]*[)]/r1 ratio, causing visible hypointensity in the final MRI signal. Furthermore, NAC adsorption significantly affects the relaxation properties of PLLMNPs, which can help monitor drug release in vitro/in vivo.},
}
@article {pmid37509878,
year = {2023},
author = {Mao, B and Ren, B and Wu, J and Tang, X and Zhang, Q and Zhao, J and Zhang, L and Chen, W and Cui, S},
title = {The Protective Effect of Broccoli Seed Extract against Lipopolysaccharide-Induced Acute Liver Injury via Gut Microbiota Modulation and Sulforaphane Production in Mice.},
journal = {Foods (Basel, Switzerland)},
volume = {12},
number = {14},
pages = {},
pmid = {37509878},
issn = {2304-8158},
support = {2020B020226008//Key-Area Research and Development Program of Guangdong Province/ ; 31972086//National Natural Science Foundation of China/ ; },
abstract = {Broccoli seed extract (BSE) is rich in glucoraphanin (GRP), which may be transformed by intestinal microbes into sulforaphane (SFN), a compound with strong anti-inflammatory and antioxidant activities. Liver injury usually presents with inflammation and oxidative damage. Thus, dietary BSE supplementation may be an effective approach for alleviating liver injury. In this study, a mouse lipopolysaccharide (LPS)-induced acute liver injury model was used to evaluate the preventive effect of BSE and explore the relevant mechanisms. Compared with the LPS model group, the mice in the BSE group showed significantly lower activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) and higher levels of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity. Meanwhile, BSE significantly reduced the levels of pro-inflammatory cytokines (including IL-6 and TNF-α) in the liver and increased the level of anti-inflammatory factor (IL-10), indicating that BSE had a good preventive effect on acute liver injury. Additionally, after BSE intervention, the diversity of intestinal microbiota in the mice was higher than that in the LPS model group. The relative abundance of Akkermansia and Lactobacillus increased, while the relative abundance of Xylanophilum decreased. A correlation analysis revealed that the activities of SOD, GSH-Px, CAT and levels of IL-10 were positively correlated with the relative abundance of Lactobacillus. Furthermore, sulforaphane (SFN) and (Sulforaphane-N-Acetyl-Cysteine) SFN-NAC were detected in the urine of the mice after BSE intervention. Both q-PCR and an immunohistochemical analysis showed that BSE significantly regulated the expression level of the NF-κB (IκB-α, NF-κB) and Nrf2 (Nrf2, p-Nrf2 and HO-1) signaling pathways in the liver. In conclusion, BSE was shown to reduce LPS-induced acute liver injury through the conversion of glucoraphanin into sulforaphane and the regulation of the gut microbiota composition. These results suggest that BSE could be a promising ingredient in functional foods.},
}
@article {pmid37508477,
year = {2023},
author = {Siemsen, BM and Denton, AR and Parrila-Carrero, J and Hooker, KN and Carpenter, EA and Prescot, ME and Brock, AG and Westphal, AM and Leath, MN and McFaddin, JA and Jhou, TC and McGinty, JF and Scofield, MD},
title = {Heroin Self-Administration and Extinction Increase Prelimbic Cortical Astrocyte-Synapse Proximity and Alter Dendritic Spine Morphometrics That Are Reversed by N-Acetylcysteine.},
journal = {Cells},
volume = {12},
number = {14},
pages = {},
pmid = {37508477},
issn = {2073-4409},
support = {F32 DA50427/NH/NIH HHS/United States ; T32 DA007288/NH/NIH HHS/United States ; DA046373/NH/NIH HHS/United States ; DA05154/NH/NIH HHS/United States ; DA037327/NH/NIH HHS/United States ; K01 DA053434/NH/NIH HHS/United States ; DA033680-11/NH/NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; P50 DA046373/DA/NIDA NIH HHS/United States ; DA044468/NH/NIH HHS/United States ; R01 DA054154/DA/NIDA NIH HHS/United States ; R01 DA037327/DA/NIDA NIH HHS/United States ; },
mesh = {Rats ; Animals ; Male ; Rats, Sprague-Dawley ; *Heroin/pharmacology ; *Acetylcysteine/pharmacology ; Astrocytes ; Synapses ; Glutamates ; Recurrence ; },
abstract = {Clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astrocyte glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observe functional adaptations in the PrL cortical astrocyte following heroin self-administration (SA) and extinction as measured by the electrophysiologically evoked plasmalemmal glutamate transporter 1 (GLT-1)-dependent current. We likewise observed the increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astrocytic plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astrocytic complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased the apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague-Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased the co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, the accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Finally, we show that the NAC treatment and elimination of thrombospondin 2 (TSP-2) block cue-induced heroin relapse. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at the synapses. Additionally, these data demonstrate that NAC reverses PrL cortical heroin SA-and-extinction-induced adaptations in both astrocytes and corticostriatal neurons.},
}
@article {pmid37507934,
year = {2023},
author = {Eligini, S and Munno, M and Atlas, D and Banfi, C},
title = {N-acetylcysteine Amide AD4/NACA and Thioredoxin Mimetic Peptides Inhibit Platelet Aggregation and Protect against Oxidative Stress.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {7},
pages = {},
pmid = {37507934},
issn = {2076-3921},
support = {Ricerca Corrente//Italian Ministry of Health, Rome, Italy/ ; },
abstract = {In the present study, we tested the effect of small-molecular-weight redox molecules on collagen-induced platelet aggregation. We used N-acetylcysteine amide (AD4/NACA), the amide form of N-acetylcysteine (NAC), a thiol antioxidant with improved lipophilicity and bioavailability compared to NAC, and the thioredoxin-mimetic (TXM) peptides, TXM-CB3, TXM-CB13, and TXM-CB30. All compounds significantly inhibited platelet aggregation induced by collagen, with TXM-peptides and AD4 being more effective than NAC. The levels of TxB2 and 12-HETE, the main metabolites derived from the cyclooxygenase and lipoxygenase pathways following platelet activation, were significantly reduced in the presence of AD4, TXM peptides, or NAC, when tested at the highest concentration (0.6 mM). The effects of AD4, TXM-peptides, and NAC were also tested on the clotting time (CT) of whole blood. TXM-CB3 and TXM-CB30 showed the greatest increase in CT. Furthermore, two representative compounds, TXM-CB3 and NAC, showed an increase in the anti-oxidant free sulfhydryl groups of plasma detected via Ellman's method, suggesting a contribution of plasma factors to the antiaggregating effects. Our results suggest that these small-molecular-weight redox peptides might become useful for the prevention and/or treatment of oxidative stress conditions associated with platelet activation.},
}
@article {pmid37507913,
year = {2023},
author = {Martinez-Banaclocha, MA},
title = {Targeting the Cysteine Redox Proteome in Parkinson's Disease: The Role of Glutathione Precursors and Beyond.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {7},
pages = {},
pmid = {37507913},
issn = {2076-3921},
abstract = {Encouraging recent data on the molecular pathways underlying aging have identified variants and expansions of genes associated with DNA replication and repair, telomere and stem cell maintenance, regulation of the redox microenvironment, and intercellular communication. In addition, cell rejuvenation requires silencing some transcription factors and the activation of pluripotency, indicating that hidden molecular networks must integrate and synchronize all these cellular mechanisms. Therefore, in addition to gene sequence expansions and variations associated with senescence, the optimization of transcriptional regulation and protein crosstalk is essential. The protein cysteinome is crucial in cellular regulation and plays unexpected roles in the aging of complex organisms, which show cumulative somatic mutations, telomere attrition, epigenetic modifications, and oxidative dysregulation, culminating in cellular senescence. The cysteine thiol groups are highly redox-active, allowing high functional versatility as structural disulfides, redox-active disulfides, active-site nucleophiles, proton donors, and metal ligands to participate in multiple regulatory sites in proteins. Also, antioxidant systems control diverse cellular functions, including the transcription machinery, which partially depends on the catalytically active cysteines that can reduce disulfide bonds in numerous target proteins, driving their biological integration. Since we have previously proposed a fundamental role of cysteine-mediated redox deregulation in neurodegeneration, we suggest that cellular rejuvenation of the cysteine redox proteome using GSH precursors, like N-acetyl-cysteine, is an underestimated multitarget therapeutic approach that would be particularly beneficial in Parkinson's disease.},
}
@article {pmid37507904,
year = {2023},
author = {Chamorro, B and Izquierdo-Bermejo, S and Martín-de-Saavedra, MD and López-Muñoz, F and Chioua, M and Marco-Contelles, J and Oset-Gasque, MJ},
title = {Neuroprotective and Antioxidant Properties of CholesteroNitrone ChN2 and QuinolylNitrone QN23 in an Experimental Model of Cerebral Ischemia: Involvement of Necrotic and Apoptotic Cell Death.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {7},
pages = {},
pmid = {37507904},
issn = {2076-3921},
support = {"MITOPI" and "NENTS"//Camilo Jos&#xe9; Cela University/ ; SAF2015-65586-R//Spanish Ministry of Economy and Competitiveness/ ; PID2021-122723OA100//Spanish Research Agency/ ; },
abstract = {Ischemic stroke is the leading cause of disability and the second leading cause of death worldwide. However, current therapeutic strategies are scarce and of limited efficacy. The abundance of information available on the molecular pathophysiology of ischemic stroke has sparked considerable interest in developing new neuroprotective agents that can target different events of the ischemic cascade and may be used in combination with existing treatments. In this regard, nitrones represent a very promising alternative due to their renowned antioxidant and anti-inflammatory effects. In this study, we aimed to further investigate the neuroprotective effects of two nitrones, cholesteronitrone 2 (ChN2) and quinolylnitrone 23 (QN23), which have previously shown great potential for the treatment of stroke. Using an experimental in vitro model of cerebral ischemia, we compared their anti-necrotic, anti-apoptotic, and antioxidant properties with those of three reference compounds. Both ChN2 and QN23 demonstrated significant neuroprotective effects (EC50 = 0.66 ± 0.23 μM and EC50 = 2.13 ± 0.47 μM, respectively) comparable to those of homo-bis-nitrone 6 (HBN6) and N-acetylcysteine (NAC) and superior to those of α-phenyl-N-tert-butylnitrone (PBN). While primarily derived from the nitrones' anti-necrotic capacities, their anti-apoptotic effects at high concentrations and antioxidant powers-especially in the case of QN23-also contribute to their neuroprotective effects.},
}
@article {pmid37507857,
year = {2023},
author = {Sahasrabudhe, SA and Terluk, MR and Kartha, RV},
title = {N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {7},
pages = {},
pmid = {37507857},
issn = {2076-3921},
abstract = {N-acetylcysteine (NAC), a precursor of cysteine and, thereby, glutathione (GSH), acts as an antioxidant through a variety of mechanisms, including oxidant scavenging, GSH replenishment, antioxidant signaling, etc. Owing to the variety of proposed targets, NAC has a long history of use as a prescription product and in wide-ranging applications that are off-label as an over-the-counter (OTC) product. Despite its discovery in the early 1960s and its development for various indications, systematic clinical pharmacology explorations of NAC pharmacokinetics (PK), pharmacodynamic targets, drug interactions, and dose-ranging are sorely limited. Although there are anecdotal instances of NAC benefits in a variety of diseases, a comprehensive review of the use of NAC in rare diseases does not exist. In this review, we attempt to summarize the existing literature focused on NAC explorations in rare diseases targeting mitochondrial dysfunction along with the history of NAC usage, approved indications, mechanisms of action, safety, and PK characterization. Further, we introduce the research currently underway on other structural derivatives of NAC and acknowledge the continuum of efforts through pre-clinical and clinical research to facilitate further therapeutic development of NAC or its derivatives for rare diseases.},
}
@article {pmid37503600,
year = {2023},
author = {Onay, ZR and Ayhan, Y and Can Oksay, S and Mavi, D and Bilgin, G and Toksoz Yıldırım, A and Canbolat Ayhan, A and Girit, S},
title = {The First Definition of Pulmonary Component of Hypereosinophilic Syndrome: Bronchial Casts.},
journal = {Thoracic research and practice},
volume = {24},
number = {1},
pages = {49-52},
pmid = {37503600},
issn = {2979-9139},
abstract = {Hypereosinophilic syndrome is a heterogeneous disease characterized by eosinophilic tissue inflammation and eosinophilia. Pulmonary involvement could be seen in up to 55% among children with hypereosinophilic syndrome. A 3-year-old boy with chronic hypereosinophilia and respiratory complaints was diagnosed with idiopathic hypereosinophilic syndrome. Atelectasis was detected in the radiological evaluation, and bronchial casts with eosinophilic structures were removed by bronchoscopy. Steroid, inhaled hypertonic saline, inhaled bronchodilator, inhaled corticosteroid, and leukotriene receptor antagonist were used for 1 year in the management of hypereosinophilic syndrome, and related eosinophilic casts and repetitive bronchoscopies were administered for removal of the casts. The patient was successfully managed with an inhaled N-acetyl cysteine treatment. In children, the long-term prognosis of hypereosinophilic syndrome is uncertain. Comprehensive diagnostic tests are required for the early diagnosis and management of pediatric hypereosinophilic syndrome. In the presented case, the rare occurrence of pulmonary involvement of hypereosinophilic syndrome in a 3 year-old-boy with recurrent hypereosinophilic casts and its management were discussed.},
}
@article {pmid37503369,
year = {2023},
author = {Methods In Medicine, CAM},
title = {Retracted: N-Acetylcysteine (NAC) Inhibits Synthesis of IL-18 in Macrophage by Suppressing NLRP3 Expression to Reduce the Production of IFN-γ from NK Cells.},
journal = {Computational and mathematical methods in medicine},
volume = {2023},
number = {},
pages = {9819038},
pmid = {37503369},
issn = {1748-6718},
abstract = {[This retracts the article DOI: 10.1155/2021/7596343.].},
}
@article {pmid37503292,
year = {2023},
author = {Piraino, L and Chen, CY and Mereness, J and Dunman, PM and Ovitt, C and Benoit, D and DeLouise, L},
title = {Identifying novel radioprotective drugs via salivary gland tissue chip screening.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.07.12.548707},
pmid = {37503292},
issn = {2692-8205},
support = {F31 DE029658/DE/NIDCR NIH HHS/United States ; UG3 DE027695/DE/NIDCR NIH HHS/United States ; UH3 DE027695/DE/NIDCR NIH HHS/United States ; },
abstract = {During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Following validation, we tested other reported radioprotective drugs, including, Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin, confirming that all drugs but NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified with mechanisms of action other than antioxidant activity. Hits were down-selected using EC 50 values and pharmacokinetics and pharmacodynamics data from the PubChem database leading to testing of Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited equivalent radioprotection to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with nonantioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.},
}
@article {pmid37499713,
year = {2023},
author = {He, D and Qian, L and Chen, X and He, B and Li, J},
title = {Durable cellulose paper by grafting thiol groups and controlling silver deposition for ultrahigh electromagnetic interference shielding.},
journal = {International journal of biological macromolecules},
volume = {248},
number = {},
pages = {125972},
doi = {10.1016/j.ijbiomac.2023.125972},
pmid = {37499713},
issn = {1879-0003},
mesh = {*Ammonia ; *Silver ; Acetylcysteine ; Cellulose ; Electric Conductivity ; Sulfhydryl Compounds ; },
abstract = {Electromagnetic interference (EMI) shielding paper with durability and high effectiveness is of significant importance to long-term service for preventing EMI pollution. Herein, we report a practical method for preparing cellulose paper/Ag composite with outstanding durable and ultrahigh EMI shielding performance by electroless silver plating. The silver deposition process, the surface morphology, the silver content and conductivity of the composite can be controlled by varying the amount of N-acetyl-L-cysteine (NAC) grafted onto the cellulose fibers and ammonia amount for silver-ammonia complex formation. Moreover, the grafted NAC with thiol groups on cellulose can enhance the adhesion between silver and cellulose paper, meanwhile, NAC as the reducing agent can result in a more complete flower-shaped silver structure and reducing the reflection of electromagnetic waves in silver layer. The composite exhibited excellent conductivity, EMI shielding effectiveness (SE) up to 106 dB and outstanding durability. After 10,000 bending times and 60 abrasion cycles respectively, the electrical resistance of the composite only increased from 0.030 Ω/sq. to 0.041 Ω/sq. and 0.050 Ω/sq., and the EMI SE decreased to 102 dB and 105 dB.},
}
@article {pmid37495528,
year = {2023},
author = {Korkmaz, Y and Gungor, H and Demirbas, A and Dik, B},
title = {Pomegranate peel extract, N-Acetylcysteine and their combination with Ornipural alleviate Cadmium-induced toxicity in rats.},
journal = {The Journal of veterinary medical science},
volume = {85},
number = {9},
pages = {990-997},
pmid = {37495528},
issn = {1347-7439},
mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology ; Rats, Wistar ; Cadmium/toxicity ; *Pomegranate ; Plant Extracts/pharmacology/therapeutic use ; },
abstract = {Cadmium is a major environmental pollutant and a highly toxic metal. It was aimed to determine the effects of pomegranate peel extract (PPE), N-acetylcysteine (NAC) alone and along with Ornipural on cadmium-induced toxicity. Forty-six Wistar Albino male rats were divided into 6 groups and the groups were formed into healthy control, Cadmium group (5 mg/kg/day, oral), Cadmium + Pomegranate peel extract (500 mg/kg, oral), Cadmium + N-acetylcysteine (100 mg/kg, oral), Cadmium + Pomegranate peel extract (500 mg/kg, oral) + Ornipural (1 mL/kg, subcutaneous) and Cadmium + N-acetylcysteine (100 mg/kg, oral) + Ornipural (1 mL/kg, subcutaneous). Cadmium accumulated heavily in both liver and kidney tissue. The administration of N-acetylcysteine and pomegranate peel extract alone reduced cadmium levels in both tissues. N-acetylcysteine treatment prevented the increase in ALT and MDA levels by cadmium damage. N-acetylcysteine + Ornipural treatment inhibited the increase in liver 8-OHdG level in the liver. N-acetylcysteine and N-acetylcysteine + Ornipural treatments prevented the reduced serum MMP2 level. N-acetylcysteine and Pomegranate peel extract + Ornipural treatments significantly reduced the increased liver iNOS level in the liver. In conclusion, NAC therapy may be a successful treatment option for cadmium toxicity. However, further research is needed on the effects of PPE and Ornipural combinations for the treatment of cadmium toxicity. In future studies, various doses of these treatment options (with chelators) should be investigated for cadmium toxicity.},
}
@article {pmid37495077,
year = {2023},
author = {Ding, Q and Sun, B and Wang, M and Li, T and Li, H and Han, Q and Liao, J and Tang, Z},
title = {N-acetylcysteine alleviates oxidative stress and apoptosis and prevents skeletal muscle atrophy in type 1 diabetes mellitus through the NRF2/HO-1 pathway.},
journal = {Life sciences},
volume = {329},
number = {},
pages = {121975},
doi = {10.1016/j.lfs.2023.121975},
pmid = {37495077},
issn = {1879-0631},
mesh = {Dogs ; Animals ; Antioxidants/metabolism ; Acetylcysteine/pharmacology/metabolism ; NF-E2-Related Factor 2/metabolism ; *Diabetes Mellitus, Type 1/complications/drug therapy/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; bcl-2-Associated X Protein/metabolism ; Signal Transduction ; Oxidative Stress ; Muscular Atrophy/drug therapy/prevention &amp; control/metabolism ; Muscle, Skeletal/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Apoptosis ; *Insulins/metabolism/pharmacology ; },
abstract = {AIMS: Type 1 diabetes mellitus (T1DM) has been linked to the occurrence of skeletal muscle atrophy. Insulin monotherapy may lead to excessive blood glucose fluctuations. N-acetylcysteine (NAC), a clinically employed antioxidant, possesses cytoprotective, anti-inflammatory, and antioxidant properties. The objective of our study was to evaluate the viability of NAC as a supplementary treatment for T1DM, specifically regarding its therapeutic and preventative impacts on skeletal muscle.<br><br>MAIN METHODS: Here, we used beagles as T1DM model for 120d to explore the mechanism of NRF2/HO-1-mediated skeletal muscle oxidative stress and apoptosis and the therapeutic effects of NAC. Oxidative stress and apoptosis related factors were analyzed by immunohistochemistry, immunofluorescence, western blotting, and RT-qPCR assay.<br><br>KEY FINDINGS: The findings indicated that the co-administration of NAC and insulin led to a reduction in creatine kinase levels, preventing weight loss and skeletal muscle atrophy. Improvement in the reduction of muscle fiber cross-sectional area. The expression of Atrogin-1, MuRF-1 and MyoD1 was downregulated, while Myh2 and MyoG were upregulated. In addition, CAT and GSH-Px levels were increased, MDA levels were decreased, and redox was maintained at a steady state. The decreased of key factors in the NRF2/HO-1 pathway, including NRF2, HO-1, NQO1, and SOD1, while KEAP1 increased. In addition, the apoptosis key factors Caspase-3, Bax, and Bak1 were found to be downregulated, while Bcl-2, Bcl-2/Bax, and CytC were upregulated.<br><br>SIGNIFICANCE: Our findings demonstrated that NAC and insulin mitigate oxidative stress and apoptosis in T1DM skeletal muscle and prevent skeletal muscle atrophy by activating the NRF2/HO-1 pathway.},
}
@article {pmid37491222,
year = {2023},
author = {Mahfouz Omer, SM and El-Sherbiny, RH and El-Desouky, SS},
title = {Effect of N-Acetylcysteine on initial Carious Enamel Lesions in primary teeth: an In-vitro study.},
journal = {BMC oral health},
volume = {23},
number = {1},
pages = {520},
pmid = {37491222},
issn = {1472-6831},
mesh = {Humans ; *Dental Caries/therapy ; Acetylcysteine/pharmacology/therapeutic use ; Dental Enamel ; Fluorides/pharmacology ; Tooth, Deciduous ; Tooth Remineralization/methods ; },
abstract = {BACKGROUND: Dental caries initiates with non-cavitated enamel lesions as the first stage. The cariogenic potential of N-Acetylcysteine (NAC) may be due to its usage frequency and form. This study aimed to evaluate the impact of exposure time of NAC on initial enamel caries-like lesions in primary teeth by assessing the morphological alteration using a scanning electron microscope (SEM) and mineral content using energy dispersive x-ray spectroscopy (EDX).<br><br>METHODS: Forty primary incisor teeth were randomly divided into 4 groups S, S1, S2, and S3 (10 specimens/group). Teeth crowns were cut from their roots and inserted into an acrylic mold with its buccal surface directed upward. Centrally isolated enamel window (2&#x2009;&#xd7;&#x2009;2&#xa0;mm) on the tooth was done. Ten specimens were selected to evaluate normal enamel while the remaining thirty specimens were immersed in demineralizing solution for 96&#xa0;h to produce enamel caries-like lesions. PH cycling was performed by immersing each tooth sample in 20 mL of demineralizing solution for 3&#xa0;h then, preserved for the remaining day hours in 10 ml of artificial saliva interspersed with treatments applications with 10 ml NAC for 10&#xa0;min twice a day for one- or three-months different treatment modalities. Thermocycling was done for all specimens then they were subjected to SEM and EDX analysis. ANOVA and Bonferroni post hoc tests were utilized in data analysis.<br><br>RESULTS: In teeth treated by NAC for 3 months (group-S3), SEM images showed severe loss of enamel architecture with large NAC deposits detected. A meaningful difference was observed among different groups concerning calcium, phosphorus, fluoride, ca/P ratio, carbon, nitrogen, and oxygen contents (P&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: NAC had a detrimental impact on enamel caries-like lesions in human primary teeth.},
}
@article {pmid37487871,
year = {2023},
author = {Wang, L and Zhang, X and Xu, M and Zheng, G and Chen, J and Li, S and Cui, J and Zhang, S},
title = {Implication of ferroptosis in hepatic toxicity upon single or combined exposure to polystyrene microplastics and cadmium.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {334},
number = {},
pages = {122250},
doi = {10.1016/j.envpol.2023.122250},
pmid = {37487871},
issn = {1873-6424},
mesh = {Humans ; Microplastics/toxicity ; Polystyrenes/toxicity ; Cadmium/toxicity ; Plastics/toxicity ; Reactive Oxygen Species ; *Ferroptosis ; Antioxidants ; *Water Pollutants, Chemical/toxicity ; },
abstract = {Microplastics (MPs) are a newly emerging type of pollutants. To date, MPs have been found in the atmosphere, soil, water, and even in human samples, posing a non-negligible threat to humans. Furthermore, multiple heavy metals have been found to co-exist with MPs or be absorbed by MPs. This leads to a widespread concern about their combined toxicity, which is currently elusive. Herein, we investigated the single or combined toxic effects of polystyrene MPs (PS-MPs) and cadmium chloride (CdCl2) on the liver and hepatocytes. After co-incubation, cadmium (Cd) can be absorbed by PS-MPs, resulting in physiochemical alterations of PS-MPs. In vivo and in vitro experiments revealed that PS-MPs solely or together with CdCl2 induced ferroptosis in hepatocytes, a newly defined programmed cell death characterized by lipid oxidation and iron accumulation. PS-MPs exerted more ferroptotic effect on hepatocytes than CdCl2, and combined exposure to PS-MPs and CdCl2 enhanced their ferroptotic effect, mainly by stimulating reactive oxygen species (ROS) production and inhibiting antioxidant activity. Upon single or combined exposure to PS-MPs and CdCl2, the induction of ferroptosis in hepatocytes can be inhibited by N-acetyl-cysteine (NAC, an ROS scavenger), deferoxamine (DFO, an iron chelator), and particularly ferrostatin-1 (Fer-1, a specific ferroptosis inhibitor). Fer-1 efficiently rescued the cell viability of hepatocytes upon exposure to PS-MPs and CdCl2 through enhancing the antioxidant system via upregulating GPX4 and SLC7A11. These findings would contribute to an in-depth understanding of the single and combined toxicity of microplastics and cadmium.},
}
@article {pmid37487865,
year = {2023},
author = {Samandari-Bahraseman, MR and Khorsand, B and Zareei, S and Amanlou, M and Rostamabadi, H},
title = {Various concentrations of hesperetin induce different types of programmed cell death in human breast cancerous and normal cell lines in a ROS-dependent manner.},
journal = {Chemico-biological interactions},
volume = {382},
number = {},
pages = {110642},
doi = {10.1016/j.cbi.2023.110642},
pmid = {37487865},
issn = {1872-7786},
mesh = {Humans ; Female ; *Hesperidin/pharmacology ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; Apoptosis ; Cell Line, Tumor ; Superoxide Dismutase/metabolism ; *Breast Neoplasms ; },
abstract = {The polyphenolic component of citrus fruits, hesperetin (Hst), is a metabolite of hesperidin. In this study, we examined the effect of varying doses and exposure times of hesperetin on MCF-7 and MDA-MB-231 cancer cells, as well as MCF-10A normal cells. By using MTT assay, real-time PCR, western blot, and flow cytometry, we determined the effects of Hst on cell viability, ROS levels, and markers of cell death. Furthermore, molecular docking was used to identify Hst targets that might be involved in ROS-dependent cell death. According to the results, different concentrations of Hst induced different modes of cell death at specific ROS levels. Paraptosis occurred in all cell lines at concentration ranges of IC35 to IC60, and apoptosis occurred at concentrations greater than IC65. In addition, MDA-MB-231 cells were subjected to senescence at sub-toxic doses when treated for a long period of time. When Hst levels were higher, N-acetylcysteine (NAC)'s effect on neutralizing ROS was more pronounced. According to the docking results, Hst may interact with several proteins involved in the regulation of ROS. As an example, the interaction of CCS (Copper chaperone for superoxide dismutase) with Hst might interfere with its chaperone function in folding SOD-1 (superoxide dismutase enzyme), contributing to an increase in cytoplasmic ROS levels. Finally, depending on the ROS level, Hst induces various modes of cell death.},
}
@article {pmid37487439,
year = {2023},
author = {Aki, T and Tanaka, H and Funakoshi, T and Unuma, K and Uemura, K},
title = {Excessive N-acetylcysteine exaggerates glutathione redox homeostasis and apoptosis during acetaminophen exposure in Huh-7 human hepatoma cells.},
journal = {Biochemical and biophysical research communications},
volume = {676},
number = {},
pages = {66-72},
doi = {10.1016/j.bbrc.2023.07.023},
pmid = {37487439},
issn = {1090-2104},
mesh = {Humans ; Acetylcysteine/metabolism ; Acetaminophen/toxicity ; *Carcinoma, Hepatocellular/pathology ; *Chemical and Drug Induced Liver Injury/pathology ; Glutathione/metabolism ; *Liver Neoplasms/pathology ; Apoptosis ; Oxidation-Reduction ; Homeostasis ; Liver/metabolism ; },
abstract = {Acetaminophen (APAP) hepatotoxicity is one of the biggest drawbacks of this relatively safe and widely used drug. In addition to its hepatotoxicity, APAP also cause comparable levels of toxicity on human hepatoma cells. Here we show activation of the intrinsic caspase-9/3 pathway of apoptosis followed by gasdermin E (GSDME) cleavage and subsequent ballooning in APAP (10 mM, 72 h)-treated Huh-7 human hepatocarcinoma cells. N-acetylcysteine (NAC), an antioxidant currently used as an antidote for APAP overdose, does not alleviate APAP toxicity in Huh-7 cells; NAC overdose (10 mM) rather aggravates APAP toxicity. NAC overdose not only aggravates cell death, but also decreases the cellular GSH/GSSG ratio, an indicator of redox homeostasis of glutathione. These results show for the first time that APAP-induced apoptosis in hepatoma cells is followed by secondary necrosis via the caspase-3/GSDME pathway. NAC overdose (10 mM) not only worsens the glutathione redox status, but also accelerates this pathway.},
}
@article {pmid37480966,
year = {2024},
author = {Ni, X and Yu, S and Jiang, X and Wu, F and Zhou, J and Mao, D and Wang, H and Tao, Y and Liu, Y and Jin, F},
title = {Celastrus orbiculatus Thunb. extract targeting DJ-1 inhibits non-small cell lung cancer invasion and metastasis through mitochondrial-induced ROS accumulation.},
journal = {Journal of ethnopharmacology},
volume = {318},
number = {Pt A},
pages = {116944},
doi = {10.1016/j.jep.2023.116944},
pmid = {37480966},
issn = {1872-7573},
mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; *Celastrus/chemistry ; Reactive Oxygen Species ; Plant Extracts/pharmacology/therapeutic use/chemistry ; Cell Line, Tumor ; *Lung Neoplasms/drug therapy ; Mitochondria ; },
abstract = {Celastrus orbiculatus Thunb. is an ancient traditional Chinese herb with a long history of medicinal use. The ethyl acetate extract of Celastrus orbiculatus Thunb. (COE) has been shown to have anti-tumor effects in various preclinical studies. However, the anti-invasive and metastatic efficacy of COE in non-small cell lung cancer (NSCLC) and the mechanism by which COE regulates cellular oxidation levels are yet to be elucidated.<br><br>AIM: To study the anti-dissemination effect of COE on NSCLC and to elucidate the molecular mechanism of COE in regulating cellular oxidation levels and its effect on lung cancer invasion and metastasis.<br><br>METHODS: CCK-8 assay was used to detect the toxic effects of COE on NSCLC. Transwell assay and high-content imaging was used to detect the Motility of NSCLC. Transmission electron microscopy and three-dimensional (3D) imaging of mitochondrial fluorescence were employed to detect the number and structure of mitochondria. JC-1 probe was used to detect the level of mitochondrial membrane potential. Firefly luciferase assay was used to detect the level of total intracellular ATP. MitoSox probe and DCFH-DA probe were applied to detect the level of reactive oxygen species (ROS) inside the mitochondria and the total intracellular ROS, respectively. Immunohistochemistry was used to detect protein expression in xenograft tumors.<br><br>RESULTS: COE inhibited motility and induced DJ-1 downregulation in NSCLC at low toxic concentrations, and the antiseptic effect of COE was reduced significantly after the overexpression of DJ-1. COE induced structural disruption of mitochondria in NSCLC and accumulation of superoxide compounds, decreased the volume of membrane potential depolarization, and impaired energy production, ultimately leading to a large accumulation of ROS at the cellular level. The antioxidant acetylcysteine (NAC) significantly reversed the antiseptic capacity of COE. In a xenograft tumor model, protein expression of DJ-1, E-cadherin, N-cadherin, and MMP-2 in COE group was significantly changed compared to the model group.<br><br>CONCLUSION: In the present study, COE inhibited NSCLC invasion and metastasis and was associated with the downregulation of DJ-1 and elevated ROS. COE-mediated downregulation of DJ-1 may be the primary cause of mitochondrial structural and functional dysfunction in NSCLC, eventually leading to ROS accumulation.},
}
@article {pmid37477247,
year = {2024},
author = {Debnath, U and Mitra, A and Dewaker, V and Prabhakar, YS and Tadala, R and Krishnan, K and Wagh, P and Velusamy, U and Baliyan, A and Kurpad, AV and Bhattacharyya, P and Mandal, AK},
title = {Conformational perturbation of SARS-CoV-2 spike protein using N-acetyl cysteine: an exploration of probable mechanism of action to combat COVID-19.},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {42},
number = {10},
pages = {5042-5052},
doi = {10.1080/07391102.2023.2234031},
pmid = {37477247},
issn = {1538-0254},
mesh = {*Spike Glycoprotein, Coronavirus/chemistry/metabolism ; *Acetylcysteine/pharmacology/chemistry ; Humans ; *SARS-CoV-2/drug effects/metabolism ; *Angiotensin-Converting Enzyme 2/metabolism/chemistry ; *Protein Binding ; *COVID-19/virology ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; COVID-19 Drug Treatment ; Protein Conformation ; Binding Sites ; Antiviral Agents/pharmacology/chemistry ; },
abstract = {The infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in a pandemic with huge death toll and economic consequences. The virus attaches itself to the human epithelial cells through noncovalent bonding of its spike protein with the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Based on in silico studies we hypothesized that perturbing the functionally active conformation of spike protein through the reduction of its solvent accessible disulfide bonds, thereby disintegrating its structural architecture, may be a feasible strategy to prevent infection by reducing the binding affinity towards ACE2 enzyme. Proteomics data showed that N-acetyl cysteine (NAC), an antioxidant and mucolytic agent been widely in use in clinical medicine, forms covalent conjugates with solvent accessible cysteine residues of spike protein that were disulfide bonded in the native state. Further, in silico analysis indicated that the presence of the selective covalent conjugation of NAC with Cys525 perturbed the stereo specific orientations of the interacting key residues of spike protein that resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. Interestingly, almost all SARS-CoV-2 variants conserved cystine residues in the spike protein. Our finding results possibly provides a molecular basis for identifying NAC and/or its analogues for targeting Cys-525 of the viral spike protein as fusion inhibitor and exploring in vivo pharmaco-preventive and its therapeutic potential activity for COVID-19 disease. However, in-vitro assay and animal model-based experiment are required to validate the probable mechanism of action.Communicated by Ramaswamy H. Sarma.},
}
@article {pmid37476961,
year = {2024},
author = {Gao, Y and Wu, F and He, W and Cai, Z and Pang, J and Zheng, Y},
title = {Reactive Oxygen Species-Related Disruptions to Cochlear Hair Cell and Stria Vascularis Consequently Leading to Radiation-Induced Sensorineural Hearing Loss.},
journal = {Antioxidants &amp; redox signaling},
volume = {40},
number = {7-9},
pages = {470-491},
doi = {10.1089/ars.2022.0161},
pmid = {37476961},
issn = {1557-7716},
mesh = {Mice ; Animals ; *Stria Vascularis/pathology/physiology ; Reactive Oxygen Species ; Mice, Inbred C57BL ; *Hearing Loss, Sensorineural/chemically induced/pathology ; Hair Cells, Auditory, Outer/pathology/physiology ; Acetylcysteine/pharmacology ; },
abstract = {Aims: Radiation-induced sensorineural hearing loss (RISNHL) is one of the major side effects of radiotherapy for head and neck cancers. At present, no effective clinical treatment or prevention is available for RISNHL. This study thus aimed to investigate the cochlear pathology so that the underlying mechanisms of RISNHL may be elucidated, consequently paving the way for potential protective strategies to be developed. Results: Functional and morphological impairment in the stria vascularis (SV) was observed after irradiation (IR), as indicated by endocochlear potential (EP) reduction, hyperpermeability, and SV atrophy. The expression of zonulae occludins-1 was found to have decreased after IR. The loss of outer hair cells (OHCs) occurred later than SV damage. The disruption to the SV and OHCs could be attributed to reactive oxygen species (ROS)-related damage. In addition, EP shifts and the loss of OHCs were reduced when ROS was reduced by N-acetylcysteine (NAC) in C57BL/6 mice, attenuating auditory threshold shifts. Innovation: The damage to the SV was found to occur before OHC loss. ROS-related damage accounted for SV damage and OHC loss. The incidences of SV damage and OHC loss were decreased through ROS modulation by NAC, subsequently preventing RISNHL, suggesting the possible role of NAC as a possible protective agent against RISNHL. Conclusion: The findings from this study suggest oxidative stress-induced early SV injury and late OHC loss to be the key factors leading to RISNHL. NAC prevents IR-induced OHC loss, and attenuates auditory brainstem response and EP shifts by regulating the level of oxidative stress. Antioxid. Redox Signal. 40, 470-491.},
}
@article {pmid37465907,
year = {2023},
author = {Morley, KC and Peruch, S and Adams, C and Towers, E and Tremonti, C and Watt, J and Jamshidi, N and Haber, PS},
title = {N acetylcysteine in the treatment of alcohol use disorder: a randomized, double-blind, placebo-controlled trial.},
journal = {Alcohol and alcoholism (Oxford, Oxfordshire)},
volume = {58},
number = {5},
pages = {553-560},
doi = {10.1093/alcalc/agad044},
pmid = {37465907},
issn = {1464-3502},
support = {//MRFF Practitioner Fellowship/ ; },
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Alcoholism/drug therapy ; Double-Blind Method ; Treatment Outcome ; Male ; Female ; Adult ; Middle Aged ; Aged ; },
abstract = {N-acetyl cysteine (NAC) is a potent antioxidant that modulates glutamatergic signalling which is thought to play a role in alcohol use disorder (AUD). There have been no clinical trials investigating NAC for AUD. We aimed to conduct a 28 day double-blind, placebo-controlled (PL) randomized trial of NAC in the treatment of AUD (NCT03879759). A total of 42 participants with AUD (56% alcohol-related liver disease) were randomized to receive placebo or NAC 2400 mg/day. Feasibility outcomes included treatment retention and adverse events. Primary clinical outcomes included alcohol consumption (heavy drinking days, standard drinks per drinking day). Secondary clinical outcome measures included craving, liver tests, and psychological outcomes. There were no significant differences in overall retention between treatment groups (χ2(1) = 0.14, P = 0.71: 86% vs 76% for placebo and NAC, respectively). The most commonly reported adverse event in NAC-treated individuals included headache (14%). For standard drinks per drinking day, there was a significant overall effect of time (F = 9.18, P < 0.001), no significant effect of treatment (F = 0.75, P = 0.79), and a significant time x treatment (NAC vs PL) effect (F = 2.73, P < 0.05). For number of heavy drinks per day, there was a significant overall effect of time (F = 3.16, P < 0.05) but no significant effect of treatment or time x treatment (P = 0.17). There were no significant NAC vs PL effects on secondary clinical outcome measures. In the first trial of NAC for the management of AUD, NAC appears to be feasible and safe. Although there was a significant effect of NAC vs placebo on some alcohol measures such as drinks per drinking day, there does appear to be a variable pattern of effect across time suggesting that a larger trial incorporating a longer treatment duration is now required to determine efficacy.},
}
@article {pmid37463651,
year = {2023},
author = {Huang, M and Zou, M and Mao, S and Xu, W and Hong, Y and Wang, H and Gui, F and Yang, L and Lian, F and Chen, R},
title = {3,5,6-Trichloro-2-pyridinol confirms ototoxicity in mouse cochlear organotypic cultures and induces cytotoxicity in HEI-OC1 cells.},
journal = {Toxicology and applied pharmacology},
volume = {475},
number = {},
pages = {116612},
doi = {10.1016/j.taap.2023.116612},
pmid = {37463651},
issn = {1096-0333},
mesh = {Animals ; Mice ; Reactive Oxygen Species/metabolism ; *Ototoxicity ; Microphysiological Systems ; *Antineoplastic Agents/pharmacology ; Pyridines/pharmacology ; Apoptosis ; Cisplatin/pharmacology ; Pyridones ; },
abstract = {The metabolite of organophosphate pesticide chlorpyrifos (CPF), 3,5,6-Trichloro-2-pyridinol (TCP), is persistent and mobile toxic substance in soil and water environments, exhibiting cytotoxic, genotoxic, and neurotoxic properties. However, little is known about its effects on the peripheral auditory system. Herein, we investigated the effects of TCP exposure on mouse postnatal day 3 (P3) cochlear culture and an auditory cell line HEI-OC1 to elucidate the underlying molecular mechanisms of ototoxicity. The damage of TCP to outer hair cells (OHC) and support cells (SC) was observed in a dose and time-dependent manner. OHC and SC were a significant loss from basal to apical turn of the cochlea under exposure over 800 μM TCP for 96 h. As TCP concentrations increased, cell viability was reduced whereas reactive oxygen species (ROS) generation, apoptotic cells, and the extent of DNA damage were increased, accordingly. TCP-induced phosphorylation of the p38 and JNK MAPK are the downstream effectors of ROS. The antioxidant agent, N-acetylcysteine (NAC), could reverse TCP-mediated intracellular ROS generation, inhibit the expressive level of cleaved-caspase 3 and block phosphorylation of p38/JNK. Overall, this is the first demonstration of TCP damaging to peripheral sensory HCs and SC in organotypic cultures from the postnatal cochlea. Data also showed that TCP exposure induced oxidase stress, cell apoptosis and DNA damage in the HEI-OC1 cells. These findings serve as an important reference for assessing the risk of TCP exposure.},
}
@article {pmid37458841,
year = {2023},
author = {Platt, I and Bisgin, A and Kilavuz, S},
title = {Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {44},
number = {11},
pages = {3827-3852},
pmid = {37458841},
issn = {1590-3478},
abstract = {BACKGROUND: Ethylmalonic encephalopathy (EE) is a rare intoxication-type metabolic disorder with multisystem involvement. It is caused by mutations in ETHE1, which encodes the ETHE1 enzyme in the mitochondrial matrix that plays a key role in hydrogen sulfide (H2S) detoxification acting as a sulphur dioxygenase.<br><br>RESULTS: This review focuses on the clinical, metabolic, genetic and neuroradiological features of 70 reported cases, including two new cases. The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively. A significant difference was found in EMA and C4 levels (p=0.003, p=0.0236)&#xa0;between classical and mild phenotypes. Urinary EMA, C4 and C5 levels were found to exhibit normal values in milder cases during attack-free periods. The most common ETHE1 gene homozygous state mutations were (p.R163Q) (c.488G>A), exon 4 deletion, (p.R163W)(c.487C>T), (p.Glu44ValfsTer62)(c.131_132delAG) and (p.M1I)(c.3G>T) mutations, respectively. Fifty-two patients underwent cranial MRI. Basal ganglia signal alterations were detected in 42 cases. Of the 70 cases, eight had a mild phenotype and slow neurological progression with low levels of ethylmalonic acid (EMA) and C4 acylcarnitine. The current age of alive patients in the published articles with mild phenotype was significantly higher than the classical phenotype. (p=0.002). Reducing the accumulation and inducing detoxification of sulfide is the main long-term treatment strategy for EE, including metronidazole, N-acetylcysteine (NAC), dietary modification, liver transplantation and continuous renal replacement therapy (CRRT).<br><br>CONCLUSION: Measuring EMA and C4 acylcarnitine during metabolic attacks is critical to diagnosing EE, allowing for early treatment initiation to prevent further encephalopathic crises. Experience with liver transplantation, diet and CRRT, is currently limited. An early multidisciplinary approach with combination therapies is vital to prevent irreversible neurological damage.},
}
@article {pmid37458150,
year = {2023},
author = {Gayatri Devi, R and Ezhilarasan, D},
title = {Concurrent administration of farnesol protects acetaminophen-induced acute hepatic necrosis in mice.},
journal = {Journal of biochemical and molecular toxicology},
volume = {37},
number = {11},
pages = {e23478},
doi = {10.1002/jbt.23478},
pmid = {37458150},
issn = {1099-0461},
mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; Antioxidants/metabolism ; Farnesol/pharmacology/metabolism ; NF-kappa B/metabolism ; Acetylcysteine/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention &amp; control/metabolism ; Liver/metabolism ; Glutathione/metabolism ; Necrosis ; Transaminases/metabolism/pharmacology ; Alanine Transaminase ; },
abstract = {Acetaminophen (APAP) is known to cause acute liver injury and acute liver failure in Western countries. This study investigates the protective role of farnesol (FAR) (C15 H26 O), a natural sesquiterpene alcohol in essential oils, against APAP-induced acute liver necrosis in mice. Mice were injected with a single dose of APAP (300 mg/kg) via an intraperitoneal route. Different groups of mice were concurrently treated with a single dose of FAR 25 mg/kg, FAR 50 mg/kg, and N-acetylcysteine. APAP administration caused a significant increase in transaminase activities and malondialdehyde (MDA) levels in the serum and liver tissue, respectively, with a concomitant decrease in intracellular antioxidants, including reduced glutathione (GSH) in the liver tissue. APAP intoxication upregulated proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, nuclear factor-κB (NF-κB), and IκB kinase β in the liver tissue. FAR and N-acetylcysteine (NAC) administrations concurrently with APAP prevented serum transaminase increase in serum and MDA levels in the liver tissue. A high dose of FAR and NAC treatments significantly inhibited GSH and other antioxidant depletion. FAR and NAC treatments also downregulated the expression of proinflammatory markers. FAR treatments protects against APAP-induced acute liver injury and offers antioxidant and anti-inflammatory effects by inhibiting the NF-κB pathway involved in the transcription of genes responsible for inflammatory cytokine synthesis.},
}
@article {pmid37454274,
year = {2023},
author = {Celebi, NK and Ozturk, SK and Palaoglu, I and Somay, A and Yaprak, G and Algul, E and Deveci, HS},
title = {Investigation of the efficacy of systemic N-Acetyl Cysteine therapy preventing nasal mucositis following radiotherapy.},
journal = {Rhinology},
volume = {61},
number = {5},
pages = {470-480},
doi = {10.4193/Rhin22.487},
pmid = {37454274},
issn = {0300-0729},
mesh = {Rats ; Animals ; Humans ; Female ; *Mucositis/etiology/prevention &amp; control/pathology ; Quality of Life ; Rats, Sprague-Dawley ; Nasal Mucosa ; Acetylcysteine/pharmacology/therapeutic use ; },
abstract = {BACKGROUND: Radiotherapy (RT) is one of the main methods used in the treatment of head and neck cancers but may cause mucosal side effects in the tumor area and surrounding structures. These include nasal mucosal disorders and chronic rhinosinusitis due to disruption of the mucociliary system. This situation seriously affects the quality of life of the patients and there is no accepted effective method for its treatment yet. In our study, we aimed to examine the side effects of RT on the nasal mucosa and mucociliary system and to investigate histopathologically and immunohistochemically the effectiveness of N-acetyl cysteine (NAC) in preventing these side effects of RT.<br><br>METHODOLOGY: The study was carried out with 30 female Sprague Dawley rats devided in three groups. No intervention was made in the control group. On the second day of the experiment, 30 Gy radiotherapy was applied to the head area in the RT group. NAC was administered intraperitoneally at a dose of 1 g/kg/day for 14 days from the first day of the study to the RT+ NAC group. On the second day, 30 Gy of radiotherapy was applied to the head area 1 hour after the NAC application. On the 14th day, 1 hour after NAC was applied to the RT+NAC group, all animals were sacrificed. The nasal mucosa samples were stained with hematoxylin-eosin, and the intensity and extent of staining sentan in the nasopharyngeal tissue samples were evaluated by immunohistochemical staining using anti-SNTN antibody.<br><br>RESULTS: The loss of cilia in the nasal tissue was lower in the RT+NAC group than in the RT group. The intensity and extent of staining in the nasopharyngeal tissue of Sentan was higher in the RT+NAC group than in the RT group. Mucosal neutrophil and mononuclear inflammatory cell infiltration in the nasal tissue, vascular dilatation, hyperemia and hemorrhage, erosion and shedding of the mucosal epithelium, mucosal ulceration were found to be similar in the RT+NAC group and the control group. It was milder in the RT+NAC group than in the RT group, but not statistically significant.<br><br>CONCLUSIONS: Radiotherapy caused pathological changes in the nasal mucosa, caused loss of cilia and a decrease in the level of Sentan, the cilia apical protein. The results of our study showed that NAC treatment can reduce the side effects of RT on the nasal mucosa. It also showed that NAC was effective in preventing the loss of cilia, which is the building block of the mucociliary system, and improving the expression of Sentan.},
}
@article {pmid37439802,
year = {2023},
author = {Park, SY and Lee, KH},
title = {Comparison of Cytotoxicity and Genotoxicity in Three Types of Indirect Restorative Materials on Human Periodontal Stem Cells.},
journal = {Oral health &amp; preventive dentistry},
volume = {21},
number = {},
pages = {243-250},
pmid = {37439802},
issn = {1757-9996},
mesh = {Humans ; Reactive Oxygen Species ; *Dental Materials ; *Glass Ionomer Cements/toxicity ; Stem Cells ; Materials Testing ; Composite Resins/toxicity ; },
abstract = {PURPOSE: This study aimed to compare the cell toxicity and biological characteristics of Ketac GIC (glass-ionomer cement), Nexus RMGIC (resin-modified glass-ionomer cement), and RelyX RC (resin cement) in human periodontal stem cells (PDSCs).<br><br>MATERIALS AND METHODS: To compare the effects of Ketac GIC, Nexus RMGIC, and RelyX RC on PDSCs, the cements were diluted from 1:2 to 1:8. PDSCs were then treated with the serially diluted cements with or without N-acetyl-cysteine (NAC), and cell survival was measured using water-soluble tetrazolium salt (WST-1) assay. Intracellular reactive oxygen species (ROS) was measured using 2',7'-dichlorofluorescin diacetate (DCFDA), and western blot analysis was performed to observe phosphorylation and activation of extracellular signal-regulated kinase (ERK) by Nexus RMGIC or RelyX RC.<br><br>RESULTS: Cell death and proliferation were dose-dependently reduced following Nexus RMGIC or RelyX RC treatment. In addition, Nexus RMGIC or RelyX RC showed an increase intracellular ROS generation compared to Ketac GIC. Pretreatment with NAC confirmed the suppression of cell toxicity and ROS generation induced by Nexus RMGIC or RelyX RC. Nexus RMGIC or RelyX RC activates ERK phosphorylation, not p38 phosphorylation, in PDSCs.<br><br>CONCLUSION: This study showed that the treatment with Nexus RMGIC or RelyX generates intracellular ROS and cell death through the ERK signaling pathway in PDSCs. In contrast, these effects were not observed with Ketac GIC, indicating that resin-based materials may have cytotoxic and genotoxic effects on PDSCs.},
}
@article {pmid37439200,
year = {2023},
author = {Kim, K and Cort, TA and Kunz, EM and Moerschel, J and Palzkill, VR and Dong, G and Moparthy, CN and Anderson, EM and Fazzone, B and O'Malley, KA and Robinson, ST and Berceli, SA and Ryan, TE and Scali, ST},
title = {N-acetylcysteine treatment attenuates hemodialysis access-related limb pathophysiology in mice with chronic kidney disease.},
journal = {American journal of physiology. Renal physiology},
volume = {325},
number = {3},
pages = {F271-F282},
pmid = {37439200},
issn = {1522-1466},
support = {P30 AG050911/AG/NIA NIH HHS/United States ; R01 HL148597/HL/NHLBI NIH HHS/United States ; },
mesh = {Male ; Female ; Animals ; Mice ; Acetylcysteine/pharmacology ; Renal Dialysis ; *Renal Insufficiency, Chronic/therapy/etiology ; *Kidney Failure, Chronic/therapy ; *Arteriovenous Shunt, Surgical/adverse effects ; *Arteriovenous Fistula ; Retrospective Studies ; },
abstract = {The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.NEW &amp; NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF.},
}
@article {pmid37435843,
year = {2023},
author = {Su, M and Zhao, Y and Li, M and Jia, C and Liu, H and Zhang, Y and Li, W and Peng, Y and Zheng, J},
title = {Evidence for the Metabolic Activation of Deferasirox In Vitro and In Vivo.},
journal = {Chemical research in toxicology},
volume = {36},
number = {8},
pages = {1255-1266},
doi = {10.1021/acs.chemrestox.2c00416},
pmid = {37435843},
issn = {1520-5010},
mesh = {Rats ; Animals ; Activation, Metabolic ; Deferasirox/pharmacology/metabolism ; *Liver/metabolism ; *Hepatocytes/metabolism ; Microsomes, Liver/metabolism ; Acetylcysteine/metabolism ; Glutathione/metabolism ; },
abstract = {Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver injury due to exposure to DFS has been documented, and the toxic mechanisms of DFS are unknown. The present study aimed to investigate the reactive metabolites of DFS in vitro and in vivo to help us understand the mechanisms of DFS hepatotoxicity. Two hydroxylated metabolites (5-OH and 5'-OH) were identified during incubation of DFS-supplemented rat liver microsomes. Such microsomal incubations fortified with glutathione (GSH) or N-acetylcysteine (NAC) as capture agents offered two GSH conjugates and two NAC conjugates. These GSH conjugates and NAC conjugates were also detected in bile and urine of rats given DFS. CYP1A2 and CYP3A4 were found to dominate the metabolic activation of DFS. Administration of DFS induced decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole and 1-aminobenzotrizole made hepatocytes less susceptible to the cytotoxicity of DFS.},
}
@article {pmid37434745,
year = {2023},
author = {Zhao, C and Yin, Y and Zhu, C and Zhu, M and Ji, T and Li, Z and Cai, J},
title = {Drug therapies for treatment of idiopathic pulmonary fibrosis: a systematic review, Bayesian network meta-analysis, and cost-effectiveness analysis.},
journal = {EClinicalMedicine},
volume = {61},
number = {},
pages = {102071},
pmid = {37434745},
issn = {2589-5370},
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis and a high economic burden for individuals and healthcare resources. Studies of the costs associated with the efficiency of IPF medications are scarce. We aimed to conduct a network meta-analysis (NMA) and cost-effectiveness analysis to identify the optimum pharmacological strategy among all currently available IPF regimens.<br><br>METHODS: We first performed a systematic review and network meta-analysis. We searched eight databases for eligible randomised controlled trials (RCTs) published, in any language, between January 1, 1992 and July 31, 2022, that investigated the efficacy or tolerability (or both) of drug therapies for the treatment of IPF. The search was updated on February 1, 2023. Eligible RCTs were enrolled, with no restriction on dose, duration, or length of follow-up, if they included at least one of: all-cause mortality, acute exacerbation rate, disease progression rate, serious adverse events, and any adverse events under investigation. A subsequent Bayesian NMA within random-effects models was performed, followed by a cost-effectiveness analysis using the data obtained from our NMA, by developing a Markov model from the US payer's perspective. Assumptions were checked by deterministic and probabilistic sensitivity approaches to identify sensitive factors. We prospectively registered the protocol (CRD42022340590) in PROSPERO.<br><br>FINDINGS: 51 publications comprising 12,551 participants with IPF were analysed for the NMA, and the findings indicated that pirfenidone and N-acetylcysteine (NAC)&#xa0;+ pirfenidone were the most efficacious and tolerable. The pharmacoeconomic analysis showed that NAC&#xa0;+&#xa0;pirfenidone was associated with the highest potentiality of being cost-effective at willingness-to-pay (WTP) thresholds of US$150,000 and $200,000, on the basis of quality-adjusted life years (QALYs), disability-adjusted life years (DALYs) and mortality, with the probability ranging from 53% to 92%. NAC was the minimum cost agent. Compared with placebo, NAC&#xa0;+&#xa0;pirfenidone improved effectiveness by increasing QALYs by 7.02, and reducing DALYs by 7.10 and deaths by 8.40, whilst raising overall costs by $516,894.<br><br>INTERPRETATION: This NMA and cost-effectiveness analysis suggests that NAC&#xa0;+&#xa0;pirfenidone is the most cost-effective option for treatment of IPF at WTP thresholds of $150,000 and $200,000. However, given that clinical practice guidelines have not addressed the application of this therapy, large well-designed and multicentre trials are warranted to provide a better picture of IPF management.<br><br>FUNDING: None.},
}
@article {pmid37429745,
year = {2023},
author = {Emelogu, IK and Tran, CN and Greene, WR and Novak, JD},
title = {Successful treatment of distal intestinal obstruction syndrome with N-acetylcysteine and polyethylene glycol via colonoscopy.},
journal = {Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society},
volume = {22},
number = {6},
pages = {1123-1124},
doi = {10.1016/j.jcf.2023.06.014},
pmid = {37429745},
issn = {1873-5010},
mesh = {Humans ; Female ; Middle Aged ; Polyethylene Glycols ; Acetylcysteine ; *Cystic Fibrosis/diagnosis ; *Intestinal Obstruction/diagnosis/etiology/therapy ; Colonoscopy ; },
abstract = {We describe a case of a 46-year-old woman with cystic fibrosis who presented with several days of abdominal pain and distension. She was found to have a small bowel obstruction with inspissated stool in the distal ileum on CT imaging. Despite initial management with conservative measures, her symptoms worsened. She was taken for urgent colonoscopy with administration of 4% N-acetylcysteine (NAC) and polyethylene glycol (PEG) at the distal ileum with resultant dissolution of the fecalith. Over the following days, her symptoms improved, and she was discharged with outpatient follow-up.},
}
@article {pmid37428372,
year = {2023},
author = {Fraguas, S and Molina, MD and Cebrià, F},
title = {Colorimetric Whole-Mount In Situ Hybridization in Planarians.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2680},
number = {},
pages = {81-91},
pmid = {37428372},
issn = {1940-6029},
mesh = {Animals ; *Planarians/genetics ; In Situ Hybridization ; Colorimetry ; RNA, Messenger/genetics ; Digoxigenin ; },
abstract = {Whole-mount in situ hybridization (WISH) is an extremely useful technique for visualizing specific mRNA targets and solving many biological questions. In planarians, this method is really valuable, for example, for determining gene expression profiles during whole-body regeneration and analyzing the effects of silencing any gene to determine their functions. In this chapter, we present in detail the WISH protocol routinely used in our lab, using a digoxigenin-labelled RNA probe and developing with NBT-BCIP. This protocol is basically that already described in Currie et al. (EvoDevo 7:7, 2016), which put together several modifications developed from several laboratories in recent years that improved the original protocol developed in the laboratory of Kiyokazu Agata in 1997. Although this protocol, or slight modifications of it, is the most common protocol in the planarian field for NBT-BCIP WISH, our results show that key steps such as the use and time of NAC treatment to remove the mucus need to be taken into account depending on the nature of the gene analyzed, especially for the epidermal markers.},
}
@article {pmid37427326,
year = {2023},
author = {Mousavinezhad-Moghaddam, M and Behnam-Rassouli, M and Valizadeh, N and Mahdavi-Shahri, N and Rezaee, SA},
title = {Thiamine as a peripheral neuro-protective agent in comparison with N-acetyl cysteine in axotomized rats.},
journal = {Iranian journal of basic medical sciences},
volume = {26},
number = {8},
pages = {919-926},
pmid = {37427326},
issn = {2008-3866},
abstract = {OBJECTIVES: In this study, the impact of thiamine (Thi), N-acetyl cysteine (NAC), and dexamethasone (DEX) were investigated in axotomized rats, as a model for neural injury.<br><br>MATERIALS AND METHODS: Sixty-five axotomized rats were divided into two different experimental approaches, the first experiments included five study groups (n=5): intrathecal Thi (Thi.it), intraperitoneal (Thi), NAC, DEX, and control. Cell survival was assessed in L5DRG in the 4[th] week by histological assessment. In the second study, 40 animals were engaged to assess Bcl-2, Bax, IL-6, and TNF-&#x3b1; expression in L4-L5DRG in the 1[st] and 2[nd] weeks after sural nerve axotomy under treatment of these agents (n=10).<br><br>RESULTS: Ghost cells were observed in morphological assessment of L5DRG sections, and following stereological analysis, the volume and neuronal cell counts significantly were improved in the NAC and Thi.it groups in the 4[th] week (P<0.05). Although Bcl-2 expression did not show significant differences, Bax was reduced in the Thi group (P=0.01); and the Bcl-2/Bax ratio increased in the NAC group (1[st] week, P<0.01). Furthermore, the IL-6 and TNF-&#x3b1; expression decreased in the Thi and NAC groups, on the 1[st] week of treatment (P&#x2264;0.05 and P<0.01). However, in the 2[nd] week, the IL-6 expression in both Thi and NAC groups (P<0.01), and the TNF-&#x3b1; expression in the DEX group (P=0.05) were significantly decreased.<br><br>CONCLUSION: The findings may classify Thi in the category of peripheral neuroprotective agents, in combination with routine medications. Furthermore, it had strong cell survival effects as it could interfere with the destructive effects of TNF-&#x3b1; by increasing Bax.},
}
@article {pmid37422055,
year = {2023},
author = {Huang, J and Pang, X and Zhang, X and Qiu, W and Zhang, X and Wang, R and Xie, W and Bai, Y and Zhou, S and Liao, J and Xiong, Z and Tang, Z and Su, R},
title = {N-acetylcysteine combined with insulin attenuates myocardial injury in canines with type 1 diabetes mellitus by modulating TNF-α-mediated apoptotic pathways and affecting linear ubiquitination.},
journal = {Translational research : the journal of laboratory and clinical medicine},
volume = {262},
number = {},
pages = {1-11},
doi = {10.1016/j.trsl.2023.07.003},
pmid = {37422055},
issn = {1878-1810},
mesh = {Humans ; Animals ; Dogs ; *NF-kappa B/metabolism ; Tumor Necrosis Factor-alpha ; Insulin/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; *Diabetes Mellitus, Type 1/complications/drug therapy ; Apoptosis ; Ubiquitination ; },
abstract = {The exact pathogenesis of type 1 diabetes mellitus (DM) is still unclear. Numerous organs, including the heart, will suffer damage and malfunction as a result of long-term hyperglycemia. Currently, insulin therapy alone is still not the best treatment for type 1 DM. In order to properly treat and manage patients with type 1 DM, it is vital to seek a combination that includes both insulin and additional medications. This study aims to explore the therapeutic effect and mechanism of N-acetylcysteine (NAC) combined with insulin on type 1 DM. By giving beagle canines injections of streptozotocin (STZ) and alloxan (ALX) (20 mg/kg each), a model of type 1 DM was created. The results showed that this combination could effectively control blood sugar level, improve heart function, avoid the damage of mitochondria and myocardial cells, and prevent the excessive apoptosis of myocardial cells. Importantly, the combination can activate nuclear factor kappa-B (NF-κB) by promoting linear ubiquitination of receptor-interacting protein kinase 1 (RIPK1) and NF-κB-essential modulator (NEMO) and inhibitor of NF-κB (IκB) phosphorylation. The combination can increase the transcription and linear ubiquitination of Cellular FLICE (FADD-like IL-1β-converting enzyme) -inhibitory protein (c-FLIP), diminish the production of cleaved-caspase-8 p18 and cleaved-caspase-3 to reduce apoptosis. This study confirmed that NAC combined with insulin can promote the linear ubiquitination of RIPK1, NEMO and c-FLIP and regulate the apoptosis pathway mediated by TNF-α to attenuate the myocardial injury caused by type 1 DM. Meanwhile, the research served as a resource when choosing a clinical strategy for DM cardiac complications.},
}
@article {pmid37419616,
year = {2023},
author = {Medipally, A and Xiao, M and Satoskar, AA and Biederman, L and Dasgupta, A and Ivanov, I and Mikhalina, G and Rovin, B and Brodsky, SV},
title = {N-acetylcysteine ameliorates hematuria-associated tubulointerstitial injury in 5/6 nephrectomy mice.},
journal = {Physiological reports},
volume = {11},
number = {13},
pages = {e15767},
pmid = {37419616},
issn = {2051-817X},
support = {R01 DK117102/DK/NIDDK NIH HHS/United States ; },
mesh = {Humans ; Mice ; Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Warfarin/adverse effects ; Reactive Oxygen Species ; Tumor Necrosis Factor-alpha ; Mice, Inbred C57BL ; Kidney ; Nephrectomy ; Hematuria/etiology/chemically induced ; *Renal Insufficiency, Chronic/complications/drug therapy/chemically induced ; Fibrosis ; },
abstract = {Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF-ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF-ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin-associated increase in SCr and BP but not hematuria. IFTA, TGF-ß, and ROS in the kidney as well as TNF-ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients.},
}
@article {pmid37419232,
year = {2023},
author = {Kwok, WT and Kwak, HA and Andreazza, AC},
title = {N-acetylcysteine modulates rotenone-induced mitochondrial Complex I dysfunction in THP-1 cells.},
journal = {Mitochondrion},
volume = {72},
number = {},
pages = {1-10},
doi = {10.1016/j.mito.2023.07.001},
pmid = {37419232},
issn = {1872-8278},
mesh = {Humans ; *Acetylcysteine/pharmacology/metabolism ; *Rotenone/toxicity ; THP-1 Cells ; Superoxides/metabolism ; Oxidative Stress ; Electron Transport Complex I/metabolism ; DNA, Mitochondrial/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Mitochondrial Complex I dysfunction and oxidative stress have been part of the pathophysiology of several diseases ranging from mitochondrial disease to chronic diseases such as diabetes, mood disorders and Parkinson's Disease. Nonetheless, to investigate the potential of mitochondria-targeted therapeutic strategies for these conditions, there is a need further our understanding on how cells respond and adapt in the presence of Complex I dysfunction. In this study, we used low doses of rotenone, a classical inhibitor of mitochondrial complex I, to mimic peripheral mitochondrial dysfunction in THP-1 cells, a human monocytic cell line, and explored the effects of N-acetylcysteine on preventing this rotenone-induced mitochondrial dysfunction. Our results show that in THP-1 cells, rotenone exposure led to increases in mitochondrial superoxide, levels of cell-free mitochondrial DNA, and protein levels of the NDUFS7 subunit. N-acetylcysteine (NAC) pre-treatment ameliorated the rotenone-induced increase of cell-free mitochondrial DNA and NDUFS7 protein levels, but not mitochondrial superoxide. Furthermore, rotenone exposure did not affect protein levels of the NDUFV1 subunit but induced NDUFV1 glutathionylation. In summary, NAC may help to mitigate the effects of rotenone on Complex I and preserve the normal function of mitochondria in THP-1 cells.},
}
@article {pmid37415931,
year = {2023},
author = {Kaya, ZB and Karakoc, E and McLean, PJ and Saka, E and Atilla, P},
title = {Post-inflammatory administration of N-acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease.},
journal = {FASEB bioAdvances},
volume = {5},
number = {7},
pages = {263-276},
pmid = {37415931},
issn = {2573-9832},
abstract = {Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain a variety of proteins and lipids including alpha-synuclein (α-syn). Although the formation of α-syn occurs intracellularly, it can also be found in the extracellular space where it can be taken up by neighboring cells. Toll-like receptor 2 (TLR2) is an immune system receptor that has been shown to recognize extracellular α-syn and modulate its uptake by other cells. Lymphocyte-activation gene 3 (LAG3), an immune checkpoint receptor, has also been proposed to play a role in extracellular α-syn internalization; however, a recent study has disputed this role. Internalized α-syn can trigger expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-2, and IL-6 and induce neuroinflammation, apoptosis, and mitophagy that results in cellular death. In this study, we tested if N-acetylcysteine (NAC), an anti-inflammatory and anti-carcinogenic drug, can circumvent the detrimental effects of neuroinflammation and induce an anti-inflammatory response by modulating transcription and expression of TLR2 and LAG3 receptors. Cells overexpressing wild-type α-syn were treated with TNF-α to induce inflammation followed by NAC to inhibit the deleterious effects of TNF-α-induced inflammation and apoptosis. SNCA gene transcription and α-syn protein expression were validated by q-PCR and Western blot (WB), respectively. Cell viability was measured, and apoptosis was evaluated by WB and terminal deoxynucleotidyl transferase nick end labeling methods. Alterations in LAG3 and TLR2 receptor levels were evaluated by immunofluorescent labeling, WB, and q-PCR. TNF-α not only increased inflammation but also increased endogenous and overexpressed α-syn levels. NAC treatment decreased expression of TLR2 and increased transcription of LAG3 receptor and diminished inflammation-mediated toxicity and cell death. Here, we demonstrate that NAC can reduce neuroinflammation that occurs as a result of alpha-synuclein overexpression, via a TLR2-associated pathway, making it a promising candidate for therapeutic intervention. Further studies are needed to elucidate molecular mechanisms and pathways related to neuroinflammation in PD and to develop possible new therapeutic approaches to slow the clinical progression of PD.},
}
@article {pmid37405379,
year = {2023},
author = {Gamarra-Morales, Y and Herrera-Quintana, L and Molina-López, J and Vázquez-Lorente, H and Machado-Casas, JF and Castaño-Pérez, J and Pérez-Villares, JM and Planells, E},
title = {Response to Intravenous N-Acetylcysteine Supplementation in Critically Ill Patients with COVID-19.},
journal = {Nutrients},
volume = {15},
number = {9},
pages = {},
pmid = {37405379},
issn = {2072-6643},
support = {Project FIS PI10/1993//Instituto de Salud Carlos III/ ; REF. A-CTS-708-UGR20//Consejer&#xed;a de Educaci&#xf3;n/ ; },
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *COVID-19 ; Critical Illness/therapy ; Glutathione ; Dietary Supplements ; },
abstract = {Administering N-acetylcysteine (NAC) could counteract the effect of free radicals, improving the clinical evolution of patients admitted to the Intensive Care Unit (ICU). This study aimed to investigate the clinical and biochemical effects of administering NAC to critically ill patients with COVID-19. A randomized controlled clinical trial was conducted on ICU patients (n = 140) with COVID-19 and divided into two groups: patients treated with NAC (NAC-treated group) and patients without NAC treatment (control group). NAC was administered as a continuous infusion with a loading dose and a maintenance dose during the study period (from admission until the third day of ICU stay). NAC-treated patients showed higher PaO2/FiO2 (p ≤ 0.014) after 3 days in ICU than their control group counterparts. Moreover, C-reactive protein (p ≤ 0.001), D-dimer (p ≤ 0.042), and lactate dehydrogenase (p ≤ 0.001) levels decreased on the third day in NAC-treated patients. Glutathione concentrations decreased in both NAC-treated (p ≤ 0.004) and control (p ≤ 0.047) groups after 3 days in ICU; whereas glutathione peroxidase did not change during the ICU stay. The administration of NAC manages to improve the clinical and analytical response of seriously ill patients with COVID-19 compared to the control group. NAC is able to stop the decrease in glutathione concentrations.},
}
@article {pmid37401850,
year = {2023},
author = {Xiao, P and Chen, X and Dong, Z and Fan, W and Chen, Y and Su, J and Wang, Q and Ma, L},
title = {BNIP3 overexpression may promote myeloma cell apoptosis by enhancing sensitivity to bortezomib via the p38 MAPK pathway.},
journal = {Hematology (Amsterdam, Netherlands)},
volume = {28},
number = {1},
pages = {2231739},
doi = {10.1080/16078454.2023.2231739},
pmid = {37401850},
issn = {1607-8454},
mesh = {Humans ; *p38 Mitogen-Activated Protein Kinases/metabolism/pharmacology ; Bortezomib/pharmacology ; Caspase 3/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/metabolism/pharmacology ; *Multiple Myeloma/drug therapy/genetics ; Apoptosis ; Proto-Oncogene Proteins c-bcl-2/metabolism/pharmacology ; Membrane Proteins/genetics/metabolism ; Proto-Oncogene Proteins/metabolism ; },
abstract = {BACKGROUND: BCL2-interacting protein 3 (BNIP3) expression varies among cancers, and its role in myeloma cells remains unknown. We investigated the role of BNIP3 overexpression in myeloma cells, and particularly its effects on apoptosis and mitochondria.<br><br>METHODS: A BNIP3-overexpressing plasmid was transfected into the MM.1S and RPMI8226 myeloma cell lines. Transfected cell apoptosis rate and mitochondrial function were determined via flow cytometry and western blotting. We verified the signaling pathway underlying myeloma cell sensitivity to bortezomib (BTZ).<br><br>RESULTS: Cell lines carrying the BNIP3-overexpressing plasmid exhibited higher rates of apoptosis and expression of Bax and Cleaved caspase 3 protein than the vector group, and less Bcl-2 protein expression than the control cells. Relative to the vector group, BNIP3-overexpressing strains contained more reactive oxygen species (ROS) and exhibited mitochondrial membrane potential (MMP) and dynamin-related protein 1 (Drp1) upregulation and mitofusin-1 (Mfn1) downregulation. BTZ supplementation increased BNIP3 expression. Relative to the BNIP3-OE group, the BNIP3-OE BTZ-treated group exhibited upregulated Bax and Cleaved caspase 3 protein expression, downregulated Bcl-2 protein expression, higher apoptosis rates, ROS levels, MMP, and Drp1 expression, and lower Mfn1 expression. BTZ treatment induced p38 MAPK (mitogen-activated protein kinase) signaling pathway activation in BNIP3-OE cells. Upon adding N-acetylcysteine (NAC) and the p38 MAPK inhibitor SB203580, the affected index levels returned to the baseline.<br><br>CONCLUSIONS: BNIP3 overexpression induced apoptosis in myeloma cells and increased myeloma cell sensitivity to BTZ. These effects may be mediated by the ROS/p38 MAPK signaling pathway.},
}
@article {pmid37399733,
year = {2023},
author = {Yi, SJ and Jang, YJ and Lee, S and Cho, SJ and Kang, K and Park, JI and Chae, HJ and Kim, HR and Kim, K},
title = {TMBIM6 deficiency leads to bone loss by accelerating osteoclastogenesis.},
journal = {Redox biology},
volume = {64},
number = {},
pages = {102804},
pmid = {37399733},
issn = {2213-2317},
mesh = {Animals ; Male ; Mice ; *Bone Resorption/genetics ; Cell Differentiation ; *Membrane Proteins/genetics ; Mice, Inbred C57BL ; Mice, Knockout ; *Osteoclasts/cytology ; *Osteogenesis ; RANK Ligand/metabolism ; Signal Transduction ; Transcription Factor RelA/metabolism ; Oxidation-Reduction ; },
abstract = {TMBIM6 is an endoplasmic reticulum (ER) protein that modulates various physiological and pathological processes, including metabolism and cancer. However, its involvement in bone remodeling has not been investigated. In this study, we demonstrate that TMBIM6 serves as a crucial negative regulator of osteoclast differentiation, a process essential for bone remodeling. Our investigation of Tmbim6-knockout mice revealed an osteoporotic phenotype, and knockdown of Tmbim6 inhibited the formation of multinucleated tartrate-resistant acid phosphatase-positive cells, which are characteristic of osteoclasts. Transcriptome and immunoblot analyses uncovered that TMBIM6 exerts its inhibitory effect on osteoclastogenesis by scavenging reactive oxygen species and preventing p65 nuclear localization. Additionally, TMBIM6 depletion was found to promote p65 localization to osteoclast-related gene promoters. Notably, treatment with N-acetyl cysteine, an antioxidant, impeded the osteoclastogenesis induced by TMBIM6-depleted cells, supporting the role of TMBIM6 in redox regulation. Furthermore, we discovered that TMBIM6 controls redox regulation via NRF2 signaling pathways. Our findings establish TMBIM6 as a critical regulator of osteoclastogenesis and suggest its potential as a therapeutic target for the treatment of osteoporosis.},
}
@article {pmid37397917,
year = {2023},
author = {Sobh, ZK and Abd-Elhameed, A},
title = {The therapeutic benefit of antioxidants on the outcome of acute aluminum phosphide poisoning: a systemic review and meta-analysis.},
journal = {Toxicology research},
volume = {12},
number = {3},
pages = {345-354},
pmid = {37397917},
issn = {2045-452X},
abstract = {This systematic review and meta-analysis pool evidence available from clinical trials to verify the effect of antioxidants on the outcome of acute aluminum phosphide (AlP) poisoning. A systematic review complied with "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) Protocols. Meta-analysis was conducted on 10 studies that fulfill eligibility criteria. Four antioxidants were implemented: N-Acetyl cysteine (NAC), L-Carnitine, Vitamin E, and Co-enzyme Q10 (Co Q10). Risk of bias, publication bias, and heterogeneity were assessed to ensure the results' reliability. Antioxidants significantly decrease mortality of acute AlP poisoning around three folds (OR = 2.684, 95% CI: 1.764-4.083; P < .001) and decrease the need for intubation and mechanical ventilation by two folds (OR = 2.391, 95% CI 1.480-3.863; P < .001) compared with control. Subgroup analysis revealed that NAC significantly decreases mortality by nearly three folds (OR = 2.752, 95% CI: 1.580-4.792; P < .001), and vitamin E significantly decreases mortality by nearly six folds (OR = 5.667, 95% CI: 1.178-27.254; P = .03) compared with control. L-Carnitine showed a borderline significance (P = .050). Co Q10 decreased the mortality compared with the control; however, the difference was not statistically significant (P = .263). This meta-analysis provides solid evidence regarding the efficacy of antioxidants in improving the outcome of acute AlP poisoning with reference to NAC. Wide confidence interval and small relative weight affect reliability regarding vitamin E efficacy. Future clinical trials and meta-analyses are recommended. To our knowledge, no previous meta-analysis was conducted to investigate the efficacy of treatment modalities for acute AlP poisoning.},
}
@article {pmid37393553,
year = {2023},
author = {Ahmad, H and Crotts, MS and Jacobs, JC and Baer, RW and Cox, JL},
title = {Shikonin Causes Non-apoptotic Cell Death in B16F10 Melanoma.},
journal = {Anti-cancer agents in medicinal chemistry},
volume = {23},
number = {16},
pages = {1880-1887},
doi = {10.2174/1871520623666230701000338},
pmid = {37393553},
issn = {1875-5992},
mesh = {Humans ; Apoptosis ; Necrosis ; Reactive Oxygen Species/metabolism ; Cysteine/pharmacology ; Cell Line, Tumor ; *Naphthoquinones/pharmacology ; *Melanoma ; },
abstract = {BACKGROUND: Melanoma treatment is highly resistant to current chemotherapeutic agents. Due to its resistance towards apoptotic cell death, non-apoptotic cell death pathways are sought after.<br><br>OBJECTIVE: We investigated a Chinese herbal medicine, shikonin, and its effect on B16F10 melanoma cells in vitro.<br><br>METHODS: Cell growth of B16F10 melanoma cells treated with shikonin was analyzed using an MTT assay. Shikonin was combined with necrostatin, an inhibitor of necroptosis; caspase inhibitor; 3-methyladenine, an inhibitor of autophagy; or N-acetyl cysteine, an inhibitor of reactive oxygen species. Flow cytometry was used to assess types of cell death resulting from treatment with shikonin. Cell proliferation was also analyzed utilizing a BrdU labeling assay. Monodansylcadaverine staining was performed on live cells to gauge levels of autophagy. Western blot analysis was conducted to identify specific protein markers of necroptosis including CHOP, RIP1, and pRIP1. MitoTracker staining was utilized to identify differences in mitochondrial density in cells treated with shikonin.<br><br>RESULTS: Analysis of MTT assays revealed a large decrease in cellular growth with increasing shikonin concentrations. The MTT assays with necrostatin, 3-methyladenine, and N-acetyl cysteine involvement, suggested that necroptosis, autophagy, and reactive oxygen species are a part of shikonin's mechanism of action. Cellular proliferation with shikonin treatment was also decreased. Western blotting confirmed that shikonin-treated melanoma cells increase levels of stress-related proteins, e.g., CHOP, RIP, pRIP.<br><br>CONCLUSION: Our findings suggest that mainly necroptosis is induced by the shikonin treatment of B16F10 melanoma cells. Induction of ROS production and autophagy are also involved.},
}
@article {pmid37393521,
year = {2023},
author = {Chen, M and Hu, C and Yang, L and Guo, Q and Liang, Y and Wang, W},
title = {Saikosaponin-D induces the pyroptosis of lung cancer by increasing ROS and activating the NF-κB/NLRP3/caspase-1/GSDMD pathway.},
journal = {Journal of biochemical and molecular toxicology},
volume = {37},
number = {8},
pages = {e23444},
doi = {10.1002/jbt.23444},
pmid = {37393521},
issn = {1099-0461},
mesh = {Reactive Oxygen Species/metabolism ; Acetylcysteine/pharmacology ; Tumor Microenvironment ; NF-kappa B/metabolism ; Phosphate-Binding Proteins/pharmacology ; Caspase 1/metabolism ; Humans ; Pore Forming Cytotoxic Proteins/metabolism/pharmacology ; Pyroptosis ; *Lung Neoplasms/drug therapy ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Inflammasomes/metabolism ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; Oleanolic Acid/analogs &amp; derivatives ; Saponins ; Gasdermins ; Bupleurum ; },
abstract = {Saikosaponin-D (SSD), an active ingredient in Bupleurum chinense, exerts anticancer effects in various cancers by inhibiting cancer proliferation and inducing apoptosis. However, whether SSD can induce other forms of cell death is unknown. The current study aims to demonstrate that SSD can induce pyroptosis in non-small-cell lung cancer. In this study, HCC827 and A549 non-small-cell lung cancer cells were treated with different concentrations of SSD for 1.5 h. HE and TUNEL staining were used to verify cell damage caused by SSD. Immunofluorescence and western blotting were performed to verify the effect of SSD on the NF-κB/NLRP3/caspase-1/gasdermin D (GSDMD) pathway. Changes in inflammatory factors were detected by ELISAs. Finally, the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) was introduced to verify that SSD induces pyroptosis through the ROS/NF-κB pathway. The results of the HE and TUNEL staining showed that SSD resulted in balloon-like swelling of NSCLC cells accompanied by increased DNA damage. Immunofluorescence and western blot assays confirmed that SSD treatment activated the NLRP3/caspase-1/GSDMD pathway, stimulated an increase in ROS levels and activated NF-κB in lung cancer cells. The ROS scavenger N-acetylcysteine significantly attenuated SSD-induced NF-κB/NLRP3/caspase-1/GSDMD pathway activation and inhibited the release of the inflammatory cytokines IL-1β and IL-18. In conclusion, SSD induced lung cancer cell pyroptosis by inducing ROS accumulation and activating the NF-κB/NLRP3/caspase-1/GSDMD pathway. These experiments lay the foundation for the application of SSD in the treatment of non-small-cell lung cancer and regulation of the lung cancer immune microenvironment.},
}
@article {pmid37392235,
year = {2024},
author = {Kouka, M and Bevern, N and Bitter, J and Guntinas-Lichius, O},
title = {N-Acetylcysteine combined with prednisolone treatment shows better hearing outcome than treatment with prednisolone alone for patients with idiopathic sudden sensorineural hearing loss: a retrospective observational study.},
journal = {European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery},
volume = {281},
number = {1},
pages = {107-116},
pmid = {37392235},
issn = {1434-4726},
mesh = {Humans ; Female ; Middle Aged ; Male ; Prednisolone/therapeutic use ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Glucocorticoids ; *Hearing Loss, Sudden/diagnosis/drug therapy ; *Hearing Loss, Sensorineural/diagnosis/drug therapy ; Audiometry, Pure-Tone ; Hearing ; Treatment Outcome ; },
abstract = {OBJECTIVES: Internationally, corticosteroids are still the mainstay treatment for patients with idiopathic sudden sensorineural hearing loss (ISSHL). This is a retrospective monocentric study investing the impact of adding N-acetylcysteine (NAC) to prednisolone treatment on patients with ISSHL at a tertiary university otorhinolaryngology department.<br><br>METHODS: 793 patients (median age 60&#xa0;years; 50.9% women) with a new diagnosis of ISSHL from 2009 to 2015 were included in the study. 663 patients received NAC administration in addition to standard tapered prednisolone treatment. Univariate and multivariable analysis were performed to identify independent factors regarding negative prognosis of hearing recovery.<br><br>RESULTS: Mean initial ISSHL and hearing gain after treatment in 10-tone pure tone audiometry (PTA) were 54.8&#x2009;&#xb1;&#x2009;34.5&#xa0;dB and 15.2&#x2009;&#xb1;&#x2009;21.2&#xa0;dB, respectively. In univariate analysis, treatment with prednisolone and NAC was associated with a positive prognosis of hearing recovery in the Japan classification in 10-tone PTA. In multivariable analysis on Japan classification in 10-tone PTA including all significant factors from univariate analysis, negative prognosis of hearing recovery were age&#x2009;>&#x2009;median (odds ratio [OR] 1.648; 95% confidence interval [CI] 1.139-2.385; p&#x2009;=&#x2009;0.008), diseased opposite ear (OR 3.049; CI 2.157-4.310; p&#x2009;<&#x2009;0.001), pantonal ISSHL (OR 1.891; CI 1.309-2.732; p&#x2009;=&#x2009;0.001) and prednisolone alone without NAC treatment (OR 1.862; CI 1.200-2.887; p&#x2009;=&#x2009;0.005).<br><br>CONCLUSIONS: Prednisolone treatment combined with NAC resulted in better hearing outcomes in patients with ISSHL than treatment without NAC.},
}
@article {pmid37387512,
year = {2023},
author = {Sobh, ZK and Kholief, M and Sobh, EK and Balah, MIF},
title = {Exploring research gaps and trends in the management of acute phosphide poisoning: a systematic review.},
journal = {Critical reviews in toxicology},
volume = {53},
number = {3},
pages = {181-206},
doi = {10.1080/10408444.2023.2225539},
pmid = {37387512},
issn = {1547-6898},
mesh = {Animals ; *Pesticides/toxicity ; Evidence Gaps ; Antidotes ; Acetylcysteine/therapeutic use ; Aluminum Compounds/toxicity ; },
abstract = {Metal phosphides are highly toxic pesticides that result in high morbidities and mortalities worldwide. This systematic review included 350 studies that fulfilled the eligibility criteria. There were significant rising trends of studies on acute aluminum phosphide (AlP) and zinc phosphide (Zn3P2) poisoning (p-values = <.001), pointing to an increased number of phosphide-intoxicated patients. Acute AlP poisoning studies represented 81%, 89.3%, and 97.7% of all descriptive, analytical, and experimental interventional studies included in this review, respectively. High AlP poisoning mortality explains great research interest in AlP poisoning. Thus, after 2016, nearly half (49.7%) of studies on acute AlP poisoning were issued. Also, 78.82% of experimental interventional studies on AlP poisoning were published after 2016. The trends of in-vitro, animal, and clinical studies on AlP poisoning significantly increased with p-values equal to .021, <.001, and <.001, respectively. Seventy-nine treatment modalities for acute AlP poisoning were pooled from 124 studies; 39 management-related case reports, 12 in-vitro studies, 39 animal studies, and 34 clinical studies. All therapeutic modalities were summarized to formulate an integrated and comprehensive overview. For clinicians, therapeutic modalities significantly decreased mortality of acute AlP poisoning in clinical trials included extracorporeal membrane oxygenation (ECMO), N-acetyl cysteine (NAC), vitamin E, glucose-insulin-potassium (GIK) infusion, fresh packed RBCs infusion, and GIT decontamination using oils. However, meta-analyses are needed to provide solid evidence regarding their efficacies. To date, there is no effective antidote nor evidence-based standardized protocol for managing acute AlP poisoning. This article outlined the potential research gaps in phosphide poisoning that might promote and direct future medical research in this context.},
}
@article {pmid37386885,
year = {2023},
author = {Khalatbari Mohseni, G and Hosseini, SA and Majdinasab, N and Cheraghian, B},
title = {Effects of N-acetylcysteine on oxidative stress biomarkers, depression, and anxiety symptoms in patients with multiple sclerosis.},
journal = {Neuropsychopharmacology reports},
volume = {43},
number = {3},
pages = {382-390},
pmid = {37386885},
issn = {2574-173X},
mesh = {Humans ; *Acetylcysteine/therapeutic use/pharmacology ; Anxiety/drug therapy/etiology ; Biomarkers ; Depression/drug therapy/etiology ; Glutathione/metabolism/pharmacology ; *Multiple Sclerosis/complications/drug therapy ; Oxidative Stress ; },
abstract = {AIM: N-acetylcysteine (NAC), a thiol-containing antioxidant and glutathione (GSH) precursor, attenuates oxidative stress, and possibly improves psychiatric disorders. This study aimed to evaluate the effects of oral NAC on oxidative stress, depression, and anxiety symptoms in patients with multiple sclerosis (MS).<br><br>METHODS: This clinical trial was conducted on 42 MS patients randomly assigned to intervention (n&#x2009;=&#x2009;21) and control (n&#x2009;=&#x2009;21) groups. The intervention group received 600&#x2009;mg of NAC twice daily for 8&#x2009;weeks, and the control group received a placebo with the same prescription form. An analysis of serum malondialdehyde (MDA), serum nitric oxide (NO), and erythrocyte GSH was carried out on both groups, along with a complete blood count. The Hospital Anxiety and Depression Scale (HADS) was used to assess symptoms of depression (HADS-D) and anxiety (HADS-A).<br><br>RESULTS: Compared to the control group, NAC consumption significantly decreased serum MDA concentrations (-0.33 [-5.85-2.50] vs. 2.75 [-0.25-5.22] &#x3bc;mol/L; p&#x2009;=&#x2009;0.03) and HADS-A scores (-1.6&#x2009;&#xb1;&#x2009;2.67 vs. 0.33&#x2009;&#xb1;&#x2009;2.83; p&#x2009;=&#x2009;0.02). No significant changes were observed in serum NO concentrations, erythrocyte GSH levels, and HADS-D scores (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSIONS: Based on the findings of the present study, NAC supplementation for 8&#x2009;weeks decreased lipid peroxidation and improved anxiety symptoms in MS patients. The aforementioned results suggest that adjunctive therapy with NAC can be considered an effective strategy for MS management. Further randomized controlled studies are warranted.},
}
@article {pmid37386836,
year = {2023},
author = {Tan, KT and Shih, YH and Gong, JY and Zhang, X and Huang, CY and Su, JH and Sheu, JH and Lin, CC},
title = {Dihydroaustrasulfone alcohol induces apoptosis in nasopharyngeal cancer cells by inducing reactive oxygen species-dependent inactivation of the PI3K/AKT pathway.},
journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology},
volume = {27},
number = {4},
pages = {383-398},
pmid = {37386836},
issn = {1226-4512},
abstract = {Dihydroaustrasulfone alcohol (DA), the synthetic precursor of a natural compound (austrasulfone) isolated from the coral species Cladiella australis, has shown cytotoxic effects against cancer cells. However, it is unknown whether DA has antitumor effects on nasopharyngeal carcinoma (NPC). In this study, we determined the antitumor effects of DA and investigated its mechanism of action on human NPC cells. The MTT assay was used to determine the cytotoxic effect of DA. Subsequently, apoptosis and reactive oxygen species (ROS) analyses were performed by using flow cytometry. Apoptotic and PI3K/AKT pathway-related protein expression was determined using Western blotting. We found that DA significantly reduced the viability of NPC-39 cells and determined that apoptosis was involved in DA-induced cell death. The activity of caspase-9, caspase-8, caspase-3, and PARP induced by DA suggested caspase-mediated apoptosis in DA-treated NPC-39 cells. Apoptosis-associated proteins (DR4, DR5, FAS) in extrinsic pathways were also elevated by DA. The enhanced expression of proapoptotic Bax and decreased expression of antiapoptotic BCL-2 suggested that DA mediated mitochondrial apoptosis. DA reduced the expression of pPI3K and p-AKT in NPC-39 cells. DA also reduced apoptosis after introducing an active AKT cDNA, indicating that DA could block the PI3K/AKT pathway from being activated. DA increased intracellular ROS, but N-acetylcysteine (NAC), a ROS scavenger, reduced DA-induced cytotoxicity. NAC also reversed the chances in pPI3K/AKT expression and reduced DA-induced apoptosis. These findings suggest that ROS-mediates DA-induced apoptosis and PI3K/AKT signaling inactivation in human NPC cells.},
}
@article {pmid37386230,
year = {2023},
author = {Li, A and Cao, W},
title = {Downregulation of SODD mediates carnosol-induced reduction in cell proliferation in esophageal adenocarcinoma cells.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {10580},
pmid = {37386230},
issn = {2045-2322},
mesh = {Cell Proliferation ; Down-Regulation ; Caspase 3 ; Humans ; *Adenocarcinoma/drug therapy ; NADPH Oxidases ; Reactive Oxygen Species ; *Hydrogen Peroxide ; Abietanes ; Esophageal Neoplasms ; },
abstract = {Esophageal adenocarcinoma carries a poor prognosis associated with a 5-year survival rate of 12.5-20%. Therefore, a new therapeutic modality is needed for this lethal tumor. Carnosol is a phenolic diterpene purified from the herbs such as rosemary and Mountain desert sage and has been shown to have anticancer activities in multiple cancers. In this study we examined the effect of carnosol on cell proliferation in esophageal adenocarcinoma cells. We found that carnosol dose-dependently decreased cell proliferation in FLO-1 esophageal adenocarcinoma cells and significantly increased caspase-3 protein, indicating that carnosol decreases cell proliferation and increases cell apoptosis in FLO-1 cells. Carnosol significantly increased H2O2 production and N-acetyl cysteine, a reactive oxygen species (ROS) scavenger, significantly inhibited carnosol-induced decrease in cell proliferation, indicating that ROS may mediate carnosol-induced decrease in cell proliferation. Carnosol-induced decrease in cell proliferation was partially reversed by NADPH oxidase inhibitor apocynin, suggesting that NADPH oxidases may be partially involved in carnosol's effect. In addition, carnosol significantly downregulated SODD protein and mRNA expression and knockdown of SODD significantly inhibited the carnosol-induced reduction in cell proliferation, suggesting that downregulation of SODD may contribute to carnosol-induced reduction in cell proliferation. We conclude that carnosol dose-dependently decreased cell proliferation and significantly increased caspase-3 protein. Carnosol's effect may be through the overproduction of ROS and the downregulation of SODD. Carnosol might be useful for the treatment of esophageal adenocarcinoma.},
}
@article {pmid37385335,
year = {2023},
author = {Wang, H and Zhang, Z and Sittirattanayeunyong, S and Hongpaisan, J},
title = {Association of Apolipoprotein E4-related Microvascular Disease in the Alzheimer's Disease Hippocampal CA1 Stratum Radiatum.},
journal = {Neuroscience},
volume = {526},
number = {},
pages = {204-222},
pmid = {37385335},
issn = {1873-7544},
support = {R01 AG058884/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Apolipoprotein E4/genetics/metabolism ; Apolipoproteins E ; CA1 Region, Hippocampal/pathology ; *Echinomycin/metabolism ; Hippocampus/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; },
abstract = {Current data suggest a hypothesis of vascular pathogenesis for the development and progression of Alzheimer's disease (AD). To investigate this, we studied the association of apolipoprotein E4 (APOE4) gene on microvessels in human autopsy-confirmed AD with and without APOE4, compared with age/sex-matched control (AC) hippocampal CA1 stratum radiatum. AD arterioles (without APOE4 gene) had mild oxidative stress and loss of vascular endothelial growth factor (VEGF) and endothelial cell density, reflecting aging progression. In AD + APOE4, an increase in strong oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), VEGF, and endothelial cell density were associated with increased diameter of arterioles and perivascular space dilation. In cultured human brain microvascular cells (HBMECs), treatment of ApoE4 protein plus amyloid-β (Aβ) oligomers increased superoxide production and the apoptotic marker cleaved caspase 3, sustained hypoxia inducible factor-1α (HIF-1α) stability that was associated with an increase in MnSOD, VEGF, and cell density. This cell over-proliferation was inhibited with the antioxidants N-acetyl cysteine and MnTMPyP, the HIF-1α inhibitor echinomycin, the VEGFR-2 receptor blocker SU1498, the protein kinase C (PKC) ε knock-down (KD) and the extracellular signal-regulated kinase 1/2 (ERK) inhibitor FR180204. The PKCε KD and echinomycin decreased VEGF and/or ERK. In conclusion, AD capillaries and arterioles in hippocampal CA1 stratum radiatum of non-APOE4 carriers are related with aging, while those in APOE4 carriers with AD are related with pathogenesis of cerebrovascular disease.},
}
@article {pmid37377100,
year = {2023},
author = {Zhang, YH and Wang, T and Li, YF and Deng, YN and He, XL and Wang, LJ},
title = {N-acetylcysteine improves autism-like behavior by recovering autophagic deficiency and decreasing Notch-1/Hes-1 pathway activity.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {248},
number = {11},
pages = {966-978},
pmid = {37377100},
issn = {1535-3699},
mesh = {Rats ; Humans ; Animals ; Female ; *Autistic Disorder/drug therapy ; Acetylcysteine/pharmacology ; Behavior, Animal ; *Neuroblastoma ; Valproic Acid/adverse effects ; Disease Models, Animal ; *Prenatal Exposure Delayed Effects/chemically induced ; },
abstract = {N-acetylcysteine (NAC) has been reported to improve social interaction behavior, irritability, self-injury, and anxiety-like behavior in autism. However, the molecular mechanism underlying the therapeutic roles of NAC in autism remains unknown. This study mainly aimed to investigate the therapeutic effect of NAC on valproic acid (VPA)-induced autism model and the underlying mechanisms. Our results showed that NAC ameliorated the deficits in sociability and the anxiety- and repetitive-like behaviors displayed by VPA-exposed rats. In addition, VPA exposure induced autophagic deficiency and enhanced Notch-1/Hes-1 pathway activity based on lowered Beclin-1 and LC3B levels, while increased expression of p62, Notch-1, and Hes-1 expression at the protein level. However, NAC recovered VPA-induced autophagic deficiency and reduced Notch-1/Hes-1 pathway activity in a VPA-exposed autism rat model and SH-SY5Y neural cells. The present results demonstrated that NAC improves autism-like behavioral abnormalities by inactivating Notch-1/Hes-1 signaling pathway and recovering autophagic deficiency. Taken together, this study helps to elucidate a novel molecular mechanism that underlies the therapeutic actions of NAC in autism and suggests its potential to ameliorate behavioral abnormalities in neurodevelopmental disorders.},
}
@article {pmid37374326,
year = {2023},
author = {Cervantes-Pérez, LA and Cervantes-Guevara, G and Cervantes-Pérez, E and Cervantes-Cardona, GA and Nápoles-Echauri, A and González-Ojeda, A and Fuentes-Orozco, C and Cervantes-Pérez, G and Reyes-Torres, CA and Hernández-Mora, FJ and Ron-Magaña, AL and Vázquez-Beltrán, JC and Hernández-Rivas, MI and Ramírez-Ochoa, S},
title = {Evaluation of the Effects of Atorvastatin and N-Acetyl Cysteine on Platelet Counts in Patients with Primary Immune Thrombocytopenia: An Exploratory Clinical Trial.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {59},
number = {6},
pages = {},
pmid = {37374326},
issn = {1648-9144},
mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; Atorvastatin/pharmacology/therapeutic use ; Platelet Count ; *Purpura, Thrombocytopenic, Idiopathic/drug therapy ; *Thrombocytopenia/drug therapy ; Treatment Outcome ; },
abstract = {Objective: We aimed to evaluate the efficacy of the combination of atorvastatin and N-acetyl cysteine in increasing platelet counts in patients with immune thrombocytopenia who were resistant to steroid therapy or had a relapse after treatment. Material and Methods: The patients included in this study received oral treatment of atorvastatin at a dose of 40 mg daily and N-acetyl cysteine at a dose of 400 mg every 8 h. The desired treatment duration was 12 months, but we included patients who completed at least 1 month of treatment in the analysis. The platelet counts were measured prior to the administration of the study treatment and in the first, third, sixth, and twelfth months of treatment (if available). A p value < 0.05 was considered statistically significant. Results: We included 15 patients who met our inclusion criteria. For the total treatment duration, the global response was 60% (nine patients); eight patients (53.3%) had a complete response and one patient (6.7%) had a partial response. Six patients (40%) were considered as having undergone treatment failure. Of the responder group, five patients maintained a complete response after treatment (55.5%), three patients maintained a partial response (33.3%), and one patient (11.1%) lost their response to the treatment. All of the patients in the responder group had significant increases in their platelet counts after treatment (p < 0.05). Conclusion: This study provides evidence of a possible treatment option for patients with primary immune thrombocytopenia. However, further studies are needed.},
}
@article {pmid37372022,
year = {2023},
author = {Notaro, A and Lauricella, M and Di Liberto, D and Emanuele, S and Giuliano, M and Attanzio, A and Tesoriere, L and Carlisi, D and Allegra, M and De Blasio, A and Calvaruso, G and D'Anneo, A},
title = {A Deadly Liaison between Oxidative Injury and p53 Drives Methyl-Gallate-Induced Autophagy and Apoptosis in HCT116 Colon Cancer Cells.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {6},
pages = {},
pmid = {37372022},
issn = {2076-3921},
support = {FFR-D15 D'Anneo; FFR-D03-Lauricella//This work was partially sustained by Finalized Research Funding (FFR 2022), FFR-D15 D'Anneo and FFR-D03-Lauricella, Universit&#xe0; degli Studi di Palermo, Palermo, Italy./ ; },
abstract = {Methyl gallate (MG), which is a gallotannin widely found in plants, is a polyphenol used in traditional Chinese phytotherapy to alleviate several cancer symptoms. Our studies provided evidence that MG is capable of reducing the viability of HCT116 colon cancer cells, while it was found to be ineffective on differentiated Caco-2 cells, which is a model of polarized colon cells. In the first phase of treatment, MG promoted both early ROS generation and endoplasmic reticulum (ER) stress, sustained by elevated PERK, Grp78 and CHOP expression levels, as well as an upregulation in intracellular calcium content. Such events were accompanied by an autophagic process (16-24 h), where prolonging the time (48 h) of MG exposure led to cellular homeostasis collapse and apoptotic cell death with DNA fragmentation and p53 and γH2Ax activation. Our data demonstrated that a crucial role in the MG-induced mechanism is played by p53. Its level, which increased precociously (4 h) in MG-treated cells, was tightly intertwined with oxidative injury. Indeed, the addition of N-acetylcysteine (NAC), which is a ROS scavenger, counteracted the p53 increase, as well as the MG effect on cell viability. Moreover, MG promoted p53 accumulation into the nucleus and its inhibition by pifithrin-α (PFT-α), which is a negative modulator of p53 transcriptional activity, enhanced autophagy, increased the LC3-II level and inhibited apoptotic cell death. These findings provide new clues to the potential action of MG as a possible anti-tumor phytomolecule for colon cancer treatment.},
}
@article {pmid37371987,
year = {2023},
author = {Caridade-Silva, R and Araújo, B and Martins-Macedo, J and Teixeira, FG},
title = {N-Acetylcysteine Treatment May Compensate Motor Impairments through Dopaminergic Transmission Modulation in a Striatal 6-Hydroxydopamine Parkinson's Disease Rat Model.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {6},
pages = {},
pmid = {37371987},
issn = {2076-3921},
support = {POCI-01-0145-FEDER-029751//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; MB-28-2019//Santa Casa da Miseric&#xf3;rdia de Lisboa/ ; },
abstract = {Preventing degeneration and the loss of dopaminergic neurons (DAn) in the brain while mitigating motor symptoms remains a challenge in Parkinson's Disease (PD) treatment development. In light of this, developing or repositioning potential disease-modifying approaches is imperative to achieve meaningful translational gains in PD research. Under this concept, N-acetylcysteine (NAC) has revealed promising perspectives in preserving the dopaminergic system capability and modulating PD mechanisms. Although NAC has been shown to act as an antioxidant and (neuro)protector of the brain, it has yet to be acknowledged how this repurposed drug can improve motor symptomatology and provide disease-modifying properties in PD. Therefore, in the present work, we assessed the impact of NAC on motor and histological deficits in a striatal 6-hydroxydopamine (6-OHDA) rat model of PD. The results revealed that NAC enhanced DAn viability, as we found that it could restore dopamine transporter (DAT) levels compared to the untreated 6-OHDA group. Such findings were positively correlated with a significant amelioration in the motor outcomes of the 6-OHDA-treated animals, demonstrating that NAC may, somehow, be a modulator of PD degenerative mechanisms. Overall, we postulated a proof-of-concept milestone concerning the therapeutic application of NAC. Nevertheless, it is extremely important to understand the complexity of this drug and how its therapeutical properties interact with the cellular and molecular PD mechanisms.},
}
@article {pmid37371878,
year = {2023},
author = {Balázs, G and Balajthy, A and Seri, I and Hegyi, T and Ertl, T and Szabó, T and Röszer, T and Papp, &#xc1; and Balla, J and Gáll, T and Balla, G},
title = {Prevention of Chronic Morbidities in Extremely Premature Newborns with LISA-nCPAP Respiratory Therapy and Adjuvant Perinatal Strategies.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {6},
pages = {},
pmid = {37371878},
issn = {2076-3921},
support = {11003//E&#xf6;tv&#xf6;s Lor&#xe1;nd Research Network/ ; OTKA-K 132828//Hungarian Government grants/ ; OTKA NKFI 142939//Hungarian Government grants/ ; TKP2021-EGA-18//Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund/ ; },
abstract = {Less invasive surfactant administration techniques, together with nasal continuous airway pressure (LISA-nCPAP) ventilation, an emerging noninvasive ventilation (NIV) technique in neonatology, are gaining more significance, even in extremely premature newborns (ELBW), under 27 weeks of gestational age. In this review, studies on LISA-nCPAP are compiled with an emphasis on short- and long-term morbidities associated with prematurity. Several perinatal preventative and therapeutic investigations are also discussed in order to start integrated therapies as numerous organ-saving techniques in addition to lung-protective ventilations. Two thirds of immature newborns can start their lives on NIV, and one third of them never need mechanical ventilation. With adjuvant intervention, these ratios are expected to be increased, resulting in better outcomes. Optimized cardiopulmonary transition, especially physiologic cord clamping, could have an additively beneficial effect on patient outcomes gained from NIV. Organ development and angiogenesis are strictly linked not only in the immature lung and retina, but also possibly in the kidney, and optimized interventions using angiogenic growth factors could lead to better morbidity-free survival. Corticosteroids, caffeine, insulin, thyroid hormones, antioxidants, N-acetylcysteine, and, moreover, the immunomodulatory components of mother's milk are also discussed as adjuvant treatments, since immature newborns deserve more complex neonatal interventions.},
}
@article {pmid37371872,
year = {2023},
author = {Petricca, S and Carnicelli, V and Luzi, C and Cinque, B and Celenza, G and Iorio, R},
title = {Oxidative Stress, Cytotoxic and Inflammatory Effects of Azoles Combinatorial Mixtures in Sertoli TM4 Cells.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {6},
pages = {},
pmid = {37371872},
issn = {2076-3921},
support = {07-RIA 2021 IORIO ROBERTO//intramural "DISCAB GRANT 2021 (code 07-RIA 2021 IORIO ROBERTO)"/ ; grant number CUP E11I18000300005//grant from MIUR (Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca, Italy) to Roberto Iorio./ ; },
abstract = {Triazole and imidazole fungicides are an emerging class of contaminants with an increasing and ubiquitous presence in the environment. In mammals, their reproductive toxicity has been reported. Concerning male reproduction, a combinatorial activity of tebuconazole (TEB; triazole fungicide) and econazole (ECO; imidazole compound) in inducing mitochondrial impairment, energy depletion, cell cycle arrest, and the sequential activation of autophagy and apoptosis in Sertoli TM4 cells (SCs) has recently been demonstrated. Given the strict relationship between mitochondrial activity and reactive oxygen species (ROS), and the causative role of oxidative stress (OS) in male reproductive dysfunction, the individual and combined potential of TEB and ECO in inducing redox status alterations and OS was investigated. Furthermore, considering the impact of cyclooxygenase (COX)-2 and tumor necrosis factor-alpha (TNF-α) in modulating male fertility, protein expression levels were assessed. In the present study, we demonstrate that azoles-induced cytotoxicity is associated with a significant increase in ROS production, a drastic reduction in superoxide dismutase (SOD) and GSH-S-transferase activity levels, and a marked increase in the levels of oxidized (GSSG) glutathione. Exposure to azoles also induced COX-2 expression and increased TNF-α production. Furthermore, pre-treatment with N-acetylcysteine (NAC) mitigates ROS accumulation, attenuates COX-2 expression and TNF-α production, and rescues SCs from azole-induced apoptosis, suggesting a ROS-dependent molecular mechanism underlying the azole-induced cytotoxicity.},
}
@article {pmid37371417,
year = {2023},
author = {Du, Y and Chen, L and Qiao, H and Zhang, L and Yang, L and Zhang, P and Wang, J and Zhang, C and Jiang, W and Xu, R and Zhang, X},
title = {Hydrogen-Rich Saline-A Novel Neuroprotective Agent in a Mouse Model of Experimental Cerebral Ischemia via the ROS-NLRP3 Inflammasome Signaling Pathway In Vivo and In Vitro.},
journal = {Brain sciences},
volume = {13},
number = {6},
pages = {},
pmid = {37371417},
issn = {2076-3425},
support = {Grant number: 81974184//the National Natural Science Foundation of China/ ; grant number : 20211706//the Key Project of Medical Science Research of Hebei Province in 2021/ ; },
abstract = {BACKGROUND: Our previous research revealed that inflammation plays an important role in the pathophysiology of cerebral ischemia. The function of the NOD-like receptor protein 3 (NLRP3) inflammasome is to activate the inflammatory process. Recent findings suggest that reactive oxygen species (ROS) are essential secondary messengers that activate the NLRP3 inflammasome. Hydrogen-rich saline (HS) has attracted attention for its anti-inflammatory properties. However, the protective effect and possible mechanism of HSin brain ischemia have not been well elucidated.<br><br>METHODS: To test the therapeutic effect of HS, we established a mouse model of distal middle cerebral artery occlusion (dMCAO) and an in vitro model of BV2 cells induced by lipopolysaccharide (LPS). The ROS scavenger N-acetylcysteine (NAC) was used to investigate the underlying mechanisms of HS.<br><br>RESULTS: HS significantly improved neurological function, reduced infarct volume, and increased cerebral blood flow in a dMCAO mouse model. ROS, NLRP3, Caspase-1, and IL-1&#x3b2; expression increased after cerebral ischemia, and this was reversed by HS treatment. In BV2 cells, the application of NAC further demonstrated that HS could effectively inhibit the expression of the ROS-activated NLRP3 inflammasome.<br><br>CONCLUSIONS: HS, as a novel therapeutic option, could exert protect the brain by inhibiting the activation of the ROS-NLRP3 signaling pathway after cerebral ischemia.},
}
@article {pmid37370701,
year = {2023},
author = {Khalil, R and Green, RJ and Sivakumar, K and Varandani, P and Bharadwaj, S and Mohapatra, SS and Mohapatra, S},
title = {Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer.},
journal = {Cancers},
volume = {15},
number = {12},
pages = {},
pmid = {37370701},
issn = {2072-6694},
support = {I01 BX003413/BX/BLRD VA/United States ; IK6 BX004212/BX/BLRD VA/United States ; },
abstract = {Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)-a herbal compound-and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS.},
}
@article {pmid37368450,
year = {2023},
author = {Choudhary, M and Pereira, J and Davidson, EB and Colee, J and Santra, S and Jones, JB and Paret, ML},
title = {Improved Persistence of Bacteriophage Formulation with Nano N-Acetylcysteine-Zinc Sulfide and Tomato Bacterial Spot Disease Control.},
journal = {Plant disease},
volume = {107},
number = {12},
pages = {3933-3942},
doi = {10.1094/PDIS-02-23-0255-RE},
pmid = {37368450},
issn = {0191-2917},
mesh = {*Bacteriophages ; Acetylcysteine/pharmacology ; *Solanum lycopersicum ; *Zinc Oxide ; Bacteria ; *Bacterial Infections ; Sulfides ; Zinc Compounds ; },
abstract = {Bacteriophages are biocontrol agents used to manage bacterial diseases. They have long been used against plant pathogenic bacteria; however, several factors impede their use as a reliable disease management strategy. Short-lived persistence on plant surfaces under field conditions results mainly from rapid degradation by exposure to ultraviolet (UV) light. Currently, there are no effective commercial formulations that protect phages from UV. The phage ΦXp06-02-1, which lyses strains of the tomato bacterial spot pathogen Xanthomonas perforans, was mixed with different concentrations of the nanomaterial N-acetylcysteine surface-coated manganese-doped zinc sulfide (NAC-ZnS; 3.5 nm). In vitro, NAC-ZnS at 10,000 μg/ml formulated phage, when exposed to UV for 1 min, provided statistically equivalent plaque-forming unit (PFU) recovery as phages that were not exposed to UV. NAC-ZnS had no negative effect on the phage's ability to lyse bacterial cells under in vitro conditions. NAC-ZnS reduced phage degradation over time in comparison with the nontreated control, whereas N-acetylcysteine-zinc oxide (NAC-ZnO) had no effect. In fluorescent light, without UV exposure, NAC-ZnO-formulated phages were more infective than NAC-ZnS-formulated phages. The nanomaterial-phage mixture did not cause any phytotoxicity when applied to tomato plants. Following exposure to sunlight, the NAC-ZnS formulation improved phage persistence in the phyllosphere by 15 times compared with nonformulated phages. NAC-ZnO-formulated phage populations were undetectable within 32 h, whereas NAC-ZnS-formulated phage populations were detected at 10[3] PFU/g. At 4 h of sunlight exposure, NAC-ZnS-formulated phages at 1,000 μg/ml significantly reduced tomato bacterial spot disease severity by 16.4% compared with nonformulated phages. These results suggest that NAC-ZnS can be used to improve the efficacy of phages for bacterial diseases.},
}
@article {pmid37368329,
year = {2023},
author = {Fesharaki Zadeh, A and Arnsten, AFT and Wang, M},
title = {Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID.},
journal = {Neurology international},
volume = {15},
number = {2},
pages = {725-742},
pmid = {37368329},
issn = {2035-8385},
support = {P30 AG066508/AG/NIA NIH HHS/United States ; R01 AG061190/AG/NIA NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; },
abstract = {Sustained cognitive deficits are a common and debilitating feature of "long COVID", but currently there are no FDA-approved treatments. The cognitive functions of the dorsolateral prefrontal cortex (dlPFC) are the most consistently afflicted by long COVID, including deficits in working memory, motivation, and executive functioning. COVID-19 infection greatly increases kynurenic acid (KYNA) and glutamate carboxypeptidase II (GCPII) in brain, both of which can be particularly deleterious to PFC function. KYNA blocks both NMDA and nicotinic-alpha-7 receptors, the two receptors required for dlPFC neurotransmission, and GCPII reduces mGluR3 regulation of cAMP-calcium-potassium channel signaling, which weakens dlPFC network connectivity and reduces dlPFC neuronal firing. Two agents approved for other indications may be helpful in restoring dlPFC physiology: the antioxidant N-acetyl cysteine inhibits the production of KYNA, and the α2A-adrenoceptor agonist guanfacine regulates cAMP-calcium-potassium channel signaling in dlPFC and is also anti-inflammatory. Thus, these agents may be helpful in treating the cognitive symptoms of long COVID.},
}
@article {pmid37368165,
year = {2023},
author = {Barrera-Chimal, J and Henley, N and Grant, MP and Cenatus, S and Geraldes, P and Pichette, V and Gerarduzzi, C},
title = {Tungsten toxicity on kidney tubular epithelial cells induces renal inflammation and M1-macrophage polarization.},
journal = {Cell biology and toxicology},
volume = {39},
number = {6},
pages = {3061-3075},
pmid = {37368165},
issn = {1573-6822},
mesh = {Male ; Mice ; Animals ; *Tungsten/toxicity ; Culture Media, Conditioned ; *Kidney ; Macrophages ; Epithelial Cells ; NF-kappa B ; Inflammation/chemically induced ; },
abstract = {Tungsten is widely used in medical, industrial, and military applications. The environmental exposure to tungsten has increased over the past several years, and few studies have addressed its potential toxicity. In this study, we evaluated the effects of chronic oral tungsten exposure (100 ppm) on renal inflammation in male mice. We found that 30- or 90-day tungsten exposure led to the accumulation of LAMP1-positive lysosomes in renal tubular epithelial cells. In addition, the kidneys of mice exposed to tungsten showed interstitial infiltration of leukocytes, myeloid cells, and macrophages together with increased levels of proinflammatory cytokines and p50/p65-NFkB subunits. In proximal tubule epithelial cells (HK-2) in vitro, tungsten induced a similar inflammatory status characterized by increased mRNA levels of CSF1, IL34, CXCL2, and CXCL10 and NFkB activation. Moreover, tungsten exposure reduced HK-2 cell viability and enhanced reactive oxygen species generation. Conditioned media from HK-2 cells treated with tungsten induced an M1-proinflammatory polarization of RAW macrophages as evidenced by increased levels of iNOS and interleukin-6 and decreased levels of the M2-antiinflammatory marker CD206. These effects were not observed when RAW cells were exposed to conditioned media from HK-2 cells treated with tungsten and supplemented with the antioxidant N-acetylcysteine (NAC). Similarly, direct tungsten exposure induced M1-proinflammatory polarization of RAW cells that was prevented by NAC co-treatment. Altogether, our data suggest that prolonged tungsten exposure leads to oxidative injury in the kidney ultimately leading to chronic renal inflammation characterized by a proinflammatory status in kidney tubular epithelial cells and immune cell infiltration.},
}
@article {pmid37360438,
year = {2023},
author = {Maria Francis, Y and Karunakaran, B and Ashfaq, F and Yahia Qattan, M and Ahmad, I and Alkhathami, AG and Idreesh Khan, M and Varadhan, M and Govindan, L and Ponnusamy Kasirajan, S},
title = {Mercuric Chloride Induced Nephrotoxicity: Ameliorative Effect of Carica papaya Leaves Confirmed by Histopathology, Immunohistochemistry, and Gene Expression Studies.},
journal = {ACS omega},
volume = {8},
number = {24},
pages = {21696-21708},
pmid = {37360438},
issn = {2470-1343},
abstract = {The present study analyzes the efficacy of the ethanolic extract of C. papaya leaves (ECP) against HgCl2-induced nephrotoxicity. The effects on the biochemical and percentage of body and organ weight against HgCl2-induced nephrotoxicity in female Wistar rats were studied. Wistar rats were divided into five groups with six animals in each group: control, HgCl2 (2.5 mg/kg b.w.), N-acetylcysteine (NAC 180 mg/kg) + HgCl2, ECP (300 mg/kg b.w.) + HgCl2, and ECP (600 mg/kg) + HgCl2 groups. After 28 days of study, animals were sacrificed on the 29th day to harvest the blood and kidneys for further analysis. The effect ECP was analyzed by immunohistochemistry (NGAL) and real-time PCR (KIM-1 and NGAL mRNA) in HgCl2-induced nephrotoxicity. The results revealed that the HgCl2 group showed prominent damage in the proximal tubules and glomerulus of nephrons and enormous expression of NGAL in immunohistochemistry and KIM-1 and NGAL in real-time PCR compared to the control group. The simultaneous pretreatment with NAC (180 mg/kg) and ECP (600 and 300 mg/kg) reduced renal damage and expression of NGAL in immunohistochemistry and KIM-1 and NGAL gene in real-time PCR. This study attests to the nephroprotective effect of ECP against HgCl2-induced toxicity.},
}
@article {pmid37360166,
year = {2023},
author = {Mazumdar, R and Eberhart, JK},
title = {Loss of Nicotinamide nucleotide transhydrogenase sensitizes embryos to ethanol-induced neural crest and neural apoptosis via generation of reactive oxygen species.},
journal = {Frontiers in neuroscience},
volume = {17},
number = {},
pages = {1154621},
pmid = {37360166},
issn = {1662-4548},
support = {T32 AA007471/AA/NIAAA NIH HHS/United States ; },
abstract = {Fetal alcohol spectrum disorders (FASD) are a continuum of birth defects caused by prenatal alcohol exposure. FASD are the most common environmentally induced birth defect and are highly variable. The genetics of an individual influence the severity of their FASD phenotype. However, the genes that sensitize an individual to ethanol-induced birth defects are largely unknown. The ethanol-sensitive mouse substrain, C57/B6J, carries several known mutations including one in Nicotinamide nucleotide transhydrogenase (Nnt). Nnt is a mitochondrial transhydrogenase thought to have an important role in detoxifying reactive oxygen species (ROS) and ROS has been implicated in ethanol teratogenesis. To directly test the role of Nnt in ethanol teratogenesis, we generated zebrafish nnt mutants via CRISPR/Cas9. Zebrafish embryos were dosed with varying concentrations of ethanol across different timepoints and assessed for craniofacial malformations. We utilized a ROS assay to determine if this could be a contributing factor of these malformations. We found that exposed and unexposed mutants had higher levels of ROS compared to their wildtype counterparts. When treated with ethanol, nnt mutants experienced elevated apoptosis in the brain and neural crest, a defect that was rescued by administration of the antioxidant, N-acetyl cysteine (NAC). NAC treatment also rescued most craniofacial malformations. Altogether this research demonstrates that ethanol-induced oxidative stress leads to craniofacial and neural defects due to apoptosis in nnt mutants. This research further supports the growing body of evidence implicating oxidative stress in ethanol teratogenesis. These findings suggest that antioxidants can be used as a potential therapeutic in the treatment of FASD.},
}
@article {pmid37356397,
year = {2023},
author = {Zhang, Q and Liu, W and Li, Q and Zeng, Y and Wu, M and Wu, T and Guo, S and Wang, L and Zhao, D and Yi, D and Hou, Y},
title = {Protective effects and mechanisms of N-acetylcysteine on indomethacin-induced intestinal injury in a porcine model.},
journal = {Ecotoxicology and environmental safety},
volume = {262},
number = {},
pages = {115173},
doi = {10.1016/j.ecoenv.2023.115173},
pmid = {37356397},
issn = {1090-2414},
abstract = {This study aimed to investigate the effect of N-acetylcysteine (NAC) on indomethacin (IDMT)-induced intestinal injury in a piglet model and explore the underlying molecular mechanisms. Piglets were randomly divided into 3 treatment groups: (1) control group; (2) IDMT group; (3) NAC+IDMT group. The results showed that NAC administration significantly increased the average daily gain of piglets, attenuated the intestine hyperemia, and restored normal jejunal morphology. Further studies indicated that NAC administration significantly increased plasma citrulline concentration and jejunal villin expression, but decreased the content of proinflammatory cytokines in plasma and jejunum of IDMT-stimulated piglets. NAC administration selectively decreased the proportion of eosinophils but not neutrophils in plasma. Furthermore, NAC administration significantly increased the activities of superoxide dismutase and catalase in plasma but decreased the concentrations of hydrogen peroxide (plasma) and malondialdehyde (plasma and jejunum), as well as the activity of myeloperoxidase (jejunum) when comparing NAC+IDMT group with IDMT group. Gene Ontology analysis showed that the significantly enriched molecular function term was "ubiquitin-like protein ligase binding" for NAC+IDMT versus IDMT differentially regulated genes. In the biological process category, differentially regulated genes of NAC+IDMT versus IDMT were mainly enriched in immune-related terms. The major enrichments for differentially regulated proteins (DRPs) of NAC+IDMT versus IDMT were terms involved in lipid metabolism and immune response. KEGG pathway enrichment analysis showed that "arginine biosynthesis" was a significant enrichment term for the DRPs of NAC+IDMT versus IDMT. Further studies demonstrated that NAC administration up-regulated argininosuccinate synthase 1 mRNA expression and down-regulated arginase mRNA expression in the jejunum of IDMT-stimulated piglets. Moreover, the content of nitric oxide was restored to a normal level with the reduction of nitric oxide synthase activity. NAC administration ameliorated intestinal injury in IDMT-challenged piglets by enhancing antioxidant and anti-inflammatory functions and modulating arginine metabolism in the small intestine.},
}
@article {pmid37351787,
year = {2023},
author = {Kim, B and Lee, SM and Park, SJ and Lee, S and Kim, T},
title = {Role of Klotho and N-acetylcysteine in Oxidative Stress Associated with the Vitrification of Ovarian Tissue Cytoprotective Function of Klotho in Cryopreservation.},
journal = {Tissue engineering and regenerative medicine},
volume = {20},
number = {4},
pages = {637-646},
pmid = {37351787},
issn = {2212-5469},
support = {NRF-2016R1C1B3015250//National Research Foundation of Korea Grant/ ; },
mesh = {*Vitrification ; *Acetylcysteine/pharmacology/metabolism ; Reactive Oxygen Species/metabolism/pharmacology ; Cryopreservation/methods ; Oxidative Stress ; },
abstract = {BACKGROUND: Cryopreservation can cause mechanical and chemical stress, ultimately leading to the formation of reactive oxygen species (ROS) and oxidative stress. ROS inhibits the expression of antioxidant enzymes in cells, resulting in increased DNA fragmentation and apoptosis. In this paper, we used a vitrification method that has the advantage of producing less ice crystal formation, cost-effectiveness, and time efficiency during cryopreservation. The objective of this paper is to evaluate the degree of protection of ovarian tissue against oxidative stress when N-acetylcysteine (NAC) and Klotho proteins are treated in the vitrification process of ovarian tissue. METHODS: The control group and the cryopreservation groups were randomly assigned, and treated NAC, Klotho, or the combination (NAC + Klotho). The cell morphological change, DNA damage, senescence, and apoptosis of each group after the freeze-thaw process were compared using transmission electron microscopy, immunohistochemistry, and western blot analysis.<br><br>RESULTS: Both NAC and Klotho were found to be more effective at protecting against DNA damage than the control; however, DNA damage was greater in the NAC&#x2009;+&#x2009;Klotho group than in the group treated with NAC and Klotho, respectively. DNA damage and cellular senescence were also reduced during the vitrification process when cells were treated with NAC, Klotho, or the combination (NAC&#x2009;+&#x2009;Klotho). NAC increased apoptosis during cryopreservation, whereas Klotho inhibited apoptosis and NAC-induced apoptosis.<br><br>CONCLUSION: This study highlights Klotho's benefits in inhibiting DNA damage, cell senescence, and apoptosis, including NAC-induced apoptosis, despite its unclear role in vitrification.},
}
@article {pmid37350963,
year = {2023},
author = {Peng, N and Geng, Y and Ouyang, J and Liu, S and Yuan, F and Wan, Y and Chen, W and Yu, B and Tang, Y and Su, L and Liang, H and Wang, JH and Liu, J},
title = {Endothelial glycocalyx injury is involved in heatstroke-associated coagulopathy and protected by N-acetylcysteine.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1159195},
pmid = {37350963},
issn = {1664-3224},
mesh = {Rats ; Animals ; Acetylcysteine/pharmacology ; Endothelial Cells ; Glycocalyx ; Reactive Oxygen Species ; Hydrogen Peroxide ; Retrospective Studies ; *Blood Coagulation Disorders/drug therapy/etiology ; *Heat Stroke/drug therapy ; *Sepsis/complications ; },
abstract = {INTRODUCTION: Damage to endothelial glycocalyx (EGCX) can lead to coagulation disorders in sepsis. Heat stroke (HS) resembles sepsis in many aspects; however, it is unclear whether EGCX injury is involved in its pathophysiology. The purpose of this study was to examine the relationship between the damage of EGCX and the development of coagulation disorders during HS.<br><br>METHODS: We retrospectively collected 159 HS patients and analyzed coagulation characteristics and prognosis of HS patients with or without disseminated intravascular coagulation (DIC). We also replicated a rat HS model and measured coagulation indexes, pulmonary capillary EGCX injury in HS rats. Finally, we evaluated the effect of the antioxidant N-acetylcysteine (NAC) on HS-initiated EGCX injury and coagulation disorders.<br><br>RESULTS: Clinical data showed that HS patients complicated with DIC had a higher risk of death than HS patients without DIC. In a rat HS model, we found that rats subjected to heat stress developed hypercoagulability and platelet activation at the core body temperature of 43&#xb0;C, just before the onset of HS. At 24&#xa0;h of HS, the rats showed a consumptive hypo-coagulation state. The pulmonary capillary EGCX started to shed at 0&#xa0;h of HS and became more severe at 24&#xa0;h of HS. Importantly, pretreatment with NAC substantially alleviated EGCX damage and reversed the hypo-coagulation state in HS rats. Mechanically, HS initiated reactive oxidative species (ROS) generation, while ROS could directly cause EGCX damage. Critically, NAC protected against EGCX injury by attenuating ROS production in heat-stressed or hydrogen peroxide (H2O2)-stimulated endothelial cells.<br><br>DISCUSSION: Our results indicate that the poor prognosis of HS patients correlates with severe coagulation disorders, coagulation abnormalities in HS rats are associated with the damage of EGCX, and NAC improves HS-induced coagulopathy, probably through its protection against EGCX injury by preventing ROS generation.},
}
@article {pmid37349241,
year = {2023},
author = {Iqbal, P and Karki, P and Abdelmottaleb, W and Al-Khazraji, Y and Mirza Fawad, A and Madani, K and Ahmed, F and Nawaz, S and Jamshaid, MB and Fernando, QM},
title = {Asymptomatic COVID-19 presenting with features of mixed pattern acute liver injury in a young healthy female, a case report.},
journal = {Journal of infection and public health},
volume = {16},
number = {9},
pages = {1481-1484},
pmid = {37349241},
issn = {1876-035X},
mesh = {Humans ; Female ; *COVID-19 ; Liver/diagnostic imaging ; Acetylcysteine ; },
abstract = {COVID-19 associated severe acute liver injury in a young healthy patient has not been reported much in the literature. And currently, there are no standard management guidelines. We want to report a case of acute liver injury of mixed pattern in a young healthy female with asymptomatic COVID-19 infection. She presented with abdominal pain, nausea, vomiting and yellowish discoloration of her skin. Further laboratory investigations revealed mixed pattern liver injury with highly raised liver enzymes. She was managed with N-acetyl cysteine protocol and monitoring of her liver enzymes. Other causes of acute liver injury were ruled out. She remained stable during her hospital stay and follow up. Our aim is to highlight the significance of acute liver injury in COVID 19 patients that may lead to fatal outcomes if not managed and monitored accordingly.},
}
@article {pmid37348685,
year = {2023},
author = {Cui, J and Xu, T and Lv, H and Guo, MY},
title = {Zinc deficiency causes oxidative stress, endoplasmic reticulum stress, apoptosis and inflammation in hepatocytes in grass carp.},
journal = {Fish &amp; shellfish immunology},
volume = {139},
number = {},
pages = {108905},
doi = {10.1016/j.fsi.2023.108905},
pmid = {37348685},
issn = {1095-9947},
mesh = {Animals ; Diet ; *Carps ; Inflammation/chemically induced/veterinary ; Oxidative Stress ; Apoptosis ; Hepatocytes ; *Malnutrition ; Zinc/pharmacology ; Endoplasmic Reticulum Stress ; RNA, Messenger ; Ethylenediamines ; },
abstract = {A lack of the trace element zinc (Zn) in freshwater environments causes slow growth and malnutrition and affects the normal biological functions of organisms. In this study, a Zn deficiency model of grass carp hepatocytes was established with TPEN. Acetylcysteine (NAC) was used as an inhibitor. TPEN was added to L8824 cell culture medium, and LDH, AST, ALT, and AKP activities were enhanced in a Zn-deficient environment, leading to abnormal hepatopancreas function. Fluorescence microscopy showed an increase in ROS levels, and antioxidant enzyme activity assays revealed that SOD, CAT, GSH-PX, and T-AOC activities were decreased, indicating oxidative stress caused by Zn deficiency. The RT‒PCR results showed that the mRNA expression of GRP78, PERK, EIF2α, ATF4, and Chop was increased due to the addition of TPEN. Calcium kits showed increased Ca[2+] levels. The RT‒PCR results showed that the mRNA expression levels of Caspase-12, Caspase-9, Caspase-3, and PARP apoptotic were increased due to the addition of TPEN. RT‒PCR and ELISA showed that the expression levels of interleukin-1β (IL-1β), interleukin-8 (IL-8), tumour necrosis factor (TNF-α), and inducible nitric oxide synthase (iNOS) were increased. This led to the conclusion that Zn deficiency in the freshwater environment caused inflammation and apoptosis in hepatocytes in grass carp. For the first time, apoptosis caused by endoplasmic reticulum stress in grass carp hepatocytes due to Zn deficiency was studied in the context of Ca[2+]. The present study provided some insight into the adverse effects of Zn deficiency in freshwater environments on fish.},
}
@article {pmid37333506,
year = {2023},
author = {Chethan, GE and De, UK and Singh, MK and Chander, V and Raja, R and Paul, BR and Choudhary, OP and Thakur, N and Sarma, K and Prasad, H},
title = {Antioxidant supplementation during treatment of outpatient dogs with parvovirus enteritis ameliorates oxidative stress and attenuates intestinal injury: A randomized controlled trial.},
journal = {Veterinary and animal science},
volume = {21},
number = {},
pages = {100300},
pmid = {37333506},
issn = {2451-943X},
abstract = {A prospective randomized controlled clinical study was conducted to determine whether antioxidant supplementation as an adjunct therapy alters hemogram, oxidative stress, serum intestinal fatty acid binding protein-2 (IFABP-2) level, fecal viral load, clinical score (CS) and survivability in outpatient canine parvovirus enteritis (CPVE) dogs. The dogs with CPVE were randomized to one of the five treatment groups: supportive treatment (ST) alone, ST with N-acetylcysteine (ST+NAC), resveratrol (ST+RES), coenzyme Q10 (ST+CoQ10) or ascorbic acid (ST+AA). The primary outcome measures were reduction of CS and fecal HA titre, and enhancement of survivability. Secondary outcome measures were reduction of oxidative stress indices and IFABP-2 level from day 0 to day 7. The mean CS and HA titre were significantly (P < 0.05) decreased from day 0 to 7 in ST and all antioxidant groups. The supplementations of NAC, RES and AA along with ST markedly (P < 0.05) reduced the concentrations of malondialdehyde, nitric oxide and IFABP-2 on day 7 as compared to ST alone. Additionally, NAC and RES supplementations markedly (P < 0.05) improved the total leukocyte count and neutrophil count in CPVE-affected dogs. NAC and RES could serve as better antioxidants for the amelioration of oxidative stress in CPVE but, the antioxidants did not confer any additional benefits in reduction of CS, fecal HA tire, or survivability when compared with ST alone.},
}
@article {pmid37332579,
year = {2023},
author = {Csiki, DM and Ababneh, H and Tóth, A and Lente, G and Szöőr, &#xc1; and Tóth, A and Fillér, C and Juhász, T and Nagy, B and Balogh, E and Jeney, V},
title = {Hypoxia-inducible factor activation promotes osteogenic transition of valve interstitial cells and accelerates aortic valve calcification in a mice model of chronic kidney disease.},
journal = {Frontiers in cardiovascular medicine},
volume = {10},
number = {},
pages = {1168339},
pmid = {37332579},
issn = {2297-055X},
abstract = {INTRODUCTION: Valve calcification (VC) is a widespread complication in chronic kidney disease (CKD) patients. VC is an active process with the involvement of in situ osteogenic transition of valve interstitial cells (VICs). VC is accompanied by the activation of hypoxia inducible factor (HIF) pathway, but the role of HIF activation in the calcification process remains undiscovered.<br><br>METHODS AND RESULT: Using in vitro and in vivo approaches we addressed the role of HIF activation in osteogenic transition of VICs and CKD-associated VC. Elevation of osteogenic (Runx2, Sox9) and HIF activation markers (HIF-1&#x3b1; and HIF-2&#x3b1;) and VC occurred in adenine-induced CKD mice. High phosphate (Pi) induced upregulation of osteogenic (Runx2, alkaline-phosphatase, Sox9, osteocalcin) and hypoxia markers (HIF-1&#x3b1;, HIF-2&#x3b1;, Glut-1), and calcification in VICs. Down-regulation of HIF-1&#x3b1; and HIF-2&#x3b1; inhibited, whereas further activation of HIF pathway by hypoxic exposure (1% O2) or hypoxia mimetics [desferrioxamine, CoCl2, Daprodustat (DPD)] promoted Pi-induced calcification of VICs. Pi augmented the formation of reactive oxygen species (ROS) and decreased viability of VICs, whose effects were further exacerbated by hypoxia. N-acetyl cysteine inhibited Pi-induced ROS production, cell death and calcification under both normoxic and hypoxic conditions. DPD treatment corrected anemia but promoted aortic VC in the CKD mice model.<br><br>DISCUSSION: HIF activation plays a fundamental role in Pi-induced osteogenic transition of VICs and CKD-induced VC. The cellular mechanism involves stabilization of HIF-1&#x3b1; and HIF-2&#x3b1;, increased ROS production and cell death. Targeting the HIF pathways may thus be investigated as a therapeutic approach to attenuate aortic VC.},
}
@article {pmid37325649,
year = {2023},
author = {Chaumond, E and Peron, S and Daniel, N and Le Gouar, Y and Guédon, &#xc9; and Williams, DL and Le Loir, Y and Jan, G and Berkova, N},
title = {Development of innate immune memory by non-immune cells during Staphylococcus aureus infection depends on reactive oxygen species.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1138539},
pmid = {37325649},
issn = {1664-3224},
mesh = {Female ; Humans ; Animals ; Cattle ; Reactive Oxygen Species ; *Immunity, Innate ; Staphylococcus aureus ; Trained Immunity ; Interleukin-8 ; Interleukin-6 ; *Staphylococcal Infections ; },
abstract = {INTRODUCTION: The mechanisms underlying innate immune memory (trained immunity) comprise epigenetic reprogramming of transcriptional pathways associated with alterations of intracellular metabolism. While the mechanisms of innate immune memory carried out by immune cells are well characterized, such processes in non-immune cells, are poorly understood. The opportunistic pathogen, Staphylococcus aureus, is responsible for a multitude of human diseases, including pneumonia, endocarditis and osteomyelitis, as well as animal infections, including chronic cattle mastitis that are extremely difficult to treat. An induction of innate immune memory may be considered as a therapeutic alternative to fight S. aureus infection.<br><br>METHODS: In the current work, we demonstrated the development of innate immune memory in non-immune cells during S. aureus infection employing a combination of techniques including Enzyme-linked immunosorbent assay (ELISA), microscopic analysis, and cytometry.<br><br>RESULTS: We observed that training of human osteoblast-like MG-63 cells and lung epithelial A549 cells with &#x3b2;-glucan increased IL-6 and IL-8 production upon a stimulation with S. aureus, concomitant with histones modifications. IL-6 and IL-8 production was positively correlated with an acetylation of histone 3 at lysine 27 (H3K27), thus suggesting epigenetic reprogramming in these cells. An addition of the ROS scavenger N-Acetylcysteine, NAC, prior to &#x3b2;-glucan pretreatment followed by an exposure to S. aureus, resulted in decreased IL-6 and IL-8 production, thereby supporting the involvement of ROS in the induction of innate immune memory. Exposure of cells to Lactococcus lactis resulted in increased IL-6 and IL-8 production by MG-63 and A549 cells upon a stimulation with S. aureus that was correlated with H3K27 acetylation, suggesting the ability of this beneficial bacterium to induce innate immune memory.<br><br>DISCUSSION: This work improves our understanding of innate immune memory in non-immune cells in the context of S. aureus infection. In addition to known inducers, probiotics may represent good candidates for the induction of innate immune memory. Our findings may help the development of alternative therapeutic approaches for the prevention of S. aureus infection.},
}
@article {pmid37323955,
year = {2022},
author = {Memudu, AE},
title = {The Efficacy of N-Acetyl-Cysteine (NAC) Supplementation in FST Model for Screening Antidepressants.},
journal = {Basic and clinical neuroscience},
volume = {13},
number = {6},
pages = {839-854},
pmid = {37323955},
issn = {2008-126X},
abstract = {INTRODUCTION: The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an antioxidant supplement in stress related disorder is well documented. This study was aimed at potential antidepressant mechanism of N-Acetyl Cysteine (NAC), a glutamate precursor on FST animal model for screening antidepressant drugs using fluoxetine, a selective serotonin reuptake inhibitors (SSRIs) as standard antidepressant drug.<br><br>METHODS: Thirty adult male Wistar rats used for this study were randomly divided into six groups each with five (n=5) rats. The control group (A) received 1 ml of normal saline daily, group B served as the FST model, group C received 200mg/kg/day of NAC, group D received 20mg/kg/day of fluoxetine, group E the FST model treated with 200mg/kg/day of NAC, and F is the FST model treated with 20mg/kg/day of fluoxetine. Drugs were given orally. The effects of NAC on brain weights, the FST paradigms, sucrose preference test (SPT) for anhedonia were assessed and data analyzed using ANOVA where Tukey post-hoc test for statistical significance was set at (p < 0.05). The brains fixed in 4% paraformaldehyde, were processed and the paraffin embedded tissue were serially sectioned at 5 &#x3bc;m thick to be stained using Haematoxylin and Eosin (H and E) stain, immuno-histochemistry for synaptophysin (p38) and astrocytes (GFAP) activities in the prefrontal cortex (PFC).<br><br>RESULTS: Findings showed that NAC prevented FST-induced anxiety-like behaviors demonstrated by an increased SPT (that alleviates anhedonia), mobility time, and reduced immobility time. NAC caused an increase in brain weights and prevented FST-induced neurodegeneration, the proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that seen in fluoxetine a standard anti-depressant drug.<br><br>CONCLUSION: NAC treatment significantly exhibits its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, which protects neurons and synapses from oxidative tissue damage induced by FST, hence an increase in synaptophysin activity that culminates in increased neural activity, increased SPT, and reduced immobility time.},
}
@article {pmid37318485,
year = {2023},
author = {Tang, W and Zhu, D and Wu, F and Xu, JF and Yang, JP and Deng, ZP and Chen, XB and Papi, A and Qu, JM},
title = {Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion.},
journal = {European review for medical and pharmacological sciences},
volume = {27},
number = {11},
pages = {5119-5127},
doi = {10.26355/eurrev_202306_32628},
pmid = {37318485},
issn = {2284-0729},
mesh = {Humans ; Acetylcysteine/therapeutic use ; Expectorants/therapeutic use ; *Ambroxol/therapeutic use ; *Respiration Disorders ; Mucus ; Double-Blind Method ; },
abstract = {OBJECTIVE: Evidence for the mucolytic and expectorant efficacy of intravenous (IV) N-acetylcysteine (NAC) is limited. This study aimed to evaluate in a large, multicenter, randomized, controlled, subject, and rater-blinded study whether IV NAC is superior to placebo and non-inferior to ambroxol in improving sputum viscosity and expectoration difficulty.<br><br>PATIENTS AND METHODS: A total of 333 hospitalized subjects from 28 centers in China with respiratory disease (such as acute bronchitis, chronic bronchitis and exacerbations, emphysema, mucoviscidosis, and bronchiectasis) and abnormal mucus secretion were randomly allocated in a 1:1:1 ratio to receive NAC 600 mg, ambroxol hydrochloride 30 mg, or placebo as an IV infusion twice daily for 7 days. Mucolytic and expectorant efficacy was assessed by ordinal categorical 4-point scales and analyzed by stratified and modified Mann-Whitney U statistics.<br><br>RESULTS: NAC showed consistent and statistically significant superiority to placebo and non-inferiority to ambroxol in change from baseline to day 7 in both sputum viscosity scores [mean (SD) difference 0.24 (0.763), p<0.001 vs. placebo] and expectoration difficulty score [mean (SD) difference 0.29 (0.783), p=0.002 vs. placebo]. Safety findings confirm the good tolerability profile of IV NAC reported from previous small studies, and no new safety concerns were identified.<br><br>CONCLUSIONS: This is the first large, robust study of the efficacy of IV NAC in respiratory diseases with abnormal mucus secretion. It provides new evidence for IV NAC administration in this indication in clinical situations where the IV route is preferred.},
}
@article {pmid37312532,
year = {2023},
author = {Gupta, M and Gupta, S and Sood, D and Gupta, A and Jesrani, G},
title = {Role of N-acetylcysteine in liver injury due to dengue fever.},
journal = {Tropical doctor},
volume = {53},
number = {4},
pages = {475-480},
doi = {10.1177/00494755231176317},
pmid = {37312532},
issn = {1758-1133},
mesh = {Humans ; Acetaminophen/toxicity ; *Acetylcysteine/therapeutic use ; *Dengue/complications/drug therapy ; *Liver Failure, Acute/drug therapy/etiology ; },
abstract = {Dengue fever (DF) is a common mosquito-borne viral infection which is endemic in Southeast Asia. Liver involvement may vary from asymptomatic elevation of liver enzymes to fulminant hepatitis. Although the valuable effects of N-acetylcysteine (NAC) in paracetamol toxicity and non-paracetamol liver failure have been extensively studied, its use in DF-associated hepatitis remains unclear. We made a literature search in an online format from libraries such as PubMed, Google Scholar, and EMBASE, and selected 33 articles including original research articles, case reports, and systemic analyses. The majority of the articles reviewed had a positive outcome but treatment strategies involved NAC together with supportive care. Hence, data on sole use of NAC from large randomised control trials remain unclear.},
}
@article {pmid37311880,
year = {2023},
author = {Li, J and Zhang, Y and Kong, D and Su, J and Wei, Y and Liu, X and Lu, S and Wang, J and Huang, F},
title = {Association between N-acetylcysteine treatment and in-hospital mortality in adult patients with acquired thrombotic thrombocytopenic purpura: a cohort study.},
journal = {Annals of hematology},
volume = {102},
number = {8},
pages = {2257-2265},
doi = {10.1007/s00277-023-05295-2},
pmid = {37311880},
issn = {1432-0584},
support = {GSWS2020006//Gusu Health Talents Programme/ ; SDFEYJC2105//Pre-Research Fund Project of the Second Affiliated Hospital of Soochow University/ ; },
mesh = {Humans ; Adult ; *Purpura, Thrombotic Thrombocytopenic/diagnosis ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Cohort Studies ; Hospital Mortality ; Plasma Exchange ; },
abstract = {Acquired thrombotic thrombocytopenic purpura (aTTP) is a fatal hematologic disease. Despite the currently high standards of care, some patients who develop refractory or recurrent disease still have a poor prognosis. Although N-acetylcysteine (NAC) is recommended for the treatment of aTTP, its use in aTTP treatment is still controversial. We aimed to evaluate the association of NAC with mortality in patients with aTTP. This was a retrospective cohort study of patients with aTTP with in-hospital mortality as the primary outcome and time to platelet recovery and neurological recovery as secondary outcomes. We used multifactorial COX regression analysis to check for an association of NAC with mortality. Moreover, we performed a sensitivity analysis check the stability of our results. Finally, 89 patients with aTTP were enrolled. After adjusting for potential confounders, we found NAC to be associated with 75% lower in-hospital mortality (HR = 0.25, 95% CI = 0.1-0.64). The results of sensitivity analyses performed remained stable as the risk of in-hospital mortality in patients reduced in patients with comorbid neurological symptoms (HR = 0.23, 95% CI = 0.06-0.89). However, NAC use did not affect the time to platelet recovery (HR = 1.19, 95% CI = 0.57-2.5) or neurological recovery (HR = 0.32, 95% CI = 0.08-1.25) in patients with aTTP. NAC treatment reduces in-hospital mortality in patients with aTTP but does not shorten the time to platelet recovery or neurological recovery.},
}
@article {pmid37309335,
year = {2023},
author = {Martini, N and Singla, P and Arbuckle, E and Goyal, G and Liu, Q and Santos-Zabala, ML and Zainah, H},
title = {SARS-CoV-2-Induced Autoimmune Hepatitis.},
journal = {Cureus},
volume = {15},
number = {5},
pages = {e38932},
pmid = {37309335},
issn = {2168-8184},
abstract = {Few case reports discuss the incidences of autoimmune hepatitis (AIH) in patients after SARS-CoV-2 infection. Here, we present a case of SARS-CoV-2-induced AIH in a male patient who came into the emergency department with complaints of weight loss, poor oral intake, nausea, dark-colored urine, clay-colored stools, and scleral icterus, which began two weeks after he tested positive for SARS-CoV-2 PCR. Liver biopsy and subsequent histology confirmed the diagnosis of AIH with the most probable etiology being SARS-CoV-2 infection. The patient was treated with N-acetylcysteine (NAC) and steroids with clinical improvement and eventual discharge home. Our goal is to provide a clinical presentation, treatment, and outcome in a patient with SARS-CoV-2-induced AIH.},
}
@article {pmid37302633,
year = {2023},
author = {He, H and Li, Q and Fang, L and Yang, W and Xu, F and Yan, Y and Mao, R},
title = {Comprehensive analysis of NAC transcription factors in Scutellaria baicalensis and their response to exogenous ABA and GA3.},
journal = {International journal of biological macromolecules},
volume = {244},
number = {},
pages = {125290},
doi = {10.1016/j.ijbiomac.2023.125290},
pmid = {37302633},
issn = {1879-0003},
mesh = {*Transcription Factors/genetics/metabolism ; *Abscisic Acid/pharmacology/metabolism ; Plant Growth Regulators/pharmacology/metabolism ; Scutellaria baicalensis ; Plant Breeding ; Gene Expression Regulation, Plant ; Plant Proteins/metabolism ; Acetylcysteine/analogs &amp; derivatives ; },
abstract = {The NAC is a plant-specific family of transcription factor that plays important roles in various biological processes. Scutellaria baicalensis Georgi, belongs to the Lamiaceae family and has been widely used as a traditional herb with a wide range of pharmacological activities, including antitumor, heat-clearing, and detoxifying functions. However, no study on the NAC family in S. baicalensis has been conducted to date. In the present study, we identified 56 SbNAC genes using genomic and transcriptome analyses. These 56 SbNACs were unevenly distributed across nine chromosomes and were phylogenetically divided into six clusters. Cis-element analysis identified plant growth and development-, phytohormone-, light-, and stress-responsive elements were present in SbNAC genes promoter regions. Protein-protein interaction analysis was performed using Arabidopsis homologous proteins. Potential transcription factors, including bHLH, ERF, MYB, WRKY, and bZIP, were identified and constructed a regulatory network with SbNAC genes. The expression of 12 flavonoid biosynthetic genes was significantly upregulated with abscisic acid (ABA) and gibberellin (GA3) treatments. Eight SbNAC genes (SbNAC9/32/33/40/42/43/48/50) also exhibited notable variation with two phytohormone treatments, among which SbNAC9 and SbNAC43 showed the most significant variation and deserved further study. Additionally, SbNAC44 displayed a positive correlation with C4H3, PAL5, OMT3, and OMT6, while SbNAC25 had negatively correlated with OMT2, CHI, F6H2, and FNSII-2. This study constitutes the first analysis of SbNAC genes and lays the basis foundation for further functional studies of SbNAC genes family members, while it may also facilitate the genetic improvement of plants and breeding of elite S. baicalensis varieties.},
}
@article {pmid37302535,
year = {2023},
author = {Scaramboni, C and Arruda Moura Campos, ML and Junqueira Dorta, D and Palma de Oliveira, D and Batistuzzo de Medeiros, SR and de Oliveira Galvão, MF and Dreij, K},
title = {Reactive oxygen species-dependent transient induction of genotoxicity by retene in human liver HepG2 cells.},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {91},
number = {},
pages = {105628},
doi = {10.1016/j.tiv.2023.105628},
pmid = {37302535},
issn = {1879-3177},
mesh = {Humans ; Reactive Oxygen Species ; Hep G2 Cells ; *Particulate Matter ; *DNA Damage ; Oxidative Stress ; Liver ; Phenanthrenes ; },
abstract = {Retene is a polycyclic aromatic hydrocarbon (PAH) emitted mainly by biomass combustion, and despite its ubiquity in atmospheric particulate matter (PM), studies concerning its potential hazard to human health are still incipient. In this study, the cytotoxicity and genotoxicity of retene were investigated in human HepG2 liver cells. Our data showed that retene had minimal effect on cell viability, but induced DNA strand breaks, micronuclei formation, and reactive oxygen species (ROS) formation in a dose- and time-dependent manner. Stronger effects were observed at earlier time points than at longer, indicating transient genotoxicity. Retene activated phosphorylation of Checkpoint kinase 1 (Chk1), an indicator of replication stress and chromosomal instability, which was in accordance with increased formation of micronuclei. A protective effect of the antioxidant N-acetylcysteine (NAC) towards ROS generation and DNA damage signaling was observed, suggesting oxidative stress as a key mechanism of the observed genotoxic effects of retene in HepG2 cells. Altogether our results suggest that retene may contribute to the harmful effects caused by biomass burning PM and represent a potential hazard to human health.},
}
@article {pmid37299425,
year = {2023},
author = {Fernández-Lázaro, D and Domínguez-Ortega, C and Busto, N and Santamaría-Peláez, M and Roche, E and Gutiérez-Abejón, E and Mielgo-Ayuso, J},
title = {Influence of N-Acetylcysteine Supplementation on Physical Performance and Laboratory Biomarkers in Adult Males: A Systematic Review of Controlled Trials.},
journal = {Nutrients},
volume = {15},
number = {11},
pages = {},
pmid = {37299425},
issn = {2072-6643},
mesh = {Male ; Adult ; Humans ; *Acetylcysteine/pharmacology ; *Antioxidants ; Dietary Supplements ; Glutathione ; Physical Functional Performance ; Biomarkers ; Randomized Controlled Trials as Topic ; },
abstract = {N-acetylcysteine (NAC) is used as a sports supplement for its ability to modulate exercise-induced oxidative damage through its antioxidant actions and maintenance of glutathione homeostasis, positioning NAC as a strategy to improve physical performance. We aimed to evaluate the current evidence on the benefits of NAC supplementation on physical performance and laboratory biomarkers in adult men. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically reviewed studies indexed in the Web of Science, Scopus, and PubMed to assess the effects of NAC on physical performance, laboratory biomarkers, and adverse effects in adult men. Original articles published up to 30 April 2023 with a controlled trial design comparing NAC supplementation with a control group were included. The modified McMaster Critical Review Form for Quantitative Studies was used as an assessment tool and the Cochrane Risk of Bias was applied. Of the 777 records identified in the search, 16 studies met the inclusion and exclusion criteria. Overall, most of the trials reported beneficial effects of NAC supplementation and no serious adverse events were reported. Participants supplemented with NAC showed significant improvements in exercise performance, antioxidant capacity, and glutathione homeostasis. However, there was no clear evidence of beneficial effects of NAC supplementation on haematological markers, inflammatory response, and muscle behaviour. NAC supplementation appears to be safe and may regulate glutathione homeostasis, have antioxidant effects, and improve exercise performance. However, further studies are needed to clarify the relevance of its use.},
}
@article {pmid37298254,
year = {2023},
author = {Tyuryaeva, I and Lyublinskaya, O},
title = {Expected and Unexpected Effects of Pharmacological Antioxidants.},
journal = {International journal of molecular sciences},
volume = {24},
number = {11},
pages = {},
pmid = {37298254},
issn = {1422-0067},
support = {21-74-20178//Russian Science Foundation/ ; },
mesh = {*Antioxidants/pharmacology ; *Acetylcysteine/pharmacology ; Hydrogen Peroxide ; Ascorbic Acid/pharmacology ; Polyphenols/pharmacology ; },
abstract = {In this review, we have collected the existing data on the bioactivity of antioxidants (N-acetylcysteine, polyphenols, vitamin C) which are traditionally used in experimental biology and, in some cases, in the clinic. Presented data show that, despite the capacity of these substances to scavenge peroxides and free radicals in cell-free systems, their ability to exhibit these properties in vivo, upon pharmacological supplementation, has not been confirmed so far. Their cytoprotective activity is explained mainly by the ability not to suppress, but to activate multiple redox pathways, which causes biphasic hormetic responses and highly pleiotropic effects in cells. N-acetylcysteine, polyphenols, and vitamin C affect redox homeostasis by generating low-molecular-weight redox-active compounds (H2O2 or H2S), known for their ability to stimulate cellular endogenous antioxidant defense and promote cytoprotection at low concentrations but exert deleterious effects at high concentrations. Moreover, the activity of antioxidants strongly depends on the biological context and mode of their application. We show here that considering the biphasic and context-dependent response of cells on the pleiotropic action of antioxidants can help explain many of the conflicting results obtained in basic and applied research and build a more logical strategy for their use.},
}
@article {pmid37297001,
year = {2023},
author = {Becker, AL and Indra, AK},
title = {Oxidative Stress in Melanoma: Beneficial Antioxidant and Pro-Oxidant Therapeutic Strategies.},
journal = {Cancers},
volume = {15},
number = {11},
pages = {},
pmid = {37297001},
issn = {2072-6694},
support = {ME210206P1//United States Department of Defense/ ; },
abstract = {Cutaneous melanoma ranks as the fifth most common cancer in the United States and represents one of the deadliest forms of skin cancer. While recent advances in systemic targeted therapies and immunotherapies have positively impacted melanoma survival, the survival rate of stage IV melanoma remains at a meager 32%. Unfortunately, tumor resistance can impede the effectiveness of these treatments. Oxidative stress is a pivotal player in all stages of melanoma progression, with a somewhat paradoxical function that promotes tumor initiation but hinders vertical growth and metastasis in later disease. As melanoma progresses, it employs adaptive mechanisms to lessen oxidative stress in the tumor environment. Redox metabolic rewiring has been implicated in acquired resistance to BRAF/MEK inhibitors. A promising approach to enhance the response to therapy involves boosting intracellular ROS production using active biomolecules or targeting enzymes that regulate oxidative stress. The complex interplay between oxidative stress, redox homeostasis, and melanomagenesis can also be leveraged in a preventive context. The purpose of this review is to provide an overview of oxidative stress in melanoma, and how the antioxidant system may be manipulated in a therapeutic context for improved efficacy and survival.},
}
@article {pmid37288204,
year = {2023},
author = {Turk, A and Ulas, M and Karadag, A and Kocaman, N and Onalan, E and Kuloglu, T},
title = {The Effects of N-acetylcysteine on Transient Receptor Potential Melastatin 2 Channels Activation and Expression in Testicular Tissue of Diabetic Rats.},
journal = {Cureus},
volume = {15},
number = {5},
pages = {e38661},
pmid = {37288204},
issn = {2168-8184},
abstract = {INTRODUCTION: Diabetes mellitus (DM) is a common, chronic metabolic disease that has harmful effects on many diverse tissues, including the testis. One of the ways of tissue damage is the modification of transient receptor potential melastatin 2 (TRPM2) channels by increased reactive oxygen species (ROS). In our study for the first time, it was aimed to investigate TRPM2 channel activation in testicular tissues of diabetic rats induced by streptozotosin (STZ) and to examine the efficacy of N-acetylcysteine (NAC) treatment, which is an antioxidant.<br><br>METHODS: In our study, 28 Wistar albino male rats aged 8-10 weeks were used, and animals were divided into four groups: control group, NAC group, DM group, and DM + NAC group. The experimental phase was designed as eight weeks. The malondialdehyde&#xa0;(MDA)&#xa0;level, which is an indicator for lipid peroxidation due to oxidative stress, was measured by the spectrophotometric method. The Tunel assay was used to determine apoptosis on testicular tissue. TRPM2 immunoreactivity was determined by the avidin-biotin-peroxidase complex method, and quantitative polymerase chain reaction (QPCR) was used to determine TRPM2 expression levels.<br><br>RESULTS: It was seen that MDA levels were significantly increased in the DM group and decreased after NAC treatment. Similarly, it was observed that apoptosis levels, which increased significantly in diabetic rats, decreased to the levels of the control group after treatment. It was seen that TRPM2 activation and expression levels were significantly decreased in the DM group.<br><br>CONCLUSION: &#xa0;The results of this study show that NAC regulates TRPM2 activation in the testicular tissue of patients with diabetes and has tissue-protective properties.},
}
@article {pmid37285741,
year = {2023},
author = {Luo, L and Pervaiz, S and Clement, MV},
title = {A superoxide-driven redox state promotes geroconversion and resistance to senolysis in replication-stress associated senescence.},
journal = {Redox biology},
volume = {64},
number = {},
pages = {102757},
pmid = {37285741},
issn = {2213-2317},
mesh = {*Superoxides/metabolism ; *Hydrogen Peroxide/metabolism ; Cellular Senescence ; Tumor Suppressor Protein p53/metabolism ; Oxidation-Reduction ; },
abstract = {Using S-phase synchronized RPE1-hTERT cells exposed to the DNA damaging agent, methyl methanesulfonate, we show the existence of a redox state associated with replication stress-induced senescence termed senescence-associated redox state (SA-redox state). SA-redox state is characterized by its reactivity with superoxide-sensing fluorescent probes such as dihydroethidine, lucigenin and mitosox and peroxynitrite or hydroxyl radical sensing probe hydroxyphenyl fluorescein (HPF) but not the hydrogen peroxide (H2O2) reactive fluorescent probe CM-H2DCFDA. Measurement of GSH and GSSH also reveals that SA-redox state mitigates the level of total GSH rather than oxidizes GSH to GSSG. Moreover, supporting the role of superoxide (O2[.-]) in the SA-redox state, we show that incubation of senescent RPE1-hTERT cells with the O2[.-] scavenger, Tiron, decreases the reactivity of SA-redox state with the oxidants' reactive probes lucigenin and HPF while the H2O2 antioxidant N-acetyl cysteine has no effect. SA-redox state does not participate in the loss of proliferative capacity, G2/M cell cycle arrest or the increase in SA-β-Gal activity. However, SA-redox state is associated with the activation of NF-κB, dictates the profile of the Senescence Associated Secretory Phenotype, increases TFEB protein level, promotes geroconversion evidenced by increased phosphorylation of S6K and S6 proteins, and influences senescent cells response to senolysis. Furthermore, we provide evidence for crosstalk between SA redox state, p53 and p21. While p53 mitigates the establishment of SA-redox state, p21 is critical for the sustained reinforcement of the SA-redox state involved in geroconversion and resistance to senolysis.},
}
@article {pmid37279380,
year = {2023},
author = {Liu, X and Hou, Y and Yang, M and Xin, X and Deng, Y and Fu, R and Xiang, X and Cao, N and Liu, X and Yu, W and Yang, B and Zhou, Y},
title = {N-Acetyl-l-cysteine-Derived Carbonized Polymer Dots with ROS Scavenging via Keap1-Nrf2 Pathway Regulate Alveolar Bone Homeostasis in Periodontitis.},
journal = {Advanced healthcare materials},
volume = {12},
number = {26},
pages = {e2300890},
doi = {10.1002/adhm.202300890},
pmid = {37279380},
issn = {2192-2659},
mesh = {Mice ; Humans ; Animals ; Reactive Oxygen Species/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; Acetylcysteine/pharmacology/metabolism ; NF-E2-Related Factor 2/metabolism ; Osteogenesis ; Antioxidants/metabolism ; Oxidative Stress ; *Periodontitis/drug therapy/metabolism ; *Bone Resorption ; Homeostasis ; },
abstract = {Periodontitis is a type of chronic inflammatory oral disease characterized by the destruction of periodontal connective tissue and progressive alveolar bone resorption. As oxidative stress is the key cause of periodontitis in the early periodontal microenvironment, antioxidative therapy has been considered a viable treatment for periodontitis. However, more stable and effective reactive oxygen species (ROS)-scavenging nanomedicines are still highly needed due to the instability of traditional antioxidants. Herein, a new type of N-acetyl-l-cysteine (NAC)-derived red fluorescent carbonized polymer dots (CPDs) has been synthesized with excellent biocompatibility, which can serve as an extracellular antioxidant to scavenge ROS effectively. Moreover, NAC-CPDs can promote osteogenic differentiation in human periodontal ligament cells (hPDLCs) under H2 O2 stimulation. In addition, NAC-CPDs are capable of targeted accumulation in alveolar bone in vivo, reducing the level of alveolar bone resorption in periodontitis mice, as well as performing fluorescence imaging in vitro and in vivo. In terms of mechanism, NAC-CPDs may regulate redox homeostasis and promote bone formation in the periodontitis microenvironment by modulating the kelch-like ECH-associated protein l (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. This study provides a new strategy for the application of CPDs theranostic nanoplatform for periodontitis.},
}
@article {pmid37278488,
year = {2023},
author = {Colli, A and Fraquelli, M and Prati, D and Casazza, G},
title = {Granulocyte colony-stimulating factor with or without stem or progenitor cell or growth factors infusion for people with compensated or decompensated advanced chronic liver disease.},
journal = {The Cochrane database of systematic reviews},
volume = {6},
number = {6},
pages = {CD013532},
pmid = {37278488},
issn = {1469-493X},
mesh = {Adult ; Humans ; *Esophageal and Gastric Varices/complications ; Quality of Life ; *Acute-On-Chronic Liver Failure/complications ; Gastrointestinal Hemorrhage ; Liver Cirrhosis/complications ; Stem Cells ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Intercellular Signaling Peptides and Proteins ; *Erythropoietin ; Growth Hormone ; },
abstract = {BACKGROUND: Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival.<br><br>OBJECTIVES: To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease.<br><br>SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type.<br><br>SELECTION CRITERIA: We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language.<br><br>DATA COLLECTION AND ANALYSIS: We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I[2] statistic values as a marker of heterogeneity. We assessed all outcomes at maximum follow-up. We determined the certainty of evidence using GRADE, evaluated the risk of small-study effects in regression analyses, and conducted subgroup and sensitivity analyses.<br><br>MAIN RESULTS: We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, &#x3b2;-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups. Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I[2] = 75%; 1419 participants; 20 trials). Very low-certainty evidence suggested no difference in serious adverse events (G-CSF alone or in combination versus placebo: RR 1.03, 95% CI 0.66 to 1.61; I[2] = 66%; 315 participants; three trials). Eight trials, with 518 participants, reported no serious adverse events. Two trials, with 165 participants, used two components of the quality of life score for assessment, with ranges from 0 to 100, where higher scores indicate better quality of life, with a mean increase from baseline of the physical component summary of 20.7 (95% CI 17.4 to 24.0; very low-certainty evidence) and a mean increase from baseline of the mental component summary of 27.8 (95% CI 12.3 to 43.3; very low-certainty evidence). G-CSF, alone or in combination, suggested a beneficial effect on the proportion of participants who developed one or more liver disease-related complications (RR 0.40, 95% CI 0.17 to 0.92; I[2] = 62%; 195 participants; four trials; very low-certainty evidence). When we analysed the occurrences of single complications, there was no suggestion of a difference between G-CSF, alone or in combination, versus control, in participants in need of liver transplantation (RR 0.85, 95% CI 0.39 to 1.85; 692 participants; five trials), in the development of hepatorenal syndrome (RR 0.65, 95% CI 0.33 to 1.30; 520 participants; six trials), in the occurrence of variceal bleeding (RR 0.68, 95% CI 0.37 to 1.23; 614 participants; eight trials), and in the development of encephalopathy (RR 0.56, 95% CI 0.31 to 1.01; 605 participants; seven trials) (very low-certainty evidence). The same comparison suggested that G-CSF reduces the development of infections (including sepsis) (RR 0.50, 95% CI 0.29 to 0.84; 583 participants; eight trials) and does not improve liver function scores (RR 0.67, 95% CI 0.53 to 0.86; 319 participants; two trials) (very low-certainty evidence).<br><br>AUTHORS' CONCLUSIONS: G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.},
}
@article {pmid37275759,
year = {2023},
author = {Karimi, M and Ghasemzadeh Rahbardar, M and Razavi, BM and Hosseinzadeh, H},
title = {Amifostine inhibits acrylamide-induced hepatotoxicity by inhibiting oxidative stress and apoptosis.},
journal = {Iranian journal of basic medical sciences},
volume = {26},
number = {6},
pages = {662-668},
pmid = {37275759},
issn = {2008-3866},
abstract = {OBJECTIVES: Acrylamide (ACR) is a toxic chemical agent that can induce hepatotoxicity through different mechanisms including oxidative stress and apoptosis. Amifostine is an important hepatoprotective and anti-oxidant compound. In this research, the hepatoprotective effect of amifostine on ACR-induced hepatotoxicity in rats has been investigated.<br><br>MATERIALS AND METHODS: Male Wistar rats were randomly divided into 7 groups, including: 1. Control group, 2. ACR (50 mg/kg, 11 days, IP), 3-5. ACR+ amifostine (25, 50, 100 mg/kg, 11 days, IP), 6. ACR+ N-acetyl cysteine (NAC) (200 mg/kg, 11 days, IP), and 7. Amifostine (100 mg/kg, 11 days, IP). At the end of the injection period, animals' liver samples were collected to determine the content of glutathione (GSH), malondialdehyde (MDA), and apoptotic proteins (B-cell lymphoma 2 (Bcl2), Bcl-2-associated X protein (Bax), and cleaved caspase-3. Serum samples were also collected to measure alanine transaminase (ALT) and aspartate transaminase (AST) levels.<br><br>RESULTS: Administration of ACR increased MDA, Bax/Bcl2 ratio, cleaved caspase-3, ALT, and AST levels, and decreased GSH content compared with the control group. The administration of amifostine with ACR decreased MDA, Bax/Bcl2 ratio, cleaved caspase-3, ALT, and AST levels, and increased GSH content compared with the ACR group. Receiving NAC along with ACR reversed the alterations induced by ACR.<br><br>CONCLUSION: This study shows that pretreatment with amifostine can reduce ACR-induced toxicity in the liver tissue of rats. Since oxidative stress is one of the most important mechanisms in ACR toxicity, amifostine probably reduces the toxicity of ACR by increasing the anti-oxidant and anti-apoptotic capacity of the hepatic cells.},
}
@article {pmid37271412,
year = {2023},
author = {Herbst, ED and Pennington, DL and Borsari, B and Manuel, J and Yalch, M and Alcid, E and Martinez Rivas, M and Delacruz, J and Rossi, N and Garcia, B and Wong, N and Batki, SL},
title = {N-acetylcysteine for smoking cessation among dual users of tobacco and cannabis: Protocol and rationale for a randomized controlled trial.},
journal = {Contemporary clinical trials},
volume = {131},
number = {},
pages = {107250},
pmid = {37271412},
issn = {1559-2030},
support = {I21 HX003410/HX/HSRD VA/United States ; IK2 CX001510/CX/CSRD VA/United States ; R25 MH060482/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; Humans ; *Smoking Cessation/methods ; *Cannabis ; Acetylcysteine/therapeutic use ; *Tobacco Use Disorder/therapy ; Randomized Controlled Trials as Topic ; },
abstract = {BACKGROUND: Tobacco and cannabis co-use is a growing public health problem. The synergistic effects of cannabis and nicotine on neurobiological systems that mediate reward and shared environmental cues reinforcing use may make tobacco smoking cessation more difficult. N-acetylcysteine (NAC), an FDA-approved medication and over-the-counter supplement, has shown promise in animal studies and randomized controlled trials (RCTs) in reducing tobacco and cannabis craving and use. NAC's potential efficacy in treating addiction may be attributable to its central nervous system effects in reducing excessive glutamatergic activity, oxidative stress, and inflammation. To date, no RCT has examined NAC for smoking cessation among dual users of tobacco and cannabis.<br><br>METHOD: In a double-blind, placebo-controlled RCT, we will examine NAC for smoking cessation among dual users of tobacco and cannabis. Sixty adult cigarette-cannabis co-users are randomized to receive NAC 3600&#xa0;mg per day or placebo over 8&#xa0;weeks. Participants in both groups receive 8 weekly cognitive behavioral therapy sessions addressing smoking cessation and cannabis reduction. Outcomes are assessed at Weeks 0, 4, 8, and 12. Primary aims are to determine NAC's efficacy in decreasing cigarette craving, nicotine dependence, and use; and cannabis craving and use. Exploratory aims include examination of changes in neurocognition with NAC and their potential mediational effects on cigarette and cannabis use outcomes.<br><br>CONCLUSION: Results will inform smoking cessation treatment among dual users of tobacco and cannabis.<br><br>CLINICALTRIALS: gov Identifier: NCT04627922.},
}
@article {pmid37271104,
year = {2023},
author = {Fujiwara, N and Yamashita, S and Okamoto, M and Cooley, MA and Ozaki, K and Everett, ET and Suzuki, M},
title = {Perfluorooctanoic acid-induced cell death via the dual roles of ROS-MAPK/ERK signaling in ameloblast-lineage cells.},
journal = {Ecotoxicology and environmental safety},
volume = {260},
number = {},
pages = {115089},
pmid = {37271104},
issn = {1090-2414},
support = {K02 DE029531/DE/NIDCR NIH HHS/United States ; R01 DE027648/DE/NIDCR NIH HHS/United States ; },
mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Ameloblasts/metabolism ; Cell Death ; Necrosis ; Caprylates ; Fluorocarbons ; },
abstract = {Perfluorooctanoic acid (PFOA) is an artificial fluorinated organic compound that has generated increased public attention due to its potential health hazards. Unsafe levels of PFOA exposure can affect reproduction, growth and development. During tooth enamel development (amelogenesis), environmental factors including fluoride can cause enamel hypoplasia. However, the effects of PFOA on ameloblasts and tooth enamel formation remain largely unknown. In the present study we demonstrate several PFOA-mediated cell death pathways (necrosis/necroptosis, and apoptosis) and assess the roles of ROS-MAPK/ERK signaling in PFOA-mediated cell death in mouse ameloblast-lineage cells (ALC). ALC cells were treated with PFOA. Cell proliferation and viability were analyzed by MTT assays and colony formation assays, respectively. PFOA suppressed cell proliferation and viability in a dose dependent manner. PFOA induced both necrosis (PI-positive cells) and apoptosis (cleaved-caspase-3, γH2AX and TUNEL-positive cells). PFOA significantly increased ROS production and up-regulated phosphor-(p)-ERK. Addition of ROS inhibitor N-acetyl cysteine (NAC) suppressed p-ERK and decreased necrosis, and increased cell viability compared to PFOA alone, whereas NAC did not change apoptosis. This suggests that PFOA-mediated necrosis was induced by ROS-MAPK/ERK signaling, but apoptosis was not associated with ROS. Addition of MAPK/ERK inhibitor PD98059 suppressed necrosis and increased cell viability compared to PFOA alone. Intriguingly, PD98059 augmented PFOA-mediated apoptosis. This suggests that p-ERK promoted necrosis but suppressed apoptosis. Addition of the necroptosis inhibitor Necrostatin-1 restored cell viability compared to PFOA alone, while pan-caspase inhibitor Z-VAD did not mitigate PFOA-mediated cell death. These results suggest that 1) PFOA-mediated cell death was mainly caused by necrosis/necroptosis by ROS-MAPK/ERK signaling rather than apoptosis, 2) MAPK/ERK signaling plays the dual roles (promoting necrosis and suppressing apoptosis) under PFOA treatment. This is the initial report to indicate that PFOA could be considered as a possible causative factor for cryptogenic enamel malformation. Further studies are required to elucidate the mechanisms of PFOA-mediated adverse effects on amelogenesis.},
}
@article {pmid37270170,
year = {2023},
author = {Guo, Y and Zhou, A and Zhang, Y and Chen, Y and Chen, Y and Gao, Y and Miao, X},
title = {Serum response factor activates peroxidasin transcription to block senescence of hepatic stellate cells.},
journal = {Life sciences},
volume = {328},
number = {},
pages = {121824},
doi = {10.1016/j.lfs.2023.121824},
pmid = {37270170},
issn = {1879-0631},
mesh = {Mice ; Animals ; *Hepatic Stellate Cells/metabolism ; *Serum Response Factor/genetics/metabolism ; Liver Cirrhosis/pathology ; Liver/metabolism ; Extracellular Matrix Proteins/metabolism ; Mice, Knockout ; Peroxidasin ; },
abstract = {AIMS: Aberrant liver fibrosis is a hallmark event in end-stage liver diseases. Hepatic stellate cells (HSCs) are considered the major source of myofibroblasts in the liver that produce extracellular matrix proteins to promote liver fibrosis. HSCs undergo senescence in response to various stimuli, a process that can be exploited to dampen liver fibrosis. We investigated the role of serum response factor (SRF) in this process.<br><br>METHODS AND MATERIALS: Senescence was induced HSCs by serum withdrawal or progressive passage. DNA-protein interaction was evaluated by chromatin immunoprecipitation (ChIP).<br><br>RESULTS: SRF expression was down-regulated in HSCs entering into senescence. Coincidently, SRF depletion by RNAi accelerated HSC senescence. Of note, treatment of an anti-oxidant (N-acetylcysteine or NAC) blocked HSC senescence by SRF deficiency suggesting that SRF may antagonize HSC senescence by eliminating excessive reactive oxygen species (ROS). PCR-array based screening identified peroxidasin (PXDN) as a potential target for SRF in HSCs. PXDN expression was inversely correlated with HSC senescence whereas PXDN knockdown accelerated HSC senescence. Further analysis reveals that SRF directly bound to the PXDN promoter and activated PXDN transcription. Consistently, PXDN over-expression protected whereas PXDN depletion amplified HSC senescence. Finally, PXDN knockout mice displayed diminished liver fibrosis compared to wild type mice when subjected to bile duct ligation (BDL).<br><br>SIGNIFICANCE: Our data suggest that SRF, via its downstream target PXDN, plays a key role in regulating HSC senescence.},
}
@article {pmid37266883,
year = {2023},
author = {Guo, W and Jing, W},
title = {N-Acetyl-L-Cysteine Reduces Cervical Carcinogenesis by Promoting Apoptosis.},
journal = {Drugs in R&amp;D},
volume = {23},
number = {2},
pages = {165-174},
pmid = {37266883},
issn = {1179-6901},
mesh = {Humans ; Female ; Animals ; Mice ; *Uterine Cervical Neoplasms/drug therapy/genetics/pathology ; Acetylcysteine/pharmacology/therapeutic use ; Cell Line, Tumor ; *Papillomavirus Infections/metabolism ; Apoptosis ; Carcinogenesis ; },
abstract = {BACKGROUND AND OBJECTIVE: Cervical cancer is the fourth leading cause of cancer death in women, and is one of the most common malignant tumors of the reproductive system. However, more effective treatment for cervical cancer is needed. In this study, we aim to investigate whether N-acetyl-L-cysteine (NAC) could inhibit the proliferation of human papillomavirus (HPV)-positive cells, and reduce cervical carcinogenesis.<br><br>METHODS: The cervical cancer cell lines SiHa, HeLa, HPV-negative cell line C33A, and the immortalized human cervical keratinocyte cells S12 were used. The protein expression was determined using Western blot assay. mRNA expression was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation was determined by Cell Counting Kit-8 assay. Cell apoptosis was evaluated using Annexin V-FITC apoptosis kits. The numbers of colonies were measured using colony-forming assay. Xenograft tumor necrosis and HPV16 E7 expression were determined using hematoxylin and eosin (H&amp;E) staining and immunohistochemistry.<br><br>RESULTS: Our results showed that NAC treatment at the concentration of 1.5&#xa0;mM significantly promoted cell apoptosis and reduced cell growth by inhibiting HPV16 E7 expression. NAC inhibited HPV16-oncoprotein-induced hypoxia-inducible factor (HIF)-1&#x3b1; protein expression and Akt activation in&#xa0;vitro. Additionally, NAC suppressed tumor growth, as evidenced by the smaller tumor size in the xenograft mouse model and decreased HPV16 E7 expression in tumor tissues.<br><br>CONCLUSION: Our findings demonstrate that NAC exhibits the potential to promote HPV-positive cell apoptosis, and suppress the proliferation of HPV-positive cells by inhibiting cell inhibitor of apoptosis protein 2 and HIF-1&#x3b1;.},
}
@article {pmid37264973,
year = {2023},
author = {Sun, J and Wang, Y and Du, Y and Zhang, W and Liu, Z and Bai, J and Cui, G and Du, Z},
title = {Involvement of the JNK/HO‑1/FTH1 signaling pathway in nanoplastic‑induced inflammation and ferroptosis of BV2 microglia cells.},
journal = {International journal of molecular medicine},
volume = {52},
number = {1},
pages = {},
pmid = {37264973},
issn = {1791-244X},
mesh = {Humans ; *Ferroptosis ; Microplastics/metabolism/pharmacology ; Microglia/metabolism ; MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Inflammation/metabolism ; Ferritins/metabolism/pharmacology ; Oxidoreductases/metabolism/pharmacology ; },
abstract = {Nanoplastics (NPs) are a newly discovered type of environmental pollutant. The potential for neurotoxicity caused by NPs and their mechanisms are unclear. The present study aimed to determine the molecular mechanism underlying neurotoxicity induced by NPs. Microglia (BV2) cells were used for in vitro studies, and it was found that NPs invaded cells, activated inflammasomes, induced the release of significant quantities of inflammatory factors by detection of inflammatory response‑associated proteins through Western blot and ELISA. By detection of FITC, SOD, GSH, cellular iron level, and ferroptosis‑related proteins, it was found that NPs compromised the anti‑oxidative mechanisms of cells, increased intracellular lipid peroxidation and Fe2+ concentration and triggered inflammatory reactions and ferroptosis. Pretreatment with reactive oxygen species (ROS) inhibitor N‑acetylcysteine (NAC) alleviated induction of inflammatory reactions and ferroptosis of cells. In addition, inhibiting expression of c‑Jun N‑terminal kinase (JNK) increased expression of heme oxygenase (HO‑1), resulting in decreased ferroptosis, indicating that the JNK/HO‑1 signaling pathway was involved in NP‑induced effects on ferroptosis in BV2 cells. In conclusion, NPs could induce inflammatory responses and ferroptosis in BV2 cells. JNK/HO‑1 mediated ferroptosis may serve an important role in the toxicity of microglia induced by NPs. This study provided novel evidence for the toxic effects of NPs and highlighted a theoretical mechanistic basis for safe prevention and treatment of plastic pollution‑induced neurotoxicity.},
}
@article {pmid37263335,
year = {2023},
author = {Zong, Q and Peng, X and Ding, Y and Wu, H and Lu, C and Ye, J and Sun, W and Zhang, J and Zhai, Y},
title = {Multifunctional hydrogel wound dressing with rapid on-demand degradation property based on aliphatic polycarbonate and chitosan.},
journal = {International journal of biological macromolecules},
volume = {244},
number = {},
pages = {125138},
doi = {10.1016/j.ijbiomac.2023.125138},
pmid = {37263335},
issn = {1879-0003},
mesh = {Humans ; *Chitosan ; Hydrogels/pharmacology ; Antioxidants/pharmacology ; Anti-Bacterial Agents/pharmacology ; Bandages ; Carbonates ; Polycarboxylate Cement ; },
abstract = {The multifunctional hydrogel dressings are effective strategy to treat chronic wounds of diabetes. In addition, the ability of selective degradation on demand to change dressings could provide better patient compliance. Here, an injectable, self-healing hydrogel with rapid degradability on-demand is designed to promote the healing of diabetes wounds. The block copolymer formed by aldehyde modified aliphatic cyclic carbonate monomer with polyethylene glycol (MBP) and chitosan (CS) were crosslinked through the Schiff base bond to obtain a hydrogel with excellent injectability and self-healing ability. Due to the presence of carbonate bonds in MBP, it showed the rapid on-demand degradation characteristics triggered by N-acetylcysteine (NAC). At the same time, gallic acid (GA) was loaded into the hydrogel, giving the hydrogel dressing antioxidant. In vivo and in vitro experiments showed that the hydrogel wound dressing possesses good natures, such as antibacterial, antioxidant, and friendly cell compatibility, which could promote wound healing. Overall, the multifunctional hydrogel wound dressings with rapid on-demand degradation characteristics are more practical for clinical applications.},
}
@article {pmid37260659,
year = {2023},
author = {Alaska, YA and Alghadeer, SM and Alrabiah, AA and Harb, A and Almadi, B},
title = {Assessment of N-acetylcysteine use for acetaminophen overdose in the emergency department of a community teaching hospital: A pilot study.},
journal = {Saudi journal of anaesthesia},
volume = {17},
number = {2},
pages = {168-173},
pmid = {37260659},
issn = {1658-354X},
abstract = {INTRODUCTION: N-acetylcysteine (NAC) is the first-line treatment for acetaminophen (APAP) overdose. However, using NAC inappropriately is associated with an increased risk of adverse effects as well as a substantial increase in hospitalization and healthcare costs. This study aims to assess NAC utilization for acute APAP overdose in the emergency department of a community teaching hospital in Saudi Arabia.<br><br>METHODS: A retrospective chart review in which the patients initiated on an NAC secondary to acute APAP overdose at KSUMC during the period of June 2015 till November 2018 were included and assessed based on developed validated evident-based protocol for administering NAC for acute APAP ingestion.<br><br>RESULTS: A total of 29 patients received NAC treatment for acute APAP overdose; 15 of which were adults, and 14 were pediatrics. Appropriate prescribing of NAC was observed in 14 (48.28%) patients, whereas NAC was inappropriately indicated for 15 (51.72%) patients; 9 of them were adults and 6 patients were pediatric. APAP-Ingestion <150 mg/kg (<200 mg/kg in children) was the most common reason for inappropriate use (n = 7, 46.67%) followed by administering NAC <4 hours post-APAP ingestion (n = 4, 26.67%).<br><br>CONCLUSION: Improper NAC administration appears to be a significant issue among patients with APAP overdose. The utilization of a protocol for the management of APAP overdose will reduce the unnecessary usage of NAC.},
}
@article {pmid37259793,
year = {2023},
author = {Li, G and Chen, Y and Wu, M and Chen, K and Zhang, D and Zhang, R and Yang, G and Huang, X},
title = {Di (2-ethyl) hexyl phthalate induces liver injury in chickens by regulating PTEN/PI3K/AKT signaling pathway via reactive oxygen species.},
journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP},
volume = {270},
number = {},
pages = {109639},
doi = {10.1016/j.cbpc.2023.109639},
pmid = {37259793},
issn = {1532-0456},
mesh = {Animals ; Female ; Male ; Apoptosis/physiology ; *Chickens/metabolism ; *Diethylhexyl Phthalate/toxicity ; Liver/metabolism ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; PTEN Phosphohydrolase/genetics/metabolism ; Reactive Oxygen Species/metabolism ; RNA, Messenger/metabolism ; Signal Transduction ; Phthalic Acids ; },
abstract = {Di (2-ethyl) hexyl phthalate (DEHP) is a common environmental endocrine disruptor that induces oxidative stress, posing a significant threat to human and animal health. Oxidative stress can activate the PTEN/PI3K/AKT pathway, which is closely related to cell apoptosis. However, it is unclear whether DEHP induces apoptosis of chicken liver cells by regulating the PTEN/PI3K/AKT pathway through oxidative stress. In this experiment, male laying hens were continuously exposed to 400 mg/kg, 800 mg/kg, and 1600 mg/kg DEHP for 14 d, 28 d, and 42 d. The results showed that liver injury was aggravated with the dose of DEHP gavage, and the ROS/MDA levels in L, M, and H DEHP exposure groups were significantly increased, while the T-AOC/T-SOD/GSH-PX levels were decreased. Meanwhile, DEHP exposure up-regulated the mRNA and protein expression levels of PTEN/Bax/Caspase-9/Caspase-3 and down-regulated the mRNA and protein expression levels of PI3K/AKT/BCL-2, indicating that DEHP may lead to hepatocyte apoptosis through ROS regulation of PTEN/PI3K/AKT axis. In order to further clarify the relationship between oxidative stress and liver injury, we treated chicken hepatocellular carcinoma cell line (LMH) with 2.5 mM N-acetylcysteine (NAC). NAC attenuated these phenomena. In summary, our study suggests that DEHP can induce apoptosis of chicken liver through ROS activation of the PTEN/PI3K/AKT axis.},
}
@article {pmid37257582,
year = {2023},
author = {Peng, H and Zhang, J and Zhang, Z and Turdi, S and Han, X and Liu, Q and Hu, H and Ye, H and Dong, M and Duan, Y and Yang, Y and Ashrafizadeh, M and Rabiee, N and Ren, J},
title = {Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced cardiac anomalies through reconciliation of autophagy and ferroptosis.},
journal = {Life sciences},
volume = {328},
number = {},
pages = {121821},
doi = {10.1016/j.lfs.2023.121821},
pmid = {37257582},
issn = {1879-0631},
mesh = {Mice ; Animals ; *Ferroptosis ; Lipopolysaccharides/pharmacology ; Caspase 3/metabolism ; Catalase/metabolism ; Antioxidants/pharmacology/metabolism ; Myocytes, Cardiac/metabolism ; *Heart Defects, Congenital/metabolism ; Autophagy ; },
abstract = {Lipopolysaccharide (LPS) from Gram-negative bacteria is a major contributor to cardiovascular failure, but the signaling mechanisms underlying its stress response are not fully understood. This study aimed to investigate the effect of the antioxidant enzyme catalase on LPS-induced cardiac abnormalities and the mechanisms involved, with particular focus on the interplay between autophagy, ferroptosis, and apoptosis. Cardiac-specific catalase (CAT) overexpression and wild-type (WT) mice were stimulated with LPS (6 mg/kg, intravenous injection), and cardiac morphology and function were evaluated. Oxidative stress, ferroptosis, apoptosis, and mitochondrial status were monitored, and survival curves were plotted based on the results of LPS stimulation. The results showed that, compared with WT mice, mice overexpressing catalase had a higher survival rate under LPS stimulation. Ultrasound echocardiography, cardiomyocyte characteristics, and Masson's trichrome staining showed that LPS inhibited cardiac function and caused cardiac fibrosis, while catalase alleviated these adverse effects. LPS increased apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), increased O2[·-] production, induced inflammation (TNF-α), autophagy, iron toxicity, and carbonyl damage, and significantly damaged mitochondria (mitochondrial membrane potential, mitochondrial proteins, and ultrastructure). These effects were significantly alleviated by catalase. Interestingly, the antioxidant N-acetylcysteine, autophagy inhibitor 3-methyladenine, and ferroptosis inhibitor lipostatin-1 all eliminated the LPS-induced contraction dysfunction and ferroptosis (using lipid peroxidation). Induction of ferroptosis could eliminate the cardioprotective effect of NAC. In conclusion, catalase rescues LPS-induced cardiac dysfunction by regulating oxidative stress, autophagy, ferroptosis, apoptosis, and mitochondrial damage in cardiomyocytes.},
}
@article {pmid37256605,
year = {2023},
author = {Wu, S and Shi, Y and Jiang, L and Bu, W and Zhang, K and Lin, W and Pan, C and Xu, Z and Du, J and Chen, H and Wang, H},
title = {N-Acetylcysteine-Derived Carbon Dots for Free Radical Scavenging in Intervertebral Disc Degeneration.},
journal = {Advanced healthcare materials},
volume = {12},
number = {24},
pages = {e2300533},
doi = {10.1002/adhm.202300533},
pmid = {37256605},
issn = {2192-2659},
mesh = {Humans ; *Intervertebral Disc Degeneration/drug therapy/metabolism ; Acetylcysteine/pharmacology/metabolism ; Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; *Nucleus Pulposus/metabolism/pathology ; },
abstract = {Intervertebral disc degeneration (IVDD) is associated with oxidative stress induced reactive oxygen species (ROS) dynamic equilibrium disturbance. Nanozymes, as nanomaterials with enzyme-like activity, can regulate intro-cellular ROS levels. In this study, a new carbon dots nanozyme, N-acetylcysteine-derived carbon dots (NAC-CDs), is developed and proved to be an ideal antioxidant and anti-senescent agent in IVDD management. The results confirmed the NAC-CDs have satisfactory biocompatibility and strong superoxide dismutase (250 U mg[-1]), catalase, glutathioneperoxidase-like activity, and total antioxidant capacity. Then, the powerful free radical scavenging and antioxidant ability of NAC-CDs are demonstrated in vitro as observing the reduced ROS in H2 O2 induced senescent nucleus pulposus cells (NPCs), in which the elimination efficiency of toxic ROS is more than 90%. NAC-CDs also maintained mitochondrial homeostasis and suppressed cellular senescence, subsequently inhibited the expression of inflammatory factors in NPCs. In vivo, evaluations of imaging and tissue morphology assessments suggested that disc height index, magnetic resonance imaging grade and histological score are significantly improved from the degenerative models when NAC-CDs is applied. In conclusion, the study developed a novel carbon dots nanozyme, which efficiently rescues IVDD from ROS induced NPCs senescence and provides a potential strategy in management of IVDD in clinic.},
}
@article {pmid37256235,
year = {2023},
author = {Yang, K and Kim, HH and Shim, YR and Ryu, T and Kim, CW},
title = {Comprehensive transcriptomic analysis and meta-analysis identify therapeutic effects of N-acetylcysteine in nonalcoholic fatty liver disease.},
journal = {Frontiers in pharmacology},
volume = {14},
number = {},
pages = {1186582},
pmid = {37256235},
issn = {1663-9812},
abstract = {Introduction: The continuous rise in the prevalence of nonalcoholic fatty liver disease (NAFLD) is emerging as a global health issue. Although the protective effects of N-acetylcysteine (NAC), an antioxidant, against various diseases have been reported, it is still unclear whether NAC has therapeutic potential in NAFLD. Thus, the present meta-analysis aimed to investigate the efficacy of NAC on NAFLD in preclinical studies. Methods: By searching PubMed, Web of Science, and Cochrane Library, 13 studies were included. The methodological quality was assessed based on the SYstematic Review Centre for Laboratory animal Experimentation guideline, and heterogeneity was evaluated with I [2] and p values. Publication bias was assessed by Egger's test and sensitivity analysis was performed. Results: The results showed that NAC treatment significantly improved systemic and hepatic lipid metabolism (p < 0.01), inflammation-related liver injury (p < 0.01), glucose intolerance (p < 0.05), and hepatic steatosis (p < 0.01) by restoring hepatic glutathione (GSH) (p < 0.05) and GSH reductase (p < 0.05) levels compared to controls in NAFLD-induced animals. Consistently, in bulk, single-cell, and spatial transcriptomics data, the abovementioned target pathways of NAC were strongly associated with NAFLD development in mice and patients. Conclusion: Our study suggests that NAC has therapeutic potential for NAFLD and should be considered for future clinical trials.},
}
@article {pmid37254915,
year = {2023},
author = {Vishnevetskii, DV and Averkin, DV and Efimov, AA and Lizunova, AA and Shamova, OV and Vladimirova, EV and Sukhareva, MS and Mekhtiev, AR},
title = {L-Cysteine and N-acetyl-L-cysteine-mediated synthesis of nanosilver-based sols and hydrogels with antibacterial and antibiofilm properties.},
journal = {Journal of materials chemistry. B},
volume = {11},
number = {25},
pages = {5794-5804},
doi = {10.1039/d3tb00261f},
pmid = {37254915},
issn = {2050-7518},
mesh = {Humans ; *Acetylcysteine/pharmacology ; Hydrogels/pharmacology ; *Metal Nanoparticles/chemistry ; Silver/pharmacology/chemistry ; Microbial Sensitivity Tests ; Anti-Bacterial Agents/chemistry ; Bacteria ; Biofilms ; },
abstract = {The need of the synthesis of a new generation of medicines aimed at combating bacteria and biofilms that cause various infections is a great urgency. There has been a gradual decrease in the conventional techniques of treatment with the use of antibiotics. Consequently, much effort has focused on the search for new methods and approaches to obtain antibacterial drugs and determine their rational use such that microorganisms do not acquire resistance. Although silver nanoparticles (AgNPs) and silver nanoclusters (AgNCs) have exhibited certain levels of effectiveness against multidrug-resistant bacteria and biofilms, there are very few simple, cheap and easy-to-scale methods to obtain AgNPs and AgNCs with well-desired characteristics. In this study, we carried out the one-pot synthesis of sols and gels containing AgNPs and AgNCs using only L-cysteine (CYS) or N-acetyl-L-cysteine (NAC), as bioreducing/capping/gel-forming agents, and different silver salts - nitrate, nitrite and acetate. HRTEM, SAED, EDX mapping, AFM, SEM, EDX, ICP-MS and FTIR spectroscopy analysis confirmed the formation of spherical/elliptical CYS-AgNP and NAC-AgNC particles consisting of AgNPs or AgNCs "core" and CYS/Ag[+] or NAC/Ag[+] complexes "shell" with mean average diameters of 10 and 5 nm, respectively. UV-Vis spectroscopy fixed the localized surface plasmon resonance (LSPR) at 390-420 nm for the CYS-AgNPs systems and LSPR absence for the NAC-AgNCs ones. DLS and nanoparticle tracking analysis (NTA) data indicated that the mean average diameter of the particles is about 80 nm for the CYS-AgNPs systems and 20 nm for the NAC-AgNCs ones. The Zeta potential measurements showed that the particles possess positive and negative charge values for CYS-AgNPs and NAC-AgNCs systems, respectively. The prepared materials demonstrated the high antibacterial activity against the most common types of bacteria at the MIC range of 10-100 μM, wherein the effect of the NAC-AgNCs systems is 2 times stronger than that of the CYS-AgNPs ones. Both systems are non-toxic or have low-toxicity at 300 μM for normal human cells: erytrocytes, fibroblasts and macrophages. Sols and hydrogels in the concentration range of 20-40 μM showed the complete inhibition of the formation of biofilms from Acinetobacter baumannii and Pseudomonas aeruginosa, which belong to the ESKAPE pathogenes group and represent the most serious problem in practical medicine. NAC-AgNCs systems were the most active. The simple strategy of the preparation of AgNP/AgNC-based sols and gels, along with their pronounced antibacterial and antibiofilm activity, could open new perspectives for its applications in medicine.},
}
@article {pmid37248505,
year = {2023},
author = {Sun, D and Zhang, G and Xie, M and Wang, Y and Liang, X and Tu, M and Su, Z and Zeng, R},
title = {Softness enhanced macrophage-mediated therapy of inhaled apoptotic-cell-inspired nanosystems for acute lung injury.},
journal = {Journal of nanobiotechnology},
volume = {21},
number = {1},
pages = {172},
pmid = {37248505},
issn = {1477-3155},
support = {210715094530570//Science and Technology Planning Project of Shaoguan/ ; 2021KQNCX085//Foundation for Young Talents in Higher Education of Guangdong/ ; 31971270//National Natural Science Foundation of China/ ; 31370974//National Natural Science Foundation of China/ ; 2020B1515120078//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 202002020001//Science and Technology Program of Guangzhou/ ; },
mesh = {Mice ; Animals ; *Lung/metabolism ; *Acute Lung Injury/chemically induced/drug therapy ; Macrophages/metabolism ; Acetylcysteine/metabolism/pharmacology/therapeutic use/analogs &amp; derivatives ; Lysine/analogs &amp; derivatives ; },
abstract = {Engineered nanosystems offer a promising strategy for macrophage-targeted therapies for various diseases, and their physicochemical parameters including surface-active ligands, size and shape are widely investigated for improving their therapeutic efficacy. However, little is known about the synergistic effect of elasticity and surface-active ligands. Here, two kinds of anti-inflammatory N-acetylcysteine (NAC)-loaded macrophage-targeting apoptotic-cell-inspired phosphatidylserine (PS)-containing nano-liposomes (PSLipos) were constructed, which had similar size and morphology but different Young's modulus (E) (H, ~ 100 kPa > Emacrophage vs. L, ~ 2 kPa < Emacrophage). Interestingly, these PSLipos-NAC showed similar drug loading and encapsulation efficiency, and in vitro slow-release behavior of NAC, but modulus-dependent interactions with macrophages. Softer PSLipos-L-NAC could resist macrophage capture, but remarkably prolong their targeting effect period on macrophages via durable binding to macrophage surface, and subsequently more effectively suppress inflammatory response in macrophages and then hasten inflammatory lung epithelial cell wound healing. Especially, pulmonary administration of PSLipos-L-NAC could significantly reduce the inflammatory response of M1-like macrophages in lung tissue and promote lung injury repair in a bleomycin-induced acute lung injury (ALI) mouse model, providing a potential therapeutic approach for ALI. The results strongly suggest that softness may enhance ligand-directed macrophage-mediated therapeutic efficacy of nanosystems, which will shed new light on the design of engineered nanotherapeutics.},
}
@article {pmid37247196,
year = {2023},
author = {Ferretti, S and Curatola, A and Chiaretti, A and Graglia, B and Gatto, A and Capossela, L and Pansini, V},
title = {Early treatment with N-acetylcysteine reduces hepatotoxicity in acute acetaminophen poisoning.},
journal = {Acta bio-medica : Atenei Parmensis},
volume = {94},
number = {S1},
pages = {e2023033},
doi = {10.23750/abm.v94iS1.13714},
pmid = {37247196},
issn = {2531-6745},
mesh = {Adult ; Child ; Female ; Adolescent ; Humans ; Acetylcysteine/therapeutic use ; Acetaminophen/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology/prevention &amp; control ; *Drug Overdose/drug therapy ; *COVID-19 ; *Digestive System Diseases ; },
abstract = {During the outbreak of COVID19 measures taken to contain the spread of the virus have influenced the mental well-being of adults and adolescents. Acetaminophen overdose is the major cause of drug intoxication among children and adolescents. We reported a case of a 15-year- old girl referred to our Emergency Department 3 hours after ingestion of 10 g of paracetamol for suicidal purposes. She promptly started the administration of intravenous N-acetylcysteine (NAC) and the patient was discharged after 5 days of hospitalization in good clinical condition and with neuropsychiatric follow-up. Our case shows that the timing of the intravenous NAC administration is considered the most important factor in the prevention of acetaminophen-induced hepatic failure, despite high serum levels after acetaminophen ingestion.},
}
@article {pmid37245532,
year = {2023},
author = {Yang, H and Li, X and Jin, H and Turkez, H and Ozturk, G and Doganay, HL and Zhang, C and Nielsen, J and Uhlén, M and Borén, J and Mardinoglu, A},
title = {Longitudinal metabolomics analysis reveals the acute effect of cysteine and NAC included in the combined metabolic activators.},
journal = {Free radical biology &amp; medicine},
volume = {204},
number = {},
pages = {347-358},
doi = {10.1016/j.freeradbiomed.2023.05.013},
pmid = {37245532},
issn = {1873-4596},
mesh = {Humans ; *Acetylcysteine/metabolism ; *Cysteine ; NAD ; Glutathione/metabolism ; Metabolomics ; Niacinamide ; },
abstract = {Growing evidence suggests that the depletion of plasma NAD[+] and glutathione (GSH) may play an important role in the development of metabolic disorders. The administration of Combined Metabolic Activators (CMA), consisting of GSH and NAD[+] precursors, has been explored as a promising therapeutic strategy to target multiple altered pathways associated with the pathogenesis of the diseases. Although studies have examined the therapeutic effect of CMA that contains N-acetyl-l-cysteine (NAC) as a metabolic activator, a system-wide comparison of the metabolic response to the administration of CMA with NAC and cysteine remains lacking. In this placebo-controlled study, we studied the acute effect of the CMA administration with different metabolic activators, including NAC or cysteine with/without nicotinamide or flush free niacin, and performed longitudinal untargeted-metabolomics profiling of plasma obtained from 70 well-characterized healthy volunteers. The time-series metabolomics data revealed the metabolic pathways affected after the administration of CMAs showed high similarity between CMA containing nicotinamide and NAC or cysteine as metabolic activators. Our analysis also showed that CMA with cysteine is well-tolerated and safe in healthy individuals throughout the study. Last, our study systematically provided insights into a complex and dynamics landscape involved in amino acid, lipid and nicotinamide metabolism, reflecting the metabolic responses to CMA administration containing different metabolic activators.},
}
@article {pmid37242324,
year = {2023},
author = {Gao, Y and Li, J and Guo, X and Guan, L and Wang, J and Huang, X and Wang, W and Yang, H},
title = {L-Tyrosine Limits Mycobacterial Survival in Tuberculous Granuloma.},
journal = {Pathogens (Basel, Switzerland)},
volume = {12},
number = {5},
pages = {},
pmid = {37242324},
issn = {2076-0817},
support = {82270006//National Natural Science Foundation of China/ ; 82070007//National Natural Science Foundation of China/ ; 2021YFA1300902//National Key R&amp;D Program of China/ ; },
abstract = {Caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), tuberculosis (TB) remains a massive global public health issue. A well-known and key TB trait is caseous necrotic granuloma, which allows mycobacteria to reactivate and disseminate, thus confounding TB eradication programs. Amino acid (AA) metabolism is key to regulating immune responses in Mtb infections; however, it is currently unclear if AAs can be used to treat tuberculous granulomas. Here, we screened 20 proteinogenic AAs using a Mycobacterium marinum-infected zebrafish granuloma model. Only L-tyrosine simultaneously reduced Mycobacterium marinum (M. marinum) levels in zebrafish larvae and adults and inhibited intracellular pathogen survival levels. Mechanistically, L-tyrosine significantly upregulated interferon-γ (IFN-γ) expression in M. marinum -infected zebrafish adults but not in larvae. Using N-acetylcysteine (NAC) to inhibit reactive oxygen species (ROS), L-tyrosine appeared to inhibit Mtb intracellular survival by promoting ROS production. Thus, L-tyrosine as a non-essential AA may reduce mycobacterial survival in both macrophages and tuberculous granulomas. Our research provides a platform for the clinical development of AAs for active or latent TB patients infected with drug-sensitive or drug-resistant Mtb.},
}
@article {pmid37239911,
year = {2023},
author = {Kenari, F and Molnár, S and Borges, ID and Napolitano, HB and Perjési, P},
title = {(E)-2-Benzylidenecyclanones: Part XVIII Study the Possible Link between Glutathione Reactivity and Cancer Cell Cytotoxic Effects of Some Cyclic Chalcone Analogs A Comparison of the Reactivity of the Open-Chain and the Seven-Membered Homologs.},
journal = {International journal of molecular sciences},
volume = {24},
number = {10},
pages = {},
pmid = {37239911},
issn = {1422-0067},
support = {EFOP-3.6.1.-16-2016-00004//European Council/ ; },
mesh = {*Chalcone/pharmacology ; *Chalcones/pharmacology ; Glutathione/metabolism ; Acetylcysteine/chemistry ; Chromatography, High Pressure Liquid ; *Antineoplastic Agents/pharmacology ; Sulfhydryl Compounds/chemistry ; *Neoplasms ; },
abstract = {Non-enzymatic thiol addition into the α,β-unsaturated carbonyl system is associated with several biological effects. In vivo, the reactions can form small-molecule thiol (e.g., glutathione) or protein thiol adducts. The reaction of two synthetic (4'-methyl- and 4'-methoxy substituted) cyclic chalcone analogs with reduced glutathione (GSH) and N-acetylcysteine (NAC) was studied by (high-pressure liquid chromatography-ultraviolet spectroscopy) HPLC-UV method. The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The structure of the formed adducts was confirmed by (high-pressure liquid chromatography-mass spectrometry) HPLC-MS. The incubations were performed under three different pH conditions (pH 3.2/3.7, 6.3/6.8, and 8.0/7.4). The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended on the substitution and the pH. The frontier molecular orbitals and the Fukui function were carried out to investigate the effects on open-chain and seven-membered cyclic analogs. Furthermore, machine learning protocols were used to provide more insights into physicochemical properties and to support the different thiol-reactivity. HPLC analysis indicated diastereoselectivity of the reactions. The observed reactivities do not directly relate to the different in vitro cancer cell cytotoxicity of the compounds.},
}
@article {pmid37237960,
year = {2023},
author = {Giustarini, D and Milzani, A and Dalle-Donne, I and Rossi, R},
title = {How to Increase Cellular Glutathione.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {5},
pages = {},
pmid = {37237960},
issn = {2076-3921},
abstract = {Glutathione (GSH) has special antioxidant properties due to its high intracellular concentration, ubiquity, and high reactivity towards electrophiles of the sulfhydryl group of its cysteine moiety. In most diseases where oxidative stress is thought to play a pathogenic role, GSH concentration is significantly reduced, making cells more susceptible to oxidative damage. Therefore, there is a growing interest in determining the best method(s) to increase cellular glutathione for both disease prevention and treatment. This review summarizes the major strategies for successfully increasing cellular GSH stores. These include GSH itself, its derivatives, NRf-2 activators, cysteine prodrugs, foods, and special diets. The possible mechanisms by which these molecules can act as GSH boosters, their related pharmacokinetic issues, and their advantages and disadvantages are discussed.},
}
@article {pmid37237933,
year = {2023},
author = {Edemann-Callesen, H and Bernhardt, N and Hlusicka, EB and Hintz, F and Habelt, B and Winter, R and Neubert, I and Pelz, M and Filla, A and Soto-Montenegro, ML and Winter, C and Hadar, R},
title = {Supplement Treatment with NAC and Omega-3 Polyunsaturated Fatty Acids during Pregnancy Partially Prevents Schizophrenia-Related Outcomes in the Poly I:C Rat Model.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {5},
pages = {},
pmid = {37237933},
issn = {2076-3921},
support = {DFG WI2140/4-1//Deutsche Forschungsgemeinschaft/ ; },
abstract = {BACKGROUND: Heightened levels of inflammation and oxidative stress are thought to be involved in the pathophysiology of schizophrenia. We aimed to assess whether intake of anti-inflammatory and anti-oxidant drugs during pregnancy prevents later schizophrenia-related outcomes in a neurodevelopmental rat model of this disorder.<br><br>METHODS: Pregnant Wistar rats were injected with polyriboinosinic-polyribocytidilic acid (Poly I:C) or saline and subsequently treated with either N-acetyl cysteine (NAC) or omega-3 polyunsaturated fatty acids (PUFAs) until delivery. Controls rats received no treatment. In the offspring, neuroinflammation and anti-oxidant enzyme activity were assessed on postnatal day (PND) 21, 33, 48, and 90. Behavioral testing was performed at PND 90, followed by post-mortem neurochemical assessment and ex vivo MRI.<br><br>RESULTS: The supplement treatment led to a quicker restoration of the wellbeing of dams. In the adolescent Poly I:C offspring, the supplement treatment prevented an increase in microglial activity and partially prevented a deregulation in the anti-oxidant defense system. In the adult Poly I:C offspring, supplement treatment partially prevented dopamine deficits, which was paralleled by some changes in behavior. Exposure to omega-3 PUFAs prevented the enlargement of lateral ventricles.<br><br>CONCLUSION: Intake of over-the-counter supplements may assist in especially targeting the inflammatory response related to schizophrenia pathophysiology, aiding in diminishing later disease severity in the offspring.},
}
@article {pmid37237886,
year = {2023},
author = {Kim, JE and Lee, DS and Kim, TH and Park, H and Kang, TC},
title = {Distinct Roles of CK2- and AKT-Mediated NF-κB Phosphorylations in Clasmatodendrosis (Autophagic Astroglial Death) within the Hippocampus of Chronic Epilepsy Rats.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {5},
pages = {},
pmid = {37237886},
issn = {2076-3921},
support = {No. 2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; },
abstract = {The downregulation of glutathione peroxidase-1 (GPx1) plays a role in clasmatodendrosis (an autophagic astroglial death) in the hippocampus of chronic epilepsy rats. Furthermore, N-acetylcysteine (NAC, a GSH precursor) restores GPx1 expression in clasmatodendritic astrocytes and alleviates this autophagic astroglial death, independent of nuclear factor erythroid-2-related factor 2 (Nrf2) activity. However, the regulatory signal pathways of these phenomena have not been fully explored. In the present study, NAC attenuated clasmatodendrosis by alleviating GPx1 downregulation, casein kinase 2 (CK2)-mediated nuclear factor-κB (NF-κB) serine (S) 529 and AKT-mediated NF-κB S536 phosphorylations. 2-[4,5,6,7-Tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazole-1-yl]acetic acid (TMCB; a selective CK2 inhibitor) relieved clasmatodendritic degeneration and GPx1 downregulation concomitant with the decreased NF-κB S529 and AKT S473 phosphorylations. In contrast, AKT inhibition by 3-chloroacetyl-indole (3CAI) ameliorated clasmatodendrosis and NF-κB S536 phosphorylation, while it did not affect GPx1 downregulation and CK2 tyrosine (Y) 255 and NF-κB S529 phosphorylations. Therefore, these findings suggest that seizure-induced oxidative stress may diminish GPx1 expression by increasing CK2-mediated NF-κB S529 phosphorylation, which would subsequently enhance AKT-mediated NF-κB S536 phosphorylation leading to autophagic astroglial degeneration.},
}
@article {pmid37235225,
year = {2023},
author = {Li, X and Zhao, Z and Qu, Z and Li, X and Zhang, Z and Liang, X and Chen, J and Li, J},
title = {A Review of Traditional and Emerging Residual Chlorine Quenchers on Disinfection By-Products: Impact and Mechanisms.},
journal = {Toxics},
volume = {11},
number = {5},
pages = {},
pmid = {37235225},
issn = {2305-6304},
support = {BK20210737//the Natural Science Foundation of Jiangsu Province/ ; 2022M713301//China Postdoctoral Science Foundation/ ; 2021YXBKWKY026//the initial Scientific Research Fund of Soochow University, the Student's Extracurricular Scientific Research Fund of Medical College of Soochow University/ ; GWZX202204//the Suzhou Found for Prevention and Control Technology of critical illness and infectious diseases/ ; },
abstract = {Disinfection by-products (DBPs) are the most common organic contaminants in tap water and are of wide concern because of their highly developmental toxic, cytotoxic, and carcinogenic properties. Typically, to control the proliferation of pathogenic microorganisms, a certain concentration of residual chlorine is retained in the factory water, which reacts with the natural organic matter and the disinfection by-products that have been formed, thus affecting the determination of DBPs. Therefore, to obtain an accurate concentration, residual chlorine in tap water needs to be quenched prior to treatment. Currently, the most commonly used quenching agents are ascorbic acid, sodium thiosulfate, ammonium chloride, sodium sulfite, and sodium arsenite, but these quenching agents can cause varying degrees of DBPs degradation. Therefore, in recent years, researchers have attempted to find emerging chlorine quenchers. However, no studies have been conducted to systematically review the effects of traditional quenchers and new ones on DBPs, as well as their advantages, disadvantages, and scope of application. For inorganic DBPs (bromate, chlorate, and chlorite), sodium sulfite has been proven to be the ideal chlorine quencher. For organic DBPs, although ascorbic acid caused the degradation of some DBPs, it remains the ideal quenching agent for most known DBPs. Among the studied emerging chlorine quenchers, n-acetylcysteine (NAC), glutathione (GSH), and 1,3,5-trimethoxybenzene are promising for their application as the ideal chlorine quencher of organic DBPs. The dehalogenation of trichloronitromethane, trichloroacetonitrile, trichloroacetamide, and bromochlorophenol by sodium sulfite is caused by nucleophilic substitution reaction. This paper takes the understanding of DBPs and traditional and emerging chlorine quenchers as a starting point to comprehensively summarize their effects on different types of DBPs, and to provide assistance in understanding and selecting the most suitable residual chlorine quenchers during DBPs research.},
}
@article {pmid37234375,
year = {2023},
author = {Chennupati, R and Solga, I and Wischmann, P and Dahlmann, P and Celik, FG and Pacht, D and Şahin, A and Yogathasan, V and Hosen, MR and Gerdes, N and Kelm, M and Jung, C},
title = {Chronic anemia is associated with systemic endothelial dysfunction.},
journal = {Frontiers in cardiovascular medicine},
volume = {10},
number = {},
pages = {1099069},
pmid = {37234375},
issn = {2297-055X},
abstract = {BACKGROUND: In acute myocardial infarction and heart failure, anemia is associated with adverse clinical outcomes. Endothelial dysfunction (ED) is characterized by attenuated nitric oxide (NO)-mediated relaxation responses which is poorly studied in chronic anemia (CA). We hypothesized that CA is associated with ED due to increased oxidative stress in the endothelium.<br><br>METHODS: CA was induced by repeated blood withdrawal in male C57BL/6J mice. Flow-Mediated Dilation (FMD) responses were assessed in CA mice using ultrasound-guided femoral transient ischemia model. Tissue organ bath was used to assess vascular responsiveness of aortic rings from CA mice, and in aortic rings incubated with red blood cells (RBCs) from anemic patients. In the aortic rings from anemic mice, the role of arginases was assessed using either an arginase inhibitor (Nor-NOHA) or genetic ablation of arginase 1 in the endothelium. Inflammatory changes in plasma of CA mice were examined by ELISA. Expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), myeloperoxidase (MPO), 3-Nitrotyrosine levels, and 4-Hydroxynonenal (4-HNE) were assessed either by Western blotting or immunohistochemistry. The role of reactive oxygen species (ROS) in ED was assessed in the anemic mice either supplemented with N-Acetyl cysteine (NAC) or by in vitro pharmacological inhibition of MPO.<br><br>RESULTS: The FMD responses were diminished with a correlation to the duration of anemia. Aortic rings from CA mice showed reduced NO-dependent relaxation compared to non-anemic mice. RBCs from anemic patients attenuated NO-dependent relaxation responses in murine aortic rings compared to non-anemic controls. CA results in increased plasma VCAM-1, ICAM-1 levels, and an increased iNOS expression in aortic vascular smooth muscle cells. Arginases inhibition or arginase1 deletion did not improve ED in anemic mice. Increased expression of MPO and 4-HNE observed in endothelial cells of aortic sections from CA mice. NAC supplementation or inhibition of MPO improved relaxation responses in CA mice.<br><br>CONCLUSION: Chronic anemia is associated with progressive endothelial dysfunction evidenced by activation of the endothelium mediated by systemic inflammation, increased iNOS activity, and ROS production in the arterial wall. ROS scavenger (NAC) supplementation or MPO inhibition are potential therapeutic options to reverse the devastating endothelial dysfunction in chronic anemia.},
}
@article {pmid37226070,
year = {2023},
author = {Torres-Maure, M and Tapia-Ib Áñez, EX and Gamarra-L Ázaro, A and Bellido-Caparó, &#xc1; and García-Encinas, C},
title = {[Use of the Scottish and Newcastle Anti-Emetic Pretreatment (SNAP) scheme in recovery from massive overdose of acetaminophen poisoning with acute liver failure - Case report].},
journal = {Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru},
volume = {43},
number = {1},
pages = {53-56},
pmid = {37226070},
issn = {1609-722X},
mesh = {Female ; Humans ; Adolescent ; *Antiemetics/therapeutic use ; Acetaminophen ; Gastrointestinal Agents ; *Liver Failure, Acute/chemically induced/drug therapy ; Scotland ; },
abstract = {Acetaminophen is a drug widely used in the world and easily accessible due to its antipyretic, analgesics characteristics, among others (1); however, exposure to toxic doses causes organic damage and even death. We present the case of an 18-year-old female patient who ingested 40 grams of acetaminophen and developed severe liver dysfunction, being treated with N-acetylcysteine (NAC) antidotal therapy according to the simplified scheme: Scottish and Newcastle Anti-emetic Pretreatment Paracetamol Poisoning Study Regimen (SNAP), presenting improvement in the clinical course and decrease in liver profiles, coagulation disorder, INR and resolution of the condition.},
}
@article {pmid37225709,
year = {2023},
author = {Zhang, S and Liu, Q and Chang, M and Pan, Y and Yahaya, BH and Liu, Y and Lin, J},
title = {Chemotherapy impairs ovarian function through excessive ROS-induced ferroptosis.},
journal = {Cell death &amp; disease},
volume = {14},
number = {5},
pages = {340},
pmid = {37225709},
issn = {2041-4889},
mesh = {Female ; Animals ; Reactive Oxygen Species ; *Ferroptosis ; Apoptosis ; Ovary ; *Antineoplastic Agents/toxicity ; },
abstract = {Chemotherapy was conventionally applied to kill cancer cells, but regrettably, they also induce damage to normal cells with high-proliferative capacity resulting in cardiotoxicity, nephrotoxicity, peripheral nerve toxicity, and ovarian toxicity. Of these, chemotherapy-induced ovarian damages mainly include but are not limited to decreased ovarian reserve, infertility, and ovarian atrophy. Therefore, exploring the underlying mechanism of chemotherapeutic drug-induced ovarian damage will pave the way to develop fertility-protective adjuvants for female patients during conventional cancer treatment. Herein, we firstly confirmed the abnormal gonadal hormone levels in patients who received chemotherapy and further found that conventional chemotherapeutic drugs (cyclophosphamide, CTX; paclitaxel, Tax; doxorubicin, Dox and cisplatin, Cis) treatment significantly decreased both the ovarian volume of mice and the number of primordial and antral follicles and accompanied with the ovarian fibrosis and reduced ovarian reserve in animal models. Subsequently, Tax, Dox, and Cis treatment can induce the apoptosis of ovarian granulosa cells (GCs), likely resulting from excessive reactive oxygen species (ROS) production-induced oxidative damage and impaired cellular anti-oxidative capacity. Thirdly, the following experiments demonstrated that Cis treatment could induce mitochondrial dysfunction through overproducing superoxide in GCs and trigger lipid peroxidation leading to ferroptosis, first reported in chemotherapy-induced ovarian damage. In addition, N-acetylcysteine (NAC) treatment could alleviate the Cis-induced toxicity in GCs by downregulating cellular ROS levels and enhancing the anti-oxidative capacity (promoting the expression of glutathione peroxidase, GPX4; nuclear factor erythroid 2-related factor 2, Nrf2 and heme oxygenase-1, HO-1). Our study confirmed the chemotherapy-induced chaotic hormonal state and ovarian damage in preclinical and clinical examination and indicated that chemotherapeutic drugs initiated ferroptosis in ovarian cells through excessive ROS-induced lipid peroxidation and mitochondrial dysfunction, leading to ovarian cell death. Consequently, developing fertility protectants from the chemotherapy-induced oxidative stress and ferroptosis perspective will ameliorate ovarian damage and further improve the life quality of cancer patients.},
}
@article {pmid37224776,
year = {2023},
author = {Li, J and Zhou, J and Zhao, N and Li, Z and Xu, X and Tang, J and Li, Z and Zhang, X and Wu, Y and Li, Q and Zhang, Q and Jiang, J},
title = {EM-2, a natural sesquiterpene lactone from Elephantopus mollis H.B.K., enhanced the sensitivity of breast cancer cells to epirubicin by blocking protective autophagy.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {116},
number = {},
pages = {154878},
doi = {10.1016/j.phymed.2023.154878},
pmid = {37224776},
issn = {1618-095X},
mesh = {Humans ; Female ; Epirubicin ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; *Breast Neoplasms/drug therapy/pathology ; Autophagy ; Apoptosis ; *Sesquiterpenes/pharmacology ; Cell Proliferation ; },
abstract = {BACKGROUND: EM-2, a natural sesquiterpene lactone isolated from Elephantopus mollis H.B.K., showed a good anti-breast cancer effect when combined with epirubicin (EPI). However, its synergistic sensitization mechanism remains unclear.<br><br>PURPOSE: This study aimed to determine the therapeutic effect and possible synergistic mechanism of EM-2 with EPI in vivo and in vitro and to provide an experimental basis for the treatment of human breast cancer.<br><br>METHODS: Cell proliferation was measured with MTT and colony formation assays. Apoptosis and reactive oxygen species (ROS) levels were examined through flow cytometry, and the expression levels of proteins related to apoptosis, autophagy, endoplasmic reticulum stress, and DNA damage were detected through Western blot analysis. Moreover, the caspase inhibitor Z-VAD-FMK, autophagy inhibitors bafilomycin A1 and chloroquine, ER stress inhibitor 4-phenylbutyric acid, and ROS scavenger N-acetyl cysteine were applied to verify signaling pathways. Breast cancer cell lines were used to evaluate the antitumor functions of EM-2 and EPI in vitro and in vivo.<br><br>RESULTS: We demonstrated that in MDA-MB-231 and SKBR3 cells, the IC50 of EPI combined with EM-2 (IC20) was 37.909 and 33.889 times lower than that of EPI alone, respectively. Further study verified that in EPI-resistant lines (MDA-MB-231/EPI), the IC50 of EPI combined with EM-2 (IC20) was 26.305 times lower than that of EPI alone. Mechanistically, EM-2 could reverse the protective effect of EPI against autophagy in SKBR3 and MDA-MB-231 cells. EM-2 and EPI could trigger ER stress. When EM-2 and EPI were used in combination, ER stress was continuously activated, and ER stress-mediated apoptosis was induced. Meanwhile, EM-2 combined with EPI promoted DNA damage then induced apoptosis. In vivo, the volume of breast cancer xenografts in the combination group was smaller than that in the control, EM-2, and EPI groups. Immunohistochemical experiments demonstrated that the combination of EM-2 and EPI could block autophagy and promote ER stress in vivo.<br><br>CONCLUSION: EM-2 enhances the sensitivity of MDA-MB-231, SKBR3, and EPI-resistant cells to EPI.},
}
@article {pmid37224750,
year = {2023},
author = {Gu, L and He, X and Zhang, Y and Li, S and Tang, J and Ma, R and Yang, X and Huang, H and Peng, Y and Xie, Y and Peng, Z and Meng, J and Hu, G and Tao, L and Liu, X and Yang, H},
title = {Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {164},
number = {},
pages = {114844},
doi = {10.1016/j.biopha.2023.114844},
pmid = {37224750},
issn = {1950-6007},
mesh = {Mice ; Animals ; *MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Acetaminophen/metabolism ; Lipopolysaccharides/pharmacology ; Anisomycin/metabolism/pharmacology ; Liver ; *Liver Failure, Acute/chemically induced/drug therapy/prevention &amp; control ; Pyridones/pharmacology ; Necrosis/metabolism ; Mice, Inbred C57BL ; Hepatocytes ; Anthracenes ; },
abstract = {AIMS: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investigate whether fluorofenidone (AKF-PD), a novel antifibrosis pyridone agent, protects against ALF in mice and explore its underlying mechanisms.<br><br>METHODS: ALF mouse models were established using APAP or lipopolysaccharide/D-galactosamine (LPS/D-Gal). Anisomycin and SP600125 were used as JNK activator and inhibitor, respectively, and NAC served as a positive control. Mouse hepatic cell line AML12 and primary mouse hepatocytes were used for in vitro studies.<br><br>RESULTS: AKF-PD pretreatment alleviated APAP-induced ALF with decreased necrosis, apoptosis, reactive oxygen species (ROS) markers, and mitochondrial permeability transition in liver. Additionally, AKF-PD alleviated mitochondrial ROS stimulated by APAP in AML12 cells. RNA-sequencing in the liver and subsequent gene set enrichment analysis showed that AKF-PD significantly impacted MAPK and IL-17 pathway. In vitro and in vivo studies demonstrated that AKF-PD inhibited APAP-induced phosphorylation of MKK4/JNK, while SP600125 only inhibited JNK phosphorylation. The protective effect of AKF-PD was abolished by anisomycin. Similarly, AKF-PD pretreatment abolished hepatotoxicity caused by LPS/D-Gal, decreased ROS levels, and diminished inflammation. Furthermore, unlike NAC, AKF-PD, inhibited the phosphorylation of MKK4 and JNK upon pretreatment, and improved survival in cases of LPS/D-Gal-induced mortality with delayed dosing.<br><br>CONCLUSIONS: In summary, AKF-PD can protect against ALF caused by APAP or LPS/D-Gal, in part, via regulating MKK4/JNK pathway. AKF-PD might be a novel candidate drug for ALF.},
}
@article {pmid37223155,
year = {2023},
author = {Stashin, AR and Fikse, DJ and Orta, AM and Briggs, RP and Wheatley, SM and Koons, AL},
title = {You Dropped the Bomb on Me: A Case Series of Carbon Tetrachloride Toxicity.},
journal = {Cureus},
volume = {15},
number = {4},
pages = {e37879},
pmid = {37223155},
issn = {2168-8184},
abstract = {Carbon tetrachloride (CCl4) is a halogenated hydrocarbon that is a colorless, clear liquid with a sweetish, ether-like, nonirritant odor. It was previously used in dry cleaning agents, refrigerants, and fire extinguishers. CCl4 toxicity is rarely observed. Two patients with acute hepatitis following exposure to a CCl4-containing antique fire extinguisher are presented. A son (patient 1) and father (patient 2) were admitted to the hospital with acute, unexplained elevated transaminases. After extensive questioning, they reported recent exposure to a large amount of CCl4 when an antique firebomb shattered in their home. Both patients cleaned the debris without personal protective equipment and slept in the contaminated area. The patients presented to the emergency department (ED) at varying times between 24 and 72 hours after CCl4 exposure. Both patients received intravenous N-acetylcysteine (NAC); patient 1 also received oral cimetidine. Both recovered uneventfully without sequelae. Extensive workup for other causes of elevated transaminases was unremarkable. Serum analyses for CCl4 were also unremarkable due to the delay between exposure and hospital presentation. CCl4 is a potent hepatotoxin. CCl4 metabolism via cytochrome CYP2E1 produces its toxic metabolite, the trichloromethyl radical. This radical covalently binds to hepatocyte macromolecules and causes lipid peroxidation and oxidative damage with ensuing centrilobular necrosis. Treatment is not well established, but NAC is likely beneficial via glutathione repletion and antioxidant effects. Cimetidine blocks cytochrome P450 and, thus, metabolite formation. Cimetidine may also promote the stimulation of regenerative processes acting on DNA synthesis. CCl4 toxicity is rare and infrequently reported in current literature but should be maintained in the differential of acute hepatitis. Two patients presenting nearly identically - at two different ages but from the same household - offered a clue to this enigmatic diagnosis.},
}
@article {pmid37217712,
year = {2023},
author = {Fakhouri, H and Bakulić, MP and Zhang, I and Yuan, H and Bain, D and Rondepierre, F and Brevet, PF and Maršić, &#x17d;S and Antoine, R and Bonačić-Koutecký, V and Maysinger, D},
title = {Ligand impact on reactive oxygen species generation of Au10 and Au25 nanoclusters upon one- and two-photon excitation.},
journal = {Communications chemistry},
volume = {6},
number = {1},
pages = {97},
pmid = {37217712},
issn = {2399-3669},
support = {RGPIN 2020-07011//Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)/ ; },
abstract = {In photodynamic therapy (PDT), light-sensitive photosensitizers produce reactive oxygen species (ROS) after irradiation in the presence of oxygen. Atomically-precise thiolate-protected gold nanoclusters are molecule-like nanostructures with discrete energy levels presenting long lifetimes, surface biofunctionality, and strong near-infrared excitation ideal for ROS generation in PDT. We directly compare thiolate-gold macromolecular complexes (Au10) and atomically-precise gold nanoclusters (Au25), and investigate the influence of ligands on their photoexcitation. With the ability of atomically-precise nanochemistry, we produce Au10SG10, Au10AcCys10, Au25SG18, and Au25AcCys18 (SG: glutathione; AcCys: N-acetyl-cysteine) fully characterized by high-resolution mass spectrometry. Our theoretical investigation reveals key factors (energetics of excited states and structural influence of surface ligands) and their relative importance in singlet oxygen formation upon one- and two-photon excitation. Finally, we explore ROS generation by gold nanoclusters in living cells with one- and two-photon excitation. Our study presents in-depth analyses of events within gold nanoclusters when photo-excited both in the linear and nonlinear optical regimes, and possible biological consequences in cells.},
}
@article {pmid37217588,
year = {2023},
author = {Beloosesky, R and Gutzeit, O and Ginsberg, Y and Khatib, N and Ross, MG and Weiner, Z and Zmora, O},
title = {Intestine and brain TLR-4 modulation following N-acetyl-cysteine treatment in NEC rodent model.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {8241},
pmid = {37217588},
issn = {2045-2322},
mesh = {Animals ; Rats ; Acetylcysteine/pharmacology ; Animals, Newborn ; Brain/metabolism ; *Brain Injuries/metabolism ; Disease Models, Animal ; *Enterocolitis, Necrotizing/drug therapy/metabolism ; Glutathione/metabolism ; Ileum/metabolism ; Intestines ; Rats, Sprague-Dawley ; Rodentia/metabolism ; Toll-Like Receptor 4/metabolism ; },
abstract = {Necrotizing enterocolitis (NEC) brain injury is mediated through Toll-like receptor 4 (TLR4) on the intestinal epithelium and brain microglia. Our aim was to determine whether postnatal and/or prenatal NAC can modify NEC associated intestinal and brain TLR4 expression and brain glutathione levels in a rat model of NEC. Newborn Sprague-Dawley rats were randomized into three groups: Control (n = 33); NEC (n = 32)-hypoxia and formula feeding; and NEC-NAC (n = 34)-received NAC (300 mg/kg IP) in addition to NEC conditions. Two additional groups included pups of dams treated once daily with NAC (300 mg/kg IV) for the last 3 days of pregnancy: NAC-NEC (n = 33) or NAC-NEC-NAC (n = 36) with additional postnatal NAC. Pups were sacrificed on the fifth day, and ileum and brains harvested for TLR-4 and glutathione protein levels. Brain and ileum TLR-4 protein levels were significantly increased in NEC offspring as compared to control (brain 2.5 ± 0.6 vs. 0.88 ± 0.12 U and ileum 0.24 ± 0.04 vs. 0.09 ± 0.01, p < 0.05). When NAC was administered only to dams (NAC-NEC) a significant decrease in TLR-4 levels was demonstrated in both offspring brain (1.53 ± 0.41 vs. 2.5 ± 0.6 U, p < 0.05) and ileum (0.12 ± 0.03 vs. 0.24 ± 0.04 U, p < 0.05) as compared to NEC. The same pattern was demonstrated when NAC was administered only or postnatally. The decrease in brain and ileum glutathione levels observed in NEC offspring was reversed with all NAC treatment groups. NAC reverses the increase in ileum and brain TLR-4 levels and the decrease in brain and ileum glutathione levels associated with NEC in a rat model, and thus may protect from NEC associated brain injury.},
}
@article {pmid37216221,
year = {2023},
author = {Aswani, SS and Mohan, MS and Aparna, NS and Boban, PT and Saja, K},
title = {Oxidized LDL-mediated upregulation of ADAMTS-4 in monocytes/macrophages involves ROS-NF-κB-SIRT-1 pathway.},
journal = {Physiology international},
volume = {110},
number = {2},
pages = {173-190},
doi = {10.1556/2060.2023.00170},
pmid = {37216221},
issn = {2498-602X},
mesh = {Humans ; *Atherosclerosis/metabolism ; Leukocytes, Mononuclear ; Macrophages/metabolism ; Monocytes/metabolism ; *NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Resveratrol/metabolism ; RNA, Messenger/metabolism ; Up-Regulation ; *ADAMTS4 Protein/metabolism ; Lipoproteins, LDL ; },
abstract = {BACKGROUND AND AIMS: ADAMTS-4 is a protease enzyme involved in vascular remodeling and atherosclerosis. It was found to be upregulated in macrophages seen in atherosclerotic lesions. This study aimed to investigate the expression and regulation of ADAMTS-4 in oxidized LDL-induced human monocytes/macrophages system.<br><br>METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from human blood,&#xa0;and treated with oxidized LDL (50 &#x3bc;g mL-1) were used as the model system for the study. mRNA and protein expressions were studied by PCR, ELISA, and western blot analysis. ROS production and cell&#xa0;viability were determined by DCFDA staining and MTT assay, respectively.<br><br>RESULTS: In the presence of oxidized LDL, monocytes get differentiated into macrophages, which were confirmed by the increased expression of macrophage differentiation markers and pro-inflammatory cytokine TNF-&#x3b1;. Oxidized LDL&#xa0;increased the mRNA and protein expression of ADAMTS-4 in monocytes/macrophages. N- Acetyl cysteine, ROS scavenger, downregulate the protein expression of ADAMTS-4. The expression of ADAMTS-4 was&#xa0;decreased significantly in the presence of NF-&#x3ba;B inhibitors. SIRT-1 activity was&#xa0;significantly downregulated in the macrophages and was reversed in the presence of the SIRT-1 agonist, resveratrol. Acetylation of NF-&#x3ba;B and hence the expression of ADAMTS-4 were significantly downregulated in the presence of SIRT-1 activator, resveratrol.<br><br>CONCLUSIONS: Our study suggests that oxidized LDL significantly upregulated the expression of ADAMTS-4 in the monocytes/macrophages through ROS- NF-&#x3ba;B- SIRT-1 pathway.},
}
@article {pmid37207578,
year = {2023},
author = {Li, XL and Liu, YL and Liu, JY and Zhu, YY and Zhu, XX and Zhang, WW and Li, J and Zhao, Y and Zhao, LL and Zhang, C and Wang, H and Xu, DX and Gao, L},
title = {1-Nitropyrene disrupts testicular steroidogenesis via oxidative stress-evoked PERK-eIF2α pathway.},
journal = {Ecotoxicology and environmental safety},
volume = {259},
number = {},
pages = {115027},
doi = {10.1016/j.ecoenv.2023.115027},
pmid = {37207578},
issn = {1090-2414},
mesh = {Male ; Mice ; Animals ; *Testis/metabolism ; *Antioxidants/metabolism ; Eukaryotic Initiation Factor-2/metabolism ; Endoplasmic Reticulum Stress/physiology ; Testosterone/metabolism ; Oxidative Stress ; Acetylcysteine/pharmacology/metabolism ; Butylamines ; Pyrenes ; },
abstract = {Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.},
}
@article {pmid37206223,
year = {2023},
author = {Porterfield, JE and Sharma, R and Jimenez, AS and Sah, N and McCracken, S and Zhang, L and An, HT and Lee, S and Kannan, S and Sharma, A and Kannan, RM},
title = {Galactosylated hydroxyl-polyamidoamine dendrimer targets hepatocytes and improves therapeutic outcomes in a severe model of acetaminophen poisoning-induced liver failure.},
journal = {Bioengineering &amp; translational medicine},
volume = {8},
number = {3},
pages = {e10486},
pmid = {37206223},
issn = {2380-6761},
support = {P30 EY001765/EY/NEI NIH HHS/United States ; R25 GM109441/GM/NIGMS NIH HHS/United States ; },
abstract = {Toxicity to hepatocytes caused by various insults including drugs is a common cause of chronic liver failure requiring transplantation. Targeting therapeutics specifically to hepatocytes is often a challenge since they are relatively nonendocytosing unlike the highly phagocytic Kupffer cells in the liver. Approaches that enable targeted intracellular delivery of therapeutics to hepatocytes have significant promise in addressing liver disorders. We synthesized a galactose-conjugated hydroxyl polyamidoamine dendrimer (D4-Gal) that targets hepatocytes efficiently through the asialoglycoprotein receptors in healthy mice and in a mouse model of acetaminophen (APAP)-induced liver failure. D4-Gal localized specifically in hepatocytes and showed significantly better targeting when compared with the non-Gal functionalized hydroxyl dendrimer. The therapeutic potential of D4-Gal conjugated to N-acetyl cysteine (NAC) was tested in a mouse model of APAP-induced liver failure. A single intravenous dose of a conjugate of D4-Gal and NAC (Gal-d-NAC) improved survival in APAP mice, decreased cellular oxidative injury and areas of necrosis in the liver, even when administered at the delayed time point of 8 h after APAP exposure. Overdose of APAP is the most common cause of acute hepatic injury and liver transplant need in the United States, and is treated with large doses of NAC administered rapidly within 8 h of overdose leading to systemic side effects and poor tolerance. NAC is not effective when treatment is delayed. Our results suggest that D4-Gal is effective in targeting and delivering therapies to hepatocytes and Gal-D-NAC has the potential to salvage and treat liver injury with a broader therapeutic window.},
}
@article {pmid37205206,
year = {2023},
author = {Ajitkumar, A and Mohan, G and Ghose, M and Yarrarapu, S and Afiniwala, S},
title = {Drug-Induced Liver Injury Secondary to Turmeric Use.},
journal = {European journal of case reports in internal medicine},
volume = {10},
number = {5},
pages = {003845},
pmid = {37205206},
issn = {2284-2594},
abstract = {UNLABELLED: Turmeric is a herbal medication and spice which has been used for thousands of years in traditional Eastern medicine for its flavour, colour, and purported anti-inflammatory, antioxidant, antineoplastic and antimicrobial properties. It has recently garnered interest and popularity worldwide for these reasons. While turmeric supplements are generally safe, some reports of toxicity are emerging. Compounds like piperine are added to turmeric to enhance its bioavailability, potentially contributing to its toxicity. Here, we describe a 55-year-old woman with progressive jaundice and elevated bilirubin and liver enzymes but no evidence of acute liver failure. She was treated with N-acetyl cysteine (NAC) for 24 hours and liver function tests (LFTs) were closely monitored. As a downtrend in LFTs was noted and the patient remained asymptomatic, she was discharged with close outpatient follow-up. LFTs eventually normalized 2 months after the initial presentation. Clinicians must keep this differential in mind when evaluating acute liver injury. With our case report, we question the utility of NAC in non-acetaminophen-related liver injury and encourage further studies.<br><br>LEARNING POINTS: Eliciting information on recent drug or supplement use should be part of comprehensive history-taking to evaluate acute liver injury.Turmeric supplements which may contain piperine to enhance bioavailability are a potential source of acute liver injury.The role of N-acetyl cysteine in managing non-acetaminophen-related liver injury is unclear and further studies are required.},
}
@article {pmid37203858,
year = {2023},
author = {Oliva, A and Pallecchi, L and Rossolini, GM and Travaglino, F and Zanatta, P},
title = {Rationale and evidence for the adjunctive use of N-acetylcysteine in multidrug-resistant infections.},
journal = {European review for medical and pharmacological sciences},
volume = {27},
number = {9},
pages = {4316-4325},
doi = {10.26355/eurrev_202305_32342},
pmid = {37203858},
issn = {2284-0729},
mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; Drug Resistance, Multiple, Bacterial ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Expectorants/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; *Klebsiella Infections/drug therapy/microbiology ; Klebsiella pneumoniae ; Microbial Sensitivity Tests ; },
abstract = {Bacterial multidrug resistance has been a serious issue for healthcare systems in recent decades, responsible for many infections and deaths. Due to the increasing incidence of antimicrobial resistance and scarce treatment options, research is focused on finding possible therapeutic adjuvants able to increase the efficacy of antibiotics. The aim of this article is a review of available evidence on the use of N-acetylcysteine (NAC). MEDLINE/PubMed was searched for appropriate keywords. In vitro and in vivo preclinical studies, clinical studies, reviews, and meta-analyses were retrieved and selected based on relevance. A narrative review article was written, reporting published evidence and the expert opinion of the authors. Among possible adjunctive treatments, NAC has attracted the interest of researchers as a candidate for re-purposing. It is a widely used drug with a good tolerability profile, mainly used as a mucolytic agent, with antioxidant, anti-inflammatory properties and antibacterial activity. NAC acts on different mechanisms and stages of infections, resulting in inhibition of biofilm formation, disruption of preformed biofilms, and reduction of bacterial viability. NAC may be administered as an aerosol in many types of infections, including cystic fibrosis, bronchiectasis and infective flare of chronic obstructive pulmonary disease (COPD), and by the intravenous route in severe systemic infections (including septic shock) such as those caused by carbapenemase (KPC)-producing Klebsiella pneumoniae (Kp) and Carbapenem-Resistant Acinetobacter baumannii (CR-Ab). A rationale exists for using NAC as an adjunctive treatment in multidrug-resistant (MDR) infections, based on in vitro, in vivo and clinical evidence, and future research is needed to identify candidate patients and optimal schedules for specific clinical conditions.},
}
@article {pmid37196773,
year = {2023},
author = {Qiu, D and Song, S and Chen, N and Bian, Y and Yuan, C and Zhang, W and Duan, H and Shi, Y},
title = {NQO1 alleviates renal fibrosis by inhibiting the TLR4/NF-κB and TGF-β/Smad signaling pathways in diabetic nephropathy.},
journal = {Cellular signalling},
volume = {108},
number = {},
pages = {110712},
doi = {10.1016/j.cellsig.2023.110712},
pmid = {37196773},
issn = {1873-3913},
mesh = {Animals ; Humans ; Mice ; Cytokines ; *Diabetes Mellitus, Type 2 ; *Diabetic Nephropathies/metabolism ; Epithelial-Mesenchymal Transition ; Fibrosis ; Inflammation/metabolism ; *NAD(P)H Dehydrogenase (Quinone)/metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; Toll-Like Receptor 4/metabolism ; Transforming Growth Factor beta1/metabolism ; },
abstract = {OBJECTIVE: Diabetic nephropathy (DN) is one of the main complications of diabetes, and inflammation and fibrosis play an important role in its progression. NAD(P)H: quinone oxidoreductase 1 (NQO1) protects cells from oxidative stress and damage caused by toxic quinones. In the present study, we aimed to investigate the protective effects of NQO1 against diabetes-induced renal inflammation and fibrosis and the underlying mechanisms.<br><br>METHODS: In vivo, the kidneys of type 2 diabetes model db/db mice were infected with adeno-associated virus vectors to induce NQO1 overexpression. In vitro, human renal tubular epithelial (HK-2) cells transfected with NQO1 pcDNA3.1(+) were cultured under high-glucose (HG) conditions. Gene and protein expression was assessed by quantitative real-time PCR, Western blotting, immunofluorescence, and immunohistochemical staining. Mitochondrial reactive oxygen species (ROS) were detected with MitoSOX Red.<br><br>RESULT: Our study revealed that the expression of NQO1 was markedly downregulated and that Toll-like receptor (TLR)4 and TGF-&#x3b2;1 expression was upregulated in vivo and in vitro under diabetic conditions. Overexpression of NQO1 suppressed proinflammatory cytokine (IL-6, TNF-&#x3b1;, MCP-1) secretion, extracellular matrix (ECM) (collagen IV, fibronectin) accumulation and epithelial-mesenchymal transition (EMT) (&#x3b1;-SMA, E-cadherin) in the db/db mouse kidneys and HG-cultured HK-2 cells. Furthermore, NQO1 overexpression ameliorated HG-induced TLR4/NF-&#x3ba;B and TGF-&#x3b2;/Smad pathways activation. Mechanistic studies demonstrated that a TLR4 inhibitor (TAK-242) suppressed the TLR4/NF-&#x3ba;B signaling pathway, proinflammatory cytokine secretion, EMT and ECM-related protein expression in HG-exposed HK-2 cells. In addition, we found that the antioxidants N-acetylcysteine (NAC) and tempol increased the expression of NQO1 and decreased the expression of TLR4, TGF-&#x3b2;1, Nox1, and Nox4 and ROS production in HK-2 cells cultured under HG conditions.<br><br>CONCLUSIONS: These data suggest that NQO1 alleviates diabetes-induced renal inflammation and fibrosis by regulating the TLR4/NF-&#x3ba;B and TGF-&#x3b2;/Smad signaling pathways.},
}
@article {pmid37193781,
year = {2023},
author = {Kuo, CW and Su, PL and Huang, TH and Lin, CC and Chen, CW and Tsai, JS and Liao, XM and Chan, TY and Shieh, CC},
title = {Cigarette smoke increases susceptibility of alveolar macrophages to SARS-CoV-2 infection through inducing reactive oxygen species-upregulated angiotensin-converting enzyme 2 expression.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {7894},
pmid = {37193781},
issn = {2045-2322},
mesh = {Humans ; Mice ; Animals ; *COVID-19 ; Reactive Oxygen Species ; Macrophages, Alveolar/metabolism ; SARS-CoV-2/metabolism ; Angiotensin-Converting Enzyme 2/genetics ; *Cigarette Smoking ; Peptidyl-Dipeptidase A/metabolism ; },
abstract = {Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical-regulatory factors for the entrance protein of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman's r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (β-coefficient: 0.791, 95% CI 0.019-1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb[-/-] mice; however, exogenous ROS increased the ACE2 in Cybb[-/-] AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS-induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.},
}
@article {pmid37190230,
year = {2023},
author = {Ajouaou, Y and Magnani, E and Madakashira, B and Jenkins, E and Sadler, KC},
title = {atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers.},
journal = {Cancers},
volume = {15},
number = {8},
pages = {},
pmid = {37190230},
issn = {2072-6694},
support = {AJF2018098//Al Jalila Foundation/ ; ADHPG-CGSB//Tamkeen under the NYU Abu Dhabi Research Institute Award/ ; RE188//REF/ ; To KCS//NYUAD Faculty Research Fund/ ; },
abstract = {The ataxia-telangiectasia mutated (atm) gene is activated in response to genotoxic stress and leads to activation of the tp53 tumor suppressor gene which induces either senescence or apoptosis as tumor suppressive mechanisms. Atm also serves non-canonical functions in the response to oxidative stress and chromatin reorganization. We previously reported that overexpression of the epigenetic regulator and oncogene Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) in zebrafish hepatocytes resulted in tp53-dependent hepatocyte senescence, a small liver and larval lethality. We investigated the role of atm on UHRF1-mediated phenotypes by generating zebrafish atm mutants. atm[-/-] adults were viable but had reduction in fertility. Embryos developed normally but were protected from lethality caused by etoposide or H2O2 exposure and failed to fully upregulate Tp53 targets or oxidative stress response genes in response to these treatments. In contrast to the finding that Tp53 prevents the small liver phenotype caused by UHRF1 overexpression, atm mutation and exposure to H2O2 further reduced the liver size in UHRF1 overexpressing larvae whereas treatment with the antioxidant N-acetyl cysteine suppressed this phenotype. We conclude that UHRF1 overexpression in hepatocytes causes oxidative stress, and that loss of atm further enhances this, triggering elimination of these precancerous cells, leading to a small liver.},
}
@article {pmid37183639,
year = {2023},
author = {Zi, Y and Liao, K and Chen, H},
title = {[Cigarette Smoke Induces Gefitinib Resistance in NSCLC Cells via ROS/Sirt3/SOD2 Pathway].},
journal = {Zhongguo fei ai za zhi = Chinese journal of lung cancer},
volume = {26},
number = {4},
pages = {245-256},
pmid = {37183639},
issn = {1999-6187},
mesh = {Humans ; Gefitinib/pharmacology/therapeutic use ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism ; *Sirtuin 3/genetics/therapeutic use ; *Lung Neoplasms/drug therapy/genetics/metabolism ; Reactive Oxygen Species/metabolism/therapeutic use ; *Antineoplastic Agents/therapeutic use ; *Cigarette Smoking ; Sincalide/therapeutic use ; ErbB Receptors/metabolism ; Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor ; Superoxide Dismutase 2 ; Fluoresceins ; },
abstract = {BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations are the most common driver mutations in non-small cell lung cancer (NSCLC). To prolong the survival of the patients, EGFR tyrosine kinase inhibitors (TKIs) resistance in NSCLC is a major challenge that needs to be addressed urgently, and this study focuses on investigating the mechanism of cigarette smoke (CS) induced Gefitinib resistance in NSCLC.<br><br>METHODS: PC-9 and A549 cells were cultured in vitro and treated with 1 &#xb5;mol/L Gefitinib for 4 h and 10% cigarette smoke extract (CSE) for 48 h. Western blot was used to detect Sirtuin 3 (Sirt3) and superoxide dismutase 2 (SOD2) protein expressions; DCFH-DA probe was used to detect intracellular reactive oxygen species (ROS); CCK-8 kit was used to detect cell activity, and EdU was used to detect cell proliferation ability. Sirt3 overexpression plasmid (OV-Sirt3) was transfected in PC-9 and A549 cells and treated with 1 &#xb5;mol/L Gefitinib for 4 h and 10% CSE for 48 h after N-acetylcysteine (NAC) action. The expressions of Sirt3 and SOD2 were detected by Western blot; the ROS level in the cells was detected by DCFH-DA probe, and the cell activity was detected by CCK-8.<br><br>RESULTS: CSE induced an increase in the 50% inhibitory concentration (IC50) of both PC-9 and A549 cells to Gefitinib (P<0.01) and enhanced the proliferation of PC-9 and A549 cells, suggesting that CS induced Gefitinib resistance in NSCLC. ROS was involved in CSE-induced Gefitinib resistance (P<0.05). CSE induced low expressions of Sirt3 and SOD2 (P<0.01), and Sirt3/SOD2 was associated with poor prognosis in lung cancer patients (P<0.05). OV-Sirt3 in PC-9 and A549 cells reversed CSE-induced Gefitinib resistance (P<0.05) and significantly reduced ROS production. NAC reversed CSE-induced Gefitinib resistance in PC-9 and A549 cells (P<0.05).<br><br>CONCLUSIONS: The ROS/Sirt3/SOD2 pathway is involved in CS-induced Gefitinib resistance in NSCLC.},
}
@article {pmid37176778,
year = {2023},
author = {Mirea, L and Cobilinschi, C and Ungureanu, R and Cotae, AM and Darie, R and Tincu, R and Avram, O and Constantinescu, S and Minoiu, C and Baetu, A and Grintescu, IM},
title = {A Trend towards Diaphragmatic Muscle Waste after Invasive Mechanical Ventilation in Multiple Trauma Patients-What to Expect?.},
journal = {Journal of clinical medicine},
volume = {12},
number = {9},
pages = {},
pmid = {37176778},
issn = {2077-0383},
abstract = {Considering the prioritization of life-threatening injuries in trauma care, secondary dysfunctions such as ventilator-induced diaphragmatic dysfunction (VIDD) are often overlooked. VIDD is an entity induced by muscle inactivity during invasive mechanical ventilation, associated with a profound loss of diaphragm muscle mass. In order to assess the incidence of VIDD in polytrauma patients, we performed an observational, retrospective, longitudinal study that included 24 polytraumatized patients. All included patients were mechanically ventilated for at least 48 h and underwent two chest CT scans during their ICU stay. Diaphragmatic thickness was measured by two independent radiologists on coronal and axial images at the level of celiac plexus. The thickness of the diaphragm was significantly decreased on both the left and right sides (left side: -0.82 mm axial p = 0.034; -0.79 mm coronal p = 0.05; right side: -0.94 mm axial p = 0.016; -0.91 coronal p = 0.013). In addition, we obtained a positive correlation between the number of days of mechanical ventilation and the difference between the two measurements of the diaphragm thickness on both sides (r =0.5; p = 0.02). There was no statistically significant correlation between the body mass indexes on admission, the use of vitamin C or N-acetyl cysteine, and the differences in diaphragmatic thickness.},
}
@article {pmid37175458,
year = {2023},
author = {Lee, MY and Shiau, JP and Tang, JY and Hou, MF and Primus, PS and Kao, CL and Choo, YM and Chang, HW},
title = {Boesenbergia stenophylla-Derived Stenophyllol B Exerts Antiproliferative and Oxidative Stress Responses in Triple-Negative Breast Cancer Cells with Few Side Effects in Normal Cells.},
journal = {International journal of molecular sciences},
volume = {24},
number = {9},
pages = {},
pmid = {37175458},
issn = {1422-0067},
support = {MOST 111-2320-B-037-015-MY3; MOST 110-2314-B-037-074-MY3; MOST 109-2923-M-037-001-MY3; MOST 111-2113-M-037-014//Ministry of Science and Technology/ ; KMU-DK(A)112008//Kaohsiung Medical University/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; GPF055B-2018 and ST004-2018//University of Malaya/ ; },
mesh = {Humans ; *Triple Negative Breast Neoplasms/drug therapy ; DNA Damage ; Cell Proliferation ; Cell Line, Tumor ; Oxidative Stress ; Apoptosis ; Acetylcysteine/pharmacology ; },
abstract = {Triple-negative breast cancer (TNBC) is insensitive to target therapy for non-TNBC and needs novel drug discovery. Extracts of the traditional herb Boesenbergia plant in Southern Asia exhibit anticancer effects and contain novel bioactive compounds but merely show cytotoxicity. We recently isolated a new compound from B. stenophylla, stenophyllol B (StenB), but the impact and mechanism of its proliferation-modulating function on TNBC cells remain uninvestigated. This study aimed to assess the antiproliferative responses of StenB in TNBC cells and examine the drug safety in normal cells. StenB effectively suppressed the proliferation of TNBC cells rather than normal cells in terms of an ATP assay. This preferential antiproliferative function was alleviated by pretreating inhibitors for oxidative stress (N-acetylcysteine (NAC)) and apoptosis (Z-VAD-FMK). Accordingly, the oxidative-stress-related mechanisms were further assessed. StenB caused subG1 and G2/M accumulation but reduced the G1 phase in TNBC cells, while normal cells remained unchanged between the control and StenB treatments. The apoptosis behavior of TNBC cells was suppressed by StenB, whereas that of normal cells was not suppressed according to an annexin V assay. StenB-modulated apoptosis signaling, such as for caspases 3, 8, and 9, was more significantly activated in TNBC than in normal cells. StenB also caused oxidative stress in TNBC cells but not in normal cells according to a flow cytometry assay monitoring reactive oxygen species, mitochondrial superoxide, and their membrane potential. StenB induced greater DNA damage responses (γH2AX and 8-hydroxy-2-deoxyguanosine) in TNBC than in normal cells. All these StenB responses were alleviated by NAC pretreatment. Collectively, StenB modulated oxidative stress responses, leading to the antiproliferation of TNBC cells with little cytotoxicity in normal cells.},
}
@article {pmid37174730,
year = {2023},
author = {Aisa-Álvarez, A and Pérez-Torres, I and Guarner-Lans, V and Manzano-Pech, L and Cruz-Soto, R and Márquez-Velasco, R and Casarez-Alvarado, S and Franco-Granillo, J and Núñez-Martínez, ME and Soto, ME},
title = {Randomized Clinical Trial of Antioxidant Therapy Patients with Septic Shock and Organ Dysfunction in the ICU: SOFA Score Reduction by Improvement of the Enzymatic and Non-Enzymatic Antioxidant System.},
journal = {Cells},
volume = {12},
number = {9},
pages = {},
pmid = {37174730},
issn = {2073-4409},
mesh = {Humans ; Antioxidants/therapeutic use ; *Shock, Septic/drug therapy ; Multiple Organ Failure/drug therapy ; Organ Dysfunction Scores ; *Selenium ; Vitamin E/therapeutic use ; Ascorbic Acid/therapeutic use ; *Melatonin ; Vitamins ; Intensive Care Units ; },
abstract = {BACKGROUND AND AIM: Here, we assess the effect of adjuvant antioxidant therapies in septic shock patients with organ dysfunction and their effect on the enzymatic and non-enzymatic antioxidant systems.<br><br>METHODS: Randomized clinical trial run between 2018 and 2022. One hundred and thirty-one patients with septic shock were included in five groups with 25, 27, 24, 26 and 29 patients each. Group 1 received vitamin C (Vit C), Group 2 vitamin E (Vit E), Group 3 n-acetylcysteine (NAC), Group 4 melatonin (MT) and group 5 no treatment. All antioxidants were administered orally or through a nasogastric tube for 5 days as an adjuvant to standard therapy.<br><br>RESULTS: All patients had multiple organ failure (MOF) and low Vit C levels. Vit C therapy decreased CRP, PCT and NO3[-]/NO2[-] but increased Vit C levels. The SOFA score decreased with MT in 75%, Vit C 63% and NAC 50% vs. controls 33% (p = 0.0001, p = 0.03 and p = 0.001 respectively). MT diminished lipid peroxidation (LPO) (p = 0.01) and improved total antioxidant capacity (TAC) (p = 0.04). Vit E increased thiol levels (p = 0.02) and tended to decrease LPO (p = 0.06). Selenium levels were decreased in the control group (p = 0.04).<br><br>CONCLUSIONS: Antioxidants used as an adjuvant therapy in the standard treatment of septic shock decrease MOF and oxidative stress markers. They increase the TAC and thiols, and maintain selenium levels.},
}
@article {pmid37171598,
year = {2023},
author = {Español, I and Leal, JD and Blanquer, M and García-Candel, F and Heredia, A and Gómez-Espuch, J and González, C and Montserrat, J and Díaz-Carrasco, MS and Martínez, A and Moraleda, JM},
title = {N-Acetylcistein for thrombotic thrombocytopenic purpura: an observational case series study.},
journal = {Annals of hematology},
volume = {102},
number = {8},
pages = {2069-2075},
pmid = {37171598},
issn = {1432-0584},
mesh = {Humans ; *Purpura, Thrombotic Thrombocytopenic/diagnosis/drug therapy ; ADAMTS13 Protein ; Rituximab/therapeutic use ; Plasma Exchange ; Acetylcysteine/therapeutic use ; },
abstract = {Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder. N-Acetylcysteine (NAC) rapidly degrades ultra-large von Willebrand factor multimers by disrupting the disulfide bonds. We report a series of twelve consecutive patients diagnosed with acquired TTP successfully treated with high-dose NAC (150 mg/kg/day) in combination with plasma exchange and steroids. Eight patients also received rituximab. Two patients presented refractory TTP. All patients achieved a quick clinical response in a median time of 5.5 days after starting NAC and are alive after a median follow-up of 29 months. The treatment was feasible and well tolerated. These data provide further evidence of the potential benefit and safety of adding NAC to the standard of care.},
}
@article {pmid37168338,
year = {2023},
author = {Lee, YP and Lin, CR and Chen, SS and Chen, RJ and Wu, YH and Chen, YH and Huang, BM},
title = {Combination treatment of cordycepin and radiation induces MA-10 mouse Leydig tumor cell death via ROS accumulation and DNA damage.},
journal = {American journal of cancer research},
volume = {13},
number = {4},
pages = {1329-1346},
pmid = {37168338},
issn = {2156-6976},
abstract = {Leydig cell tumor is the most frequent non-germ cell tumors of testis. The biggest challenge of using radiotherapy to treat testicular cancer is in effectively killing cancer cells and maintaining reproductive function after treatment. Our recently published article showed that cordycepin could enhance radiosensitivity to induce mouse Leydig tumor cell apoptosis by inducing cell cycle arrest, caspase pathway and endoplasmic reticulum (ER) stress. In the present study, the potency and mechanism of a previous combination treatment protocol on reactive oxygen species (ROS) induction and DNA damage were further investigated. Our results reveal that 25 μM cordycepin plus 4 Gy radiation leads to ROS accumulation accompanied by a decrease in heme oxygenase (HO)-1 protein expression in MA-10 mouse Leydig tumor cells. Subsequently, pronounced DNA damage with phosphorylated H2A histone family member X (γ-H2AX) increase and activation of DNA damage-related signaling pathways including double and single stranded break-induced ataxia telangiectasia mutated (ATM)/checkpoint kinase (Chk)2 and ataxia telangiectasia mutated and Rad3 related (ATR)/Chk1 signaling axes were identified. p53-dependent pathway was then initiated ultimately leading to cell death. Preincubated with free radical scavenger, N-acetylcysteine (NAC), down-regulated γ-H2AX expression in treated cells and partially reduced cell death, indicating that ROS overproduction is involved in combination treatment-induced DNA damage. Furthermore, the combination treatment effectively inhibited tumor growth as reflected in the reduction of tumor volume, size and weight, and high expression level of γ-H2AX in tumor tissue in vivo, suggesting that the combination treatment inhibited tumor growth via causing DNA damage in MA-10 cells. In summary, these results expound that the combination treatment of cordycepin and radiation induces MA-10 mouse Leydig tumor cell death through ROS accumulation and DNA damage. This finding can serve as a reference guideline for future clinical therapy of testicular cancer and provide potential targets for anti-cancer drug design.},
}
@article {pmid37162825,
year = {2023},
author = {Jung, IR and Ahima, RS and Kim, SF},
title = {IPMK modulates FFA-induced insulin resistance in primary mouse hepatocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {37162825},
issn = {2692-8205},
support = {R01 DK135751/DK/NIDDK NIH HHS/United States ; },
abstract = {Insulin resistance is a critical mediator of the development of non-alcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of non-alcoholic fatty liver disease (NAFLD). Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of Akt phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-Acetyl Cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.},
}
@article {pmid37155080,
year = {2023},
author = {Wang, W and Zeng, J and Luo, P and Fang, J and Pei, Q and Yan, J and Zhu, C and Chen, W and Liu, Y and Huang, Z and Huang, Y and Wu, C and Pan, X},
title = {Engineered lipid liquid crystalline nanoparticles as an inhaled nanoplatform for mucus penetration enhancement.},
journal = {Drug delivery and translational research},
volume = {13},
number = {11},
pages = {2834-2846},
pmid = {37155080},
issn = {2190-3948},
mesh = {*Drug Carriers/chemistry ; *Nanoparticles/chemistry ; Mucus/metabolism ; Mucins ; Acetylcysteine ; Lipids/chemistry ; },
abstract = {Nanocarrier-assisted pulmonary drug delivery system has been widely employed for lung local disease treatment due to its enhanced drug lesion accumulation and reduced systematical side effects. However, the mucus barriers covered on the epithelia of trachea and bronchial tree construct a dense barrier for inhaled nanocarrier transport, which compromises the therapeutical effects. In this study, a lipid liquid crystalline nanoparticle NLP@Z with surface zwitterion material hexadecyl betaine (HB) modification and N-acetylcysteine (NAC) encapsulation was presented to exert the combination strategy of mucus-inert surface and mucus degradation. The HB modification endowed NLP@Z mucus-inert surface to inhibit the interaction between NLP@Z and mucins, and the encapsulated NAC could effectively degrade the mucins and further decrease the mucus viscosity. This combination strategy was proved to significantly promote the mucus penetration performance and enhance epithelial cell uptake. In addition, the proposed NLP@Z was equipped with desired nebulization property, which could be served as a potential pulmonary delivery nanoplatform. In summary, the proposed NLP@Z highlights the employment of the combination strategy for mucus penetration enhancement in pulmonary delivery, which may become a versatile platform for lung disease therapy.},
}
@article {pmid37151623,
year = {2023},
author = {Wu, X and Cao, Z and Ni, J and Zheng, X and Zhu, L and Xin Wang, and Lv, J and Zhou, S and Ding, Y and Wu, R},
title = {Compatibility and aerosol characteristics of beclomethasone mixed with N-acetylcysteine.},
journal = {Heliyon},
volume = {9},
number = {4},
pages = {e15357},
pmid = {37151623},
issn = {2405-8440},
abstract = {Mixing different kind inhalation medications for simultaneous inhalation is widely used in the treatment of chronic respiratory diseases, and it can minimize the administration time and improve patient adherence. To our knowledge, it is unclear whether beclomethasone (BDP, Clenil®) can bemixed with acetylcysteine (NAC, Fluimucil®), because the in vitro physico-chemical compatibility and aerosol characteristics of the mixture are unknown. In this study, we investigated physical compatibility, including the appearance, pH, osmotic pressure and chemical stability, as well as aerosol characteristics, including particle size corresponding to 10%/50%/90% of the cumulative percentage of total particle volume (X10/X50/X90), volume median droplet diameter (VMD), mass median aerodynamic diameter (MMAD), fine particle fraction (FPF), fine particle dose (FPD) and geometric standard deviation (GSD), delivery rate, and total delivery of the above solutions. After mixing, there were no significant changes in visual appearance, pH, osmolality and drug content of the mixtures at room temperature for 12 h. The FDP of BDP in the mixture decreased by 16.49%, whereas the NAC increased by 10.85%. The delivery rates of BDP and NAC in the mixture decreased by 66.05% and 45.54%, and total delivery increased by 13.20% and 25.29%, respectively. However, the MMAD, FPF, particle size and GSD of the mixture were almost unchanged. We demonstrated that these admixtures are physico-chemically compatible but that coadministration of beclomethasone with acetylcysteine can markedly affect output and aerosol characteristics.},
}
@article {pmid37151359,
year = {2023},
author = {Elkhateeb, N and Hyde, S and Hogg, SL and Allsop, D and Shankar, A and Deegan, P and Tan, CY},
title = {Paracetamol toxicity in classic homocystinuria: Effect of N-acetylcysteine on total homocysteine.},
journal = {JIMD reports},
volume = {64},
number = {3},
pages = {238-245},
pmid = {37151359},
issn = {2192-8304},
abstract = {Classical homocystinuria (HCU) is caused by cystathionine β-synthase deficiency leading to impaired homocysteine transsulfuration and accumulation of homocysteine and methionine. Patients present with a wide spectrum of manifestations including ocular, skeletal, neuropsychiatric, and vascular manifestations. We report a 48-year-old female with pyridoxine-unresponsive HCU treated with betaine, cyanocobalamin, and folate. Her diet was non-restricted due to intolerance of low-methionine diet. She was admitted to hospital following a fall, with multiple fractures and subsequently developed acute liver failure with encephalopathy. Shock, sepsis, and liver ischaemia/thrombosis were excluded. In the context of glutathione depletion expected in HCU, hepatic dysfunction was presumed to be due to iatrogenic paracetamol toxicity, despite paracetamol intake at conventional therapeutic dose, with role of hypermethioninemia as a contributing factor being uncertain. Betaine was discontinued on hospital admission. N-Acetylcysteine (NAC) infusion was initiated. Plasma total homocysteine (tHcy) was 3.4 μmol/L 9 days following initiation of NAC treatment with a markedly elevated plasma methionine of 1278 μmol/L. tHcy concentration returned to pre-admission baseline after NAC was discontinued. Recovery following this episode was slow with a prolonged cholestatic phase and gradual improvement in jaundice and coagulopathy. We recommend that paracetamol should be administered cautiously in HCU patients due to underlying glutathione depletion and risk of toxicity even at therapeutic doses. NAC is clearly effective in lowering tHcy in classical HCU in the short-term however further research is required to assess clinical efficacy and use as a potential therapy in classical HCU.},
}
@article {pmid37147916,
year = {2023},
author = {Hamedinasab, H and Rezayan, AH and Jaafari, MR and Mashreghi, M and Alvandi, H},
title = {The protective effect of N-acetylcysteine against liposome and chitosan-induced cytotoxicity.},
journal = {Journal of microencapsulation},
volume = {40},
number = {5},
pages = {357-365},
doi = {10.1080/02652048.2023.2209646},
pmid = {37147916},
issn = {1464-5246},
mesh = {Acetylcysteine/pharmacology ; Antioxidants ; *Chitosan/toxicity ; Drug Liberation ; Liposomes ; *Nanoparticles ; Particle Size ; },
abstract = {AIM: N-acetylcysteine (NAC) is an antioxidant used to moderate liposome and chitosan-induced cell cytotoxicity at their high concentrations.<br><br>METHODS: Liposome and chitosan were prepared and characterised. The cytotoxicity effect of liposome with NAC-loaded liposome (liposome-NAC) and chitosan solution with chitosan solution containing NAC (chitosan-NAC) on the A549 cell line was compared.<br><br>RESULTS: Particle size, zeta potential, and NAC drug release for liposome were 125.9&#x2009;&#xb1;&#x2009;8&#x2009;nm, -34.7&#x2009;&#xb1;&#x2009;2.1&#x2009;mV, and 51.1%&#x2009;&#xb1;&#x2009;3%, respectively. Scanning electron microscope (SEM) and transmission electron microscope (TEM) indicated spherical shape of liposome. Encapsulation efficiency of liposome-NAC was 12%&#x2009;&#xb1;&#x2009;0.98%. Particle size and zeta potential for chitosan solution were 361&#x2009;&#xb1;&#x2009;11.3&#x2009;nm and 10.8&#x2009;&#xb1;&#x2009;1.52&#x2009;mV. Stability storage study indicated good stability of chitosan and liposome. Cell viability of liposome-NAC and chitosan-NAC significantly was higher than liposome and chitosan at all four concentrations.<br><br>CONCLUSIONS: NAC has a protective effect against liposome and chitosan-induced cell toxicity.},
}
@article {pmid37147040,
year = {2023},
author = {Bhatara, VS and Daniel, J and Whitman, C and Vik, T and Bernstein, B and Simkin, DR},
title = {Complementary/Integrative Medicine Treatment and Prevention of Youth Psychosis.},
journal = {Child and adolescent psychiatric clinics of North America},
volume = {32},
number = {2},
pages = {273-296},
doi = {10.1016/j.chc.2022.08.009},
pmid = {37147040},
issn = {1558-0490},
mesh = {Adolescent ; Humans ; *Integrative Medicine ; *Psychotic Disorders/drug therapy/prevention &amp; control ; *Antipsychotic Agents/therapeutic use ; *Fatty Acids, Omega-3/therapeutic use ; },
abstract = {The rationale for CIM treatments in youth psychoses is to optimize treatment by targeting symptoms not resolved by antipsychotics, such as negative symptoms (major drivers of disability). Adjunctive omega-3 fatty acids (ω-3 FA) or N-acetyl cystine (NAC usage for > 24-week) can potentially reduce negative symptoms and improve function. ω-3 FA or exercise may prevent progression to psychosis in youth (in prodromal stage). Weekly 90-minute moderate to vigorous physical activity or aerobic exercise can reduce positive and negative symptoms. Awaiting better research, CIM agents are also recommended because they are devoid of any serious side-effects.},
}
@article {pmid37142668,
year = {2023},
author = {Cheng, G and Hardy, M and Kalyanaraman, B},
title = {Antiproliferative effects of mitochondria-targeted N-acetylcysteine and analogs in cancer cells.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {7254},
pmid = {37142668},
issn = {2045-2322},
mesh = {Humans ; Mice ; Animals ; *Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Reactive Oxygen Species/pharmacology ; Mitochondria ; *Pancreatic Neoplasms/drug therapy ; },
abstract = {N-acetylcysteine (NAC) has been used as an antioxidant drug in tumor cells and preclinical mice tumor xenografts, and it improves adaptive immunotherapy in melanoma. NAC is not readily bioavailable and is used in high concentrations. The effects of NAC have been attributed to its antioxidant and redox signaling role in mitochondria. New thiol-containing molecules targeted to mitochondria are needed. Here, mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito10-NAC) that is functionally similar to NAC was synthesized and studied. Mito10-NAC has a free sulfhydryl group and is more hydrophobic than NAC. Mito10-NAC is nearly 2000-fold more effective than NAC in inhibiting several cancer cells, including pancreatic cancer cells. Methylation of NAC and Mito10-NAC also inhibited cancer cell proliferation. Mito10-NAC inhibits mitochondrial complex I-induced respiration and, in combination with monocarboxylate transporter 1 inhibitor, synergistically decreased pancreatic cancer cell proliferation. Results suggest that the antiproliferative effects of NAC and Mito10-NAC are unlikely to be related to their antioxidant mechanism (i.e., scavenging of reactive oxygen species) or to the sulfhydryl group-dependent redox modulatory effects.},
}
@article {pmid37140849,
year = {2023},
author = {Zhao, Y and Wang, L and Liu, M and Du, A and Qiu, M and Shu, H and Li, L and Kong, X and Sun, W},
title = {ROS inhibition increases KDM6A-mediated NOX2 transcription and promotes macrophages oxidative stress and M1 polarization.},
journal = {Cell stress &amp; chaperones},
volume = {28},
number = {4},
pages = {375-384},
pmid = {37140849},
issn = {1466-1268},
mesh = {Reactive Oxygen Species/metabolism ; *Histones ; *Macrophages ; Oxidative Stress ; Interleukin-6/metabolism ; Histone Demethylases/pharmacology ; },
abstract = {Reactive oxygen species (ROS) play an essential role in macrophage polarization. However, the adverse effects of ROS reduction by influencing epigenetics are often ignored. In this study, lipopolysaccharide (LPS) was used to stimulate macrophages to increase the ROS in cells, and N-acetylcysteine (NAC) was used to reduce ROS. Inflammatory factors such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were used to evaluate the M1 polarization level of macrophages. Chip was used to detect the tri-methylation at lysine 27 of histone H3 (H3K27me3) level at the promoter site. It was found that the decrease of ROS in macrophages would also cause the increase of the H3K27me3 demethylase KDM6A and lead to the reduction of H3K27me3 in the NOX2 promoter, which would increase the transcription level of NOX2 and the production of ROS and ultimately promote the production of inflammatory factors. Knockout of KDM6A can reduce the transcription of NOX2 and the production of ROS of macrophages, thus preventing the M1 polarization of macrophages. The elimination of ROS in macrophages will affect macrophages by increasing KDM6A and making them produce more ROS, thus inducing oxidative stress. In comparison, direct inhibition of KDM6A can reduce ROS production and inhibit macrophage M1 polarization more effectively.},
}
@article {pmid37139830,
year = {2023},
author = {Maiti, S and Nazmeen, A and Banerjee, A},
title = {Significant impact of redox regulation of estrogen-metabolizing proteins on cellular stress responses.},
journal = {Cell biochemistry and function},
volume = {41},
number = {4},
pages = {461-477},
doi = {10.1002/cbf.3796},
pmid = {37139830},
issn = {1099-0844},
mesh = {Humans ; *Cysteine/metabolism ; *Estrogens ; Estradiol ; Oxidation-Reduction ; Mutagenesis, Site-Directed ; },
abstract = {The ultimate driving force, stress, promotes adaptability/evolution in proliferating organisms, transforming tumorigenic growth. Estradiol (E2) regulates both phenomena. In this study, bioinformatics-tools, site-directed-mutagenesis (human estrogen-sulfotransferase/hSULT1E1), HepG2 cells tested with N-acetyl-cysteine (NAC/thiol-inducer) or buthionine-sulfoxamine (BSO/thiol-depletory) were evaluated for hSULT1E1 (estradiol-sulphating/inactivating) functions. Reciprocal redox regulation of steroid sulfatase (STS, E2-desulfating/activating) results in the Cys-formylglycine transition by the formylglycine-forming enzyme (FGE). The enzyme sequences and structures were examined across the phylogeny. Motif/domain and the catalytic conserve sequences and protein-surface-topography (CASTp) were investigated. The E2 binding to SULT1E1 suggests that the conserved-catalytic-domain in this enzyme has critical Cysteine 83 at position. This is strongly supported by site-directed mutagenesis/HepG2-cell research. Molecular-docking and superimposition studies of E2 with the SULT1E1 of representative species and to STS reinforce this hypothesis. SULT1E1-STS are reciprocally activated in response to the cellular-redox-environment by the critical Cys of these two enzymes. The importance of E2 in organism/species proliferation and tissue tumorigenesis is highlighted.},
}
@article {pmid37137784,
year = {2023},
author = {Beyler, O and Demir, C},
title = {Use of n-acetylcysteine therapy in patients with relapsed refractory thrombotic thrombocytopenic purpura.},
journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis},
volume = {62},
number = {4},
pages = {103713},
doi = {10.1016/j.transci.2023.103713},
pmid = {37137784},
issn = {1473-0502},
mesh = {Humans ; *Purpura, Thrombotic Thrombocytopenic/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; von Willebrand Factor/therapeutic use ; Plasma Exchange ; *Anemia, Hemolytic ; *Thrombosis/drug therapy ; ADAMTS13 Protein/therapeutic use ; },
abstract = {There is limited data on the use of NAC in the literature. We would like to present the satisfactory results we obtained in our resistant and relapsed patients as a case series.Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by ADAMTS13 (a disintegrin with thrombospondin type 1 motif and metalloprotease activity, member13) deficiency. Von Willebrand factor (vWF) initiates platelet aggregation and thus thrombus formation. The multimers of vWF are cleaved by ADAMTS13. Because of the decreased activity of ADAMTS13, ultra-large multimers accumulate and end-organ damage occurs. TTP is characterized by microangiopathic hemolytic anemia (MAHA), severe thrombocytopenia, and organ ischemia resulting from vascular occlusion caused by thrombi. Plasma exchange therapy (PEX) remains the mainstay of TTP therapy. Patients who do not respond to PEX and corticosteroids require additional treatments such as rituximab and caplacizumab. NAC reduces disulfide bonds in mucin polymers through its free sulfhydryl group. Thus, the size and viscosity of the mucins are reduced. VWF is structurally similar to mucin. Based on this similarity, Chen and colleagues showed that NAC can reduce the size and reactivity of ultralarge multimers of vWF, such as ADAMTS13. Currently, there is not much information to suggest that NAC has any clinical value in the treatment of TTP. In this case series of 4 refractory patients, we would like to present the responses we obtained with the addition of NAC therapy. NAC can be added to PEX and glucocorticoid therapy as supportive therapy, especially in unresponsive patients.},
}
@article {pmid37134194,
year = {2023},
author = {Orgel, E and Knight, KR and Chi, YY and Malvar, J and Rushing, T and Mena, V and Eisenberg, LS and Rassekh, SR and Ross, CJD and Scott, EN and Neely, M and Neuwelt, EA and Muldoon, LL and Freyer, DR},
title = {Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {29},
number = {13},
pages = {2410-2418},
pmid = {37134194},
issn = {1557-3265},
support = {K23 DC014291/DC/NIDCD NIH HHS/United States ; UL1 TR000130/TR/NCATS NIH HHS/United States ; UL1 TR001855/TR/NCATS NIH HHS/United States ; },
mesh = {Adolescent ; Humans ; Child ; Cisplatin/adverse effects ; Acetylcysteine/therapeutic use/adverse effects ; *Hearing Loss/chemically induced/prevention &amp; control ; *Neoplasms/drug therapy/chemically induced ; Administration, Intravenous ; },
abstract = {PURPOSE: Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL.<br><br>PATIENTS AND METHODS: In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations.<br><br>RESULTS: Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021-0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011-0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection.<br><br>CONCLUSIONS: NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant.},
}
@article {pmid37134105,
year = {2023},
author = {Shim, JY and Chung, JO and Jung, D and Kang, PS and Park, SY and Kendi, AT and Lowe, VJ and Lee, S},
title = {Parkin-mediated mitophagy is negatively regulated by FOXO3A, which inhibits Plk3-mediated mitochondrial ROS generation in STZ diabetic stress-treated pancreatic β cells.},
journal = {PloS one},
volume = {18},
number = {5},
pages = {e0281496},
pmid = {37134105},
issn = {1932-6203},
mesh = {Humans ; Mitophagy ; Reactive Oxygen Species/metabolism ; Streptozocin/pharmacology ; *Insulin-Secreting Cells/metabolism ; Protein Kinases/metabolism ; *Diabetes Mellitus/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Tumor Suppressor Proteins/metabolism ; Polo-like Kinases ; },
abstract = {Diabetes mellitus (DM) is one of the most researched metabolic diseases worldwide. It leads to extensive complications such as cardiovascular disease, nephropathy, retinopathy, and peripheral and central nervous system through an inability to produce or respond to insulin. Although oxidative stress-mediated mitophagy has been reported to play an important role in the pathogenesis of DM, specific studies are still lacking as well as remain highly controversial. Here, we found that Parkin-mediated mitophagy in pancreatic β cells under streptozotocin (STZ)-diabetic stress was induced by Polo-like kinase 3 (Plk3) and inhibited by the transcription factor Forkhead Box O3A (FOXO3A). STZ stress induces mitochondrial recruitment of Parkin through Plk3-mediated mitochondrial reactive oxygen species (ROS) generation, which causes pancreatic cell damage. Conversely, FOXO3A acts as negative feedback to prevent diabetic stress by inhibiting Plk3. Meanwhile, antioxidants including N-acetylcysteine (NAC) and natural COA water scientifically block these mitochondrial ROS and mitochondrial recruitment of Parkin by inhibiting Plk3. Through a 3D organoid ex vivo model, we confirmed that not only ROS inhibitors but also mitophagy inhibitory factors such as 3-MA or Parkin deletion can compensate for pancreatic cell growth and insulin secretion under STZ diabetic stress. These findings suggest that the Plk3-mtROS-PINK1-Parkin axis is a novel mitophagy process that inhibits pancreatic β-cell growth and insulin secretion and FOXO3A and antioxidants may provide new alternatives for effective diabetes treatment strategies in the future.},
}
@article {pmid37132544,
year = {2023},
author = {Wilson, MM and Danielian, PS and Salus, G and Ferretti, R and Whittaker, CA and Lees, JA},
title = {BMI1 is required for melanocyte stem cell maintenance and hair pigmentation.},
journal = {Pigment cell &amp; melanoma research},
volume = {36},
number = {5},
pages = {399-406},
pmid = {37132544},
issn = {1755-148X},
support = {P30 CA014051/CA/NCI NIH HHS/United States ; P01 CA042063/CA/NCI NIH HHS/United States ; },
mesh = {Mice ; Animals ; Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism ; *Melanoma/metabolism ; Proto-Oncogene Proteins ; *Skin Neoplasms/metabolism ; Stem Cells/metabolism ; Polycomb Repressive Complex 1/genetics/metabolism ; Pigmentation ; Melanocytes/metabolism ; Hair/metabolism ; },
abstract = {The epigenetic repressor BMI1 plays an integral role in promoting the self-renewal and proliferation of many adult stem cell populations, and also tumor types, primarily through silencing the Cdkn2a locus, which encodes the tumor suppressors p16[Ink4a] and p19[Arf] . However, in cutaneous melanoma, BMI1 drives epithelial-mesenchymal transition programs, and thus metastasis, while having little impact on proliferation or primary tumor growth. This raised questions about the requirement and role for BMI1 in melanocyte stem cell (McSC) biology. Here, we demonstrate that murine melanocyte-specific Bmi1 deletion causes premature hair greying and gradual loss of melanocyte lineage cells. Depilation enhances this hair greying defect, accelerating depletion of McSCs in early hair cycles, suggesting that BMI1 acts to protect McSCs against stress. RNA-seq of McSCs, harvested before onset of detectable phenotypic defects, revealed that Bmi1 deletion derepresses p16[Ink4a] and p19[Arf] , as observed in many other stem cell contexts. Additionally, BMI1 loss downregulated the glutathione S-transferase enzymes, Gsta1 and Gsta2, which can suppress oxidative stress. Accordingly, treatment with the antioxidant N-acetyl cysteine (NAC) partially rescued melanocyte expansion. Together, our data establish a critical function for BMI1 in McSC maintenance that reflects a partial role for suppression of oxidative stress, and likely transcriptional repression of Cdkn2a.},
}
@article {pmid37131727,
year = {2023},
author = {Everton, E and Del Rio-Moreno, M and Villacorta-Martin, C and Singh Bawa, P and Lindstrom-Vautrin, J and Muramatsu, H and Rizvi, F and Smith, AR and Tam, Y and Pardi, N and Kineman, R and Waxman, DJ and Gouon-Evans, V},
title = {Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.04.17.537197},
pmid = {37131727},
issn = {2692-8205},
support = {I01 BX004448/BX/BLRD VA/United States ; R01 DK116878/DK/NIDDK NIH HHS/United States ; TL1 TR001410/TR/NCATS NIH HHS/United States ; },
abstract = {BACKGROUND AND AIMS: Acetaminophen (APAP) overdose is the leading cause of acute liver failure, with one available treatment, N-acetyl cysteine (NAC). Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. This study addresses this need by deciphering a mechanism of sexual dimorphism in APAP-induced liver injury, and leveraging it to accelerate liver recovery via growth hormone (GH) treatment. GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. Here, we aim to establish GH as a novel therapy to treat APAP hepatotoxicity.<br><br>APPROACH AND RESULTS: Our results demonstrate sex-dependent APAP toxicity, with females showing reduced liver cell death and faster recovery than males. Single-cell RNA sequencing analyses reveal that female hepatocytes have significantly greater levels of GH receptor expression and GH pathway activation compared to males. In harnessing this female-specific advantage, we demonstrate that a single injection of recombinant human GH protein accelerates liver recovery, promotes survival in males following sub-lethal dose of APAP, and is superior to standard-of-care NAC. Alternatively, slow-release delivery of human GH via the safe nonintegrative lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP), a technology validated by widely used COVID-19 vaccines, rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice.<br><br>CONCLUSIONS: Our study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients.},
}
@article {pmid37123961,
year = {2023},
author = {Mitra, JK and Hansda, U and Bandyopadhyay, D and Sarkar, S and Sahoo, J},
title = {The role of a combination of N-acetylcysteine and magnesium sulfate as adjuvants to standard therapy in acute organophosphate poisoning: A randomized controlled trial.},
journal = {Heliyon},
volume = {9},
number = {4},
pages = {e15376},
pmid = {37123961},
issn = {2405-8440},
abstract = {BACKGROUND: Mortality in acute organophosphate (OP) poisoning remains high despite current standard therapy with atropine and oximes. Due to dose-limiting side effects of atropine, novel therapies are targeting other putative mechanisms of injury, including oxidative damage, to reduce atropine dosage.<br><br>OBJECTIVES: N-acetylcysteine (NAC) and magnesium sulfate (MgSO4) have different mechanisms of actions and should act synergistically in OP poisoning. In this study, we wanted to evaluate whether this novel combination, used as an adjuvant to standard care, could improve clinical outcomes.<br><br>METHODS: The study was conducted in the Emergency Department and ICU of AIIMS Bhubaneswar (a tertiary care center and government teaching institute) between July 2019 and July 2021. Eighty-eight adult patients with history and clinical features of acute OP poisoning were randomly allocated (1:1) into two groups. The Study group received 600&#xa0;mg NAC via nasogastric tube thrice daily for 3 days plus a single dose of 4&#xa0;g Inj. MgSO4 IV on first day and the Control group received suitably matched placebo (double-blinding) - in addition to standard care in both the groups. The primary outcome measure was to compare the total dose of Inj. Atropine required (cumulative over the entire treatment duration) between the control group and the study group receiving NAC and MgSO4. The secondary outcome measures were lengths of ICU and hospital stays, need and duration of mechanical ventilation, the differences in BuChE activity, oxidative stress biomarkers - MDA and GSH levels, the incidences of adverse effects including delayed sequalae like intermediate syndrome and OPIDN, and comparison of mortality between the two groups.<br><br>RESULTS: Data from 43 patients in Control and 42 patients in Study group was finally analyzed. The baseline parameters were comparable. Total atropine requirements were lower in the Study group [175.33&#xa0;&#xb1;&#xa0;81.25&#xa0;mg (150.01-200.65)] compared to the Control [210.63&#xa0;&#xb1;&#xa0;102.29&#xa0;mg (179.15-242.11)] [Mean&#xa0;&#xb1;&#xa0;SD (95% CI)], but was not statistically significant. No significant differences in any of the other clinical or biochemical parameters were noted.<br><br>CONCLUSION: The N-acetylcysteine and MgSO4 combination as adjuvants failed to significantly reduce atropine requirements, ICU/hospital stay, mechanical ventilatory requirements, mortality and did not offer protection against oxidative damage.},
}
@article {pmid37122089,
year = {2023},
author = {Huang, S and Zhang, L and Luo, J and Wu, D and Ma, K and Chen, Y and Ma, S and Feng, L and Li, F and Liu, D and Deng, J and Tan, C},
title = {Cysteamine and N-Acetyl-cysteine Alleviate Placental Oxidative Stress and Barrier Function Damage Induced by Deoxynivalenol.},
journal = {Journal of agricultural and food chemistry},
volume = {71},
number = {18},
pages = {6846-6858},
doi = {10.1021/acs.jafc.3c00399},
pmid = {37122089},
issn = {1520-5118},
mesh = {Pregnancy ; Animals ; Female ; Swine ; *Placenta/metabolism ; *Cysteamine/metabolism/pharmacology ; Antioxidants/pharmacology/metabolism ; Acetylcysteine/pharmacology/metabolism ; Oxidative Stress ; Trichothecenes ; },
abstract = {Sows are highly sensitive to deoxynivalenol (DON) and susceptible to reproductive toxicity caused by oxidative stress, but the potential mechanisms and effective interventions remain unclear. Here, we investigated the role of two antioxidants (cysteamine and N-acetyl-cysteine) in regulating the reproductive performance, redox status, and placental barrier function of sows and their potential mechanisms under DON exposure. Maternal dietary supply of antioxidants from day 85 of gestation to parturition reduced the incidence of stillbirths and low-birth-weight piglets under DON exposure. Moreover, the alleviation of DON-induced reproductive toxicity by dietary antioxidants was associated with the alleviation of placental oxidative stress, the enhancement of the placental barrier, and the vascular function of sows. Furthermore, in vivo and in vitro vascularized placental barrier modeling further demonstrated that antioxidants could reverse both DON transport across the placenta and DON-induced increase of placental barrier permeability. The molecular mechanism of antioxidant resistance to DON toxicity may be related to the signal transducer and activator of the transcription-3-occludin/zonula occludens-1 signaling pathway. Collectively, these results demonstrate the potential of antioxidants to protect the mother from DON-induced reproductive toxicity by alleviating placental oxidative stress and enhancing the placental barrier.},
}
@article {pmid37119245,
year = {2023},
author = {Wong, KK and Kua, KP and Ooi, KS and Cheah, FC},
title = {The effects of N-acetylcysteine on lung alveolar epithelial cells infected with respiratory syncytial virus.},
journal = {The Malaysian journal of pathology},
volume = {45},
number = {1},
pages = {43-50},
pmid = {37119245},
issn = {0126-8635},
mesh = {Child ; Infant ; Humans ; Child, Preschool ; Acetylcysteine/pharmacology/metabolism ; Alveolar Epithelial Cells/metabolism ; Epithelial Cells/metabolism ; *Respiratory Syncytial Virus, Human/metabolism ; Lung ; *Respiratory Syncytial Virus Infections/drug therapy/metabolism ; },
abstract = {INTRODUCTION: Respiratory syncytial virus (RSV) is one of the most common causes of acute lower respiratory infection in infants and young children. Mucolytic agents, such as acetylcysteine and carbocysteine have reported benefits in alleviating acute upper or lower respiratory infections. Among these, N-acetylcysteine (NAC) has cyto-protective effects when cells are infected with the RSV.<br><br>MATERIALS AND METHODS: Our study investigated primarily the dose-dependent effects of NAC on respiratory alveolar epithelial (A549) cells when co-cultured with RSV in vitro. Three different concentrations of NAC were used, 0.1 mM, 1 mM, and 10 mM. The cytotoxicity of RSV-infected cells was measured by lactate dehydrogenase and antiviral activity of NAC on cell cultures was evaluated by immunofluorescence.<br><br>RESULTS: Pre-treatment with the highest dose, 10 mM NAC, resulted in features of cell injury even without RSV infection. The proportion of cells infected by RSV and RSV-induced cell death decreased by more than 3-fold when cells were pre-treated with 1 mM NAC. Pre-treatment at the lowest dose, 0.1 mM, did not show any significant changes.<br><br>CONCLUSION: A moderate dose of NAC (1 mM) appeared protective of RSV infection to lung alveolar epithelial cells. However, a higher dose of NAC (10 mM) may be relatively toxic and injurious to these cells.},
}
@article {pmid37119225,
year = {2023},
author = {Russell, SE and Skvarc, DR and Mohebbi, M and Camfield, D and Byrne, LK and Turner, A and Ashton, MM and Berk, M and Dodd, S and Malhi, GS and Cotton, SM and Bush, AI and Dean, OM},
title = {The Impact of N-acetylcysteine on Major Depression: Qualitative Observation and Mixed Methods Analysis of Participant Change during a 12-week Randomised Controlled Trial.},
journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology},
volume = {21},
number = {2},
pages = {320-331},
pmid = {37119225},
issn = {1738-1088},
abstract = {OBJECTIVE: N-acetylcysteine (NAC) is a novel therapeutic agent with multiple mechanisms of action in the central nervous system and a favourable side effect profile. Clinical evidence indicates that adjunctive NAC may reduce the severity of depressive symptoms in individuals with major depressive disorder (MDD).<br><br>METHODS: A 12-week randomised controlled trial of 2,000 mg/day adjunctive NAC for MDD found no significant improvement at the primary endpoint (week 12) but did see improvements at the post-discontinuation interview (week 16). Within the context of patient-centered treatment, mixed-methods qualitative analysis was also included to explore factors that may determine individual responses to adjunctive NAC treatment. These data were drawn, under blinded conditions, from clinician notes recorded in the case report form. Using the DSM-5 symptom profile for MDD as the initial framework, themes were developed and explored. Frequencies were compared between placebo and NAC groups.<br><br>RESULTS: Per protocol analysis of individual themes across the six interviews revealed group differences in favour of NAC for overall depressive affect, optimism, relationships and reduced functional impairment.<br><br>CONCLUSION: This study provides further evidence for the utility of the mixed methods approach complimenting the primary findings using traditional quantitative analyses, as well as being able to capture additional, often more subtle, evidence of individual symptom-level change that reflects improvement in functional abilities in response to NAC supplementation. The use of mixed methods to explore outcomes from psychiatric studies should be considered in future to work towards improved patient-centred care and both confirm quantitative findings and generate novel hypotheses.},
}
@article {pmid37118950,
year = {2023},
author = {Kim, KH and Park, MJ and Park, NC and Park, HJ},
title = {Effect of N-acetyl-L-cysteine on Testicular Tissue in Busulfan-Induced Dysfunction in the Male Reproductive System.},
journal = {The world journal of men's health},
volume = {41},
number = {4},
pages = {882-891},
pmid = {37118950},
issn = {2287-4208},
support = {20200007/PNUH/Pusan National University Hospital/Korea ; },
abstract = {PURPOSE: This study aimed to evaluate the protective effect of N-acetyl-L-cysteine (NAC) as an antioxidant on busulfan-induced testicular dysfunction in mice and elucidate its possible mechanism of action.<br><br>MATERIALS AND METHODS: Thirty-two C57BL/6 male mice were randomly divided into four groups (n=8/group) as follows: (1) control group (oral administration of saline [0.1 mL daily] for 35 days); (2) NAC group (oral administration of NAC [10 mg/kg daily] for 35 days); (3) busulfan group (double intraperitoneal injections of 20 mg/kg; total dose of 40 mg/kg); and (4) busulfan+NAC group (after double intraperitoneal injections of 20 mg/kg; total dose of 40 mg/kg, NAC administration [10 mg/kg daily] for 35 days). The testes were removed, weighed, and subjected to sperm parameter analysis and morphology assessment. Reproductive hormone, serum/testicular reactive oxygen species (ROS) level, oxidative stress and antioxidant markers were evaluated. The testicular expression of Nrf2 and HO-1 was examined using RT-qPCR.<br><br>RESULTS: Busulfan treatment significantly decreased testicular weight, sperm count, and serum testosterone levels. Atrophy and degeneration of germinal epithelium were observed in the busulfan group. NAC administration after busulfan treatment partially attenuated the deterioration of testis weight, sperm quality, serum hormones, histomorphometric changes, and oxidative and antioxidative status. NAC treatment resulted in a considerable improvement in Nrf2 and HO-1 mRNA expression levels.<br><br>CONCLUSIONS: This study provides compelling evidence that NAC as a potent antioxidant has significant protective effects against busulfan-induced male reproductive impairment possibly through modification of the Nrf2/HO-1 signaling pathway.},
}
@article {pmid37116249,
year = {2023},
author = {Bilister Egilmez, C and Azak Pazarlar, B and Erdogan, MA and Erbas, O},
title = {N-acetyl cysteine: A new look at its effect on PTZ-induced convulsions.},
journal = {Epilepsy research},
volume = {193},
number = {},
pages = {107144},
doi = {10.1016/j.eplepsyres.2023.107144},
pmid = {37116249},
issn = {1872-6844},
mesh = {Rats ; Animals ; Pentylenetetrazole/toxicity ; Rats, Sprague-Dawley ; *Myoclonus/drug therapy ; Acetylcysteine/adverse effects ; Electroencephalography ; *Epilepsy/drug therapy ; Seizures/chemically induced/drug therapy ; Superoxide Dismutase ; Anticonvulsants/adverse effects ; Disease Models, Animal ; },
abstract = {INTRODUCTION/AIM: Epilepsy is widely investigated as a common neurological disease requiring pharmacologically effective agents. N-acetyl cysteine (NAC), has become a remarkable molecule with its role in both antioxidant and glutaminergic modulation. There are many points and processes waiting to be revealed regarding the role of NAC in epilepsy.<br><br>MATERIALS AND METHODS: Pentylenetetrazole (PTZ) was administered to induce seizures in a total number of 48 Sprague-Dawley rats. 35&#xa0;mg/kg PTZ dose as a sub-convulsive dose was administered to 24 animals to monitor EEG changes, while 70&#xa0;mg/kg PTZ dose which was a convulsive dose was administered to 24 animals to determine seizure-related behavioral changes with the Racine's scale. 30&#xa0;min before the seizure-induced procedure, NAC was administered at doses of 300 and 600&#xa0;mg/kg as pretreatment to investigate anti-seizure and anti-oxidative effects. The spike percentage, the stage of convulsion, and the onset time of the first myoclonic jerk were evaluated to determine the anti-seizure effect. Furthermore, its effect on oxidative stress was determined by measuring both malondialdehyde (MDA) level and superoxide dismutase (SOD) enzyme activity.<br><br>RESULTS: There was a dose-dependent reduction in the seizure stage and prolonged onset time of the first myoclonic jerk in rats with NAC pretreatment. EEG recordings resulted in a dose-dependent decrease in spike percentages. Moreover, the same dose-dependent changes were observed in oxidative stress biomarkers, both 300&#xa0;mg/kg NAC and 600&#xa0;mg/kg decreased MDA levels and ameliorated SOD activity.<br><br>CONCLUSION: We can report that 300&#xa0;mg/kg and 600&#xa0;mg/kg doses of NAC are promising with their reducing effect on convulsions and have a beneficial effect by preventing oxidative stress. In addition, NAC has been also determined that this effect is dose-dependent. Detailed and comparative studies are needed on the convulsion-reducing effect of NAC in epilepsy.},
}
@article {pmid37113636,
year = {2023},
author = {Salajegheh, F and Shafieipour, S and Najminejad, Z and Pourzand, P and Nakhaie, M and Jahangiri, S and Sarmadian, R and Gilani, A and Rukerd, MRZ},
title = {HAV-induced acalculous cholecystitis: A case report and literature review.},
journal = {Clinical case reports},
volume = {11},
number = {4},
pages = {e7254},
pmid = {37113636},
issn = {2050-0904},
abstract = {Hepatitis A virus (HAV) has some life-threatening extrahepatic complications, such as acute acalculous cholecystitis (AAC). We present HAV-induced AAC in a young female, based on clinical, laboratory, and imaging findings, and conduct a literature review. The patient became irritable, which progressed to lethargy, as well as a significant decline in liver function, indicating acute liver failure (ALF). She was immediately managed in the intensive care unit with close airway and hemodynamic monitoring after being diagnosed with ALF (ICU). The patient's condition was improving, despite only close monitoring and supportive treatment with ursodeoxycholic acid (UDCA) and N-acetyl cysteine (NAC).},
}
@article {pmid37111348,
year = {2023},
author = {Soto, ME and Manzano-Pech, L and Palacios-Chavarría, A and Valdez-Vázquez, RR and Guarner-Lans, V and Pérez-Torres, I},
title = {N-Acetyl Cysteine Restores the Diminished Activity of the Antioxidant Enzymatic System Caused by SARS-CoV-2 Infection: Preliminary Findings.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {16},
number = {4},
pages = {},
pmid = {37111348},
issn = {1424-8247},
support = {312167//Consejo Nacional de Ciencia y Tecnolog&#xed;a (CONACYT) M&#xe9;xico/ ; },
abstract = {SARS-CoV-2 infects type II pneumocytes and disrupts redox homeostasis by overproducing reactive oxygen species (ROS). N-acetyl cysteine (NAC) is a precursor of the synthesis of glutathione (GSH) and it restores the loss of redox homeostasis associated to viral infections. The aim of the study is to evaluate the effect of the treatment with NAC on the enzymatic antioxidant system in serum from patients infected by SARS-CoV-2. We evaluated the enzymatic activities of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), -S-transferase (GST), and reductase (GR) by spectrophotometry and the concentrations of the glutathione (GSH), total antioxidant capacity (TAC), thiols, nitrites (NO2[-]), and lipid peroxidation (LPO) in serum. The activity of the extracellular super oxide dismutase (ecSOD) was determined by native polyacrylamide gels, and 3-nitrotyrosine (3-NT) was measured by ELISA. A decrease in the activities of the ecSOD, TrxR, GPx, GST GR, (p = 0 ≤ 0.1), and the GSH, TAC, thiols, and NO2[-] (p ≤ 0.001) concentrations and an increase in LPO and 3-NT (p = 0.001) concentrations were found in COVID-19 patients vs. healthy subjects. The treatment with NAC as an adjuvant therapy may contribute to a reduction in the OS associated to the infection by SARS-CoV-2 through the generation of GSH. GSH promotes the metabolic pathways that depend on it, thus contributing to an increase in TAC and to restore redox homeostasis.},
}
@article {pmid37109533,
year = {2023},
author = {Amante, C and De Soricellis, C and Luccheo, G and Luccheo, L and Russo, P and Aquino, RP and Del Gaudio, P},
title = {Flogomicina: A Natural Antioxidant Mixture as an Alternative Strategy to Reduce Biofilm Formation.},
journal = {Life (Basel, Switzerland)},
volume = {13},
number = {4},
pages = {},
pmid = {37109533},
issn = {2075-1729},
abstract = {The National Institute of Health has reported that approximately 80% of chronic infections are associated with biofilms, which are indicated as one of the main reasons for bacteria's resistance to antimicrobial agents. Several studies have revealed the role of N-acetylcysteine (NAC), in reducing biofilm formation induced by different microorganisms. A novel mixture made up of NAC and different natural ingredients (bromelain, ascorbic acid, Ribes nigrum, resveratrol, and pelargonium) has been developed in order to obtain a pool of antioxidants as an alternative strategy for biofilm reduction. The study has demonstrated that the mixture is able to significantly enhance NAC activity against different Gram-positive and Gram-negative bacteria. It has shown an increase in NAC permeation in vitro through an artificial fluid, moving from 2.5 to 8 μg/cm[2] after 30 min and from 4.4 to 21.6 μg/cm[2] after 180 min, and exhibiting a strongly fibrinolytic activity compared to the single components of the mixture. Moreover, this novel mixture has exhibited an antibiofilm activity against S aureus and the ability to reduce S. aureus growth by more than 20% in a time-killing assay, while on E. coli, and P. mirabilis, the growth was reduced by more than 80% compared to NAC. The flogomicina mixture has also been proven capable of reducing bacterial adhesion to abiotic surfaces of E.coli, by more than 11% concerning only the NAC. In combination with amoxicillin, it has been shown to significantly increase the drug's effectiveness after 14 days, offering a safe and natural way to reduce the daily dosage of antibiotics in prolonged therapies and consequently, reduce antibiotic resistance.},
}
@article {pmid37108758,
year = {2023},
author = {Zadrożniak, M and Szymański, M and Łuszczki, JJ},
title = {N-Acetyl-L-cysteine Affects Ototoxicity Evoked by Amikacin and Furosemide Either Alone or in Combination in a Mouse Model of Hearing Threshold Decrease.},
journal = {International journal of molecular sciences},
volume = {24},
number = {8},
pages = {},
pmid = {37108758},
issn = {1422-0067},
support = {474/CU/CSP VA/United States ; },
mesh = {Mice ; Animals ; Amikacin/toxicity ; Furosemide/adverse effects ; Acetylcysteine/adverse effects ; *Ototoxicity ; *Hearing Loss/chemically induced/drug therapy/prevention &amp; control ; Anti-Bacterial Agents/adverse effects ; Hearing ; Aminoglycosides ; *Deafness ; Auditory Threshold ; },
abstract = {Drug-induced ototoxicity resulting from therapy with aminoglycoside antibiotics and loop diuretics is one of the main well-known causes of hearing loss in patients. Unfortunately, no specific protection and prevention from hearing loss are recommended for these patients. This study aimed at evaluating the ototoxic effects produced by mixtures of amikacin (AMI, an aminoglycoside antibiotic) and furosemide (FUR, a loop diuretic) in the mouse model as the hearing threshold decreased by 20% and 50% using auditory brainstem responses (ABRs). Ototoxicity was produced by the combinations of a constant dose of AMI (500 mg/kg; i.p.) on FUR-induced hearing threshold decreases, and a fixed dose of FUR (30 mg/kg; i.p.) on AMI-induced hearing threshold decreases, which were determined in two sets of experiments. Additionally, the effects of N-acetyl-L-cysteine (NAC; 500 mg/kg; i.p.) on the hearing threshold decrease of 20% and 50% were determined by means of an isobolographic transformation of interactions to detect the otoprotective action of NAC in mice. The results indicate that the influence of a constant dose of AMI on FUR-induced hearing threshold decreases was more ototoxic in experimental mice than a fixed dose of FUR on AMI-induced ototoxicity. Moreover, NAC reversed the AMI-induced, but not FUR-induced, hearing threshold decreases in this mouse model of hearing loss. NAC could be considered an otoprotectant in the prevention of hearing loss in patients receiving AMI alone and in combination with FUR.},
}
@article {pmid37108481,
year = {2023},
author = {Brivio, P and Gallo, MT and Gruca, P and Lason, M and Litwa, E and Fumagalli, F and Papp, M and Calabrese, F},
title = {Chronic N-Acetyl-Cysteine Treatment Enhances the Expression of the Immediate Early Gene Nr4a1 in Response to an Acute Challenge in Male Rats: Comparison with the Antidepressant Venlafaxine.},
journal = {International journal of molecular sciences},
volume = {24},
number = {8},
pages = {},
pmid = {37108481},
issn = {1422-0067},
mesh = {Animals ; Male ; Rats ; *Acetylcysteine/pharmacology/therapeutic use ; Antidepressive Agents/therapeutic use ; *Genes, Immediate-Early ; Rats, Wistar ; Venlafaxine Hydrochloride/pharmacology/therapeutic use ; },
abstract = {Despite several antidepressant treatments being available in clinics, they are not effective in all patients. In recent years, N-acetylcysteine (NAC) has been explored as adjunctive therapy for many psychiatric disorders, including depression, for its antioxidant properties. Given the promising efficacy of this compound for the treatment of such pathologies, it is fundamental to investigate, at the preclinical level, the ability of the drug to act in the modulation of neuroplastic mechanisms in basal conditions and during challenging events in order to highlight the potential features of the drug useful for clinical efficacy. To this aim, adult male Wistar rats were treated with the antidepressant venlafaxine (VLX) (10 mg/kg) or NAC (300 mg/kg) for 21 days and then subjected to 1 h of acute restraint stress (ARS). We found that NAC enhanced the expression of several immediate early genes, markers of neuronal plasticity in the ventral and dorsal hippocampus, prefrontal cortex and amygdala, and in particular it mediated the acute-stress-induced upregulation of Nr4a1 expression more than VLX. These data suggested the ability of NAC to induce coping strategies to face external challenges, highlighting its potential for the improvement of neuroplastic mechanisms for the promotion of resilience, in particular via the modulation of Nr4a1.},
}
@article {pmid37108119,
year = {2023},
author = {Chadwick, W and Maudsley, S and Hull, W and Havolli, E and Boshoff, E and Hill, MDW and Goetghebeur, PJD and Harrison, DC and Nizami, S and Bedford, DC and Coope, G and Real, K and Thiemermann, C and Maycox, P and Carlton, M and Cole, SL},
title = {The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {24},
number = {8},
pages = {},
pmid = {37108119},
issn = {1422-0067},
mesh = {Mice ; Humans ; Animals ; *Alzheimer Disease/genetics/pathology ; Amyloid beta-Peptides/genetics ; Memory ; *Cognition Disorders ; Animals, Genetically Modified ; Disease Models, Animal ; },
abstract = {Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.},
}
@article {pmid37107344,
year = {2023},
author = {Romero-Miguel, D and Casquero-Veiga, M and Fernández, J and Lamanna-Rama, N and Gómez-Rangel, V and Gálvez-Robleño, C and Santa-Marta, C and Villar, CJ and Lombó, F and Abalo, R and Desco, M and Soto-Montenegro, ML},
title = {Maternal Supplementation with N-Acetylcysteine Modulates the Microbiota-Gut-Brain Axis in Offspring of the Poly I:C Rat Model of Schizophrenia.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {4},
pages = {},
pmid = {37107344},
issn = {2076-3921},
support = {project number PI17/01766, and grant number BA21/00030//Ministerio de Ciencia e Innovaci&#xf3;n, Instituto de Salud Carlos III, co-financed by the European Regional Development Fund (ERDF), "A way to make Europe"/ ; project PID2021-128862OB-I00//MCIN /AEI /10.13039/501100011033 / FEDER, UE/ ; project number CB07/09/0031//CIBER de Salud Mental - Instituto de Salud Carlos III/ ; project numbers 2017/085, 2022/008917//Delegaci&#xf3;n del Gobierno para el Plan Nacional sobre Drogas/ ; 2016/01//Fundaci&#xf3;n Alicia Koplowitz/ ; grant, PEJD-2018-PRE/BMD-7899//Consejer&#xed;a de Educaci&#xf3;n e investigaci&#xf3;n, Comunidad de Madrid, co-funded by the European Social Fund "Investing in your future"/ ; "Programa Intramural de Impulso a la I+D+I 2019"//Instituto de investigaci&#xf3;n Sanitaria Gregorio Mara&#xf1;&#xf3;n/ ; PT20/00044//Ministerio de Ciencia e Innovaci&#xf3;n, Instituto de Salud Carlos III/ ; x//The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovaci&#xf3;n (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505)/ ; Contrato Intramural Postdoctoral//FINBA/ ; SV-PA-21-AYUD/2021/51347//Ayudas para grupos de investigaci&#xf3;n de organismos del Principado de Asturias/ ; },
abstract = {The microbiota-gut-brain axis is a complex interconnected system altered in schizophrenia. The antioxidant N-acetylcysteine (NAC) has been proposed as an adjunctive therapy to antipsychotics in clinical trials, but its role in the microbiota-gut-brain axis has not been sufficiently explored. We aimed to describe the effect of NAC administration during pregnancy on the gut-brain axis in the offspring from the maternal immune stimulation (MIS) animal model of schizophrenia. Pregnant Wistar rats were treated with PolyI:C/Saline. Six groups of animals were studied according to the study factors: phenotype (Saline, MIS) and treatment (no NAC, NAC 7 days, NAC 21 days). Offspring were subjected to the novel object recognition test and were scanned using MRI. Caecum contents were used for metagenomics 16S rRNA sequencing. NAC treatment prevented hippocampal volume reduction and long-term memory deficits in MIS-offspring. In addition, MIS-animals showed lower bacterial richness, which was prevented by NAC. Moreover, NAC7/NAC21 treatments resulted in a reduction of proinflammatory taxons in MIS-animals and an increase in taxa known to produce anti-inflammatory metabolites. Early approaches, like this one, with anti-inflammatory/anti-oxidative compounds, especially in neurodevelopmental disorders with an inflammatory/oxidative basis, may be useful in modulating bacterial microbiota, hippocampal size, as well as hippocampal-based memory impairments.},
}
@article {pmid37107324,
year = {2023},
author = {Zhou, Z and Qi, J and Wu, Y and Li, C and Bao, W and Lin, X and Zhu, A},
title = {Nuciferine Effectively Protects Mice against Acetaminophen-Induced Liver Injury.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {4},
pages = {},
pmid = {37107324},
issn = {2076-3921},
support = {82104520//National Natural Science Foundation of China/ ; 82200663//National Natural Science Foundation of China/ ; 2021J05045//Natural Science Foundation of Fujian Province/ ; 2022J01199//Natural Science Foundation of Fujian Province/ ; },
abstract = {Acetaminophen (APAP) overdose still poses a major clinical challenge and is a leading cause of acute liver injury (ALI). N-acetylcysteine (NAC) is the only approved antidote to treat APAP toxicity while NAC therapy can trigger side effects including severe vomiting and even shock. Thus, new insights in developing novel therapeutic drugs may pave the way for better treatment of APAP poisoning. Previous research has reported that nuciferine (Nuci) possesses anti-inflammatory and antioxidant properties. Therefore, the objective of this study was proposed to investigate the hepatoprotective effects of Nuci and explore its underlying mechanisms. Mice were intraperitoneally (i.p.) administered with APAP (300 mg/kg) and subsequently injected with Nuci (25, 50, and 100 mg/kg, i.p.) at 30 min after APAP overdose. Then, all mice were sacrificed at 12 h after APAP challenge for further analysis. Nuci-treated mice did not show any side effects and our results revealed that treating Nuci significantly attenuated APAP-induced ALI, as confirmed by histopathological examinations, biochemical analysis, and diminished hepatic oxidative stress and inflammation. The in silico prediction and mRNA-sequencing analysis were performed to explore the underlying mechanisms of Nuci. GO and KEGG enrichment of the predicted target proteins of Nuci includes reactive oxygen species, drug metabolism of cytochrome P450 (CYP450) enzymes, and autophagy. Furthermore, the mRNA-sequencing analyses indicated that Nuci can regulate glutathione metabolic processes and anti-inflammatory responses. Consistently, we found that Nuci increased the hepatic glutathione restoration but decreased APAP protein adducts in damaged livers. Western blot analysis further confirmed that Nuci effectively promoted hepatic autophagy in APAP-treated mice. However, Nuci could not affect the expression levels of the main CYP450 enzymes (CYP1A2, CYP2E1, and CYP3A11). These results demonstrated that Nuci may be a potential therapeutic drug for APAP-induced ALI via amelioration of the inflammatory response and oxidative stress, regulation of APAP metabolism, and activation of autophagy.},
}
@article {pmid37107239,
year = {2023},
author = {Boonnate, P and Kariya, R and Okada, S},
title = {Shikonin Induces ROS-Dependent Apoptosis Via Mitochondria Depolarization and ER Stress in Adult T Cell Leukemia/Lymphoma.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {4},
pages = {},
pmid = {37107239},
issn = {2076-3921},
support = {22K08482//Grants-in-Aid for Science Research from the Ministry of Education, Science, Sports, and Culture of Japan/ ; },
abstract = {Adult T cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy that develops in some elderly human T-cell leukemia virus (HTVL-1) carriers. ATLL has a poor prognosis despite conventional and targeted therapies, and a new safe and efficient therapy is required. Here, we examined the anti-ATLL effect of Shikonin (SHK), a naphthoquinone derivative that has shown several anti-cancer activities. SHK induced apoptosis of ATLL cells accompanied by generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, and induction of endoplasmic reticulum (ER) stress. Treatment with a ROS scavenger, N-acetylcysteine (NAC), blocked both loss of mitochondrial membrane potential and ER stress, and prevented apoptosis of ATLL cells, indicating that ROS is an upstream trigger of SHK-induced apoptosis of ATLL cells through disruption of the mitochondrial membrane potential and ER stress. In an ATLL xenografted mouse model, SHK treatment suppressed tumor growth without significant adverse effects. These results suggest that SHK could be a potent anti-reagent against ATLL.},
}
@article {pmid37107211,
year = {2023},
author = {Dimitriadis, F and Borgmann, H and Struck, JP and Salem, J and Kuru, TH},
title = {Antioxidant Supplementation on Male Fertility-A Systematic Review.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {4},
pages = {},
pmid = {37107211},
issn = {2076-3921},
abstract = {UNLABELLED: Our aim was to review the current literature regarding the effect of antioxidant supplementation (AS) on male fertility parameters, as AS is commonly used to treat male infertility due to the availability and affordability of antioxidants in many parts of the world.<br><br>MATERIALS AND METHODS: PubMed, Medline, and Cochrane electronic bibliographies were searched using the modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate studies on the benefit of antioxidant therapy on infertile men. Results were analyzed regarding the following aspects: (a) ingredient and dose; (b) potential mechanism of action and rationale for use; and (c) effect on various reported outcomes.<br><br>RESULTS: Thus, 29 studies found a substantial positive effect of AS on outcomes of assisted reproductive therapy (ART), WHO semen parameters, and live-birth rate. Carnitines, Vitamin E and C, N-acetyl cysteine, coenzyme Q10, selenium, zinc, folic acid, and lycopene were beneficial ingredients. Nevertheless, some studies did not show a substantial change in one or more factors.<br><br>CONCLUSION: AS seems to have a positive effect on male fertility. Environmental factors may play an increasing role in fertility. Further studies are needed to determine the optimal AS combination and the influence of environmental factors.},
}
@article {pmid37102780,
year = {2023},
author = {Pillai, K and Mekkawy, AH and Akhter, J and Morris, DL},
title = {Effect of Nebulized BromAc on Rheology of Artificial Sputum: Relevance to Muco-Obstructive Respiratory Diseases.},
journal = {Advances in respiratory medicine},
volume = {91},
number = {2},
pages = {146-163},
pmid = {37102780},
issn = {2543-6031},
support = {N.A//Mucpahrm pty ltd/ ; },
mesh = {Humans ; Acetylcysteine/therapeutic use/pharmacology ; Sputum ; Bromelains/therapeutic use/pharmacology ; *COVID-19 ; Expectorants/therapeutic use/pharmacology ; *Respiration Disorders ; Rheology ; },
abstract = {Respiratory diseases such as cystic fibrosis, COPD, and COVID-19 are difficult to treat owing to viscous secretions in the airways that evade mucocilliary clearance. Earlier studies have shown success with BromAc as a mucolytic agent. Hence, we tested the formulation on two gelatinous airway representative sputa models, to determine whether similar efficacy exist. Sputum lodged in an endotracheal tube was treated to aerosol N-acetylcysteine, bromelain, or their combination (BromAc). After measuring the particle size of aerosolized BromAc, the apparent viscosity was measured using a capillary tube method, whilst the sputum flow was assessed using a 0.5 mL pipette. Further, the concentration of the agents in the sputa after treatment were quantified using chromogenic assays. The interaction index of the different formulations was also determined. Results indicated that the mean particle size of BromAc was suitable for aerosol delivery. Bromelain and N-acetylcysteine affected both the viscosities and pipette flow in the two sputa models. BromAc showed a greater rheological effect on both the sputa models compared to individual agents. Further, a correlation was found between the rheological effects and the concentration of agents in the sputa. The combination index using viscosity measurements showed synergy only with 250 µg/mL bromelain + 20 mg/mL NAC whilst flow speed showed synergy for both combinations of bromelain (125 and 250 µg/mL) with 20 mg/mL NAC. Hence, this study indicates that BromAc may be used as a successful mucolytic for clearing airway congestion caused by thick mucinous immobile secretions.},
}
@article {pmid37100568,
year = {2023},
author = {Balani, KA and Sahasrabudhe, TR and Mehta, K and Mirza, S},
title = {TB patients: Is sputum disinfection important?.},
journal = {The Indian journal of tuberculosis},
volume = {70},
number = {2},
pages = {142-146},
doi = {10.1016/j.ijtb.2022.03.027},
pmid = {37100568},
issn = {0019-5707},
mesh = {Humans ; *Mycobacterium tuberculosis ; Case-Control Studies ; Disinfection ; Sputum/microbiology ; *Tuberculosis, Pulmonary/drug therapy/prevention &amp; control/microbiology ; *Disinfectants/pharmacology/therapeutic use ; Phenols/pharmacology/therapeutic use ; Xylenes ; },
abstract = {BACKGROUND: Patients with pulmonary tuberculosis (TB) may produce large amount of infectious sputum which needs to be handled carefully both in health care and household settings. As mycobacteria may survive for long duration in sputum; proper collection, disinfection and disposal is necessary to avoid potential disease transmission. We aimed to assess the efficacy of bedside disinfectant treatment of sputum produced by TB patients using easily available disinfectants that can be used both in TB wards and household settings, to sterilize the infected sputum and compared it with sputum without disinfectant treatment.<br><br>METHODS: It was a prospective case control study. Sputum of total 95 patients with sputum smear positive pulmonary tuberculosis was collected in sputum containers with lids. Patients on anti-tubercular treatment for more than 2 weeks were excluded. Each patient was given 3 sterile sputum containers to expectorate, Container A containing 5% Phenol solution, Container B containing 4.8% Chloroxylenol and Container C without any disinfectant, acting as a control. Thick sputum was liquified with Mucolytic agent N-acetyl cysteine (NAC). Aliquots of the sputum were sent for culture in Lowenstein-Jensen medium on day 0 (to confirm alive mycobacteria) and on day 1 i.e., after 24 hours (to evaluate effective sterilization). Drug resistance testing was done on all grown mycobacteria.<br><br>RESULTS: If the samples on day 0 did not grow mycobacteria (indicating non-viable mycobacteria) or day 1 sample grew contaminants in any of the three containers, they were excluded from the analysis (15/95). In remaining 80 patients, bacilli were alive on day 0 and remained alive even after 24 hours (day 1) in control samples (without disinfectants). The sputum was effectively disinfected resulting in no growth after 24 hours (day 1) in 71/80 (88.75%) containing 5% Phenol and 72/80 (90%) with 4.8% Chloroxylenol. The efficacy of disinfection was 71/73 (97.2%) and 72/73 (98.6%) for drug sensitive mycobacteria respectively. The mycobacteria however remained alive with these disinfectants in all 7 samples of drug-resistant mycobacteria with an efficacy of 0%.<br><br>CONCLUSION: We recommend use of simple disinfectants like 5% Phenol or 4.8% Chloroxylenol for safe disposal of sputum of pulmonary tuberculosis patients. It is necessary as sputum collected without disinfection remained infectious after 24 hours. Resistance of all drug resistant mycobacteria to disinfectants was a novel chance finding. This needs further confirmatory studies.},
}
@article {pmid37090713,
year = {2023},
author = {Zhang, X and Xu, L and Ma, W and Shi, B and Liu, Q and Song, Y and Fang, C and Liu, P and Qiao, S and Cai, J and Zhang, Z},
title = {N-acetyl-L-cysteine alleviated the oxidative stress-induced inflammation and necroptosis caused by excessive NiCl2 in primary spleen lymphocytes.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1146645},
pmid = {37090713},
issn = {1664-3224},
mesh = {Mice ; Animals ; *Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; Spleen/metabolism ; Necroptosis ; Hydrogen Peroxide/metabolism ; Oxidative Stress ; Inflammation/metabolism ; Lymphocytes/metabolism ; RNA, Messenger/metabolism ; },
abstract = {INTRODUCTION: Nickel (Ni) is widely used in industrial manufacturing and daily life due to its excellent physical and chemical properties. However, Ni has the potential to harm animals' immune system, and spleen is a typical immune organ. Therefore, it is crucial to understand the mechanism of NiCl2 damage to the spleen. The purpose of this study is to investigate the effects of different concentrations of NiCl2 exposure and intervening with strong antioxidants on spleen lymphocytes to better understand the damage mechanism of Ni on spleen lymphocytes.<br><br>METHODS: In this experiment, mice spleen lymphocytes were used as the research object. We first measured the degree of oxidative stress, inflammation, and necroptosis caused by different NiCl2 concentrations. Subsequently, we added the powerful antioxidant N-acetyl-L-cysteine (NAC) and used hydrogen peroxide (H2O2) as the positive control in subsequent experiments.<br><br>RESULTS: Our findings demonstrated that NiCl2 could cause spleen lymphocytes to produce a large number of reactive oxygen species (ROS), which reduced the mRNA level of antioxidant enzyme-related genes, the changes in GSH-PX, SOD, T-AOC, and MDA, the same to the mitochondrial membrane potential. ROS caused the body to produce an inflammatory response, which was manifested by tumor necrosis factor (TNF-&#x3b1;) in an immunofluorescence experiment, and the mRNA level of related inflammatory genes significantly increased. In the case of caspase 8 inhibition, TNF-&#x3b1; could cause the occurrence of necroptosis mediated by RIP1, RIP3, and MLKL. AO/EB revealed that spleen lymphocytes exposed to NiCl2 had significant necroptosis, and the mRNA and protein levels of RIP1, RIP3, and MLKL increased significantly. Moreover, the findings demonstrated that NAC acted as an antioxidant to reduce oxidative stress, inflammation, and necroptosis caused by NiCl2 exposure.<br><br>DISCUSSION: Our findings showed that NiCl2 could cause oxidative stress, inflammation, and necroptosis in mice spleen lymphocytes, which could be mitigated in part by NAC. The study provides a point of reference for understanding the toxicological effect of NiCl2. The study suggests that NAC may be useful in reducing the toxicological effect of NiCl2 on the immune system. The research may contribute to the development of effective measures to prevent and mitigate the toxicological effects of NiCl2 on the immune system.},
}
@article {pmid37087805,
year = {2023},
author = {Dong, H and Li, H and Fang, L and Zhang, A and Liu, X and Xue, F and Chen, Y and Liu, W and Chi, Y and Wang, W and Sun, T and Ju, M and Dai, X and Yang, R and Fu, R and Zhang, L},
title = {Increased reactive oxygen species lead to overactivation of platelets in essential thrombocythemia.},
journal = {Thrombosis research},
volume = {226},
number = {},
pages = {18-29},
doi = {10.1016/j.thromres.2023.04.001},
pmid = {37087805},
issn = {1879-2472},
mesh = {Mice ; Animals ; *Thrombocythemia, Essential/drug therapy/genetics ; Reactive Oxygen Species/metabolism ; Janus Kinases/metabolism/pharmacology ; Signal Transduction ; STAT Transcription Factors/metabolism/pharmacology ; Blood Platelets/metabolism ; *Thrombosis/metabolism ; Acetylcysteine/metabolism/pharmacology ; },
abstract = {INTRODUCTION: Platelet function, rather than platelet count, plays a crucial role in thrombosis in essential thrombocythemia (ET). However, little is known about the abnormal function of platelets in ET. Here, we investigated the functional characteristics of platelets in ET hemostasis to explore the causes of ET platelet dysfunction and new therapeutic strategies for ET.<br><br>MATERIALS AND METHODS: We analyzed platelet aggregation, activation, apoptosis, and reactive oxygen species (ROS) in ET patients and JAK2V617F-positive ET-like mice. The effects of ROS on platelet function and the underlying mechanism were investigated by inhibiting ROS using N-acetylcysteine (NAC).<br><br>RESULTS: Platelet aggregation, activation, apoptosis, ROS, and clot retraction were elevated in ET. No significant differences were observed between ET patients with JAK2V617F or CALR mutations. Increased ROS activated the JAK-STAT pathway, which may further influence platelet function. Inhibition of platelet ROS by NAC reduced platelet aggregation, activation, and apoptosis, and prolonged bleeding time. Furthermore, NAC treatment reduced platelet count in ET-like mice by inhibiting platelet production from megakaryocytes.<br><br>CONCLUSIONS: Elevated ROS in ET platelets resulted in enhanced platelet activation, function and increased risk of thrombosis. NAC offers a potential therapeutic strategy for reducing platelet count.},
}
@article {pmid37084995,
year = {2023},
author = {Li, Y and Guo, M and Niu, S and Shang, M and Chang, X and Sun, Z and Zhang, R and Shen, X and Xue, Y},
title = {ROS and DRP1 interactions accelerate the mitochondrial injury induced by polystyrene nanoplastics in human liver HepG2 cells.},
journal = {Chemico-biological interactions},
volume = {379},
number = {},
pages = {110502},
doi = {10.1016/j.cbi.2023.110502},
pmid = {37084995},
issn = {1872-7786},
mesh = {Humans ; *Microplastics/toxicity ; Reactive Oxygen Species/metabolism ; *Polystyrenes/toxicity ; Hep G2 Cells ; Plastics/metabolism/pharmacology ; Dynamins/metabolism ; Mitochondria ; Liver/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Apoptosis ; },
abstract = {Microplastics have become a serious environmental pollutant and subsequently have harmful effects on human health. Thus, the impacts of microplastics on human cells need to be explored. In the present study, the cytotoxic effects at the subcellular-organelle levels to polystyrene nanoplastics (PS-NPs, diameter 21.5 ± 2.7 nm) were investigated in the human hepatocellular carcinoma (HepG2) cell line. The cell viability exposed to PS-NPs at the concentrations of 6.25, 12.5, 25 and 50 μg/mL for 24 h diminished in a concentration-dependent manner. The PS-NPs treatment induced mitochondrial injuries, including morphological changes, decreased adenosine triphosphate (ATP) production and the loss of mitochondrial membrane potentials (MMP). The PS-NPs treatment could further spark cell apoptosis by upregulating caspase 3, caspase 9, cytochrome c, and Bcl-2 associated X protein (Bax)/B-cell lymphoma-2 (Bcl-2) in HepG2 cells, which is related to the mitochondrial dysfunction. PS-NPs exposure stimulated the excessive cellular reactive oxygen species (ROS) production and also induced mitochondrial fission by upregulating dynamin-related protein 1 (DRP1) and P-DRP1, but downregulating optic atrophy protein 1 (OPA1) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) expression levels. The above effects on mitochondria damage induced by PS-NPs were reversed by the pretreatment of N-acetylcysteine (NAC), mitochondrial division inhibitor 1 (Mdivi-1) and DRP1 siRNA. The results suggested that the interaction between ROS and DRP1-dependent mitochondrial division could promote mitochondrial lesions and mitochondria-related apoptosis caused by PS-NPs. These findings on molecular mechanisms provide a theoretical basis for preventing the hazards caused by microplastics to human health.},
}
@article {pmid37080569,
year = {2023},
author = {Addante, A and Raymond, W and Gitlin, I and Charbit, A and Orain, X and Scheffler, AW and Kuppe, A and Duerr, J and Daniltchenko, M and Drescher, M and Graeber, SY and Healy, AM and Oscarson, S and Fahy, JV and Mall, MA},
title = {A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases.},
journal = {The European respiratory journal},
volume = {61},
number = {5},
pages = {},
pmid = {37080569},
issn = {1399-3003},
support = {P01 HL128191/HL/NHLBI NIH HHS/United States ; R01 HL080414/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Humans ; Mice ; Animals ; Expectorants/therapeutic use ; Sulfhydryl Compounds/pharmacology/therapeutic use ; *Cystic Fibrosis ; Acetylcysteine/pharmacology/therapeutic use ; Sputum ; *Lung Diseases, Obstructive/drug therapy ; Inflammation/pathology ; Carbohydrates/pharmacology/therapeutic use ; Lung ; },
abstract = {BACKGROUND: Mucin disulfide cross-links mediate pathologic mucus formation in muco-obstructive lung diseases. MUC-031, a novel thiol-modified carbohydrate compound, cleaves disulfides to cause mucolysis. The aim of this study was to determine the mucolytic and therapeutic effects of MUC-031 in sputum from patients with cystic fibrosis (CF) and mice with muco-obstructive lung disease (βENaC-Tg mice).<br><br>METHODS: We compared the mucolytic efficacy of MUC-031 and existing mucolytics (N-acetylcysteine (NAC) and recombinant human deoxyribonuclease I (rhDNase)) using rheology to measure the elastic modulus (G') of CF sputum, and we tested effects of MUC-031 on airway mucus plugging, inflammation and survival in &#x3b2;ENaC-Tg mice to determine its mucolytic efficacy in vivo.<br><br>RESULTS: In CF sputum, compared to the effects of rhDNase and NAC, MUC-031 caused a larger decrease in sputum G', was faster in decreasing sputum G' by 50% and caused mucolysis of a larger proportion of sputum samples within 15&#x2005;min of drug addition. Compared to vehicle control, three treatments with MUC-031 in 1&#x2005;day in adult &#x3b2;ENaC-Tg mice decreased airway mucus content (16.8&#xb1;3.2 versus 7.5&#xb1;1.2&#x2005;nL&#xb7;mm[-2], p<0.01) and bronchoalveolar lavage cells (73&#x2009;833&#xb1;6930 versus 47&#x2009;679&#xb1;7736 cells&#xb7;mL[-1], p<0.05). Twice-daily treatment with MUC-031 for 2&#x2005;weeks also caused decreases in these outcomes in adult and neonatal &#x3b2;ENaC-Tg mice and reduced mortality from 37% in vehicle-treated &#x3b2;ENaC-Tg neonates to 21% in those treated with MUC-031 (p<0.05).<br><br>CONCLUSION: MUC-031 is a potent and fast-acting mucolytic that decreases airway mucus plugging, lessens airway inflammation and improves survival in &#x3b2;ENaC-Tg mice. These data provide rationale for human trials of MUC-031 in muco-obstructive lung diseases.},
}
@article {pmid37079050,
year = {2023},
author = {Hannon Barroeta, P and O'Sullivan, MJ and Zisterer, DM},
title = {The role of the Nrf2/GSH antioxidant system in cisplatin resistance in malignant rhabdoid tumours.},
journal = {Journal of cancer research and clinical oncology},
volume = {149},
number = {11},
pages = {8379-8391},
pmid = {37079050},
issn = {1432-1335},
mesh = {Humans ; Child ; *Cisplatin/pharmacology ; Antioxidants/pharmacology ; *Rhabdoid Tumor/drug therapy ; NF-E2-Related Factor 2/metabolism ; Reactive Oxygen Species/metabolism ; Glutathione/metabolism ; Buthionine Sulfoximine ; Apoptosis ; Cell Line, Tumor ; },
abstract = {PURPOSE: Malignant rhabdoid tumour (MRT) is a rare and aggressive childhood malignancy that occurs in the kidneys or central nervous system and is associated with very poor prognosis. Chemoresistance is a major issue in the treatment of this malignancy leading to an urgent need for a greater understanding of its underlying mechanisms in MRT and novel treatment strategies for MRT patients. The balance between oxidative stress mediated by reactive oxygen species (ROS) and the antioxidant system has become a subject of interest in cancer therapy research. Studies have implicated key players of the antioxidant system in chemotherapeutic including the well-known antioxidant glutathione (GSH) and the transcription factor nuclear erythroid-related factor-2 (Nrf2). METHODS: This study evaluated the role of these components in the response of MRT cells to treatment with the commonly used chemotherapeutic agent, cisplatin.<br><br>RESULTS: This study characterised the basal levels of GSH, ROS and Nrf2 in a panel of MRT cell lines and found a correlation between the expression profile of the antioxidant defence system and cisplatin sensitivity. Results showed that treatment with ROS scavenger N-acetylcysteine (NAC) protected cells from cisplatin-induced ROS and apoptosis. Interestingly, depleting GSH levels with the inhibitor buthionine sulphoximine (BSO) enhanced cisplatin-induced ROS and sensitised cells to cisplatin. Lastly, targeting Nrf2 with the small molecule inhibitor ML385 or by siRNA diminished GSH levels, enhanced ROS and sensitised resistant MRT cells to cisplatin.<br><br>CONCLUSIONS: These results suggest that targeting the Nrf2/GSH antioxidant system may present a novel therapeutic strategy to combat chemoresistance in rhabdoid tumours.},
}
@article {pmid37075699,
year = {2023},
author = {Yap, YS and Hu, J},
title = {Exploiting metabolic vulnerabilities in breast cancers with NF1 loss.},
journal = {Cell reports. Medicine},
volume = {4},
number = {4},
pages = {101010},
pmid = {37075699},
issn = {2666-3791},
mesh = {Humans ; Female ; Neurofibromin 1/genetics/metabolism ; *Breast Neoplasms/drug therapy ; Phosphatidylinositol 3-Kinases/metabolism ; *Biochemical Phenomena ; },
abstract = {Auf der Maur et al.[1] identify neurofibromin 1 (NF1) loss as a mechanism of resistance to PI3K inhibitor in breast cancer cells. NF1 loss leads to enhanced glycolysis, which may be targeted with the antioxidant N-acetyl cysteine (NAC).},
}
@article {pmid37072676,
year = {2023},
author = {Jensen, GS and Cruickshank, D and Hamilton, DE},
title = {Disruption of Established Bacterial and Fungal Biofilms by a Blend of Enzymes and Botanical Extracts.},
journal = {Journal of microbiology and biotechnology},
volume = {33},
number = {6},
pages = {715-723},
pmid = {37072676},
issn = {1738-8872},
mesh = {Humans ; Anti-Bacterial Agents/pharmacology/metabolism ; Staphylococcus aureus ; *Anti-Infective Agents/pharmacology ; *Staphylococcal Infections/microbiology ; Biofilms ; Pseudomonas aeruginosa ; Microbial Sensitivity Tests ; },
abstract = {Microbial biofilms are resilient, immune-evasive, often antibiotic-resistant health challenges, and increasingly the target for research into novel therapeutic strategies. We evaluated the effects of a nutraceutical enzyme and botanical blend (NEBB) on established biofilm. Five microbial strains with known implications in chronic human illnesses were tested: Candida albicans, Staphylococcus aureus, Staphylococcus simulans (coagulase-negative, penicillin-resistant), Borrelia burgdorferi, and Pseudomonas aeruginosa. The strains were allowed to form biofilm in vitro. Biofilm cultures were treated with NEBB containing enzymes targeted at lipids, proteins, and sugars, also containing the mucolytic compound N-acetyl cysteine, along with antimicrobial extracts from cranberry, berberine, rosemary, and peppermint. The post-treatment biofilm mass was evaluated by crystal-violet staining, and metabolic activity was measured using the MTT assay. Average biofilm mass and metabolic activity for NEBB-treated biofilms were compared to the average of untreated control cultures. Treatment of established biofilm with NEBB resulted in biofilm-disruption, involving significant reductions in biofilm mass and metabolic activity for Candida and both Staphylococcus species. For B. burgdorferi, we observed reduced biofilm mass, but the remaining residual biofilm showed a mild increase in metabolic activity, suggesting a shift from metabolically quiescent, treatment-resistant persister forms of B. burgdorferi to a more active form, potentially more recognizable by the host immune system. For P. aeruginosa, low doses of NEBB significantly reduced biofilm mass and metabolic activity while higher doses of NEBB increased biofilm mass and metabolic activity. The results suggest that targeted nutraceutical support may help disrupt biofilm communities, offering new facets for integrative combinational treatment strategies.},
}
@article {pmid37072331,
year = {2023},
author = {Khazaie, S and Jafari, M and Golamloo, M and Asgari, A and Heydari, J and Salehi, M and Salem, F},
title = {Cumulative Effects of Paraoxon and Leptin on Oxidative Damages in Rat Tissues: Prophylactic and Therapeutic Roles of N-Acetylcysteine.},
journal = {Biochemistry. Biokhimiia},
volume = {88},
number = {2},
pages = {165-178},
doi = {10.1134/S0006297923020013},
pmid = {37072331},
issn = {1608-3040},
mesh = {Rats ; Male ; Animals ; *Antioxidants/pharmacology/metabolism ; *Acetylcysteine/pharmacology ; Paraoxon/toxicity ; Rats, Wistar ; Leptin/pharmacology ; Oxidative Stress ; },
abstract = {Exposure to paraoxon (POX) and leptin (LP) could cause an imbalance between oxidants and antioxidants in an organism, which can be prevented by introduction of exogenous antioxidants such as N-acetylcysteine (NAC). The aim of this study was to evaluate synergic or additive effects of administration of exogenous LP plus POX on the antioxidant status, as well as the prophylactic and therapeutic roles of NAC in various rat tissues. Fifty-four male Wistar rats were divided into nine groups treated with different compounds: Control (no treatment), POX (0.7 mg/kg), NAC (160 mg/kg), LP (1 mg/kg), POX+LP, NAC-POX, POX-NAC, NAC-POX+LP, and POX+LP-NAC. In the last five groups, only the order of administered compounds differed. After 24 h, plasma and tissues were sampled and examined. The results showed that administration of POX plus LP significantly increased biochemical indices in plasma and antioxidant enzymes activities and decreased glutathione content in the liver, erythrocytes, brain, kidney, and heart. In addition, cholinesterase and paraoxonase 1 activities in the POX+LP-treated group were decreased and malondialdehyde level was increased in the liver, erythrocytes, and brain. However, administration of NAC rectified induced changes although not to the same extent. Our study suggests that POX or LP administration engage the oxidative stress system per se; however, their combination did not produce significantly greater effects. Moreover, both prophylactic and therapeutic treatments of rats with NAC supported the antioxidant defense against oxidative damage in tissues, most probably through both its free radical scavenging ability and maintaining intracellular GSH levels. It can therefore be suggested that NAC has particularly protective effects against POX or/and LP toxicity.},
}
@article {pmid37072049,
year = {2023},
author = {Hao, XS and Feng, PP and Zhang, YY and Wang, FZ and Wang, GL and Fei, HR},
title = {Scutebarbatine A induces ROS-mediated DNA damage and apoptosis in breast cancer cells by modulating MAPK and EGFR/Akt signaling pathway.},
journal = {Chemico-biological interactions},
volume = {378},
number = {},
pages = {110487},
doi = {10.1016/j.cbi.2023.110487},
pmid = {37072049},
issn = {1872-7786},
mesh = {Humans ; Female ; Reactive Oxygen Species/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Superoxides ; *Breast Neoplasms/drug therapy ; Signal Transduction ; *Antineoplastic Agents/pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; Apoptosis ; DNA Damage ; ErbB Receptors/metabolism ; MAP Kinase Signaling System ; Cell Line, Tumor ; Naphthols ; Niacin ; },
abstract = {Scutebarbatine A (SBT-A), a diterpenoid alkaloid, has exerted cytotoxicity on hepatocellular carcinoma cells in our previous works. Here, the antitumor activity of SBT-A in breast cancer cells and the underlying mechanism were explored. The anti-proliferative effect of SBT-A was measured by trypan blue staining, 5-ethynyl-2'-deoxyuridine (EdU) incorporation and colony formation assay. DNA double-strand breaks (DSBs) were evaluated by observing the nuclear focus formation of γ-H2AX. Cell cycle distribution was assessed by flow cytometry. Apoptosis was determined by a TUNEL assay. Intracellular reactive oxygen species (ROS) generation and superoxide production were measured with 2', 7'-dichlorofluorescein diacetate (DCFH-DA) and dihydroethidium (DHE) staining, respectively. The results indicated that SBT-A showed a dose-dependent cytotoxic effect against breast cancer cells while revealing less toxicity toward MCF-10A breast epithelial cells. Moreover, SBT-A remarkably induced DNA damage, cell cycle arrest and apoptosis in both MDA-MB-231 and MCF-7 cells. SBT-A treatment increased the levels of ROS and cytosolic superoxide production. Pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to block viability reduction, DNA damage, apoptosis and endoplasmic reticulum (ER) stress caused by SBT-A. By exposure to SBT-A, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) was upregulated, while the phosphorylation of extracellular signal-regulated kinase (ERK) was downregulated. In addition, SBT-A inhibited the EGFR signaling pathway by decreasing EGFR expression and phosphorylation of Akt and p70S6K. As mentioned above, SBT-A has a potent inhibitory effect on breast cancer cells through induction of DNA damage, apoptosis and ER stress via ROS generation and modulation of MAPK and EGFR/Akt signaling pathway.},
}
@article {pmid37071164,
year = {2023},
author = {Maestro, C and Leache, L and Gutiérrez-Valencia, M and Saiz, LC and Gómez, H and Bacaicoa, MC and Erviti, J},
title = {Efficacy and safety of N-acetylcysteine for preventing post-intravenous contrast acute kidney injury in patients with kidney impairment: a systematic review and meta-analysis.},
journal = {European radiology},
volume = {33},
number = {9},
pages = {6569-6581},
pmid = {37071164},
issn = {1432-1084},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/adverse effects ; *Acute Kidney Injury/etiology/prevention &amp; control ; *Contrast Media/adverse effects ; Kidney/drug effects ; },
abstract = {OBJECTIVES: N-Acetylcysteine (NAC) may confer protection against post-contrast acute kidney injury (PC-AKI), although evidence is sparse and conflicting. The objective was to analyse the evidence on the efficacy and safety of NAC vs no administration of NAC in preventing PC-AKI in patients with pre-existing kidney impairment undergoing a non-interventional radiological examination requiring intravenous (IV) contrast media (CM) administration.<br><br>METHODS: We carried out a systematic review including randomised controlled trials (RCTs) published in MEDLINE, EMBASE, and Clinicaltrials.gov up to May 2022. The primary outcome was PC-AKI. Secondary outcomes included the requirement of renal replacement therapy, all-cause mortality, serious adverse events, and length of hospital stay. We conducted the meta-analyses using the Mantel-Haenszel method and following a random-effects model.<br><br>RESULTS: NAC was not associated with a significant reduction in PC-AKI (RR 0.47, 95%CI 0.20 to 1.11; 8 studies; 545 participants; I[2]: 56%; low certainty), all-cause mortality (RR 0.67, 95%CI 0.29 to 1.54; 2 studies; 129 participants; very low certainty), or length of hospital stay (mean difference 9.2&#xa0;days, 95%CI&#x2009;-&#x2009;20.08 to 38.48; 1 study; 42 participants; very low certainty). The impact on other outcomes could not be determined.<br><br>CONCLUSIONS: NAC may not reduce the risk of PC-AKI or all-cause mortality in people with kidney impairment who receive an IV CM prior to radiological imaging, although the certainty of the evidence is very low or low.<br><br>CLINICAL RELEVANCE STATEMENT: Our review concludes that prophylactic administration of N-acetylcysteine may not significantly reduce the risk of acute kidney injury in patients with kidney impairment receiving an intravenous contrast media prior to non-interventional radiological imaging, which may support decision making in this common clinical scenario.<br><br>KEY POINTS: &#x2022; N-Acetylcysteine may not significantly reduce the risk of acute kidney injury in patients with kidney impairment receiving an intravenous contrast media prior to non-interventional radiological imaging. &#x2022; All-cause mortality and length of hospital stay would not be decreased with the administration of N-Acetylcysteine in this setting.},
}
@article {pmid37069635,
year = {2023},
author = {Jia, D and Guo, S and Jia, Z and Gao, Z and You, K and Gong, J and Li, S},
title = {N-acetylcysteine in the Donor, Recipient, or Both Donor and Recipient in Liver Transplantation: A Systematic Review With Meta-analysis and Trial Sequential Analysis.},
journal = {Transplantation},
volume = {107},
number = {9},
pages = {1976-1990},
doi = {10.1097/TP.0000000000004597},
pmid = {37069635},
issn = {1534-6080},
mesh = {Humans ; Acetylcysteine/adverse effects ; *Liver Transplantation/adverse effects ; Graft Survival ; Transferases ; *Reperfusion Injury/etiology/prevention &amp; control ; },
abstract = {BACKGROUND: N-acetylcysteine (NAC) is a potentially effective drug for treating ischemia-reperfusion injury in transplanted livers, but its effect remains controversial.<br><br>METHODS: A systematic review and meta-analysis of relevant clinical trials published and registered in the Cochrane Library, MEDLINE, EMBASE, ClinicalTrial.gov , WHO ICTRP, etc, before March 20, 2022 were conducted and registered with PROSPERO (CRD42022315996). Data were pooled using a random effects model or a fixed effects model based on the amount of heterogeneity.<br><br>RESULTS: Thirteen studies with 1121 participants, 550 of whom received NAC, were included. Compared with the control, NAC significantly reduced the incidence of primary graft nonfunction (relative risk [RR], 0.27; 95% confidence interval [CI], 0.08-0.96), the incidence of postoperative complications (RR, 0.52; 95% CI, 0.41-0.67), the peak postoperative aspartate transferase level (mean difference [MD], -267.52; 95% CI, -345.35 to -189.68), and the peak alanine transferase level (MD, -293.29; 95% CI, -370.39 to -216.20). NAC also improved 2-y (RR, 1.18; 95% CI, 1.01-1.38) graft survival rate. However, NAC increased the intraoperative cryoprecipitate (MD, 0.94; 95% CI, 0.42-1.46) and red blood cell (MD, 0.67; 95% CI, 0.15-1.19) requirements. Moreover, NAC was administered in various modes in these studies, including to the donor, recipient, or both. Subgroup analysis and network meta-analysis showed that NAC administration to recipients could play a more significant role than the other 2 administration modes.<br><br>CONCLUSIONS: Our study supports the protective effect of NAC against LT-induced ischemia-reperfusion injury and shows better clinical outcomes of NAC administration to recipients.},
}
@article {pmid37066621,
year = {2023},
author = {Mazrad, ZAI and Leiske, MN and Tabor, RF and Nicolazzo, JA and Kempe, K},
title = {Comparison of the Anti-inflammatory Activity and Cellular Interaction of Brush Polymer-N-Acetyl Cysteine Conjugates in Human and Murine Microglial Cell Lines.},
journal = {Molecular pharmaceutics},
volume = {20},
number = {5},
pages = {2686-2701},
doi = {10.1021/acs.molpharmaceut.3c00140},
pmid = {37066621},
issn = {1543-8392},
mesh = {Mice ; Humans ; Animals ; *Microglia/metabolism ; *Polymers/metabolism ; Lipopolysaccharides/pharmacology ; Neuroinflammatory Diseases ; Anti-Inflammatory Agents/pharmacology/metabolism ; Acetylcysteine/chemistry ; },
abstract = {Microglia-mediated neuroinflammation is commonly associated with neurodegeneration and has been implicated in several neurological disorders, such as Alzheimer's disease and Parkinson's disease. Therefore, it is crucial to develop a detailed understanding of the interaction of potential nanocarriers with microglial cells to efficiently deliver anti-inflammatory molecules. In this study, we applied brush polymers as a modular platform to systematically investigate their association with murine (BV-2) and human (HMC3) microglial cell lines in the presence and absence of the pro-inflammatory inducer lipopolysaccharide (LPS) using flow cytometry. Brush polymers of different sizes and shapes, ranging from ellipsoid to worm-like cylinders, were prepared through a combination of the two building blocks carboxylated N-acylated poly(aminoester)s (NPAEs)-based polymers and poly(2-ethyl-2-oxazoline)-NH2 (PEtOx-NH2) and characterized by [1]H NMR spectroscopy, size exclusion chromatography, and small-angle neutron scattering. Generally, ellipsoidal particles showed the highest cellular association. Moreover, while no significant differences in murine cell association were observed, the brush polymers revealed a significant accumulation in LPS-activated human microglia compared to resting cells, emphasizing their higher affinity to activated HMC3 cells. Brush polymers with the highest cell association were further modified with the anti-inflammatory agent N-acetyl cysteine (NAC) in a reversible manner. The brush polymer-NAC conjugates were found to significantly attenuate the production of interleukin 6 (p < 0.001) in LPS-activated HMC3 cells compared to LPS-activated BV-2 cells. Thus, the presented brush polymer-NAC conjugates showed a high anti-inflammatory activity in human microglia, suggesting their potential for disease-targeted therapy of microglial-mediated neuroinflammation in the future.},
}
@article {pmid37065769,
year = {2023},
author = {Gonzales-Moreno, C and Fernandez-Hubeid, LE and Holgado, A and Virgolini, MB},
title = {Low-dose N-acetyl cysteine prevents paraquat-induced mortality in Caenorhabditis elegans.},
journal = {microPublication biology},
volume = {2023},
number = {},
pages = {},
pmid = {37065769},
issn = {2578-9430},
abstract = {Exposure to the herbicide paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium dichloride) affects the redox balance of the cell, an effect that can be restored by antioxidants, including N-acetyl cysteine (NAC). One hour of exposure to PQ (0 mM, 10 mM, 50 mM, or 100 mM) dose-dependently increased mortality in Caenorhabditis elegans after exposure (immediate toxicity), while this effect was more evident 24 hours thereafter (delayed toxicity). Importantly, pretreatment with NAC 0.5 mM for one hour partially prevented mortality in the immediate assay, while it had no effect in the delayed test, revealing the importance of long-term studies when evaluating toxicity.},
}
@article {pmid37062330,
year = {2023},
author = {Xue, J and Li, Z and Li, X and Hua, C and Shang, P and Zhao, J and Liu, K and Xie, F},
title = {Evaluation of cigarette smoke-induced oxidative stress and inflammation in BEAS-2B cells based on a lung microfluidic chip.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {176},
number = {},
pages = {113787},
doi = {10.1016/j.fct.2023.113787},
pmid = {37062330},
issn = {1873-6351},
mesh = {*Microfluidics ; *Cigarette Smoking ; Lung ; Oxidative Stress ; Inflammation/chemically induced/pathology ; Nicotiana ; },
abstract = {Oxidative stress and inflammation induced by cigarette smoking are associated with the pathology process of various chronic respiratory diseases, including asthma, emphysema, chronic obstructive pulmonary disease and cancer. Compared with conventional cell culture techniques, microfluidic chips can provide a continuous nutrient supply, mimic the in vivo physiological microenvironment of the cells, and conduct an integrated and flexible analysis of cell status and functions. Here, we designed and fabricated a bionic-lung chip, which was applied to perform cigarette smoke exposure of BEAS-2B cells cultured at the gas-liquid interface. The oxidative stress and inflammation in the cells exposed to cigarette smoke were investigated on chip. The results showed that cellular damage, oxidative stress and inflammatory response induced by cigarette smoke in the chip were dependent on smoke concentration and time after smoke exposure. N-Acetylcysteine (NAC) significantly inhibited these effects of cigarette smoke exposure on the cells at the gas-liquid interface within the chip.},
}
@article {pmid37059385,
year = {2023},
author = {Mao, Z and Li, H and Zhao, XL and Zeng, XH},
title = {Hydrogen sulfide protects Sertoli cells against toxicant Acrolein-induced cell injury.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {176},
number = {},
pages = {113784},
doi = {10.1016/j.fct.2023.113784},
pmid = {37059385},
issn = {1873-6351},
mesh = {Male ; Humans ; *Hydrogen Sulfide/pharmacology/metabolism ; Sertoli Cells/metabolism ; Acrolein/toxicity ; Sulfides/pharmacology ; Antioxidants/pharmacology ; },
abstract = {Acrolein (ACR), a highly toxic α,β-unsaturated aldehyde, is considered to be a common mediator behind the reproductive injury induced by various factors. However, the understanding of its reproductive toxicity and prevention in reproductive system is limited. Given that Sertoli cells provide the first-line defense against various toxicants and that dysfunction of Sertoli cell causes impaired spermatogenesis, we, therefore, examined ACR cytotoxicity in Sertoli cells and tested whether hydrogen sulfide (H2S), a gaseous mediator with potent antioxidative actions, could have a protective effect. Exposure of Sertoli cells to ACR led to cell injury, as indicated by reactive oxygen species (ROS) generation, protein oxidation, P38 activation and ultimately cell death that was prevented by antioxidant N-acetylcysteine (NAC). Further studies revealed that ACR cytotoxicity on Sertoli cells was significantly exacerbated by the inhibition of H2S-synthesizing enzyme cystathionine γ-lyase (CSE), while significantly suppressed by H2S donor Sodium hydrosulfide (NaHS). It was also attenuated by Tanshinone IIA (Tan IIA), an active ingredient of Danshen that stimulated H2S production in Sertoli cells. Apart from Sertoli cells, H2S also protected the cultured germ cells from ACR-initiated cell death. Collectively, our study characterized H2S as endogenous defensive mechanism against ACR in Sertoli cells and germ cells. This property of H2S could be used to prevent and treat ACR-related reproductive injury.},
}
@article {pmid37058841,
year = {2023},
author = {Wang, Y and Zhang, F and Liu, J and Yang, B and Yuan, Y and Zhou, Y and Bi, S},
title = {A fluorescence nanoprobe of N-Acetyl-L-Cysteine capped CdTe QDs for sensitive detection of nitrofurazone.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {297},
number = {},
pages = {122709},
doi = {10.1016/j.saa.2023.122709},
pmid = {37058841},
issn = {1873-3557},
mesh = {Animals ; Cattle ; *Quantum Dots/chemistry ; Acetylcysteine ; *Cadmium Compounds/chemistry ; Fluorescence ; Tellurium/chemistry ; Nitrofurazone ; Spectroscopy, Fourier Transform Infrared ; Spectrometry, Fluorescence/methods ; },
abstract = {A method was established for detecting the content of nitrofurazone (NFZ) by fluorescence quenching of N-Acetyl-L-Cysteine (NAC) coated cadmium telluride quantum dots (CdTe QDs). By means of transmission electron microscopy (TEM) and multispectral methods such as fluorescence and ultraviolet visible spectra (UV-vis), the synthesized CdTe QDs were characterized. The quantum yield (φ) of CdTe QDs was measured as 0.33 by reference method. The CdTe QDs had a better stability, the RSD of fluorescence intensity was 1.51% in three months. NFZ quenching the emission light of CdTe QDs was observed. The analyses of Stern-Volmer and time-resolved fluorescence suggested the quenching was static. The binding constants (Ka) between NFZ and CdTe QDs were 1.14 × 10[4] (293 K), 0.74 × 10[4] (303 K) and 0.51 × 10[4] (313 K) L mol[-1]. The hydrogen bond or van der Waals force was the dominated binding force between NFZ and CdTe QDs. The interaction was further characterized by UV-vis absorption as well as Fourier transform infrared spectra (FT-IR). Using fluorescence quenching effect, a quantitative determination of NFZ was carried out. The optimal experimental conditions were studied and determined as following: pH was 7 and contact time was 10 min. The effects of reagent addition sequence, temperature and the foreign substances including some metals (Mg[2+]; Zn[2+]; Ca[2+]; K[+]; Cu[2+]), glucose, bovine serum albumin (BSA) and furazolidone on the determination were studied. There was a high correlation between the concentration of NFZ (0.40 - 39.63 μg mL[-1]) and F0/F with the standard curve F0/F = 0.0262c + 0.9910 (r = 0.9994). The detection limit (LOD) reached 0.04 μg mL[-1] (3S0/S). The contents of NFZ in beef and bacteriostatic liquid were detected. The recovery of NFZ was 95.13% - 103.03% and RSD was 0.66% - 1.37% (n = 5).},
}
@article {pmid37056637,
year = {2023},
author = {Mokhtari, Z and Raeeszadeh, M and Akradi, L},
title = {Comparative Effect of the Active Substance of Thyme with N-Acetyl Cysteine on Hematological Parameters and Histopathological Changes of Bone Marrow and Liver in Rat Models of Acetaminophen Toxicity.},
journal = {Analytical cellular pathology (Amsterdam)},
volume = {2023},
number = {},
pages = {1714884},
pmid = {37056637},
issn = {2210-7185},
mesh = {Animals ; Rats ; Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Bone Marrow ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology ; Liver ; Rats, Wistar ; *Thymus Plant ; Plant Extracts ; },
abstract = {Acetaminophen has always been at the center of attention as a non-steroidal anti-inflammatory drug, which is generally associated with the serious side effects on liver and the hematological parameters. This study aimed to compare the effect of N-acetyl cysteine (NAC) and thyme extract on rat models of acetaminophen-induced toxicity. The present experimental study was conducted on 48 Wistar rats randomized into six groups, including the control group (no treatment); the Ac group (470 mg/kg of acetaminophen); the Ac + 100Ex, Ac + 200Ex, and Ac + 400Ex groups (acetaminophen + thyme extract at doses of 100, 200, 400 mg/kg); and Ac + NA group (acetaminophen + NAC). After weighing, a blood sample was taken from heart at the end of the period. The measured parameters were hematological, liver biochemical, and oxidative stress profiles. A part of the liver tissue was also fixed for the pathological examinations. The bone marrow was aspirated to check for cellular changes as well. The lowest mean of the final weight and liver weight to body weight ratio was observed in the Ac group. Weight loss was compensated in Ac + NA and Ac + 200Ex groups (P = 0.035). White blood cell (WBC), red blood cell (RBC), Hemoglobin (Hgb), and Hematocrit (HCT) in Ac and Ac + 400Ex groups showed significant differences from those of the other test groups (P < 0.001). Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) enzymes in Ac + 200Ex and Ac + NA groups showed a significant decrease compared to those of the other treatment groups (P = 0.043). Total antioxidant capacity (TAC) and glutathione peroxidase (GPx) had the lowest levels in Ac and Ac + 400Ex groups, while malondialdehyde (MDA) had the highest content. In this regard, the liver histopathological indices (necrosis, hyperemia, and hemorrhage) in the Ac + 200Ex and Ac + NA groups reached their lowest grades in the treatment groups. The mean number of erythroid and myeloid cells in the Ac group reached the lowest (17.40 ± 3.48). The microscopic appearance of the bone marrow cells was different from normocytosis in the control group to hypocytosis in the Ac and Ac + 400Ex groups. Thymol, as an effective ingredient in thyme extract at a dose of 200 mg/kg compared to NAC, had a unique effect on reducing bone marrow and liver cell-tissue changes due to the acetaminophen toxicity.},
}
@article {pmid37055935,
year = {2023},
author = {Xue, Q and Kang, R and Klionsky, DJ and Tang, D and Liu, J and Chen, X},
title = {Copper metabolism in cell death and autophagy.},
journal = {Autophagy},
volume = {19},
number = {8},
pages = {2175-2195},
pmid = {37055935},
issn = {1554-8635},
support = {R35 GM131919/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *Autophagy/physiology ; Tumor Suppressor Protein p53 ; Apoptosis Inducing Factor ; Copper ; Ubiquinone ; Electron Transport Complex IV ; Autophagy-Related Protein-1 Homolog ; Proto-Oncogene Proteins p21(ras) ; Apoptosis/physiology ; Caspases ; Hypoxia-Inducible Factor 1 ; Superoxide Dismutase ; *Neoplasms ; Ions ; Proto-Oncogene Proteins c-bcl-2 ; Molecular Chaperones ; Copper Transport Proteins ; Ubiquitin Thiolesterase ; Intracellular Signaling Peptides and Proteins ; },
abstract = {Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high concentrations, copper ions show increased toxicity by inducing regulated cell death, such as apoptosis, paraptosis, pyroptosis, ferroptosis, and cuproptosis. Furthermore, copper ions can trigger macroautophagy/autophagy, a lysosome-dependent degradation pathway that plays a dual role in regulating the survival or death fate of cells under various stress conditions. Pathologically, impaired copper metabolism due to environmental or genetic causes is implicated in a variety of human diseases, such as rare Wilson disease and common cancers. Therapeutically, copper-based compounds are potential chemotherapeutic agents that can be used alone or in combination with other drugs or approaches to treat cancer. Here, we review the progress made in understanding copper metabolic processes and their impact on the regulation of cell death and autophagy. This knowledge may help in the design of future clinical tools to improve cancer diagnosis and treatment.Abbreviations: ACSL4, acyl-CoA synthetase long chain family member 4; AIFM1/AIF, apoptosis inducing factor mitochondria associated 1; AIFM2, apoptosis inducing factor mitochondria associated 2; ALDH, aldehyde dehydrogenase; ALOX, arachidonate lipoxygenase; AMPK, AMP-activated protein kinase; APAF1, apoptotic peptidase activating factor 1; ATF4, activating transcription factor 4; ATG, autophagy related; ATG13, autophagy related 13; ATG5, autophagy related 5; ATOX1, antioxidant 1 copper chaperone; ATP, adenosine triphosphate; ATP7A, ATPase copper transporting alpha; ATP7B, ATPase copper transporting beta; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCS, bathocuproinedisulfonic acid; BECN1, beclin 1; BID, BH3 interacting domain death agonist; BRCA1, BRCA1 DNA repair associated; BSO, buthionine sulphoximine; CASP1, caspase 1; CASP3, caspase 3; CASP4/CASP11, caspase 4; CASP5, caspase 5; CASP8, caspase 8; CASP9, caspase 9; CCS, copper chaperone for superoxide dismutase; CD274/PD-L1, CD274 molecule; CDH2, cadherin 2; CDKN1A/p21, cyclin dependent kinase inhibitor 1A; CDKN1B/p27, cyclin-dependent kinase inhibitor 1B; COMMD10, COMM domain containing 10; CoQ10, coenzyme Q 10; CoQ10H2, reduced coenzyme Q 10; COX11, cytochrome c oxidase copper chaperone COX11; COX17, cytochrome c oxidase copper chaperone COX17; CP, ceruloplasmin; CYCS, cytochrome c, somatic; DBH, dopamine beta-hydroxylase; DDIT3/CHOP, DNA damage inducible transcript 3; DLAT, dihydrolipoamide S-acetyltransferase; DTC, diethyldithiocarbamate; EIF2A, eukaryotic translation initiation factor 2A; EIF2AK3/PERK, eukaryotic translation initiation factor 2 alpha kinase 3; ER, endoplasmic reticulum; ESCRT-III, endosomal sorting complex required for transport-III; ETC, electron transport chain; FABP3, fatty acid binding protein 3; FABP7, fatty acid binding protein 7; FADD, Fas associated via death domain; FAS, Fas cell surface death receptor; FASL, Fas ligand; FDX1, ferredoxin 1; GNAQ/11, G protein subunit alpha q/11; GPX4, glutathione peroxidase 4; GSDMD, gasdermin D; GSH, glutathione; HDAC, histone deacetylase; HIF1, hypoxia inducible factor 1; HIF1A, hypoxia inducible factor 1 subunit alpha; HMGB1, high mobility group box 1; IL1B, interleukin 1 beta; IL17, interleukin 17; KRAS, KRAS proto-oncogene, GTPase; LOX, lysyl oxidase; LPCAT3, lysophosphatidylcholine acyltransferase 3; MAP1LC3, microtubule associated protein 1 light chain 3; MAP2K1, mitogen-activated protein kinase kinase 1; MAP2K2, mitogen-activated protein kinase kinase 2; MAPK, mitogen-activated protein kinases; MAPK14/p38, mitogen-activated protein kinase 14; MEMO1, mediator of cell motility 1; MT-CO1/COX1, mitochondrially encoded cytochrome c oxidase I; MT-CO2/COX2, mitochondrially encoded cytochrome c oxidase II; MTOR, mechanistic target of rapamycin kinase; MTs, metallothioneins; NAC, N-acetylcysteine; NFKB/NF-Κb, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NPLOC4/NPL4, NPL4 homolog ubiquitin recognition factor; PDE3B, phosphodiesterase 3B; PDK1, phosphoinositide dependent protein kinase 1; PHD, prolyl-4-hydroxylase domain; PIK3C3/VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3; PMAIP1/NOXA, phorbol-12-myristate-13-acetate-induced protein 1; POR, cytochrome P450 oxidoreductase; PUFA-PL, PUFA of phospholipids; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SCO1, synthesis of cytochrome C oxidase 1; SCO2, synthesis of cytochrome C oxidase 2; SLC7A11, solute carrier family 7 member 11; SLC11A2/DMT1, solute carrier family 11 member 2; SLC31A1/CTR1, solute carrier family 31 member 1; SLC47A1, solute carrier family 47 member 1; SOD1, superoxide dismutase; SP1, Sp1 transcription factor; SQSTM1/p62, sequestosome 1; STEAP4, STEAP4 metalloreductase; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TFEB, transcription factor EB; TM, tetrathiomolybdate; TP53/p53, tumor protein p53; TXNRD1, thioredoxin reductase 1; UCHL5, ubiquitin C-terminal hydrolase L5; ULK1, Unc-51 like autophagy activating kinase 1; ULK1, unc-51 like autophagy activating kinase 1; ULK2, unc-51 like autophagy activating kinase 2; USP14, ubiquitin specific peptidase 14; VEGF, vascular endothelial gro wth factor; XIAP, X-linked inhibitor of apoptosis.},
}
@article {pmid37054769,
year = {2023},
author = {Vongsfak, J and Apaijai, N and Chunchai, T and Pintana, H and Arunsak, B and Maneechote, C and Singhanat, K and Wu, D and Liang, G and Chattipakorn, N and Chattipakorn, SC},
title = {Acute administration of myeloid differentiation factor 2 inhibitor and N-acetyl cysteine attenuate brain damage in rats with cardiac ischemia/reperfusion injury.},
journal = {Archives of biochemistry and biophysics},
volume = {740},
number = {},
pages = {109598},
doi = {10.1016/j.abb.2023.109598},
pmid = {37054769},
issn = {1096-0384},
mesh = {Rats ; Male ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; *Myocardial Reperfusion Injury/drug therapy/metabolism ; *Reperfusion Injury/drug therapy/pathology ; Brain/metabolism ; Oxidative Stress ; *Encephalitis/pathology ; Ischemia/pathology ; },
abstract = {Inflammation and oxidative stress are mechanisms which potentially underlie the brain damage that can occur after cardiac ischemic and reperfusion (I/R) injury. 2i-10 is a new anti-inflammatory agent, acting via direct inhibition of myeloid differentiation factor 2 (MD2). However, the effects of 2i-10 and the antioxidant N-acetylcysteine (NAC) on pathologic brain in cardiac I/R injury are unknown. We hypothesized that 2i-10 and NAC offer similar neuroprotection levels against dendritic spine reduction through attenuation of brain inflammation, loss of tight junction integrity, mitochondrial dysfunction, reactive gliosis, and suppression of AD protein expression in rats with cardiac I/R injury. Male rats were allocated to either sham or acute cardiac I/R group (30 min of cardiac ischemia and 120 min of reperfusion). Rats in cardiac I/R group were given one of following treatments intravenously at the onset of reperfusion: vehicle, 2i-10 (20 or 40 mg/kg), and NAC (75 or 150 mg/kg). The brain was then used to determine biochemical parameters. Cardiac I/R led to cardiac dysfunction with dendritic spine loss, loss of tight junction integrity, brain inflammation, and mitochondrial dysfunction. Treatment with 2i-10 (both doses) effectively reduced cardiac dysfunction, tau hyperphosphorylation, brain inflammation, mitochondrial dysfunction, dendritic spine loss, and improved tight junction integrity. Although both doses of NAC effectively reduced brain mitochondrial dysfunction, treatment using a high dose of NAC reduced cardiac dysfunction, brain inflammation, and dendritic spine loss. In conclusion, treatment with 2i-10 and a high dose of NAC at the onset of reperfusion alleviated brain inflammation and mitochondrial dysfunction, consequently reducing dendritic spine loss in rats with cardiac I/R injury.},
}
@article {pmid37052190,
year = {2023},
author = {Chin, HK and Lu, MC and Hsu, KC and El-Shazly, M and Tsai, TN and Lin, TY and Shih, SP and Lin, TE and Wen, ZH and Yang, YSH and Liu, YC},
title = {Exploration of anti-leukemic effect of soft coral-derived 13-acetoxysarcocrassolide: Induction of apoptosis via oxidative stress as a potent inhibitor of heat shock protein 90 and topoisomerase II.},
journal = {The Kaohsiung journal of medical sciences},
volume = {39},
number = {7},
pages = {718-731},
pmid = {37052190},
issn = {2410-8650},
support = {KAFGH_D_110031//Kaohsiung Armed Forces General Hospital/ ; KMUH DK(B)110001-3//Kaohsiung Medical University Hospital/ ; MOST 107-2320-B-259-004-MY3//Ministry of Science and Technology/ ; MOST 110-2314-B-037-083//Ministry of Science and Technology/ ; MOST 110-2320-B259-001-MY3//Ministry of Science and Technology/ ; 109T2560-5//National Dong Hwa University/ ; 110T2560-5//National Dong Hwa University/ ; NHRI-111A1-CACO-03222109//National Health Research Institutes/ ; },
mesh = {Humans ; Animals ; Mice ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Molecular Docking Simulation ; *Anthozoa/metabolism ; Oxidative Stress ; Apoptosis ; *Antineoplastic Agents/pharmacology/therapeutic use ; DNA Topoisomerases, Type II/metabolism ; Heat-Shock Proteins/metabolism/pharmacology ; Diterpenes ; },
abstract = {13-Acetoxysarcocrassolide (13-AC) is a marine cembranoid derived from the aquaculture soft coral of Lobophytum crassum. The cytotoxic effect of 13-AC against leukemia cells was previously reported but its mechanism of action is still unexplored. In the current study, we showed that 13-AC induced apoptosis of human acute lymphoblastic leukemia Molt4 cells, as evidenced by the cleavage of PARP and caspases, phosphatidylserine externalization, as well as the disruption of mitochondrial membrane potential. The use of N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, attenuated the cytotoxic effect induced by 13-AC. Molecular docking and thermal shift assay indicated that the cytotoxic mechanism of action of 13-AC involved the inhibition of heat shock protein 90 (Hsp 90) activity by eliciting the level of Hsp 70 and topoisomerase IIα in Molt4 cells. 13-AC also exhibited potent antitumor activity by reducing the tumor volume (48.3%) and weight (72.5%) in the in vivo Molt4 xenograft mice model. Our findings suggested that the marine cembranoid, 13-AC, acted as a dual inhibitor of Hsp 90 and topoisomerase IIα, exerting more potent apoptotic activity via the enhancement of ROS generation.},
}
@article {pmid37051421,
year = {2022},
author = {Sharma, S and Anand, A and Bhatia, A and Sharma, V and Singh, AK and Banerjee, D and Patil, AN},
title = {Pharmacological Evaluation of Scopoletin in the Carbon Tetrachloride-Induced Hepatotoxicity Model in Wistar Rats.},
journal = {Journal of pharmacy &amp; bioallied sciences},
volume = {14},
number = {4},
pages = {201-206},
pmid = {37051421},
issn = {0976-4879},
abstract = {BACKGROUND: Several phyto-chemicals have been identified and suggested as potential therapeutic options for hepatotoxicity management.<br><br>OBJECTIVE: To assess the hepatoprotective effect of scopoletin, a pure phyto-chemical, in carbon tetrachloride (CCl4)-induced hepatotoxicity model in Wistar rats.<br><br>METHODS: Thirty-six rats in total, six in each group, were utilized in this study. Animals in group 1 received normal saline; those in group 2 received carbon tetrachloride in olive oil (0.5 ml/kg, i.p. in ratio 1:1); those in groups 3, 4, and 5 received oral scopoletin (1 mg/kg, 5 mg/kg, 10 mg/kg dose-wise groups); and those in group 6 received N-acetyl cysteine (NAC) 150 mg/kg. Blood sampling was performed on day -3, day 1, and day 7 of the CCl4 administration. Rats were sacrificed on day 7 of the experiment for histological examination and oxidative stress measurement of the liver.<br><br>RESULTS: The 5 mg/kg scopoletin group showed a maximum reduction in AST levels [727.33 &#xb1; 29.15 in medium dose (MD) group vs 1526.66 &#xb1; 60.72 in the experimental control (EC) group (P < 0.001) and ALT levels of 532.66 &#xb1; 24.23 in MD group vs 894.83 &#xb1; 52.47 in EC (P < 0.01)]. The dose-dependent action was not observed with scopoletin doses. The protective effect of scopoletin was confirmed by MDA and GSH levels (P < 0.05) coupled with histo-pathological findings. In the present study, a reversible model of CCl4-induced hepatotoxicity was observed to get normalized in a week's time.<br><br>CONCLUSION: The study confirms the hepatoprotective action of scopoletin in an acute model of hepatic injury with the putative anti-oxidant mechanism.},
}
@article {pmid37049804,
year = {2023},
author = {Xu, Y and Geng, Z and Yang, C and Zhou, H and Wang, Y and Kuerban, B and Luo, G},
title = {Effect of N-acetyl-l-cysteine on Cell Phenotype and Autophagy in Pichia pastoris Expressing Human Serum Albumin and Porcine Follicle-Stimulating Hormone Fusion Protein.},
journal = {Molecules (Basel, Switzerland)},
volume = {28},
number = {7},
pages = {},
pmid = {37049804},
issn = {1420-3049},
support = {32102542//National Natural Science Foundation of China/ ; },
mesh = {Saccharomycetales ; Recombinant Proteins/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Autophagy ; Follicle Stimulating Hormone/metabolism ; Phenotype ; Swine ; Humans ; *Serum Albumin, Human/metabolism ; Recombinant Fusion Proteins/genetics ; Animals ; Pichia/genetics/metabolism ; },
abstract = {Pichia pastoris is widely used for the production of recombinant proteins, but the low secretion efficiency hinders its wide application in biopharmaceuticals. Our previous study had shown that N-acetyl-l-cysteine (NAC) promotes human serum albumin and porcine follicle-stimulating hormone fusion protein (HSA-pFSHβ) secretion by increasing intracellular GSH levels, but the downstream impact mechanism is not clear. In this study, we investigated the roles of autophagy as well as cell phenotype in NAC promoting HSA-pFSHβ secretion. Our results showed that NAC slowed down the cell growth rate, and its effects were unaffected by Congo Red and Calcofluor White. Moreover, NAC affected cell wall composition by increasing chitin content and decreasing β-1,3-glucan content. In addition, the expressions of vesicular pathway and autophagy-related genes were significantly decreased after NAC treatment. Further studies revealed that autophagy, especially the cytoplasm-to-vacuole targeting (Cvt) pathway, mitophagy and pexophagy, was significantly increased with time, and NAC has a promoting effect on autophagy, especially at 48 h and 72 h of NAC treatment. However, the disruption of mitophagy receptor Atg32, but not pexophagy receptor Atg30, inhibited HSA-pFSHβ production, and neither of them inhibited the NAC-promoted effect of HSA-pFSHβ. In conclusion, vesicular transport, autophagy and cell wall are all involved in the NAC-promoted HSA-pFSHβ secretion and that disruption of the autophagy receptor alone does not inhibit the effect of NAC.},
}
@article {pmid37048082,
year = {2023},
author = {Seo, YN and Baik, JS and Lee, SM and Lee, JE and Ahn, HR and Lim, MS and Park, MT and Kim, SD},
title = {Ionizing Radiation Selectively Increases CXC Ligand 10 Level via the DNA-Damage-Induced p38 MAPK-STAT1 Pathway in Murine J774A.1 Macrophages.},
journal = {Cells},
volume = {12},
number = {7},
pages = {},
pmid = {37048082},
issn = {2073-4409},
mesh = {Animals ; Mice ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Endothelial Cells/metabolism ; Ligands ; Macrophages/metabolism ; Radiation, Ionizing ; DNA ; STAT1 Transcription Factor/metabolism ; },
abstract = {Ionizing radiation (IR) is an important means of tumor treatment in addition to surgery and drugs. Attempts have been made to improve the efficiency of radiotherapy by identifying the various biological effects of IR on cells. Components of the tumor microenvironment, such as macrophages, fibroblasts, and vascular endothelial cells, influence cancer treatment outcomes through communication with tumor cells. In this study, we found that IR selectively increased the production of CXC motif chemokine ligand 10 (CXCL10), which is emerging as an important biomarker for determining the prognosis of anticancer treatments, without changing the levels of CXCL9 and CXCL11 in murine J774A.1 macrophages. Pretreatment with KU55933, an ataxia telangiectasia mutated (ATM) kinase inhibitor, significantly inhibited IR-induced CXCL10 production. In contrast, pretreatment with N-acetyl-cysteine or glutathione, a reactive oxygen species scavenger, did not inhibit IR-induced CXCL10 production. Further, we attempted to identify the intracellular molecular target associated with the IR-induced increase in CXCL10 secretion by J774A.1 macrophages. IR phosphorylated p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1) in J774A.1 macrophages, and p38 MAPK and STAT1 were involved in CXCL10 via IR using pharmacological inhibitors (SB203580 and fludarabine, respectively) and the siRNA technique.},
}
@article {pmid37044095,
year = {2023},
author = {Auf der Maur, P and Trefny, MP and Baumann, Z and Vulin, M and Correia, AL and Diepenbruck, M and Kramer, N and Volkmann, K and Preca, BT and Ramos, P and Leroy, C and Eichlisberger, T and Buczak, K and Zilli, F and Okamoto, R and Rad, R and Jensen, MR and Fritsch, C and Zippelius, A and Stadler, MB and Bentires-Alj, M},
title = {N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer.},
journal = {Cell reports. Medicine},
volume = {4},
number = {4},
pages = {101002},
pmid = {37044095},
issn = {2666-3791},
mesh = {Humans ; Mice ; Animals ; Female ; *Breast Neoplasms/drug therapy/genetics/metabolism ; Phosphatidylinositol 3-Kinase ; Acetylcysteine/pharmacology ; Class I Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Thiazoles ; },
abstract = {A genome-wide PiggyBac transposon-mediated screen and a resistance screen in a PIK3CA[H1047R]-mutated murine tumor model reveal NF1 loss in mammary tumors resistant to the phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor alpelisib. Depletion of NF1 in PIK3CA[H1047R] breast cancer cell lines and a patient-derived organoid model shows that NF1 loss reduces sensitivity to PI3Kα inhibition and correlates with enhanced glycolysis and lower levels of reactive oxygen species (ROS). Unexpectedly, the antioxidant N-acetylcysteine (NAC) sensitizes NF1 knockout cells to PI3Kα inhibition and reverts their glycolytic phenotype. Global phospho-proteomics indicates that combination with NAC enhances the inhibitory effect of alpelisib on mTOR signaling. In public datasets of human breast cancer, we find that NF1 is frequently mutated and that such mutations are enriched in metastases, an indication for which use of PI3Kα inhibitors has been approved. Our results raise the attractive possibility of combining PI3Kα inhibition with NAC supplementation, especially in patients with drug-resistant metastases associated with NF1 loss.},
}
@article {pmid37040789,
year = {2023},
author = {Xing, S and Guo, Z and Lang, J and Zhou, M and Cao, J and He, H and Yu, L and Zhou, Y},
title = {N-Acetyl-l-cysteine ameliorates gestational diabetes mellitus by inhibiting oxidative stress.},
journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology},
volume = {39},
number = {1},
pages = {2189969},
doi = {10.1080/09513590.2023.2189969},
pmid = {37040789},
issn = {1473-0766},
mesh = {Pregnancy ; Female ; Humans ; Mice ; Animals ; *Diabetes, Gestational ; Acetylcysteine ; Blood Glucose ; NF-E2-Related Factor 2 ; Oxidative Stress ; },
abstract = {Objective: Gestational diabetes mellitus (GDM) affects 7% of pregnant women worldwide. How to effectively treat GDM has always been a concern of people.Research methods: In this study, a diabetes model was established by drug-induced mice. Subsequently, the blood glucose levels and serum insulin changes of the mice after N-acetyl-l-cysteine (NAC) treatment were observed. At the same time, the effect of NAC on reproduction of GDM mice was recorded.Results of the study: Mice fed NAC showed significantly improved glucose tolerance and insulin sensitivity compared to Diabetic/Control. Total serum cholesterol, serum triglycerides, and serum low-density lipoprotein were significantly reduced, and atherosclerosis index was much lower than in control mice. In addition, Diabetic/Control mice had lower litter sizes and higher birth weights. NAC treatment significantly restored litter size and reduced birth weight in Diabetic/Control mice. It was found in WB assay that the NAC-fed group significantly increased nuclear Nrf2 and HO-1 expression levels.Conclusion: NAC can improve blood glucose tolerance in GDM mice; NAC effectively relieves the symptoms of hyperlipidemia caused by GDM; NAC enhances the expression of Nrf2/HO-1 in the liver, thereby restoring redox homeostasis. NAC can reduce gestational diabetes-related disease indicators by oral administration, and has a beneficial effect on the offspring of pregnant mice (reduces its diabetes disease indicators).},
}
@article {pmid37033589,
year = {2023},
author = {Sharieff, S and Idrees, A and Rafai, W and Bukhari, SUS},
title = {Use of Oral N-Acetylcysteine (NAC) in Non-Acetaminophen-Induced Acute Hepatic Failure.},
journal = {Cureus},
volume = {15},
number = {3},
pages = {e35852},
pmid = {37033589},
issn = {2168-8184},
abstract = {BACKGROUND: Acute liver failure (ALF) is a syndrome rather than a specific disease with several possible causes, and viral hepatitis is a major cause. The objective of the study was to assess the benefit of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF).<br><br>METHODS: A total of six patients with a diagnosis of acute liver failure (ALF) were included in the study. All six patients received oral NAC for 72 hrs. The parameters evaluated were demographic, clinical, biochemical, outcome, and length of ICU and hospital stay. The primary outcome was a reduction in mortality with the use of NAC in NAI-ALF. The secondary outcomes were to evaluate the safety of NAC and assess factors predicting mortality.<br><br>RESULTS: All patients improved and returned to normal or near-normal liver function with the use of NAC. No side effects were noted, and the use of NAC was associated with a shorter hospital stay.<br><br>CONCLUSION: In patients with non-acetaminophen-related acute liver failure, N-acetyl-L-cysteine (NAC)&#xa0;significantly improves overall survival and also decreases the length of hospital stay.},
}
@article {pmid37027944,
year = {2023},
author = {Wang, M and Xu, J and Zhao, Z and Gong, L and Su, Y and Fang, Z and Chen, P and Liu, Y and Zhang, L and Xu, F},
title = {Triphenyl phosphate induced apoptosis of mice testicular Leydig cells and TM3 cells through ROS-mediated mitochondrial fusion inhibition.},
journal = {Ecotoxicology and environmental safety},
volume = {256},
number = {},
pages = {114876},
doi = {10.1016/j.ecoenv.2023.114876},
pmid = {37027944},
issn = {1090-2414},
mesh = {Mice ; Animals ; Male ; *Leydig Cells/metabolism ; Reactive Oxygen Species/metabolism ; *Mitochondrial Dynamics ; Mice, Inbred C57BL ; Apoptosis ; Mitochondrial Proteins/metabolism ; Organophosphates/metabolism ; Testosterone/metabolism ; },
abstract = {Triphenyl phosphate (TPHP) is a widely used organophosphate flame retardant and has biological toxicity. Previous studies showed TPHP can restrain testosterone biosynthesis in Leydig cells, while the underlying mechanisms remain unclear. In this study, C57BL/6J male mice were exposed to 0, 5, 50, and 200 mg/kg B.W. of TPHP for 30 d by oral, as well as TM3 cells were treated with 0, 50, 100, and 200 μM of TPHP for 24 h. Results showed that TPHP induced testes damage, including spermatogenesis disorders and testosterone synthesis inhibition. Meanwhile, TPHP can cause apoptosis in testicular Leydig cells and TM3 cells, as evidenced by the increased apoptosis rate and decreased Bcl-2/Bax ratio. Moreover, TPHP disrupted mitochondrial ultrastructure of testicular Leydig cells and TM3 cells, reduced healthy mitochondria content and depressed mitochondrial membrane potential of TM3 cells, as well as inhibited mitochondrial fusion proteins mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (Opa1) expression, without effect on mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission 1 (Fis1) in testicular tissue and/or TM3 cells. Then, the mitochondrial fusion promoter M1 was used to pre-treat TPHP-exposed TM3 cells to determine the roles of mitochondrial fusion inhibition in TPHP-induced Leydig cells apoptosis. The results showed M1 pretreatment alleviated the above changes and further mitigated TM3 cells apoptosis and testosterone levels decreased, indicating TPHP induced TM3 cells apoptosis by inhibited mitochondrial fusion. Intriguingly, the intervention experiment of N-acetylcysteine (NAC) showed that TPHP-induced mitochondrial fusion inhibition is ROS dependent, because inhibition of ROS overproduction alleviated mitochondrial fusion inhibition, and subsequently relieved TPHP-induced apoptosis in TM3 cells. In summary, above data revealed that apoptosis is a specific mechanism for TPHP-induced male reproductive toxicity, and that ROS-mediated mitochondrial fusion inhibition is responsible for Leydig cells apoptosis caused by TPHP.},
}
@article {pmid37017249,
year = {2023},
author = {Uehara, H and Itoigawa, Y and Morikawa, D and Koga, A and Tsurukami, H and Maruyama, Y and Ishijima, M},
title = {The Effect of Vitamin C and N-Acetylcysteine on Tendon-to-Bone Healing in a Rodent Model of Rotator Cuff Repair.},
journal = {The American journal of sports medicine},
volume = {51},
number = {6},
pages = {1596-1607},
doi = {10.1177/03635465231160772},
pmid = {37017249},
issn = {1552-3365},
mesh = {Rats ; Animals ; *Rotator Cuff/physiology ; Acetylcysteine/pharmacology/therapeutic use ; Matrix Metalloproteinase 13 ; Wound Healing/physiology ; Collagen/metabolism ; Rodentia/metabolism ; Rats, Sprague-Dawley ; Ascorbic Acid/pharmacology/therapeutic use ; Superoxide Dismutase-1/pharmacology ; Tendons/surgery ; *Rotator Cuff Injuries/drug therapy/surgery/pathology ; Biomechanical Phenomena ; },
abstract = {BACKGROUND: Oxidative stress inhibits tendon-to-bone healing after rotator cuff repair. Regulation of oxidative stress has the potential to accelerate this healing, but its mechanism remains unclear.<br><br>PURPOSE: To investigate the effects of reducing oxidative stress by applying antioxidants, such as N-acetylcysteine (NAC) and vitamin C (VC), on rotator cuff repair in a rat rotator cuff repair model.<br><br>STUDY DESIGN: Controlled laboratory study.<br><br>METHODS: A total of 48 Sprague Dawley rats underwent bilateral surgery to repair the infraspinatus tendon to its insertion site 1 week after detachment. Rats were assigned to either the NAC group, the VC group, or a control group. Histological evaluation was performed via hematoxylin-eosin or toluidine blue staining, and oxidative stress was assessed via dihydroethidium intensity and protein carbonyl concentration at 3 and 6 weeks. Superoxide dismutase 1 (SOD1), SOD2, SOD3, peroxiredoxin 5, collagen type I (COL1), COL3, matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-13 expression and SOD activity were determined at 3 and 6 weeks. Biomechanical tests were performed at 6 and 12 weeks.<br><br>RESULTS: Histological evaluation showed that the number of chondrocytes in the NAC group at 6 weeks and in the VC group at 3 and 6 weeks, the area of fibrocartilage at 6 weeks in the VC group, and collagen fibers at 6 weeks in the NAC and VC groups were significantly increased compared with those in the control group. Dihydroethidium intensity at 3 and 6 weeks and protein carbonyls at 6 weeks in the NAC and VC groups were significantly decreased. SOD1 expression and SOD activity at 3 weeks in the VC group and peroxiredoxin 5 expression at 6 weeks in the NAC group were significantly upregulated compared with that in the control group. COL3 expression was significantly upregulated at 6 weeks in the VC group, and MMP-13 expression was significantly decreased at 6 weeks in the NAC and VC groups. The biomechanical strength showed no significant difference.<br><br>CONCLUSION: Antioxidant treatment, via NAC or VC administration, reduced oxidative stress in the rotator cuff repair site and accelerated healing.<br><br>CLINICAL RELEVANCE: These findings provide essential indications to develop clinical strategies for improved healing after rotator cuff surgical repair in patients.},
}
@article {pmid37016183,
year = {2023},
author = {Yalçın, T and Kaya, S and Kuloğlu, T and Yiğin, A},
title = {N-Acetylcysteine May Regulate Altered Meteorin-Like Levels in Testicular Tissue due to Aluminum Exposure.},
journal = {Biological trace element research},
volume = {201},
number = {11},
pages = {5335-5345},
pmid = {37016183},
issn = {1559-0720},
mesh = {Rats ; Animals ; Male ; *Acetylcysteine/pharmacology ; *Aluminum/metabolism ; Testis ; Rats, Sprague-Dawley ; Antioxidants/pharmacology/metabolism ; Oxidative Stress ; Inflammation/metabolism ; },
abstract = {Aluminum (AL) is a heavy metal known to have toxic effects on the reproductive system. It is known that N-acetylcysteine (NAC), which has an antioxidant effect, is a useful chelator for heavy metals. This study aimed to determine whether NAC may reduce AL-induced oxidative stress, inflammation, and germ cell apoptosis in testicular tissues and its effects on meteorin-like (METRNL) levels, which are known to play a role in energy metabolism. In this experimental study, 28 Sprague-Dawley male rats were randomly divided into 4 groups (n = 7): control, AL (30 mg/kg/day AL), AL + NAC (30 mg/kg/day AL + 150 mg/kg/day NAC), and NAC (150 mg/kg/day NAC). All AL and NAC applications were performed intraperitoneally for 14 days. At the end of the experiment, the effects of AL and/or NAC applications on testicular tissue were examined histomorphometrically, histopathologically, immunohistochemically, and biochemically. It was determined that AL exposure caused histomorphometric and histopathological changes, oxidative stress, apoptosis of germ cells, and inflammation in testicular tissues. In addition, AL caused an increase in METRNL levels. It was determined that NAC treatment significantly reduced the negative effects of AL. NAC therapy may be a protective strategy in reproductive toxicity due to AL exposure.},
}
@article {pmid37015815,
year = {2023},
author = {Fleming, K and George, JL and Bazelak, SJ and Roeske, JA and Biggs, AD and Landry, CM and Lipchik, RJ and Truwit, JD},
title = {Optimizing Respiratory Therapy Resources by De-Implementing Low-Value Care.},
journal = {Respiratory care},
volume = {68},
number = {5},
pages = {559-564},
pmid = {37015815},
issn = {1943-3654},
mesh = {Humans ; *Low-Value Care ; Pandemics ; *COVID-19/therapy ; Respiratory Therapy ; Acetylcysteine ; },
abstract = {BACKGROUND: Our institution was experiencing a respiratory therapy staffing crisis during the COVID-19 pandemic, in part due to excessive workload. We identified an opportunity to reduce burden by limiting use of 3% hypertonic saline and/or N-acetylcysteine nebulizer therapies (3%HTS/NAC).<br><br>METHODS: Leveraging the science of de-implementation, we established a policy empowering respiratory therapists to discontinue 3%HTS/NAC not meeting the American Association for Respiratory Care (AARC) Clinical Practice Guideline: Effectiveness of Pharmacologic Airway Clearance Therapies in Hospitalized Patients. After a 3-month period of educating physicians and advanced practice practitioners the policy went to into effect. Outcomes measured included monthly number of treatments, orders, and full-time employees associated with administering nebulized 3%HTS/NAC.<br><br>RESULTS: Post policy activation, the monthly mean 3%HTS/NAC treatments were significantly reduced to 547.5 &#xb1; 284.3 from 3,565.2 &#xb1; 596.4 (P < .001) as were the associated monthly mean of full-time employees, 0.8 &#xb1; 0.41 from 5.1 &#xb1; 0.86 (P < .001). The monthly mean 3%HTS/NAC orders also fell to 93.8 &#xb1; 31.5 from 370.0 &#xb1; 46.9 (P < .001). Monthly mean non-3%HTS/NAC treatments remained stable; post policy was 3,089.4 &#xb1; 611.4 and baseline 3,279.6 &#xb1; 695.0 (P = 1.0).<br><br>CONCLUSIONS: Implementing a policy that empowers respiratory therapists to promote adherence to AARC Clinical Guidelines reduced low-value therapies, costs, and staffing needs.},
}
@article {pmid37010946,
year = {2023},
author = {Sumit, and Maravajjala, KS and Khanna, S and Kachwal, V and Swetha, KL and Manabala, S and Chowdhury, R and Roy, A and Laskar, IR},
title = {Rational Molecular Designing of Aggregation-Enhanced Emission (AEE) Active Red-Emitting Iridium(III) Complexes: Effect of Lipophilicity and Nanoparticle Encapsulation on Photodynamic Therapy Efficacy.},
journal = {ACS applied bio materials},
volume = {6},
number = {4},
pages = {1445-1459},
doi = {10.1021/acsabm.2c00998},
pmid = {37010946},
issn = {2576-6422},
mesh = {Humans ; Iridium/pharmacology ; Reactive Oxygen Species ; *Coordination Complexes/pharmacology ; *Photochemotherapy ; Polyethylene Glycols ; Polyvinyls ; },
abstract = {Two "aggregation-enhanced emission" (AEE) active cyclometalated phosphorescent iridium(III) complexes, SM2 and SM4, were synthesized to evaluate the influence of lipophilicity on photodynamic therapy efficacy. Compared to SM2, SM4 had a higher logP due to the presence of naphthyl groups. As observed by confocal microscopy, this increased lipophilicity of SM4 significantly enhanced its cellular uptake in breast cancer cells. Both the molecules were found to be noncytotoxic under nonirradiating conditions. However, with light irradiation, SM4 exhibited significant cytotoxicity at a 500 nM dose, whereas SM2 remained noncytotoxic, signifying the influence of lipophilicity on cellular internalization and cytotoxicity. Mechanistically, light-irradiated SM4-treated cancer cells exhibited a significant increase in the intracellular reactive oxygen species (ROS) level. Neutralizing ROS with N-acetylcysteine (NAC) pretreatment partly abolished the cytotoxic ability, indicating ROS as one of the major effectors of cell cytotoxicity. Two nanoparticle (NP) formulations of SM4 were developed to improve the intracellular delivery: a PLGA-based NP and a Soluplus-based micelle. Interestingly, PLGA and Soluplus NP formulations exhibited a 10- and 22-fold increased emission intensity, respectively, compared to SM4. There was also an increase in the excited-state lifetime. Additionally, the Soluplus-based micelles encapsulating SM4 exhibited enhanced cellular uptake and increased cytotoxicity compared to the PLGA NPs encapsulating SM4. Altogether, the current study indicates the importance of rational molecular designing and the significance of a proper delivery vector for improving photodynamic therapy efficacy.},
}
@article {pmid37005695,
year = {2023},
author = {Mpagama, SG and Mvungi, HC and Mbelele, PM and Semvua, HH and Liyoyo, AA and de Guex, KP and Sloan, D and Kibiki, GS and Boeree, M and Phillips, PPJ and Heysell, SK},
title = {Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania.},
journal = {Pilot and feasibility studies},
volume = {9},
number = {1},
pages = {55},
pmid = {37005695},
issn = {2055-5784},
support = {D43 TW012247/TW/FIC NIH HHS/United States ; R34 AI112371/AI/NIAID NIH HHS/United States ; },
abstract = {BACKGROUND: Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications.<br><br>METHODS: This is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900&#xa0;mg daily, and an interventional arm of NAC 900&#xa0;mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong'oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24&#xa0;weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis. Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model.<br><br>DISCUSSION: Given that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials.<br><br>TRIAL REGISTRATION: PACTR202007736854169 Registered 03 July 2020.},
}
@article {pmid37003188,
year = {2023},
author = {Dong, Y and Han, F and Su, Y and Sun, B and Zhao, W and Pan, C},
title = {High uric acid aggravates apoptosis of lung epithelial cells induced by cigarette smoke extract through downregulating PRDX2 in chronic obstructive pulmonary disease.},
journal = {International immunopharmacology},
volume = {118},
number = {},
pages = {110056},
doi = {10.1016/j.intimp.2023.110056},
pmid = {37003188},
issn = {1878-1705},
mesh = {Humans ; Animals ; Mice ; Uric Acid/adverse effects ; Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; *Cigarette Smoking/adverse effects ; Lung ; *Pulmonary Disease, Chronic Obstructive/metabolism ; Apoptosis ; Nicotiana ; Epithelial Cells ; RNA, Small Interfering/genetics ; Peroxiredoxins/genetics/adverse effects ; },
abstract = {Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke heightens the elevation of reactive oxygen species (ROS) and thus leads to apoptosis. Hyperuricemia has been considered as a risk factor for COPD. However, the underlying mechanism for this aggravating effect remains unclear. The current study sought to examine the role of high uric acid (HUA) in COPD using cigarette smoke extract (CSE) exposed murine lung epithelial (MLE-12) cells. Our data showed that CSE induced the increase of ROS, mitochondrial dynamics disorder, and apoptosis, while HUA treatment aggravated the effects of CSE. Further studies suggested that HUA decreased the expression of antioxidant enzyme-peroxiredoxin-2 (PRDX2). Overexpression of PRDX2 inhibited excessive ROS generation, mitochondrial dynamics disorder, and apoptosis induced by HUA. Knockdown of PRDX2 by small interfering RNA (siRNA) promoted ROS generation, mitochondrial dynamics disorder, and apoptosis in MLE-12 cells treated with HUA. However, antioxidant N-acetylcysteine (NAC) reversed the effects of PRDX2-siRNA on MLE-12 cells. In conclusion, HUA aggravated CSE-induced cellular ROS levels and led to ROS-dependent mitochondrial dynamics disorder and apoptosis in MLE-12 cells through downregulating PRDX2.},
}
@article {pmid36991205,
year = {2023},
author = {Jin, X and Wu, P and Li, P and Xiong, C and Gui, M and Huang, W},
title = {Transcriptome analysis reveals insight into the protective effect of N-acetylcysteine against cadmium toxicity in Ganoderma lucidum (Polyporales: Polyporaceae).},
journal = {Environmental science and pollution research international},
volume = {30},
number = {20},
pages = {58436-58449},
pmid = {36991205},
issn = {1614-7499},
support = {2019ZG00906//Yunnan Agricultural University/ ; 2022ZZCX028-001//Sichuan Academy of Agricultural Sciences/ ; },
mesh = {Humans ; Animals ; *Reishi/genetics/metabolism ; Acetylcysteine/pharmacology ; Cadmium/metabolism ; *Polyporaceae/genetics/metabolism ; *Polyporales/genetics/metabolism ; Hydrogen Peroxide/metabolism ; Gene Expression Profiling ; *Ganoderma/metabolism ; },
abstract = {Ganoderma lucidum is widely cultivated and used as traditional medicine in China and other Asian countries. As a member of macrofungi, Ganoderma lucidum is also prone to bioaccumulation of cadmium and other heavy metals in a polluted environment, which affects the growth and production of Ganoderma lucidum, as well as human health. N-Acetyl-L-cysteine (NAC) is considered a general antioxidant and free radical scavenger that is involved in the regulation of various stress responses in plants and animals. However, whether NAC could regulate cadmium stress responses in macrofungi, particularly edible fungi, is still unknown. In this work, we found that the exogenous NAC could alleviate Cd-induced growth inhibition and reduce the cadmium accumulation in Ganoderma lucidum. The application of the NAC cloud also inhibit cadmium-induced H2O2 production in the mycelia. By using transcriptome analysis, 2920 and 1046 differentially expressed unigenes were identified in "Cd100 vs CK" and "NAC_Cd100 vs Cd100," respectively. These differential unigenes were classified into a set of functional categories and pathways, which indicated that various biological pathways may play critical roles in the protective effect of NAC against Cd‑induced toxicity in Ganoderma lucidum. Furthermore, it suggested that the ATP-binding cassette transporter, ZIP transporter, heat shock protein, glutathione transferases, and Cytochrome P450 genes contributed to the increased tolerance to cadmium stress after NAC application in Ganoderma lucidum. These results provide new insight into the physiological and molecular response of Ganoderma lucidum to cadmium stress and the protective role of NAC against cadmium toxicity.},
}
@article {pmid36988041,
year = {2023},
author = {Nesterowicz, M and Żendzian-Piotrowska, M and Ładny, JR and Zalewska, A and Maciejczyk, M},
title = {Biochemical and Biophysical in Vitro Studies and Systematic Literature Review on the Antioxidant and Antiglycation Activities of Trazodone.},
journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology},
volume = {57},
number = {2},
pages = {82-104},
doi = {10.33594/000000617},
pmid = {36988041},
issn = {1421-9778},
support = {SUB/1/DN/22/002/3330//Medical University of Bialystok/Poland ; SUB/1/DN/20/001/3330//Medical University of Bialystok/Poland ; SUB/1/DN/21/001/3330//Medical University of Bialystok/Poland ; },
mesh = {*Antioxidants/metabolism ; *Trazodone/pharmacology ; Glycosylation ; Advanced Oxidation Protein Products/metabolism ; Molecular Docking Simulation ; Glycation End Products, Advanced/metabolism ; Serum Albumin, Bovine/chemistry/metabolism ; Glyoxal/chemistry ; Glucose ; Guanidines ; },
abstract = {BACKGROUND/AIMS: Trazodone is a selective serotonin reuptake inhibitor; however, other mechanisms of the drug's anti-depressive properties have also been postulated. Hence, the aim of the study was to perform a systematic review and assess antiglycoxidative properties of trazodone in in vitro models.<br><br>METHODS: Trazodone's scavenging and chelating properties were measured with spectrophotometric method. The impact of the drug on carbonyl/oxidative stress was marked in the bovine serum albumin (BSA) model where sugars (glucose, fructose, galactose, ribose) and aldehydes (glyoxal and methylglyoxal) were used as glycation agents. Aminoguanidine and N-acetylcysteine (NAC) were applied as reference glycation/free radical inhibitors. Glycation biomarkers (kynurenine, N-formylkynurenine, dityrosine as well as advanced glycation end products contents) were assessed spectrofluorometrically. Concentrations of oxidation parameters (total thiols (TTs), protein carbonyls (PCs) and also advanced oxidation protein products (AOPPs) levels) were determined spectrophotometrically.<br><br>RESULTS: We demonstrated that trazodone poorly scavenged radicals (hydroxyl radical, nitric oxide, hydrogen peroxide and 2,2-diphenyl-1-picrylhydrazyl radical) and showed low ferrous ion chelating, unlike aminoguanidine and NAC. Sugars/aldehydes caused enhancement of glycation parameters, as well as a decrease of TTs and an increase of PCs and AOPPs levels compared to BSA incubated alone. Trazodone did not reduce oxidation parameters to the baseline (BSA) and significantly exacerbated glycation markers in comparison with both BSA and BSA+glycators. The content of glycation products was markedly lower in aminoguanidine and NAC than in trazodone. The molecular docking of trazodone to BSA revealed its very low affinity, which may indicate non-specific binding of trazodone, facilitating the attachment of glycation factors.<br><br>CONCLUSION: According to our findings, it may be concluded that trazodone poorly counteracts oxidation and intensifies glycation in vitro. A possible mechanism for antiglycoxidative effect of trazodone in vivo may be the enhancement of the body's adaptive response, as indicated by the results of our systematic review.},
}
@article {pmid36986816,
year = {2023},
author = {Eulálio, D and Pires Figueiredo, M and Taviot-Gueho, C and Leroux, F and Dos Reis Serra, CH and Faria, DLA and Constantino, VRL},
title = {Development of Dipeptide N-acetyl-L-cysteine Loaded Nanostructured Carriers Based on Inorganic Layered Hydroxides.},
journal = {Pharmaceutics},
volume = {15},
number = {3},
pages = {},
pmid = {36986816},
issn = {1999-4923},
support = {88887.352040/2019-00//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de N&#xed;vel Superior/ ; 149404/2018-2//National Council for Scientific and Technological Development/ ; 2016/13862-9//S&#xe3;o Paulo Research Foundation/ ; 2012/13119-3//S&#xe3;o Paulo Research Foundation/ ; 2016/21070-5//S&#xe3;o Paulo Research Foundation/ ; INCT-INEO 2014/50869-6//S&#xe3;o Paulo Research Foundation/ ; 314034/2021-8//National Council for Scientific and Technological Development/ ; PRC-Projets de recherch&#xe9; conjoints 1688 and SPRINT-S&#xe3;o Paulo Researchers in International Collaboration 2016/50317-9//Research Academic Cooperation Agreement PRC-CNRS-FAPESP/ ; },
abstract = {N-acetyl-L-cysteine (NAC), a derivative of the L-cysteine amino acid, presents antioxidant and mucolytic properties of pharmaceutical interest. This work reports the preparation of organic-inorganic nanophases aiming for the development of drug delivery systems based on NAC intercalation into layered double hydroxides (LDH) of zinc-aluminum (Zn2Al-NAC) and magnesium-aluminum (Mg2Al-NAC) compositions. A detailed characterization of the synthesized hybrid materials was performed, including X-ray diffraction (XRD) and pair distribution function (PDF) analysis, infrared and Raman spectroscopies, solid-state [13]carbon and [27]aluminum nuclear magnetic resonance (NMR), simultaneous thermogravimetric and differential scanning calorimetry coupled to mass spectrometry (TG/DSC-MS), scanning electron microscopy (SEM), and elemental chemical analysis to assess both chemical composition and structure of the samples. The experimental conditions allowed to isolate Zn2Al-NAC nanomaterial with good crystallinity and a loading capacity of 27.3 (m/m)%. On the other hand, NAC intercalation was not successful into Mg2Al-LDH, being oxidized instead. In vitro drug delivery kinetic studies were performed using cylindrical tablets of Zn2Al-NAC in a simulated physiological solution (extracellular matrix) to investigate the release profile. After 96 h, the tablet was analyzed by micro-Raman spectroscopy. NAC was replaced by anions such as hydrogen phosphate by a slow diffusion-controlled ion exchange process. Zn2Al-NAC fulfil basic requirements to be employed as a drug delivery system with a defined microscopic structure, appreciable loading capacity, and allowing a controlled release of NAC.},
}
@article {pmid36986437,
year = {2023},
author = {Badr, AM and Al-Kharashi, LA and Attia, H and Alshehri, S and Alajami, HN and Ali, RA and Mahran, YF},
title = {TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {16},
number = {3},
pages = {},
pmid = {36986437},
issn = {1424-8247},
support = {NA//King Saud University/ ; },
abstract = {BACKGROUND: Cisplatin (Cp) is an antineoplastic agent with a dose-limiting nephrotoxicity. Cp-induced nephrotoxicity is characterized by the interplay of oxidative stress, inflammation, and apoptosis. Toll-4 receptors (TLR4) and NLPR3 inflammasome are pattern-recognition receptors responsible for activating inflammatory responses and are assigned to play a significant role with gasdermin (GSDMD) in acute kidney injuries. N-acetylcysteine (NAC) and chlorogenic acid (CGA) have documented nephroprotective effects by suppressing oxidative and inflammatory pathways. Therefore, the current study aimed to investigate the contribution of the upregulation of TLR4/inflammasomes/gasdermin signaling to Cp-induced nephrotoxicity and their modulation by NAC or CGA.<br><br>METHODS: A single injection of Cp (7 mg/kg, i.p.) was given to Wistar rats. Rats received either NAC (250 mg/kg, p.o.) and/or CGA (20 mg/kg, p.o.) one week before and after the Cp injection.<br><br>RESULTS: Cp-induced acute nephrotoxicity was evident by the increased blood urea nitrogen and serum creatinine and histopathological insults. Additionally, nephrotoxicity was associated with increased lipid peroxidation, reduced antioxidants, and elevated levels of inflammatory markers (NF-&#x3ba;B and TNF-&#x3b1;) in the kidney tissues. Moreover, Cp upregulated both TLR4/NLPR3/interleukin-1beta (IL-1&#x3b2;) and caspase-1/GSDMD-signaling pathways, accompanied by an increased Bax/BCL-2 ratio, indicating an inflammatory-mediated apoptosis. Both NAC and/or CGA significantly corrected these changes.<br><br>CONCLUSIONS: This study emphasizes that inhibition of TLR4/NLPR3/IL-1&#x3b2;/GSDMD might be a novel mechanism of the nephroprotective effects of NAC or CGA against Cp-induced nephrotoxicity in rats.},
}
@article {pmid36982552,
year = {2023},
author = {Meliante, PG and Zoccali, F and Cascone, F and Di Stefano, V and Greco, A and de Vincentiis, M and Petrella, C and Fiore, M and Minni, A and Barbato, C},
title = {Molecular Pathology, Oxidative Stress, and Biomarkers in Obstructive Sleep Apnea.},
journal = {International journal of molecular sciences},
volume = {24},
number = {6},
pages = {},
pmid = {36982552},
issn = {1422-0067},
support = {Prot. N.0000625//BANCA D'ITALIA/ ; DSB.AD007.256//National Research Council/ ; },
mesh = {Humans ; *Pathology, Molecular ; Oxidative Stress ; *Sleep Apnea, Obstructive/pathology ; Antioxidants/therapeutic use/metabolism ; Biomarkers/metabolism ; Hypoxia/metabolism ; },
abstract = {Obstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxia (IH) during sleep due to recurrent upper airway obstruction. The derived oxidative stress (OS) leads to complications that do not only concern the sleep-wake rhythm but also systemic dysfunctions. The aim of this narrative literature review is to investigate molecular alterations, diagnostic markers, and potential medical therapies for OSAS. We analyzed the literature and synthesized the evidence collected. IH increases oxygen free radicals (ROS) and reduces antioxidant capacities. OS and metabolic alterations lead OSAS patients to undergo endothelial dysfunction, osteoporosis, systemic inflammation, increased cardiovascular risk, pulmonary remodeling, and neurological alterations. We treated molecular alterations known to date as useful for understanding the pathogenetic mechanisms and for their potential application as diagnostic markers. The most promising pharmacological therapies are those based on N-acetylcysteine (NAC), Vitamin C, Leptin, Dronabinol, or Atomoxetine + Oxybutynin, but all require further experimentation. CPAP remains the approved therapy capable of reversing most of the known molecular alterations; future drugs may be useful in treating the remaining dysfunctions.},
}
@article {pmid36981595,
year = {2023},
author = {Anastasi, E and Scaramuzzino, S and Viscardi, MF and Viggiani, V and Piccioni, MG and Cacciamani, L and Merlino, L and Angeloni, A and Muzii, L and Porpora, MG},
title = {Efficacy of N-Acetylcysteine on Endometriosis-Related Pain, Size Reduction of Ovarian Endometriomas, and Fertility Outcomes.},
journal = {International journal of environmental research and public health},
volume = {20},
number = {6},
pages = {},
pmid = {36981595},
issn = {1660-4601},
mesh = {Pregnancy ; Female ; Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; *Endometriosis/complications/drug therapy ; Dysmenorrhea/complications ; Acetylcysteine/therapeutic use ; *Dyspareunia/complications ; Prospective Studies ; Cohort Studies ; Neoplasm Recurrence, Local ; Fertility ; },
abstract = {BACKGROUND: Endometriosis is a chronic, estrogen-dependent, inflammatory disease, whose pivotal symptoms are dysmenorrhea, dyspareunia, and chronic pelvic pain (CPP). Besides the usual medical treatments, recent evidence suggests there are potential benefits of oral N-acetylcysteine (NAC) on endometriotic lesions and pain. The primary objective of this prospective single-cohort study was to confirm the effectiveness of NAC in reducing endometriosis-related pain and the size of ovarian endometriomas. The secondary objective was to assess if NAC may play a role in improving fertility and reducing the Ca125 serum levels.<br><br>METHODS: Patients aged between 18-45 years old with a clinical/histological diagnosis of endometriosis and no current hormonal treatment or pregnancy were included in the study. All patients received quarterly oral NAC 600 mg, 3 tablets/day for 3 consecutive days of the week for 3 months. At baseline and after 3 months, dysmenorrhea, dyspareunia and CPP were assessed using the Visual Analog Scale score (VAS), while the size of the endometriomas was estimated through a transvaginal ultrasound. Analgesics (NSAIDs) intake, the serum levels of Ca125 and the desire for pregnancy were also investigated. Finally, the pregnancy rate of patients with reproductive desire was evaluated.<br><br>RESULTS: One hundred and twenty patients were recruited. The intensity of dysmenorrhea, dyspareunia and CPP significantly improved (p < 0.0001). The use of NSAIDs (p = 0.001), the size of the endometriomas (p < 0.0001) and the serum levels of Ca125 (p < 0.0001) significantly decreased. Among the 52 patients with reproductive desire, 39 successfully achieved pregnancy within 6 months of starting therapy (p = 0.001).<br><br>CONCLUSIONS: Oral NAC improves endometriosis-related pain and the size of endometriomas. Furthermore, it decreases Ca125 serum levels and may improve fertility in patients with endometriosis.},
}
@article {pmid36978904,
year = {2023},
author = {Kwak, AW and Kim, WK and Lee, SO and Yoon, G and Cho, SS and Kim, KT and Lee, MH and Choi, YH and Lee, JY and Park, JW and Shim, JH},
title = {Licochalcone B Induces ROS-Dependent Apoptosis in Oxaliplatin-Resistant Colorectal Cancer Cells via p38/JNK MAPK Signaling.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {3},
pages = {},
pmid = {36978904},
issn = {2076-3921},
support = {2019R1A2C1005899//the Basic Science Research Program of the National Research Foundation Korea (NRF/ ; 2022R1A5A8033794//NRF grant funded by the Korean government (MSIT)/ ; },
abstract = {Licochalcone B (LCB) exhibits anticancer activity in oral cancer, lung cancer, and hepatocellular carcinoma cells. However, little is known about its antitumor mechanisms in human oxaliplatin-sensitive and -resistant colorectal cancer (CRC) cells. The purpose of the present study was to investigate the antitumor potential of LCB against human colorectal cancer in vitro and analyze its molecular mechanism of action. The viability of CRC cell lines was evaluated using the MTT assay. Flow cytometric analyses were performed to investigate the effects of LCB on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. The results demonstrated that LCB induced a reduction in cell viability, apoptosis, G2/M cell cycle arrest, ROS generation, MMP depolarization, activation of multi-caspase, and JNK/p38 MAPK. However, p38 (SB203580) and JNK (SP600125) inhibitors prevented the LCB-induced reduction in cell viability. The ROS scavenger N-acetylcysteine (NAC) inhibited LCB-induced reduction in cell viability, apoptosis, cell cycle arrest, ROS generation, MMP depolarization, and multi-caspase and JNK/p38 MAPK activities. Taken together, LCB has a potential therapeutic effect against CRC cells through the ROS-mediated JNK/p38 MAPK signaling pathway. Therefore, we expect LCB to have promising potential as an anticancer therapeutic and prophylactic agent.},
}
@article {pmid36978427,
year = {2023},
author = {Walter, H and Verspohl, J and Meißner, J and Oltmanns, H and Geks, AK and Busse, C},
title = {In Vitro Antimicrobial Activity of N-Acetylcysteine against Pathogens Most Commonly Associated with Infectious Keratitis in Dogs and Cats.},
journal = {Antibiotics (Basel, Switzerland)},
volume = {12},
number = {3},
pages = {},
pmid = {36978427},
issn = {2079-6382},
support = {60013053//CP Pharma/ ; },
abstract = {To determine the in vitro antimicrobial activity of N-acetylcysteine (NAC) against common pathogens associated with infectious keratitis in dogs and cats, clinical isolates of Staphylococcus (S.) pseudintermedius (n = 20), Streptococcus (St.) canis (n = 10) and Pseudomonas (P.) aeruginosa (n = 7) of canine and feline infectious ulcerative keratitis and a quality control strain (P. aeruginosa DSM 19880) were tested. The minimal inhibitory concentration (MIC) of NAC concentrations was determined using microdilution methodology. For S. pseudintermedius and P. aeruginosa, NAC concentrations in the range of 1.56 mg/mL (0.156%) to 100 mg/mL (10%), and for St. canis, concentrations ranging from 0.195 mg/mL (0.0195%) to 6.25 mg/mL (0.625%) were tested. For S. pseudintermedius, the MIC was 3.12 mg/mL (0.312%) for all tested isolates. For P. aeruginosa isolates and the quality control strain, the MIC ranged from 3.12 mg/mL (0.312%) to 6.25 mg/mL (0.625%). For St. canis, the MIC ranged from 1.56 mg/mL (0.156%) to 3.12 mg/mL (0.312%). NAC has an in vitro antimicrobial activity against three bacterial species commonly found in infectious keratitis in dogs and cats and therefore may be a promising alternative or adjuvant to topical antibiotics. The results warrant a clinical pilot study to assess the potential of NAC to reduce or replace the use of topical antibiotics in line with the One Health approach.},
}
@article {pmid36976990,
year = {2023},
author = {Wang, W and Guan, J and Feng, Y and Liu, S and Zhao, Y and Xu, Y and Xu, H and Fu, F},
title = {Polystyrene Microplastics Induced Ovarian Toxicity in Juvenile Rats Associated with Oxidative Stress and Activation of the PERK-eIF2α-ATF4-CHOP Signaling Pathway.},
journal = {Toxics},
volume = {11},
number = {3},
pages = {},
pmid = {36976990},
issn = {2305-6304},
support = {20194BCJ22004//Research Foundation from Academic and Technical Leaders of Major Disciplines in Jiangxi Province, China/ ; },
abstract = {Numerous reports confirm that microplastics exposure could induce reproductive toxicity in mammals. However, the effects of microplastics exposure during juveniles on ovarian apoptosis through oxidative and endoplasmic reticulum (ER) stresses remains unclear, which is the focus of our study. In the present study, female rats (4 weeks old) were exposed to polystyrene microplastics (PS-MPs, 1 μm) at different dosages (0, 0.5, and 2.0 mg/kg) for 28 days. Findings revealed that 2.0 mg/kg of PS-MPs distinctly increased the atretic follicle ratio in the ovary and dramatically reduced the serum levels of estrogen and progesterone. Additionally, the oxidative stress indicators declined, including the activity of superoxide dismutase and catalase, whereas the malondialdehyde content in the ovary was considerably enhanced in the 2.0 mg/kg PS-MPs group. Furthermore, the expressions of genes related to ER stress (PERK, eIF2α, ATF4, and CHOP) and apoptosis were remarkably elevated in the 2.0 mg/kg PS-MPs group compared with those in the control group. We found that PS-MPs induced oxidative stress and activated the PERK-eIF2α-ATF4-CHOP signaling pathway in juvenile rats. Moreover, with the oxidative stress inhibitor N-acetyl-cysteine and eIF2α dephosphorylation blocker Salubrinal treatment, ovarian damage induced by PS-MPs was repaired and associated enzyme activities were improved. Overall, our results indicated that PS-MPs exposure induced ovarian injury associated with oxidative stress and activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in juvenile rats, providing new prospects for assessing the health risks of children exposed to microplastics.},
}
@article {pmid36974638,
year = {2023},
author = {Fayed, A and Hammad, AA and Abdulazim, DO and Hammad, H and Amin, M and Elhadidy, S and Salem, MM and ElAzim, IMA and Zsom, L and Csongradi, E and Soliman, KM and Sharaf El Din, UA},
title = {Is the combination of linagliptin and allopurinol better prophylaxis against post-contrast acute kidney injury? A multicenter prospective randomized controlled study.},
journal = {Renal failure},
volume = {45},
number = {1},
pages = {2194434},
pmid = {36974638},
issn = {1525-6049},
mesh = {Humans ; *Acute Kidney Injury/chemically induced/etiology/prevention &amp; control ; *Allopurinol/administration &amp; dosage/therapeutic use ; *Diabetic Nephropathies/classification/complications/diagnosis ; Kidney Failure, Chronic/complications/diagnosis ; *Linagliptin/administration &amp; dosage/therapeutic use ; Prospective Studies ; Renal Insufficiency, Chronic/classification/complications/diagnosis ; *Contrast Media/adverse effects ; Chemoprevention/methods ; Drug Therapy, Combination ; Acetylcysteine/administration &amp; dosage/therapeutic use ; *Protective Agents/administration &amp; dosage/adverse effects/therapeutic use ; Saline Solution/administration &amp; dosage/therapeutic use ; },
abstract = {BACKGROUND: Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD.<br><br>METHODS: Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2&#x2009;days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2[nd] received allopurinol, the 3[rd] group received linagliptin, and the 4[th] received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2&#x2009;weeks in all patients.<br><br>RESULTS: 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p&#x2009;<&#x2009;0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis.<br><br>CONCLUSION: Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view.<br><br>NCT03470454.},
}
@article {pmid36974603,
year = {2023},
author = {Zhang, C and Zhou, T and Li, Y and Dai, W and Du, S},
title = {Activation of the CncC pathway is involved in the regulation of P450 genes responsible for clothianidin resistance in Bradysia odoriphaga.},
journal = {Pest management science},
volume = {79},
number = {9},
pages = {3071-3079},
doi = {10.1002/ps.7482},
pmid = {36974603},
issn = {1526-4998},
support = {//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Reactive Oxygen Species ; Neonicotinoids/pharmacology/metabolism ; *Insecticides/pharmacology ; Nematocera/genetics ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Insecticide Resistance/genetics ; Larva/genetics/metabolism ; Guanidines ; Thiazoles ; },
abstract = {BACKGROUND: Insect cytochrome P450 monooxygenases (P450s) play a key role in the detoxification metabolism of insecticides and their overexpression is often associated with insecticide resistance. Our previous research showed that the overexpression of four P450 genes is responsible for clothianidin resistance in B. odoriphaga. In this study, we characterized another P450 gene, CYP6FV21, associated with clothianidin resistance. However, the molecular basis for the overexpression of P450 genes in clothianidin-resistant strain remains obscure in B. odoriphaga.<br><br>RESULTS: In this study, the CYP6FV21 gene was significantly overexpressed in the clothianidin-resistant (CL-R) strain. Clothianidin exposure significantly increased the expression level of CYP6FV21. Knockdown of CYP6FV21 significantly increased the susceptibility of B. odoriphaga larvae to clothianidin. The transcription factor Cap 'n' Collar isoform-C (CncC) was highly expressed in the midgut of larvae in B. odoriphaga. The expression level of CncC was higher in the CL-R strain compared with the susceptible (SS) strain. Clothianidin exposure caused reactive oxygen species (ROS) accumulation and significantly increased the expression level of CncC. Knockdown of CncC caused a significant decrease in the expression of CYP3828A1 and CYP6FV21, and P450 enzyme activity, and led to a significant increase in mortality after exposure to lethal concentration at 30% (LC30) of&#xa0;clothianidin. After treatment with CncC agonist curcumin, the P450 activity and the expression levels of CYP3828A1 and CYP6FV21 significantly increased, and larval sensitivity to clothianidin decreased. The ROS scavenger N-acetylcysteine (NAC) treatment significantly inhibited the expression levels of CncC, CYP3828A1 and CYP6FV21 in response to clothianidin exposure and increased larval sensitivity to clothianidin.<br><br>CONCLUSION: Taken together, these results indicate that activation of the CncC pathway by the ROS burst plays a critical role in clothianidin resistance by regulating the expression of CYP3828A1 and CYP6FV21 genes in B. odoriphaga. This study provides more insight into the mechanisms underlying B. odoriphaga larval resistance to clothianidin. &#xa9; 2023 Society of Chemical Industry.},
}
@article {pmid36971326,
year = {2023},
author = {Patwardhan, RS and Kundu, K and Purohit, V and Kumar, BK and Singh, B and Thoh, M and Undavia, K and Bhilwade, HN and Nayak, SK and Sharma, D and Sandur, SK},
title = {Malabaricone C, a constituent of spice Myristica malabarica, exhibits anti-inflammatory effects via modulation of cellular redox.},
journal = {Journal of biosciences},
volume = {48},
number = {2},
pages = {},
pmid = {36971326},
issn = {0973-7138},
mesh = {Mice ; Animals ; *Myristica/metabolism ; Spices ; Oxidation-Reduction ; NF-kappa B/genetics/metabolism ; Cytokines/genetics/metabolism ; Anti-Inflammatory Agents/pharmacology ; Resorcinols ; },
abstract = {The present study primarily focuses on the efficacy of Malabaricone C (Mal C) as an anti-inflammatory agent. Mal C inhibited mitogen-induced T-cell proliferation and cytokine secretion. Mal C significantly reduced cellular thiols in lymphocytes. N-acetyl cysteine (NAC) restored cellular thiol levels and abrogated Mal C-mediated inhibition of T-cell proliferation and cytokine secretion. Physical interaction between Mal C and NAC was evinced from HPLC and spectral analysis. Mal C treatment significantly inhibited concanavalin A-induced phosphorylation of ERK/JNK and DNA binding of NF-κB. Administration of Mal C to mice suppressed T-cell proliferation and effector functions ex vivo. Mal C treatment did not alter the homeostatic proliferation of T-cells in vivo but completely abrogated acute graft-versus-host disease (GvHD)-associated morbidity and mortality. Our studies indicate probable use of Mal C for prophylaxis and treatment of immunological disorders caused due to hyper-activation of T-cells.},
}
@article {pmid36968922,
year = {2023},
author = {Altaf, F and Qureshi, ZA and Kandhi, S and Khaja, M},
title = {Clinical Conundrum of Acute Hepatitis B With Concurrent Hepatitis E Infection Leading to Severe Acute Liver Injury.},
journal = {Cureus},
volume = {15},
number = {2},
pages = {e35216},
pmid = {36968922},
issn = {2168-8184},
abstract = {Acute liver injury in the setting of acute fulminant hepatitis caused by the hepatitis B virus (HBV) can occur both during primary infection and after chronic HBV reactivation. Guidelines recommend considering antiviral therapy in both cases. Antiviral therapy with a nucleoside analog may be beneficial in patients with acute liver failure from acute HBV infection, though not all studies have shown a benefit. This is a case of a 53-year-old woman with a past medical history of untreated hepatitis C with undetectable viral load and right breast cancer status post lumpectomy, who presented to the emergency department with complaints of yellowish skin and sclera discoloration with right upper quadrant pain for one week. She was a known intravenous drug abuser and binge alcohol user. Her labs were positive for hepatitis B, hepatitis E, and hepatitis C viruses. She also had elevated liver enzymes with hyperbilirubinemia showing severe acute liver injury. Computed tomography of the abdomen and pelvis with contrast was normal, and the abdominal ultrasound showed homogenous echotexture of the liver without a focal lesion. The patient was diagnosed with acute fulminant hepatitis B. After initial hemodynamic stabilization, N-acetylcysteine (NAC) and tenofovir were started, and transaminases were followed. Liver function tests showed a downtrend, and, in a few weeks, they came to baseline. Hepatitis B viral load became undetectable as well. Acute hepatitis B infection is seldom treated. The presented case depicts the use of tenofovir in the setting of severe acute liver injury due to hepatitis B. Starting antiviral therapy (especially tenofovir disoproxil fumarate) early in the disease course was shown to have very assuring results with complete resolution of symptoms and normalization of liver function tests. The treatment protocol for acute HBV deserves further investigation.},
}
@article {pmid36965604,
year = {2023},
author = {Camus, MF and Rodriguez, E and Kotiadis, V and Carter, H and Lane, N},
title = {Redox stress shortens lifespan through suppression of respiratory complex I in flies with mitonuclear incompatibilities.},
journal = {Experimental gerontology},
volume = {175},
number = {},
pages = {112158},
doi = {10.1016/j.exger.2023.112158},
pmid = {36965604},
issn = {1873-6815},
support = {BB/S003681/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Female ; *Longevity/genetics ; *Electron Transport Complex I ; Drosophila melanogaster/genetics ; Hydrogen Peroxide ; Oxidation-Reduction ; },
abstract = {Incompatibilities between mitochondrial and nuclear genes can perturb respiration, biosynthesis, signaling and gene expression. Here we investigate whether mild mitonuclear incompatibilities alter the physiological response to redox stress induced by N-acetyl cysteine (NAC). We studied three Drosophila melanogaster lines with mitochondrial genomes that were either coevolved (WT) or mildly mismatched (BAR, COX) to an isogenic nuclear background. Responses to NAC varied substantially with mitonuclear genotype, sex, tissue and dose. NAC caused infertility and high mortality in some groups, but not others. Using tissue-specific high-resolution fluorespirometry, we show that NAC did not alter H2O2 flux but suppressed complex I-linked respiration in female flies, while maintaining a reduced glutathione pool. The high mortality in BAR females was associated with severe (>50 %) suppression of complex I-linked respiration, rising H2O2 flux in the ovaries, and significant oxidation of the glutathione pool. Our results suggest that redox stress is attenuated by the suppression of complex-I linked respiration, to the point of death in some mitonuclear lines. We propose that suppression of complex I-linked respiration is a general mechanism to maintain redox homeostasis in tissues, which could offset oxidative stress in ageing, producing a metabolic phenotype linked with epigenetic changes and age-related decline.},
}
@article {pmid36964576,
year = {2023},
author = {Peng, C and Li, X and Ao, F and Li, T and Guo, J and Liu, J and Zhang, X and Gu, J and Mao, J and Zhou, B},
title = {Mitochondrial ROS driven by NOX4 upregulation promotes hepatocellular carcinoma cell survival after incomplete radiofrequency ablation by inducing of mitophagy via Nrf2/PINK1.},
journal = {Journal of translational medicine},
volume = {21},
number = {1},
pages = {218},
pmid = {36964576},
issn = {1479-5876},
mesh = {Humans ; Mitophagy ; *Carcinoma, Hepatocellular/pathology ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2/metabolism ; Up-Regulation ; Cell Survival ; Protein Kinases/metabolism ; *Liver Neoplasms/pathology ; Neoplasm Recurrence, Local/pathology ; Mitochondria/metabolism ; *Radiofrequency Ablation ; NADPH Oxidase 4/metabolism ; },
abstract = {BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains a major clinical problem. Cells that survive the sublethal heat stress that is induced by incomplete RFA are the main source of HCC relapse. Heat stress has long been reported to increase intracellular reactive oxygen species (ROS) generation. Although ROS can induce apoptosis, a pro-survival effect of ROS has also been demonstrated. However, the role of ROS in HCC cells exposed to sublethal heat stress remains unclear.<br><br>METHODS: HepG2 and HuH7 cells were used for this experiment. Insufficient RFA was performed in cells and in a xenograft model. ROS and antioxidant levels were measured. Apoptosis was analyed by Annexin-V/PI staining and flow cytometry. Protein expression was measured using western blotting. Colocalization of lysosomes and mitochondria was analyzed to assess mitophagy. Corresponding activators or inhibitors were applied to verify the function of specific objectives.<br><br>RESULTS: Here,we showed that sublethal heat stress induced a ROS burst, which caused acute oxidative stress. This ROS burst was generated by mitochondria, and it was initiated by upregulated NOX4 expression in the mitochondria. N-acetylcysteine (NAC) decreased HCC cell survival under sublethal heat stress conditions in vivo and in vitro. NOX4 triggers the production of mitochondrial ROS (mtROS), and NOX4 inhibitors or siNOX4 also decreased HCC cell survival under sublethal heat stress conditions in vitro. Increased mtROS trigger PINK1-dependent mitophagy to eliminate the mitochondria that are damaged by sublethal heat stress and to protect cells from apoptosis. Nrf2 expression was elevated in response to this ROS burst and mediated the ROS burst-induced increase in PINK1 expression after sublethal heat stress.<br><br>CONCLUSION: These data confirmed that the ROS burst that occurs after iRFA exerted a pro-survival effect. NOX4 increased the generation of ROS by mitochondria. This short-term ROS burst induced PINK1-dependent mitophagy to eliminate damaged mitochondria by increasing Nrf2 expression.},
}
@article {pmid36963348,
year = {2023},
author = {Zhao, K and Han, D and He, SR and Wu, LY and Liu, WY and Zhong, ZM},
title = {N-acetyl-L-cysteine attenuates oxidative stress-induced bone marrow endothelial cells apoptosis by inhibiting BAX/caspase 3 pathway.},
journal = {Biochemical and biophysical research communications},
volume = {656},
number = {},
pages = {115-121},
doi = {10.1016/j.bbrc.2023.03.045},
pmid = {36963348},
issn = {1090-2104},
mesh = {*Acetylcysteine/pharmacology/metabolism ; bcl-2-Associated X Protein/metabolism ; *Endothelial Cells/metabolism ; Caspase 3/metabolism ; Bone Marrow/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Apoptosis ; },
abstract = {Bone marrow endothelial cells (BMECs) play a crucial role in the maintenance of bone homeostasis. The decline in BMECs is associated with abnormal bone development and loss. At present, the mechanism of age-related oxidative stress enhancement in BMEC dysfunction remains unclear. Our experiment explored injury caused by oxidative stress enhancement in BMECs both in vivo and in vitro. The BMECs, indicators of oxidative stress, bone mass, and apoptosis-related proteins were analyzed in different age groups. We also evaluated the ability of N-Acetyl-L-cysteine (NAC) attenuate oxidative stress injury in BMECs. NAC treatment attenuated reactive oxygen species (ROS) overgeneration and apoptosis in BMECs in vitro and alleviated the loss of BMECs and bone mass in vivo. In conclusion, this study could improve our understanding of the mechanism of oxidative stress-induced BMECs injury and whether NAC has therapeutic potential in senile osteoporosis.},
}
@article {pmid36961435,
year = {2023},
author = {Li, Z and Wu, L and Huang, Z and Lv, B and Fu, Y and Zhou, L and Fu, X},
title = {CCCP Facilitates Aminoglycoside to Kill Late Stationary-Phase Escherichia coli by Elevating Hydroxyl Radical.},
journal = {ACS infectious diseases},
volume = {9},
number = {4},
pages = {801-814},
doi = {10.1021/acsinfecdis.2c00522},
pmid = {36961435},
issn = {2373-8227},
mesh = {Humans ; *Escherichia coli ; *Aminoglycosides/pharmacology/chemistry ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology ; Hydroxyl Radical/pharmacology ; Anti-Bacterial Agents/pharmacology ; Tobramycin/pharmacology ; },
abstract = {Improving the efficacy of existing antibiotics is significant for combatting antibiotic resistance that poses a major threat to human health. Carbonyl cyanide m-chlorophenylhydrazine (CCCP), a well-known protonophore for dissipating proton motive force (PMF), has been widely used to block the PMF-dependent uptake of aminoglycoside antibiotics and thus suppress aminoglycoside lethality. Here, we report that CCCP and its functional analog FCCP, but not other types of protonophores, unprecedently potentiate aminoglycosides (e.g., tobramycin and gentamicin) by 3-4 orders of magnitude killing of Escherichia coli, Staphylococcus aureus, Shigella flexneri, and Vibrio alginolyticus cells in stationary phase but not these cells in exponential phase nor other 12 bacterial species we examined. Overall, the effect of CCCP on aminoglycoside lethality undergoes a gradual transition from suppression against E. coli exponential-phase cells to potentiation against late stationary-phase cells, with the cell growth status and culture medium being crucial. Consistently, disturbance of the PMF by changing transmembrane proton gradient (ΔpH) or electric potential (ΔΨ) also potentiates tobramycin. Nevertheless, CCCP neither increases the intracellular concentration of tobramycin nor decreases the MIC of the antibiotic, thus excluding that CCCP acts as an efflux pump inhibitor to potentiate aminoglycosides. Rather, we show that the combined treatment dramatically enhances the cellular level of hydroxyl radical under both aerobic and anaerobic culturing conditions, under which the antioxidant N-acetyl cysteine fully suppresses both hydroxyl radical accumulation and cell death. Together, these findings open a new avenue to develop certain protonophores as aminoglycoside adjuvants against pathogens in stationary phase and also illustrate an essential role of hydroxyl radical in aminoglycoside lethality regardless of aerobic respiration.},
}
@article {pmid36950489,
year = {2023},
author = {Thomas, L and Chandran, J and Goel, A and Jacob, E and Chacko, B and Subramani, K and Agarwal, I and Varughese, S and David, VG and Daniel, D and Mammen, J and Balakrishnan, V and Balasubramanian, KA and Lionel, AP and Adhikari, DD and Abhilash, KPP and Elias, E and Eapen, CE and Zachariah, U},
title = {Improving Transplant-free Survival With Low-volume Plasma Exchange to Treat Children With Rodenticide Induced Hepatotoxicity.},
journal = {Journal of clinical and experimental hepatology},
volume = {13},
number = {2},
pages = {252-258},
pmid = {36950489},
issn = {0973-6883},
abstract = {BACKGROUND: In a prior report, no patient with rodenticidal hepatotoxicity who met Kochi criteria (MELD score ≥36 or baseline INR ≥6 with hepatic encephalopathy) (PMID: 26310868) for urgent liver transplantation survived with medical management alone. Plasma exchange (PLEX) may improve survival in these patients.<br><br>OBJECTIVES: We describe our experience with low-volume PLEX (PLEX-LV) in treating rodenticide ingestion induced hepatotoxicity in children.<br><br>METHODS: From prospectively collected database of rodenticidal hepatotoxicity patients managed as in-patient with department of Hepatology from December 2017 to August 2021, we retrospectively studied outcomes in children (&#x2264;18 years). Hepatotoxicity was categorized as acute liver injury (ALI, coagulopathy alone) or acute liver failure (ALF, coagulopathy and encephalopathy). Kochi criteria was used to assess need for urgent liver transplantation. The primary study outcome was one-month survival.<br><br>RESULTS: Of the 110 rodenticidal hepatotoxicity patients, 32 children (females: 56%; age: 16 [4.7-18] years; median, range) constituted the study patients. The study patients presented 4 (1-8) days after poison consumption (impulsive suicidal intent:31, accidental:1). Twenty children (62%) had ALI [MELD: 18 (8-36)] and 12 (38%) had ALF [MELD: 37 (24-45)].All children received standard medical care, including N-acetyl cysteine; ALF patients also received anti-cerebral edema measures. None of the patient families opted for liver transplantation. Seventeen children (ALI: 6, ALF: 11) were treated with PLEX-LV (3 [1-5] sessions, volume of plasma exchanged per session: 26 [13-38] ml/kg body weight) and peri-procedure low dose prednisolone.At 1 month, 28 of the 32 children (87.5%) were alive (4 ALF patients died). Of 10 children who met Kochi listing criteria for urgent liver transplantation, two children were ineligible for PLEX-LV (due to hemodynamic instability) and of the remaining 8 children treated by PLEX-LV, 6 (75%) survived.<br><br>CONCLUSIONS: PLEX-LV shows promise as an effective non-liver transplant treatment in children with rodenticidal hepatotoxicity.},
}
@article {pmid36947366,
year = {2023},
author = {Ezzat, GM and Nassar, AY and Bakr, MH and Mohamed, S and Nassar, GA and Kamel, AA},
title = {Acetylated Oligopeptide and N-acetyl cysteine Protected Against Oxidative Stress, Inflammation, Testicular-Blood Barrier Damage, and Testicular Cell Death in Iron-Overload Rat Model.},
journal = {Applied biochemistry and biotechnology},
volume = {195},
number = {8},
pages = {5053-5071},
pmid = {36947366},
issn = {1559-0291},
mesh = {Male ; Rats ; Animals ; *Acetylcysteine/pharmacology/metabolism ; Testis ; NF-kappa B/metabolism ; Beclin-1/metabolism ; Claudin-1/metabolism ; Dextrans/metabolism ; Oxidative Stress ; Antioxidants/pharmacology ; *Iron Overload/drug therapy/metabolism/pathology ; Inflammation/drug therapy/metabolism ; Glutathione/metabolism ; Cell Death ; Testosterone/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Iron/metabolism ; },
abstract = {Multiple organs, including the testes, are damaged by iron overload. It has been shown that N-acetyl cysteine (NAC) influences oxidative stress in iron overload. The present study aimed to evaluate the roles of acetylated peptide (AOP) and NAC in the inhibition of iron-overload induced-testicular damage. At the beginning of the experiment, NAC (150 mg /kg) was given for a week to all 40 rats. Then, four groups were formed by dividing the animals (10 rats/group). Group I included healthy control rats. Group II (iron overload) was given intraperitoneal iron dextran (60 mg/kg/day) 5 days a week for 4 weeks. Group III (NAC) was given NAC orally at a dose of 150 mg/kg/day for 4 weeks in addition to iron dextran. Group IV (AOP) was given AOP orally at a dose of 150 mg/kg/day for 4 weeks besides iron dextran. When the experiment time was over, testosterone serum level, testicular B cell lymphoma-2 (BCL-2) and protein kinase B (PKB) protein levels, nuclear factor kappa-B (NF-κB), and Beclin1 mRNA expression levels, and malondialdehyde (MDA), and reduced glutathione (GSH) were determined by ELISA, quantitative reverse transcription-PCR, and chemical methods. Finally, histopathological examinations and immunohistochemical detection of claudin-1 and CD68 were performed. The iron overload group exhibited decreased testosterone, BCL-2, PKB, claudin-1, and GSH and increased MDA, NF-κB, Beclin1, and CD68, while both NAC and AOP treatments protected against the biochemical and histopathological disturbances occurring in the iron overload model. We concluded that NAC and AOP can protect against testes damage by iron overload via their antioxidant, anti-inflammatory, antiapoptotic, and ant-autophagic properties. The NAC and AOP may be used as preventative measures against iron overload-induced testicular damage.},
}
@article {pmid36945164,
year = {2023},
author = {Kemahli, E and Uyeturk, U and Cetinkaya, A and Erimsah, S and Uyeturk, U and Gucuk, A},
title = {Protective Effects of N-Acetyl Cysteine on Undescended Testis after Orchiopexy: A Rat-model Study.},
journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP},
volume = {33},
number = {3},
pages = {319-324},
doi = {10.29271/jcpsp.2023.03.319},
pmid = {36945164},
issn = {1681-7168},
mesh = {Humans ; Pregnancy ; Female ; Male ; Rats ; Animals ; *Testis ; *Cryptorchidism/surgery ; Orchiopexy ; Acetylcysteine/pharmacology ; Flutamide ; Semen ; Antioxidants/pharmacology ; },
abstract = {UNLABELLED: ABSTRACT Objective: To assess the effectiveness of utilising N-acetyl cysteine (NAC) to treat tissue damage brought on by undescended testis (UT) in rats after orchiopexy.<br><br>STUDY DESIGN: Experimental study. Place and Duration of the Study: Bolu Abant &#x130;zzet Baysal University, Bolu, Turkey, from January 2018 to June 2020.<br><br>METHODOLOGY: The UT model was created by administering flutamide to pregnant rats. Four groups of animals were created as the control group (offsprings of pregnant rats without flutamide), group II (UT), group III (UT + orchiopexy), and group IV (UT + orchiopexy + NAC); each containing eight animals.<br><br>RESULTS: Group IV had a higher level of glutathione peroxidase than groups III and II (p=0.001 and p=0.002, respectively). Malondialdehyde was reduced in group IV compared with groups III and II (both p<0.001). There were differences in mean apoptotic cell counts (ACC) among the groups (p<0.001). ACC in group IV was lower than in group III (p<0.001). Sperm counts were higher in group IV than &#x131;n groups III and II, and in group III they were higher than group II (p<0.001 all) and similar between groups IV and control group (p=0.102).<br><br>CONCLUSION: Orchiopexy reduced UT-related testicular damage, additionally using NAC following orchiopexy may further reduce testicular damage through its antioxidant effects.<br><br>KEY WORDS: Undescended testis, Testis damage, Orchiopexy, N-acetyl cysteine, Antioxidant.},
}
@article {pmid36941865,
year = {2023},
author = {Sztolsztener, K and Bzdęga, W and Hodun, K and Chabowski, A},
title = {N-Acetylcysteine Decreases Myocardial Content of Inflammatory Mediators Preventing the Development of Inflammation State and Oxidative Stress in Rats Subjected to a High-Fat Diet.},
journal = {International journal of inflammation},
volume = {2023},
number = {},
pages = {5480199},
pmid = {36941865},
issn = {2090-8040},
abstract = {Arachidonic acid (AA) is a key precursor for proinflammatory and anti-inflammatory derivatives that regulate the inflammatory response. The modulation of AA metabolism is a target for searching a therapeutic agent with potent anti-inflammatory action in cardiovascular disorders. Therefore, our study aims to determine the potential preventive impact of N-acetylcysteine (NAC) supplementation on myocardial inflammation and the occurrence of oxidative stress in obesity induced by high-fat feeding. The experiment was conducted for eight weeks on male Wistar rats fed a standard chow or a high-fat diet (HFD) with intragastric NAC supplementation. The Gas-Liquid Chromatography (GLC) method was used to quantify the plasma and myocardial AA levels in the selected lipid fraction. The expression of proteins included in the inflammation pathway was measured by the Western blot technique. The concentrations of arachidonic acid derivatives, cytokines and chemokines, and oxidative stress parameters were determined by the ELISA, colorimetric, and multiplex immunoassay kits. We established that in the left ventricle tissue NAC reduced AA concentration, especially in the phospholipid fraction. NAC administration ameliorated the COX-2 and 5-LOX expression, leading to a decrease in the PGE2 and LTC4 contents, respectively, and augmented the 12/15-LOX expression, increasing the LXA4 content. In obese rats, NAC ameliorated NF-κB expression, inhibiting the secretion of proinflammatory cytokines. NAC also affected the antioxidant levels in HFD rats through an increase in GSH and CAT contents with a simultaneous decrease in the levels of 4-HNE and MDA. We concluded that NAC treatment weakens the NF-κB signaling pathway, limiting the development of myocardial low-grade inflammation, and increasing the antioxidant content that may protect against the development of oxidative stress in rats with obesity induced by an HFD.},
}
@article {pmid36941180,
year = {2023},
author = {Danışan, G and Taydaş, O and Özdemir, M and Ateş, &#xd6;F and Küpeli, A and Öğüşlü, U and Erkin, A and Neşelioğlu, S and Eren, F},
title = {Dynamic thiol-disulphide homeostasis as a biomarker for predicting the development of contrast medium-associated acute kidney injury in the endovascular treatment of peripheral arterial disease: should intravenous N-acetylcysteine be given before the procedure?.},
journal = {Clinical radiology},
volume = {78},
number = {6},
pages = {466-472},
doi = {10.1016/j.crad.2023.02.016},
pmid = {36941180},
issn = {1365-229X},
mesh = {Adult ; Humans ; Acetylcysteine ; Biomarkers ; Disulfides ; Sulfhydryl Compounds ; Serum Albumin ; Contrast Media/adverse effects ; *Acute Kidney Injury/prevention &amp; control ; Homeostasis ; *Peripheral Arterial Disease ; },
abstract = {AIM: To determine the predictive ability of serum thiol-disulphide levels for contrast medium-associated acute kidney injury (CA-AKI) after endovascular treatment (EVT) of peripheral arterial disease (PAD) and evaluate the efficacy of intravenous N-acetylcysteine (NAC) in preventing CA-AKI.<br><br>MATERIAL AND METHODS: This double-blind, randomised controlled study included 85 consecutive adult patients who underwent EVT for PAD. Patients were divided into NAC negative (NAC-) and positive (NAC+) groups. While the NAC- group received only 500 ml saline, the NAC&#xa0;+&#xa0;group received 500 ml saline plus intravenous 600 mg NAC before the procedure. Intra- and intergroup patient characteristics, procedural details, preoperative thiol-disulphide levels, and ischaemia-modified albumin (IMA) levels were recorded.<br><br>RESULTS: There was a significant difference between NAC- and NAC&#xa0;+&#xa0;groups regarding native thiol, total thiol, disulphide/native thiol ratio (D/NT), and disulphide/total thiol ratio (D/TT). There was also a significant difference between the NAC- (33.3%) and NAC+ (13%) groups in CA-AKI development. Logistic regression analysis showed that the D/TT (OR 2.463) and D/NT (OR 2.121) were the most influential parameters for CA-AKI development. In the receiver operating characteristic (ROC) curve analysis, the sensitivity of native thiol to detect the development of CA-AKI was 89.1%. The negative predictive values of native thiol and total thiol were 95.6% and 94.1%, respectively.<br><br>CONCLUSION: The serum thiol-disulphide level can be used as a biomarker to detect CA-AKI development and reveal patients with a low risk for CA-AKI development before EVT of PAD. Furthermore, thiol-disulphide levels allow for the indirect quantitative monitoring of NAC. Preprocedural intravenous NAC administration significantly inhibits CA-AKI development.},
}
@article {pmid36933581,
year = {2023},
author = {Ayed-Boussema, I and Rjiba-Touati, K and Hamdi, H and Chaabani, H and Abid-Essefi, S},
title = {Oxidative stress-mediated mitochondrial apoptosis induced by the acaricide, fenpyroximate, on cultured human colon cancer HCT 116 cells.},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {89},
number = {},
pages = {105587},
doi = {10.1016/j.tiv.2023.105587},
pmid = {36933581},
issn = {1879-3177},
mesh = {Humans ; HCT116 Cells ; *Acaricides/pharmacology ; Reactive Oxygen Species/metabolism ; Caspase 3/metabolism ; Oxidative Stress ; *Colonic Neoplasms ; Apoptosis ; RNA, Messenger/metabolism ; Membrane Potential, Mitochondrial ; Benzoates ; Pyrazoles ; },
abstract = {Fenpyroximate (FEN) is an acaricide that inhibits mitochondrial electron transport at the NADH-coenzyme Q oxidoreductase (complex I). The present study was designed to investigate the molecular mechanisms underling FEN toxicity on cultured human colon carcinoma cells (HCT116). Our data showed that FEN induced HCT116 cell mortality in a concentration dependent manner. FEN arrested cell cycle in G0/G1 phase and increased DNA damage as assessed by comet assay. Induction of apoptosis was confirmed in HCT116 cells exposed to FEN by AO-EB staining and Annexin V-FITC/PI double staining assay. Moreover, FEN induced a loss in mitochondrial membrane potential (MMP), increased p53 and Bax mRNA expression and decreased bcl2 mRNA level. An increase in caspase 9 and caspase 3 activities was also detected. All toghether, these data suggest that FEN induce apoptosis in HCT116 cells via mitochondrial pathway. To check the implication of oxidative stress in FEN-induced cell toxicity, we examined the oxidative stress statue in HCT116 cells exposed to FEN and we tested the effect of a powerful antioxidant, N-acetylcystein (NAC), on FEN-caused toxicity. It was observed that FEN enhanced ROS generation and MDA levels and disturbed SOD and CAT activities. Besides, cell treatment with NAC significantly protected cells from mortality, DNA damage, loss of MMP, and caspase 3 activity induced by FEN. To the best of our knowledge, this is the first study showing that FEN induced mitochondrial apoptosis via ROS generation and oxidative stress.},
}
@article {pmid36927162,
year = {2023},
author = {Huang, C and Kuo, S and Lin, L and Yang, Y},
title = {The efficacy of N-acetylcysteine in chronic obstructive pulmonary disease patients: a meta-analysis.},
journal = {Therapeutic advances in respiratory disease},
volume = {17},
number = {},
pages = {17534666231158563},
pmid = {36927162},
issn = {1753-4666},
mesh = {Humans ; *Acetylcysteine/adverse effects ; Disease Progression ; Vital Capacity ; *Pulmonary Disease, Chronic Obstructive/diagnosis/drug therapy ; },
abstract = {BACKGROUND: N-acetylcysteine (NAC) may reduce acute exacerbations of chronic obstructive pulmonary disease through an antioxidant effect. Due to the heterogeneity in studies, the currently available data do not confirm the efficacy of oral NAC therapy in chronic obstructive pulmonary disease patients. We hypothesize that chronic obstructive pulmonary disease patients receiving regular oral NAC therapy do not achieve improved clinical outcomes.<br><br>OBJECTIVES: The purpose of this meta-analysis was to determine the efficacy of long-term oral NAC therapy in chronic obstructive pulmonary disease patients.<br><br>DATA SOURCES AND METHODS: The literature search was performed using the PubMed, Web of Science, and Cochrane Library databases to identify all included clinical studies. Studies were eligible for inclusion only if they directly compared the outcomes of NAC versus placebo in adults with chronic obstructive pulmonary disease between 1 January 2000 and 30 May 2022. All studies were included if they reported one or more of the following outcomes: number of patients with no acute exacerbations, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), St George's Respiratory Questionnaire score, glutathione level, and adverse events.<br><br>RESULTS: Nine randomized controlled trials were included in the meta-analysis. There were 1061 patients in the NAC group and 1076 patients in the placebo group. The current meta-analysis provides evidence that the number of patients with no acute exacerbations (965 patients receiving NAC therapy, 979 control group patients), change in FEV1 (433 patients receiving NAC therapy, 447 control group patients), change in FVC (177 patients receiving NAC therapy, 180 control group patients), change in St George's Respiratory Questionnaire score (128 patients receiving NAC therapy, 131 control group patients), change in glutathione levels (38 patients receiving NAC therapy, 40 control group patients), and adverse events (832 patients receiving NAC therapy, 846 control group patients) were not significantly different between the two groups.<br><br>CONCLUSION: NAC did not reduce the risk of acute exacerbation or ameliorate the decline in lung volume in chronic obstructive pulmonary disease patients.},
}
@article {pmid36923901,
year = {2023},
author = {Lima, EMF and Almeida, FA and Sircili, MP and Bueris, V and Pinto, UM},
title = {N-acetylcysteine (NAC) attenuates quorum sensing regulated phenotypes in Pseudomonas aeruginosa PAO1.},
journal = {Heliyon},
volume = {9},
number = {3},
pages = {e14152},
pmid = {36923901},
issn = {2405-8440},
abstract = {The expression of many virulence genes in bacteria is regulated by quorum sensing (QS), and the inhibition of this mechanism has been intensely investigated. N-acetylcysteine (NAC) has good antibacterial activity and is able to interfere with biofilm-related respiratory infections, but little is known whether this compound has an effect on bacterial QS communication. This work aimed to evaluate the potential of NAC as a QS inhibitor (QSI) in Pseudomonas aeruginosa PAO1 through in silico and in vitro analyses, as well as in combination with the antibiotic tobramycin. Initially, a molecular docking analysis was performed between the QS regulatory proteins, LasR and RhlR, of P. aeruginosa with NAC, 3-oxo-C12-HSL, C4-HSL, and furanone C30. The NAC sub-inhibitory concentration was determined by growth curves. Then, we performed in vitro tests using the QS reporter strains P. aeruginosa lasB-gfp and rhlA-gfp, as well as the expression of QS-related phenotypes. Finally, the synergistic effect of NAC with the antibiotic tobramycin was calculated by fractional inhibitory concentrations index (FICi) and investigated against bacterial growth, pigment production, and biofilm formation. In the molecular docking study, NAC bound to LasR and RhlR proteins in a similar manner to the AHL cognate, suggesting that it may be able to bind to QS receptor proteins in vivo. In the biosensor assay, the GFP signal was turned down in the presence of NAC at 1000, 500, 250, and 125 μM for lasB-gfp and rhlA-gfp (p < 0.05), suggesting a QS inhibitory effect. Pyocyanin and rhamnolipids decreased (p < 0.05) up to 34 and 37%, respectively, in the presence of NAC at 125 μM. Swarming and swimming motilities were inhibited (p < 0.05) by NAC at 250 to 10000 μM. Additionally, 2500 and 10000 μM of NAC reduced biofilm formation. NAC-tobramycin combination showed synergistic effect with FICi of 0.8, and the best combination was 2500-1.07 μM, inhibiting biofilm formation up to 60%, besides reducing pyocyanin and pyoverdine production. Confocal microscopy images revealed a stronger, dense, and compact biofilm of P. aeruginosa PAO1 control, while the biofilm treated with NAC-tobramycin became thinner and more dispersed. Overall, NAC at low concentrations showed promising anti-QS properties against P. aeruginosa PAO1, adding to its already known effect as an antibacterial and antibiofilm agent.},
}
@article {pmid36923240,
year = {2023},
author = {Zhai, T and Zhang, J and Zhang, J and Liu, B and Zhou, Z and Liu, F and Wu, Y},
title = {Cathelicidin promotes liver repair after acetaminophen-induced liver injury in mice.},
journal = {JHEP reports : innovation in hepatology},
volume = {5},
number = {4},
pages = {100687},
pmid = {36923240},
issn = {2589-5559},
abstract = {BACKGROUND &amp; AIMS: Acetaminophen (APAP)-induced acute liver injury (AILI) is a leading cause of acute liver failure (ALF). N-acetylcysteine (NAC) is only effective within 24 h after APAP intoxication, raising an urgent need for alternative approaches to treat this disease. This study aimed to test whether cathelicidin (Camp), which is a protective factor in chronic liver diseases, protects mice against APAP-induced liver injury and ALF.<br><br>METHODS: A clinically relevant AILI model and an APAP-induced ALF model were generated in mice. Genetic and pharmacological approaches were used to interfere with the levels of cathelicidin in&#xa0;vivo.<br><br>RESULTS: An increase in hepatic pro-CRAMP/CRAMP (the precursor and mature forms of mouse cathelicidin) was observed in APAP-intoxicated mice. Upregulated cathelicidin was derived from liver-infiltrating neutrophils. Compared with wild-type littermates, Camp knockout had no effect on hepatic injury but dampened hepatic repair in AILI and reduced survival in APAP-induced ALF. CRAMP administration reversed impaired liver recovery observed in APAP-challenged Camp knockout mice. Delayed CRAMP, CRAMP(1-39) (the extended form of CRAMP), or LL-37 (the mature form of human cathelicidin) treatment exhibited a therapeutic benefit for AILI. Co-treatment of cathelicidin and NAC in AILI displayed a stronger hepatoprotective effect than NAC alone. A similar additive effect of CRAMP(1-39)/LL-37 and NAC was observed in APAP-induced ALF. The pro-reparative role of cathelicidin in the APAP-damaged liver was attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced neutrophil phagocytosis of necrotic cell debris in an autocrine manner.<br><br>CONCLUSIONS: Cathelicidin reduces APAP-induced liver injury and ALF in mice by promoting liver recovery via facilitating inflammation resolution, suggesting a therapeutic potential for late-presenting patients with AILI with or without ALF.<br><br>IMPACT AND IMPLICATIONS: Acetaminophen-induced acute liver injury is a leading cause of acute liver failure. The efficacy of N-acetylcysteine, the only clinically approved drug against acetaminophen-induced acute liver injury, is significantly reduced for late-presenting patients. We found that cathelicidin exhibits a great therapeutic potential in mice with acetaminophen-induced liver injury or acute liver failure, which makes up for the limitation of N-acetylcysteine therapy by specifically promoting liver repair after acetaminophen intoxication. The pro-reparative role of cathelicidin, as a key effector molecule of neutrophils, in the APAP-injured liver is attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced phagocytic function of neutrophils in an autocrine manner.},
}
@article {pmid36922946,
year = {2023},
author = {El Khoury, R and Ramirez, SP and Loyola, CD and Joddar, B},
title = {Demonstration of doxorubicin's cardiotoxicity and screening using a 3D bioprinted spheroidal droplet-based system.},
journal = {RSC advances},
volume = {13},
number = {12},
pages = {8338-8351},
pmid = {36922946},
issn = {2046-2069},
support = {G12 MD007592/MD/NIMHD NIH HHS/United States ; SC1 HL154511/HL/NHLBI NIH HHS/United States ; },
abstract = {Doxorubicin (DOX) is a highly effective anthracycline chemotherapy agent effective in treating a broad range of life-threatening malignancies but it causes cardiotoxicity in many subjects. While the mechanism of its cardiotoxic effects remains elusive, DOX-related cardiotoxicity can lead to heart failure in patients. In this study, we investigated the effects of DOX-induced cardiotoxicity on human cardiomyocytes (CMs) using a three-dimensional (3D) bioprinted cardiac spheroidal droplet based-system in comparison with the traditional two-dimensional cell (2D) culture model. The effects of DOX were alleviated with the addition of N-acetylcysteine (NAC) and Tiron. Caspase-3 activity was quantified, and reactive oxygen species (ROS) production was measured using dihydroethidium (DHE) staining. Application of varying concentrations of DOX (0.4 μM-1 μM) to CMs revealed a dose-specific response, with 1 μM concentration imposing maximum cytotoxicity and 0.22 ± 0.11% of viable cells in 3D samples versus 1.02 ± 0.28% viable cells in 2D cultures, after 5 days of culture. Moreover, a flow cytometric analysis study was conducted to study CMs proliferation in the presence of DOX and antioxidants. Our data support the use of a 3D bioprinted cardiac spheroidal droplet as a robust and high-throughput screening model for drug toxicity. In the future, this 3D spheroidal droplet model can be adopted as a human-derived tissue-engineered equivalent to address challenges in other various aspects of biomedical pre-clinical research.},
}
@article {pmid36917985,
year = {2023},
author = {Duan, J and Matute, JD and Unger, LW and Hanley, T and Schnell, A and Lin, X and Krupka, N and Griebel, P and Lambden, C and Sit, B and Grootjans, J and Pyzik, M and Sommer, F and Kaiser, S and Falk-Paulsen, M and Grasberger, H and Kao, JY and Fuhrer, T and Li, H and Paik, D and Lee, Y and Refetoff, S and Glickman, JN and Paton, AW and Bry, L and Paton, JC and Sauer, U and Macpherson, AJ and Rosenstiel, P and Kuchroo, VK and Waldor, MK and Huh, JR and Kaser, A and Blumberg, RS},
title = {Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.},
journal = {Immunity},
volume = {56},
number = {5},
pages = {1115-1131.e9},
pmid = {36917985},
issn = {1097-4180},
support = {R37 DK044319/DK/NIDDK NIH HHS/United States ; R01 DK088199/DK/NIDDK NIH HHS/United States ; R01 DK051362/DK/NIDDK NIH HHS/United States ; R01 DK053056/DK/NIDDK NIH HHS/United States ; R01 AI169075/AI/NIAID NIH HHS/United States ; 106260/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; R01 DK117565/DK/NIDDK NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; 222497/Z/21/Z/WT_/Wellcome Trust/United Kingdom ; R01 DK044319/DK/NIDDK NIH HHS/United States ; R01 DK015070/DK/NIDDK NIH HHS/United States ; R01 AI042347/AI/NIAID NIH HHS/United States ; R37 DK015070/DK/NIDDK NIH HHS/United States ; R01 DK110559/DK/NIDDK NIH HHS/United States ; K12 HD000850/HD/NICHD NIH HHS/United States ; P30 DK034854/DK/NIDDK NIH HHS/United States ; R56 DK053056/DK/NIDDK NIH HHS/United States ; P30 DK020595/DK/NIDDK NIH HHS/United States ; },
mesh = {*Endoplasmic Reticulum Stress/drug effects ; *Intestinal Mucosa/drug effects/metabolism ; *Th17 Cells/cytology/metabolism ; Cell Differentiation ; Humans ; Animals ; Mice ; Mice, Transgenic ; Anti-Bacterial Agents/pharmacology ; Purines ; },
abstract = {Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.},
}
@article {pmid36916401,
year = {2023},
author = {Lin, YP and Hseu, YC and Thiyagarajan, V and Vadivalagan, C and Pandey, S and Lin, KY and Hsu, YT and Liao, JW and Lee, CC and Yang, HL},
title = {The in vitro and in vivo anticancer activities of Antrodia salmonea through inhibition of metastasis and induction of ROS-mediated apoptotic and autophagic cell death in human glioblastoma cells.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {158},
number = {},
pages = {114178},
doi = {10.1016/j.biopha.2022.114178},
pmid = {36916401},
issn = {1950-6007},
mesh = {Polyporales ; Phosphatidylinositol 3-Kinases/metabolism ; Autophagy ; *Glioblastoma/drug therapy ; Apoptosis ; *Autophagic Cell Death ; Mice ; Animals ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Annexin A5 ; Humans ; Mice, Nude ; },
abstract = {BACKGROUND: Antrodia salmonea (AS) exhibits anticancer activities against various cancers.<br><br>OBJECTIVE: This study investigated the anticancer activities of AS on human glioblastoma (GBM8401 and U87MG) cells both in vitro and in vivo and explained the underlying molecular mechanism.<br><br>METHODS: MTT, colony formation, migration/invasion assay, immunoblotting, immunofluorescence, TUNEL, Annexin V/PI staining, AO staining, GFP-LC3 transfection, TEM, qPCR, siLC3, DCFH2-DA assay, and xenografted-nude mice were used to assess the potential of AS therapy.<br><br>RESULTS: AS treatment retarded growth and suppressed colony formation in glioblastoma cells. AS attenuates EMT by suppressing invasion and migration, increasing E-cadherin expression, decreasing Twist, Snail, and N-cadherin expression, and inhibiting Wnt/&#x3b2;-catenin pathways in GBM8401 and U87MG cells. Furthermore, AS induced apoptosis by activating caspase-3, cleaving PARP, and dysregulating Bax and Bcl-2 in both cell lines. TUNEL assay and Annexin V/PI staining indicated AS-mediated late apoptosis. Interestingly, AS induced autophagic cell death by LC3-II accumulation, AVO formation, autophagosome GFP-LC3 puncta, p62/SQSTM1 expression, and ATG4B inhibition in GBM8401 and U87MG cells. TEM data revealed that AS favored autophagosome and autolysosome formation. The autophagy inhibitors 3-MA/CQ and LC3 knockdown suppressed AS-induced apoptosis in glioblastoma cells, indicating that the inhibition of autophagy decreased AS-induced apoptosis. Notably, the antioxidant N-acetylcysteine (NAC) inhibited AS-mediated ROS production and AS-induced apoptotic and autophagic cell death. Furthermore, AS induced ROS-mediated inhibition of the PI3K/AKT/mTOR signaling pathway. AS reduced the tumor burden in GBM8401-xenografted nude mice and significantly modulated tumor xenografts by inducing anti-EMT, apoptosis, and autophagy. AS could be a potential antitumor agent in human glioblastoma treatment.},
}
@article {pmid36916093,
year = {2023},
author = {Zhou, Z and Zhang, H},
title = {CHAC1 exacerbates LPS-induced ferroptosis and apoptosis in HK-2 cells by promoting oxidative stress.},
journal = {Allergologia et immunopathologia},
volume = {51},
number = {2},
pages = {99-110},
pmid = {36916093},
issn = {1578-1267},
mesh = {Animals ; Humans ; Mice ; *Acute Kidney Injury/chemically induced ; Apoptosis ; Caspase 3/metabolism/pharmacology ; *Ferroptosis ; Lipopolysaccharides/adverse effects ; Oxidative Stress ; Poly(ADP-ribose) Polymerase Inhibitors/adverse effects ; *Sepsis/metabolism ; gamma-Glutamylcyclotransferase ; },
abstract = {BACKGROUND: Sepsis-induced acute kidney injury (AKI) is a singularly grievous and life-threatening syndrome. Its pathogenesis is closely related to inflammatory response, apoptosis, oxidative stress, and ferroptosis. Cation transport regulator-like protein 1 (CHAC1), as a proapoptic factor, may be involved in apoptosis, oxidative stress, and ferroptosis. This study aimed to explore the role of CHAC1 in the lipopolysaccharide (LPS)-induced the human renal proximal tubular epithelial (HK-2) cells.<br><br>METHODS: HK-2 cells were challenged with LPS to construct a model of sepsis-induced AKI in vitro. The role of CHAC1 in the LPS-induced HK-2 cells was explored using Western blot assay, cell counting kit-8 (CCK-8), flow cytometry, and colorimetric assays. Additionally, N-acetyl cysteine (NAC) was incubated with HK-2 cells to define deeply the relation between oxidative stress and apoptosis or ferroptosis.<br><br>RESULTS: The expression of CHAC1 was enhanced in the kidney tissues of mice with sepsis--induced multiple organ dysfunction syndrome (MODS), through the Gene Expression Omnibus database (GSE60088 microarray dataset), and in the LPS-induced HK-2 cells. The cell viability was significantly reduced by LPS treatment, which was at least partly restored by the transfection of siCHAC1#1 and siCHAC1#2 but not siNC. In addition, down-regulation of CHAC1 counteracted the LPS-induced reactive oxygen species level and malonaldehyde concentrations while restored the LPS-induced glutathione concentrations. Meanwhile, interference of CHAC1 neutralized LPS-induced apoptosis rate, and the relative level of cleaved poly(ADP-ribose) polymerase (PARP)/PARP, and cleaved caspase-3/caspase-3. In addition, silencing of CHAC1 recovered the LPS-induced enhanced protein level of glutathione peroxidase 4 (GPx4) whereas antagonized the LPS-induced relative protein level of ACSL4 and that of iron. Moreover, application of NAC inverted the effect of CHAC1 on apoptosis and ferroptosis in HK-2 cells.<br><br>CONCLUSION: CHAC1 exacerbated ferroptosis and apoptosis by enhancing oxidative stress in LPS-induced HK-2 cells.},
}
@article {pmid36915477,
year = {2023},
author = {Jin, S and Yoon, SJ and Jung, NY and Lee, WS and Jeong, J and Park, YJ and Kim, W and Oh, DB and Seo, J},
title = {Antioxidants prevent particulate matter-induced senescence of lung fibroblasts.},
journal = {Heliyon},
volume = {9},
number = {3},
pages = {e14179},
pmid = {36915477},
issn = {2405-8440},
abstract = {Particulate matter (PM) contributes to human diseases, particularly lung disease; however, the molecular mechanism of its action is yet to be determined. Herein, we found that prolonged PM exposure induced the cellular senescence of normal lung fibroblasts via a DNA damage-mediated response. This PM-induced senescence (PM-IS) was only observed in lung fibroblasts but not in A549 lung adenocarcinoma cells. Mechanistic analysis revealed that reactive oxygen species (ROS) activate the DNA damage response signaling axis, increasing p53 phosphorylation, ultimately leading to cellular senescence via an increase in p21 expression without affecting the p16-pRB pathway. A549 cells, instead, were resistant to PM-IS due to the PM-induced ROS production suppression. Water-soluble antioxidants, such as vitamin C and N-Acetyl Cysteine, were found to alleviate PM-IS by suppressing ROS production, implying that antioxidants are a promising therapeutic intervention for PM-mediated lung pathogenesis.},
}
@article {pmid36914351,
year = {2023},
author = {Song, WJ and Liu, PP and Meng, ZQ and Jie Ding, S and Xia Li, H},
title = {N-acetylcysteine promotes the proliferation of porcine adipose-derived stem cells during in vitro long-term expansion for cultured meat production.},
journal = {Food research international (Ottawa, Ont.)},
volume = {166},
number = {},
pages = {112606},
doi = {10.1016/j.foodres.2023.112606},
pmid = {36914351},
issn = {1873-7145},
mesh = {Animals ; Swine ; *Adipose Tissue/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Stem Cells/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Cell Proliferation ; },
abstract = {Cultured meat is an efficient, safe and sustainable meat production technology. Adipose-derived stem cell (ADSC) is a promising cell type for cultured meat. In vitro, obtaining numerous of ADSCs is a pivotal step for cultured meat. In this research, we demonstrated that the proliferation and adipogenic differentiation of ADSCs significantly decreased during serial passage. Then, senescence β-galactosidase (SA-β-gal) staining showed that the positive rate of P9 ADSCs was 7.74-fold than P3 ADSCs. Subsequently, RNA sequencing (RNA-seq) was performed for P3 and P9 ADSCs and found that PI3K-AKT pathway was up-regulated, but cell cycle and DNA repair pathway were down-regulated in P9 ADSCs. Then, N-Acetylcysteine (NAC) was added during long-term expansion and showed that NAC enhanced the ADSCs proliferation and maintained adipogenic differentiation. Finally, RNA-seq was performed for P9 ADSCs cultured with or without NAC and showed that NAC restored the cell cycle and DNA repair pathway in P9 ADSCs. These results highlighted that NAC was an excellent supplement for large-scale expansion of porcine ADSCs for cultured meat.},
}
@article {pmid36913130,
year = {2023},
author = {Arteaga-Henríquez, G and Gisbert, L and Ramos-Quiroga, JA},
title = {Immunoregulatory and/or Anti-inflammatory Agents for the Management of Core and Associated Symptoms in Individuals with Autism Spectrum Disorder: A Narrative Review of Randomized, Placebo-Controlled Trials.},
journal = {CNS drugs},
volume = {37},
number = {3},
pages = {215-229},
pmid = {36913130},
issn = {1179-1934},
mesh = {Humans ; Acetylcysteine/therapeutic use ; *Anti-Inflammatory Agents/therapeutic use ; *Autism Spectrum Disorder/drug therapy ; Celecoxib/therapeutic use ; *Fatty Acids, Omega-3/therapeutic use ; Minocycline/therapeutic use ; Prednisolone/therapeutic use ; Randomized Controlled Trials as Topic ; *Immunologic Factors/therapeutic use ; },
abstract = {Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a so far poorly understood underlying pathogenesis, and few effective therapies for core symptoms. Accumulating evidence supports an association between ASD and immune/inflammatory processes, arising as a possible pathway for new drug intervention. However, current literature on the efficacy of immunoregulatory/anti-inflammatory interventions on ASD symptoms is still limited. The aim of this narrative review was to summarize and discuss the latest evidence on the use of immunoregulatory and/or anti-inflammatory agents for the management of this condition. During the last 10 years, several randomized, placebo-controlled trials on the effectiveness of (add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, N-acetylcysteine (NAC), sulforaphane (SFN), and/or omega-3 fatty acids have been performed. Overall, a beneficial effect of prednisolone, pregnenolone, celecoxib, and/or omega-3 fatty acids on several core symptoms, such as stereotyped behavior, was found. (Add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, NAC, SFN, and/or omega-3 fatty acids was also associated with a significantly higher improvement in other symptoms, such as irritability, hyperactivity, and/or lethargy when compared with placebo. The mechanisms by which these agents exert their action and improve symptoms of ASD are not fully understood. Interestingly, studies have suggested that all these agents may suppress microglial/monocyte proinflammatory activation and also restore several immune cell imbalances (e.g., T regulatory/T helper-17 cell imbalances), decreasing the levels of proinflammatory cytokines, such as interleukin (IL)-6 and/or IL-17A, both in the blood and in the brain of individuals with ASD. Although encouraging, the performance of larger randomized placebo-controlled trials, including more homogeneous populations, dosages, and longer periods of follow-up, are urgently needed in order to confirm the findings and to provide stronger evidence.},
}
@article {pmid36912486,
year = {2023},
author = {Tashiro, M and Konishi, M and Watanabe, M and Yokoyama, U},
title = {Reduction of intracellular Mg[2+] caused by reactive oxygen species in rat ventricular myocytes.},
journal = {American journal of physiology. Cell physiology},
volume = {324},
number = {4},
pages = {C963-C969},
doi = {10.1152/ajpcell.00490.2022},
pmid = {36912486},
issn = {1522-1563},
mesh = {Rats ; Animals ; *Myocytes, Cardiac/metabolism ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; *Hydrogen Peroxide/metabolism ; Biological Transport ; Ions/metabolism ; Calcium/metabolism ; },
abstract = {The concentration of intracellular free Mg[2+] ([Mg[2+]]i) should be maintained strictly for the regulation of cellular functions. Since reactive oxygen species (ROS) are liable to increase in various pathological conditions and induce cellular damage, we investigated whether ROS affect intracellular Mg[2+] homeostasis. We measured [Mg[2+]]i in ventricular myocytes from Wistar rats using the fluorescent indicator, mag-fura-2. The administration of hydrogen peroxide (H2O2) decreased [Mg[2+]]i in Ca[2+]-free Tyrode's solution. Intracellular free Mg[2+] was also reduced by endogenous ROS as generated by pyocyanin, which was inhibited by pretreatment with n-acetyl cysteine (NAC). The rate of change in [Mg[2+]]i by 500 μM H2O2 in 5 min (on average, -0.61 μM/s) was independent of extracellular Na[+], and intra- and extracellular Mg[2+] concentrations. When extracellular Ca[2+] was present, the rate of Mg[2+] decrease was significantly reduced, on average, by ∼60%. The half-maximal effective concentration of H2O2 on the Mg[2+] decrease was estimated to be between 400 and 425 μM. The Mg[2+] decrease by H2O2 in the absence of Na[+] was inhibited by 200 μM imipramine, a known inhibitor of Na[+]/Mg[2+] exchange. We perfused rat hearts with the Ca[2+]-free Tyrode's solution containing H2O2 (500 μM, 5 min) on the Langendorff apparatus,. H2O2 stimulation increased Mg[2+] concentration in the perfusate, suggesting the H2O2-induced decrease in [Mg[2+]]i was caused by Mg[2+] extrusion. Collectively, these results suggest the existence of a Na[+]-independent Mg[2+] efflux system activated by ROS in cardiomyocytes. The lower [Mg[2+]]i may in part be attributed to ROS-mediated cardiac dysfunction.},
}
@article {pmid36907467,
year = {2023},
author = {Wang, Y and Singh, A and Li, G and Yue, S and Hertel, K and Wang, ZJ},
title = {Opioid induces increased DNA damage in prefrontal cortex and nucleus accumbens.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {224},
number = {},
pages = {173535},
pmid = {36907467},
issn = {1873-5177},
support = {DP1 DA056804/DA/NIDA NIH HHS/United States ; K01 DA050908/DA/NIDA NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; },
mesh = {Mice ; Animals ; *Analgesics, Opioid ; *Heroin/pharmacology ; Nucleus Accumbens ; Prefrontal Cortex ; Recurrence ; Self Administration ; },
abstract = {Opioid use disorder (OUD) is a chronic disease characterized by compulsive opioid taking and seeking, affecting millions of people worldwide. The high relapse rate is one of the biggest challenges in treating opioid addiction. However, the cellular and molecular mechanisms underlying relapse to opioid seeking are still unclear. Recent studies have shown that DNA damage and repair processes are implicated in a broad spectrum of neurodegenerative diseases as well as in substance use disorders. In the present study, we hypothesized that DNA damage is related to relapse to heroin seeking. To test our hypothesis, we aim to examine the overall DNA damage level in prefrontal cortex (PFC) and nucleus accumbens (NAc) after heroin exposure, as well as whether manipulating DNA damage levels can alter heroin seeking. First, we observed increased DNA damage in postmortem PFC and NAc tissues from OUD individuals compared to healthy controls. Next, we found significantly increased levels of DNA damage in the dorsomedial PFC (dmPFC) and NAc from mice that underwent heroin self-administration. Moreover, increased accumulation of DNA damage persisted after prolonged abstinence in mouse dmPFC, but not in NAc. This persistent DNA damage was ameliorated by the treatment of reactive oxygen species (ROS) scavenger N-acetylcysteine, along with attenuated heroin-seeking behavior. Furthermore, intra-PFC infusions of topotecan and etoposide during abstinence, which trigger DNA single-strand breaks and double-strand breaks respectively, potentiated heroin-seeking behavior. These findings provide direct evidence that OUD is associated with the accumulation of DNA damage in the brain (especially in the PFC), which may lead to opioid relapse.},
}
@article {pmid36901935,
year = {2023},
author = {Hsieh, MJ and Ho, HY and Lo, YS and Lin, CC and Chuang, YC and Abomughaid, MM and Hsieh, MC and Chen, MK},
title = {Semilicoisoflavone B Induces Apoptosis of Oral Cancer Cells by Inducing ROS Production and Downregulating MAPK and Ras/Raf/MEK Signaling.},
journal = {International journal of molecular sciences},
volume = {24},
number = {5},
pages = {},
pmid = {36901935},
issn = {1422-0067},
mesh = {Humans ; Apoptosis/drug effects ; *Carcinoma, Squamous Cell/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Mitogen-Activated Protein Kinase Kinases ; *Mouth Neoplasms/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Mitogen-Activated Protein Kinases/drug effects/metabolism ; ras Proteins/drug effects/metabolism ; Proto-Oncogene Proteins c-raf/drug effects/metabolism ; Flavonoids ; },
abstract = {Oral squamous cell carcinoma (OSCC) is the sixth most common type of cancer worldwide. Despite advancement in treatment, advanced-stage OSCC is associated with poor prognosis and high mortality. The present study aimed to investigate the anticancer activities of semilicoisoflavone B (SFB), which is a natural phenolic compound isolated from Glycyrrhiza species. The results revealed that SFB reduces OSCC cell viability by targeting cell cycle and apoptosis. The compound caused cell cycle arrest at the G2/M phase and downregulated the expressions of cell cycle regulators including cyclin A and cyclin-dependent kinase (CDK) 2, 6, and 4. Moreover, SFB induced apoptosis by activating poly-ADP-ribose polymerase (PARP) and caspases 3, 8, and 9. It increased the expressions of pro-apoptotic proteins Bax and Bak, reduced the expressions of anti-apoptotic proteins Bcl-2 and Bcl-xL, and increased the expressions of the death receptor pathway protein Fas cell surface death receptor (FAS), Fas-associated death domain protein (FADD), and TNFR1-associated death domain protein (TRADD). SFB was found to mediate oral cancer cell apoptosis by increasing reactive oxygen species (ROS) production. The treatment of the cells with N-acetyl cysteine (NAC) caused a reduction in pro-apoptotic potential of SFB. Regarding upstream signaling, SFB reduced the phosphorylation of AKT, ERK1/2, p38, and JNK1/2 and suppressed the activation of Ras, Raf, and MEK. The human apoptosis array conducted in the study identified that SFB downregulated survivin expression to induce oral cancer cell apoptosis. Taken together, the study identifies SFB as a potent anticancer agent that might be used clinically to manage human OSCC.},
}
@article {pmid36891481,
year = {2023},
author = {Schechter, J and Brown, GW and Janda, M},
title = {A preliminary evaluation of N-acetylcysteine's effects on patient adherence to treatment for cocaine use disorder.},
journal = {The mental health clinician},
volume = {13},
number = {1},
pages = {4-10},
pmid = {36891481},
issn = {2168-9709},
abstract = {INTRODUCTION: Cocaine use disorder (CUD) is a disabling disease associated with high rates of relapse and intense cravings. Patients with CUD struggle to adhere to treatment, which contributes to relapse and frequent readmissions to residential rehab (RR) facilities. Preliminary studies suggest that N-acetylcysteine (NAC) attenuates cocaine-induced neuroplasticity and, therefore, may assist with cocaine abstinence and adherence to treatment.<br><br>METHODS: This retrospective cohort study obtained data from 20 RR facilities across Western New York. Eligible subjects were 18 or older, diagnosed with CUD, and were divided based on their exposure to 1200 mg NAC twice daily during RR. The primary outcome was treatment adherence measured by outpatient treatment attendance rates (OTA). Secondary outcomes included length of stay (LOS) in RR and craving severity on a 1 to 100 visual analog scale.<br><br>RESULTS: One hundred eighty-eight (N = 188) patients were included in this investigation: NAC, n = 90; control, n = 98. NAC did not significantly impact OTA (% appointments attended), NAC 68%; control 69%, (P = .89) or craving severity NAC 34 &#xb1; 26; control 30 &#xb1; 27, (P = .38). Subjects treated with NAC had a significantly longer average LOS in RR compared with controls, NAC 86 &#xb1; 30; control 78 &#xb1; 26, (P = .04).<br><br>DISCUSSION: In this study, NAC did not impact treatment adherence but was associated with a significantly longer LOS in RR for patients with CUD. Owing to limitations, these results may not be applicable to the general population. More rigorous studies examining NAC's impact on treatment adherence in CUD are warranted.},
}
@article {pmid36880836,
year = {2023},
author = {Tang, Y and Zhang, Z and Liu, S and Yao, Y and Pan, T and Qi, J and Kang, H and Liu, Y and Cai, C and Zhou, M and He, X and Hu, X and Ma, X and Wu, D and Han, Y},
title = {Conditioning therapy with N-acetyl-L-cysteine, decitabine and modified BUCY regimen for myeloid malignancies patients prior to allogeneic hematopoietic stem cell transplantation.},
journal = {American journal of hematology},
volume = {98},
number = {6},
pages = {881-889},
doi = {10.1002/ajh.26903},
pmid = {36880836},
issn = {1096-8652},
mesh = {Humans ; Decitabine ; Acetylcysteine/therapeutic use ; Busulfan ; Prospective Studies ; Reactive Oxygen Species ; *Myeloproliferative Disorders/complications ; *Hematopoietic Stem Cell Transplantation/methods ; Behavior Therapy ; *Neoplasms/complications ; Transplantation Conditioning/adverse effects ; *Leukemia, Myeloid, Acute/therapy ; *Graft vs Host Disease/etiology ; },
abstract = {Conditioning therapy is an essential procedure prior to hematopoietic stem cell transplant (HSCT), imposing a great impact on the outcomes of recipients. We performed a prospective randomized controlled trial to assess the outcome of HSCT recipients with myeloid malignancies after receiving the conditioning therapy consisting of modified BUCY (mBUCY), N-acetyl-L-cysteine (NAC), and decitabine. Enrolled patients were randomly allocated to either Arm A (decitabine, day -12 to -10; NAC, day -9 to +30; mBUCY, day -9 to -2), or Arm B (mBUCY regimen followed by stem cells infusion). Seventy-six patients in Arm A and 78 patients in Arm B were finally evaluated. The results showed platelet recovery accelerate in Arm A, with more patients achieving a platelet count of ≥50 × 10[9] /L than Arm B at day +30 and +60 (p = .004 and .043, respectively). The cumulative incidence of relapse is 11.8% (95% CI 0.06-0.22) in Arm A, and 24.4% (95% CI 0.16-0.35) in Arm B (p = .048). The estimated 3-year overall survival rate was 86.4% (±4.4%) and 79.9% (±4.7%) in 2 arms, respectively (p = .155). EFS at 3 years was 79.2% (±4.9%) in Arm A and 60.0% (±5.9%) in Arm B (p = .007). Intracellular reactive oxygen species (ROS) level was found to be reversely correlated with platelet recovery, and fewer patients in Arm A displayed excessive ROS within hematopoietic progenitor cells compared to Arm B. In conclusion, the addition of decitabine and NAC to mBUCY is a feasible and promising conditioning therapy for myeloid malignancies patients.},
}
@article {pmid36880428,
year = {2023},
author = {Shen, J and Kom, MC and Huang, H and Fu, G and Xie, Y and Gao, Y and Tang, Y and Yan, J and Jin, L},
title = {Role of NF-κB signaling pathway in hexavalent chromium-induced hepatotoxicity.},
journal = {Environmental toxicology},
volume = {38},
number = {6},
pages = {1361-1371},
doi = {10.1002/tox.23769},
pmid = {36880428},
issn = {1522-7278},
support = {SXAB202015//Open Fund of Shaoxing Academy of Biomedicine of Zhejiang Sci-Tech University/ ; 2018C37105//Zhejiang Province Science and Technology Project of China/ ; },
mesh = {Mice ; Humans ; Animals ; *NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Signal Transduction ; Chromium/toxicity ; Acetylcysteine/pharmacology ; *Chemical and Drug Induced Liver Injury ; },
abstract = {Hexavalent chromium Cr (VI) is a primary human carcinogen with damaging toxic effects on multiple organs. Cr (VI) exposure can induce hepatotoxicity through oxidative stress, but its exact mechanism of action was still unclear. In our study, a model of acute Cr (VI) induced liver injury was established by exposing mice to different concentrations (0, 40, 80, and 160 mg/kg) of Cr (VI); RNA-seq was used to characterize changes in liver tissue transcriptome of C57BL/6 mice after exposing to 160 mg/kg Bw of Cr (VI). Changes in liver tissue structures, proteins, and genes were observed by hematoxylin and eosin (H&amp;E), western blot, immunohistochemistry and RT-PCR. After Cr (VI) exposure, abnormal liver tissue structure, hepatocyte injury, and hepatic inflammatory response were observed in mice in a dose-dependent manner. RNA-seq transcriptome results indicated that oxidative stress, apoptosis, and inflammatory response pathways were increased after Cr (VI) exposure; KEGG pathway analysis found that activation of NF-κB signaling pathway was significantly upregulated. Consistent with the RNA-seq results, immunohistochemistry showed that Cr (VI) exposure resulted in infiltrating of Kupffer cells and neutrophils, increasing expression of inflammatory factors (TNF-α, IL-6, IL-1β), and activating of NF-κB signaling pathways (p-IKKα/β and p-p65). However, ROS inhibitor, N-acetyl-L-cysteine (NAC), could reduce infiltration of Kupffer cells and neutrophils and expression of inflammatory factors. Besides, NAC could inhibit NF-κB signaling pathway activation, and alleviate Cr (VI)-induced liver tissue damage. Our findings strongly suggested that inhibition of ROS by NAC might help in the development of new strategies for Cr (VI)-associated liver fibrosis. Our findings revealed for the first time that Cr (VI) induced liver tissue damage through the inflammatory response mediated by the NF-κB signaling pathway, and inhibition of ROS by NAC might help in the development of new strategies for Cr (VI)-associated hepatotoxicity.},
}
@article {pmid36874025,
year = {2023},
author = {Tan, J and Xiang, Y and Xiong, Y and Zhang, Y and Qiao, B and Zhang, H},
title = {Crebanine induces ROS-dependent apoptosis in human hepatocellular carcinoma cells via the AKT/FoxO3a signaling pathway.},
journal = {Frontiers in pharmacology},
volume = {14},
number = {},
pages = {1069093},
pmid = {36874025},
issn = {1663-9812},
abstract = {Background: Hepatocellular carcinoma (HCC), as an aggressive cancer with a high mortality rate, needs high-efficiency and low-toxicity drug therapy. Natural products have great potential as candidate lead compounds for the development of new HCC drugs. Crebanine is an isoquinoline alkaloid derived from Stephania with various potential pharmacological effects such as anti-cancer. However, the molecular mechanism underlying crebanine-induced liver cancer cells apoptosis has not been reported. Here, we investigated the effect of crebanine on HCC and identified a potential mechanism of action. Methods: In this paper, we intend to detect the toxic effects of crebanine on hepatocellular carcinoma HepG2 cells through a series of in vitro experiments, including detecting the effects of crebanine on the proliferation of HepG2 cells using the CCK8 method and plate cloning assay, observing the growth status and morphological changes of crebanine on HepG2 cells by inverted microscopy; and using the Transwell method to determine the the effect of crebanine on the migration and invasion ability of HepG2 cells; using Hoechst 33258 assay to stain cancer cells, thus observing the effect of crebanine on the morphology of HepG2 apoptotic cells, and detecting the apoptotic state and level of HepG2 cells by flow cytometry; using ROS kit and JC-1 assay kit to detect the changes of reactive oxygen species and mitochondrial membrane potential of HepG2 The immunofluorescence assay was taken to verify whether crebanine had an effect on the expression of p-FoxO3a in cancer cells; the Wetern blot assay was also used to examine the effect of crebanine on proteins related to the mitochondrial apoptotic pathway and its effect on the regulation of the relative protein expression of AKT/FoxO3a axis; after this, NAC and AKT inhibitor LY294002 were used to cells were pretreated with NAC and AKT inhibitor LY294002, respectively, in order to further validate the inhibitory effect of crebanine. Results: It was shown that crebanine effectively inhibited the growth and capacity of HepG2 cells migration and invasion in a dose-dependent manner. Furthermore, the effect of crebanine on the morphology of HepG2 cells was observed through microscopy. Meanwhile, crebanine induced apoptosis by causing reactive oxygen species (ROS) burst and mitochondrial membrane potential (MMP) disrupt. We found that crebanine could down-regulate Bcl-2 and up-regulate Bax, cleaved-PARP, cleaved-caspase-3 and cleaved-caspase-9, but these effects were overturned by ROS inhibitor N-acetylcysteine (NAC). Crebanine also down-regulated p-AKT and p-FoxO3a, and the PI3K inhibitor LY294002 significantly enhances this effect. We also found that the expression of AKT/FoxO3a signaling pathway was ROS-dependent. As shown by Western blots, NAC could partially attenuate the inhibitory effect of crebanine on AKT and FoxO3a phosphorylation. Conclusion: Based on our results, our results suggest that crebanine, as a compound with potential anticancer activity, has significant cytotoxic effects on hepatocellular carcinoma,and it likely induces apoptosis via ROS in the mitochondrial pathway and simultaneously affects the biological function of HCC via the ROS-AKT-FoxO3a signaling axis.},
}
@article {pmid36873280,
year = {2023},
author = {Maghsadi, Z and Azadmehr, A and Moghadamnia, AA and Feizi, F and Hamidi, N},
title = {N-Acetylcysteine attenuated pulmonary fibrosis induced by bleomycin via immunomodulation responses.},
journal = {Research in pharmaceutical sciences},
volume = {18},
number = {2},
pages = {177-184},
pmid = {36873280},
issn = {1735-5362},
abstract = {BACKGROUND AND PURPOSE: Pulmonary fibrosis (PF) is a chronic and life-threatening interstitial lung disease. N-acetyl cysteine (NAC) is an antioxidant pharmaceutically available to reduce endothelial dysfunction, inflammation, and fibrosis, however, the therapeutic effect of NAC on PF has not been clearly identified. This research aimed to investigate the possible therapeutic impact of NAC on PF induced by bleomycin in the rat model.<br><br>EXPERIMENTAL APPROACH: Rats received intraperitoneal injections of NAC at 150, 300, and 600 mg/kg for 28 days before bleomycin, while the positive and negative control groups were treated with bleomycin alone and normal saline, respectively. Then, rats' lung tissues were isolated and leukocyte infiltration and also collagen deposition were evaluated using hematoxylin and eosin and Mallory trichrome stainings, respectively. In addition, the levels of IL-17, and TGF-&#x3b2; cytokines in bronchoalveolar lavage fluid and hydroxyproline in homogenized lung tissues were assayed using the ELISA method.<br><br>FINDINGS/RESULTS: Histological findings indicated that NAC decreased leukocyte infiltration, collagen deposition, and fibrosis score in the bleomycin-induced PF tissue. Moreover, NAC significantly reduced TGF-&#x3b2; and hydroxyproline levels at 300-600 mg/kg, as well as IL-17 cytokine at 600 mg/kg.<br><br>CONCLUSION AND IMPLICATIONS: NAC showed a potential anti-fibrotic effect by reducing hydroxyproline and TGF-&#x3b2; as well as an anti-inflammatory effect by decreasing IL-17 cytokine. So, it may be administered as a prophylactic or therapeutic candidate agent to attenuate PF via immunomodulatory effects. Although, future studies are suggested.},
}
@article {pmid36866174,
year = {2023},
author = {Redwan, A and Kiriaev, L and Kueh, S and Morley, JW and Houweling, P and Perry, BD and Head, SI},
title = {Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in MDX mouse dystrophic fast-twitch skeletal muscle.},
journal = {Frontiers in physiology},
volume = {14},
number = {},
pages = {1109587},
pmid = {36866174},
issn = {1664-042X},
abstract = {Introduction: It has been proposed that an increased susceptivity to oxidative stress caused by the absence of the protein dystrophin from the inner surface of the sarcolemma is a trigger of skeletal muscle necrosis in the destructive dystrophin deficient muscular dystrophies. Here we use the mdx mouse model of human Duchenne Muscular Dystrophy to test the hypothesis that adding the antioxidant NAC at 2% to drinking water for six weeks will treat the inflammatory phase of the dystrophic process and reduce pathological muscle fiber branching and splitting resulting in a reduction of mass in mdx fast-twitch EDL muscles. Methods: Animal weight and water intake was recorded during the six weeks when 2% NAC was added to the drinking water. Post NAC treatment animals were euthanised and the EDL muscles dissected out and placed in an organ bath where the muscle was attached to a force transducer to measure contractile properties and susceptibility to force loss from eccentric contractions. After the contractile measurements had been made the EDL muscle was blotted and weighed. In order to assess the degree of pathological fiber branching mdx EDL muscles were treated with collagenase to release single fibers. For counting and morphological analysis single EDL mdx skeletal muscle fibers were viewed under high magnification on an inverted microscope. Results: During the six-week treatment phase NAC reduced body weight gain in three- to nine-week-old mdx and littermate control mice without effecting fluid intake. NAC treatment also significantly reduced the mdx EDL muscle mass and abnormal fiber branching and splitting. Discussion: We propose chronic NAC treatment reduces the inflammatory response and degenerative cycles in the mdx dystrophic EDL muscles resulting in a reduction in the number of complexed branched fibers reported to be responsible for the dystrophic EDL muscle hypertrophy.},
}
@article {pmid36863618,
year = {2023},
author = {Xue, Y and Zhang, D and Wei, Y and Guo, C and Song, B and Cui, Y and Zhang, C and Xu, D and Zhang, S and Fang, J},
title = {Polymeric nano-micelle of carbon monoxide donor SMA/CORM2 ameliorates acetaminophen-induced liver injury via suppressing HMGB1/TLR4 signaling pathway.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {184},
number = {},
pages = {106413},
doi = {10.1016/j.ejps.2023.106413},
pmid = {36863618},
issn = {1879-0720},
mesh = {Animals ; Mice ; Acetaminophen ; Anti-Inflammatory Agents/pharmacology ; Carbon Monoxide/metabolism/pharmacology ; *Chemical and Drug Induced Liver Injury/metabolism ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy/metabolism/pathology ; Disease Models, Animal ; *HMGB1 Protein/metabolism ; Liver/metabolism ; Mice, Inbred C57BL ; Micelles ; Signal Transduction ; Toll-Like Receptor 4/metabolism ; Organometallic Compounds ; },
abstract = {Acetaminophen (APAP) overdose-induced hepatotoxicity is the most common cause of acute liver failure. Excessive generation of reactive oxygen species (ROS) and inflammatory responses are the major causes of necrosis and/or necroptosis of the liver cells. Currently, the treatment options for APAP-induced liver injury are very limited, N-acetylcysteine (NAC) is the only approved drug to treat APAP overdose patients. It is of great necessity to develop new therapeutic strategies. In a previous study, we focused on the anti-oxidative, anti-inflammatory signal molecule carbon monoxide (CO), and developed a nano-micelle encapsulating CO donor, i.e., SMA/CORM2. Administration of SMA/CORM2 to the mice exposed to APAP significantly ameliorated the liver injury and inflammatory process, in which modulating macrophage reprogramming plays a critical role. Along this line, in this study, we investigated the potential effect of SMA/CORM2 on toll-like receptor 4 (TLR4) and high mobility group protein B1 (HMGB1) signaling pathways that are known to be closely involved in many inflammatory responses and necroptosis. In a mouse APAP-induced liver injury model, similar to the previous study, SMA/CORM2 at 10 mg/kg remarkably improved the condition of the liver after injury as evidenced by histological examination and liver function. During the process of liver injury triggered by APAP, TLR4 expression gradually increased over time, and it was significantly upregulated as early as 4 h after APAP exposure, whereas, an increase of HMGB1 was a late-stage event. Notably, SMA/CORM2 treatment suppressed significantly both TLR4 and HMGB1, consequently inhibiting the progression of inflammation and liver injury. Compared to CORM2 without SMA modification (native CORM2) of 1 mg/kg that is equivalent to 10 mg/kg of SMA/CORM2 (the amount of CORM2 in SMA/CORM2 is 10% [w/w]), SMA/CORM2 exhibited a much better therapeutic effect, indicating its superior therapeutic efficacy to native CORM2. These findings revealed that SMA/CORM2 protects against APAP-induced liver injury via mechanisms involving the suppression of TLR4 and HMGB1 signaling pathways. Taking together the results in this study and previous studies, SMA/CORM2 exhibits great therapeutic potential for APAP overdose-induced liver injury, we thus anticipate the clinical application of SMA/CORM2 for the treatment of APAP overdose, as well as other inflammatory diseases.},
}
@article {pmid36860857,
year = {2023},
author = {Lee, SH and Han, MS and Lee, TH and Lee, DB and Park, JH and Lee, SH and Kim, TH},
title = {Hydrogen peroxide attenuates rhinovirus-induced anti-viral interferon secretion in sinonasal epithelial cells.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1086381},
pmid = {36860857},
issn = {1664-3224},
mesh = {Humans ; Antiviral Agents/pharmacology ; Hydrogen Peroxide ; Rhinovirus ; *Nasal Polyps ; Toll-Like Receptor 3 ; Epithelial Cells ; Acetylcysteine/pharmacology ; *Interferon Type I ; Antioxidants ; },
abstract = {BACKGROUND: Altered innate defense mechanisms, including an imbalance between oxidants and antioxidants release, have been implicated in the pathogenesis of chronic rhinosinusitis (CRS). The aim of this study is to investigate whether oxidative stress may attenuate the secretion of anti-viral interferons in human sinonasal mucosa.<br><br>METHODS: The levels of H2O2 in nasal secretion were increased in patients with CRS with nasal polyps, compared with that of CRS patients without nasal polyps and control subjects. Normal sinonasal epithelial cells derived from healthy subjects were cultured under an air-liquid interface. The cultured cells were infected with rhinovirus 16 (RV 16) or treated with poly (I: C), TLR3 agonist, after being pretreated with an oxidative stressor, H2O2 or antioxidant, N-acetylcysteine (NAC). Thereafter, the expression levels of type I (IFN-&#x3b2;) and type III (IFN-&#x3bb;1 and &#x3bb;2) interferons and interferon-stimulated genes (ISGs) were evaluated with RT-qPCR, ELISA, and western blot.<br><br>RESULTS: The data showed that the production of type I (IFN-&#x3b2;) and type III (IFN-&#x3bb;1 and &#x3bb;2) interferons and ISGs was upregulated in cells infected with RV 16 or treated with poly (I: C). However, their up-regulated expression was attenuated in cells pretreated with H2O2, but not inhibited in cells pretreated with NAC. In line with these data, the up-regulated expression of TLR3, RIG-1, MDA5, and IRF3 was reduced in cells pretreated with H2O2, but not attenuated in cells treated with NAC. Furthermore, cells transfected with Nrf2 siRNA showed decreased secretion of anti-viral interferons whereas sulforaphane treatment enhanced the secretory capacity of antiviral interferons.<br><br>CONCLUSIONS: These results suggest that the production of RV16-induced antiviral interferons may be attenuated by oxidative stress.},
}
@article {pmid36860082,
year = {2023},
author = {Wei, M and Dhanasekaran, S and Ji, Q and Yang, Q and Zhang, H},
title = {Sustainable and efficient method utilizing N-acetyl-L-cysteine for complete and enhanced ochratoxin A clearance by antagonistic yeast.},
journal = {Journal of hazardous materials},
volume = {448},
number = {},
pages = {130975},
doi = {10.1016/j.jhazmat.2023.130975},
pmid = {36860082},
issn = {1873-3336},
mesh = {Humans ; *Saccharomyces cerevisiae ; Acetylcysteine ; *Mycotoxins ; Biodegradation, Environmental ; Ochratoxins ; },
abstract = {With the increasing global climate change, ochratoxin A (OTA) pollution in food and environment has become a serious and potential risk element threatening food safety and human health. Biodegradation of mycotoxin is an eco-friendly and efficient control strategy. Still, research works are warranted to develop low-cost, efficient, and sustainable approaches to enhance the mycotoxin degradation efficiency of microorganisms. In this study, the activities of N-acetyl-L-cysteine (NAC) against OTA toxicity were evidenced, and its positive effects on the OTA degradation efficiency of antagonistic yeast, Cryptococcus podzolicus Y3 were verified. Co-culturing C. podzolicus Y3 with 10 mM NAC improved 100% and 92.6% OTA degradation rate into ochratoxin α (OTα) at 1 d and 2 d. The excellent promotion role of NAC on OTA degradation was observed even at low temperatures and alkaline conditions. C. podzolicus Y3 treated with OTA or OTA+NAC promoted reduced glutathione (GSH) accumulation. GSS and GSR genes were highly expressed after OTA and OTA+NAC treatment, contributing to GSH accumulation. In the early stages of NAC treatment, yeast viability and cell membrane were reduced, but the antioxidant property of NAC prevented lipid peroxidation. Our finding provides a sustainable and efficient new strategy to improve mycotoxin degradation by antagonistic yeasts, which could be applied to mycotoxin clearance.},
}
@article {pmid36855363,
year = {2023},
author = {Concessao, PL and Bairy, KL and Raghavendra, AP},
title = {Ameliorating effect of Mucuna pruriens seed extract on sodium arsenite-induced testicular toxicity and hepato-renal histopathology in rats.},
journal = {Veterinary world},
volume = {16},
number = {1},
pages = {82-93},
pmid = {36855363},
issn = {0972-8988},
abstract = {BACKGROUND AND AIM: A significant cause of arsenic poisoning is polluted groundwater. Arsenic poisoning results in the suppression of spermatogenesis and the liver and kidneys are vulnerable to the toxic effects as well. Mucuna pruriens has been identified to have fertility-enhancing and anti-lipid peroxidation properties. Based on these properties of M. pruriens, this study aimed to investigate the efficacy of M. pruriens seed extract in reducing sodium arsenite-induced testicular impairment and hepato-renal histopathology in rats.<br><br>MATERIALS AND METHODS: The study was divided into two groups; short-term (45 days) and long-term (90 days) treatment groups and each group was divided into nine subgroups. Subgroups 1 and 2 served as normal and N-acetyl cysteine (NAC) controls, respectively. Subgroups 3-9 received sodium arsenite in the drinking water (50 mg/L). Subgroup-4 received NAC (210 mg/kg body weight [BW]) orally once daily. Subgroups 5-7 received aqueous seed extract of M. pruriens (350, 530, and 700 mg/kg BW, respectively) orally once daily. Subgroups 8 and 9 received a combination of NAC and aqueous seed extract (350 and 530 mg/kg BW, respectively) orally once daily. Following the treatment, animals were sacrificed and sperm parameters and DNA damage were evaluated. Testis, liver, and kidneys were analyzed for histopathology.<br><br>RESULTS: Sodium arsenite-induced a significant reduction in sperm parameters and increase in the abnormal architecture of spermatozoa. Histology revealed tissue necrosis. The M. pruriens seed extract ameliorated the damaging effects of sodium arsenite with respect to tissue architecture and sperm parameters when coadministered.<br><br>CONCLUSION: Mucuna pruriens has beneficial effects against the deleterious effects of sodium arsenite on various tissues. Thus, M. pruriens (530 and 700 mg/kg BW) supplementation would reduce the adverse changes observed with sodium arsenite exposure.},
}
@article {pmid36854537,
year = {2023},
author = {Musa, MA and Kolawole, Q},
title = {7,8-Diacetoxy-3-(4-methylsulfonylphenyl)-4-phenylcoumarin Induces ROS-dependent Cell Death in the A549 Human Lung Cancer Cell Line.},
journal = {Anticancer research},
volume = {43},
number = {3},
pages = {1001-1007},
doi = {10.21873/anticanres.16244},
pmid = {36854537},
issn = {1791-7530},
mesh = {Male ; Humans ; Reactive Oxygen Species ; A549 Cells ; *Lung Neoplasms/drug therapy ; Cell Death ; Coumarins/pharmacology ; Cell Line ; },
abstract = {BACKGROUND/AIM: Coumarins comprise of a very large class of naturally occurring compounds with growing interest in their synthesis and possible applications in the treatment of various diseases. We herein report the in-vitro cytotoxic activity of 3,4-Diarylcoumarins (4a-i) in A549 (lung) and PC-3 (prostate) cancer cell lines.<br><br>MATERIALS AND METHODS: The cytotoxic activity was evaluated using crystal violet dye-binding. The most active compound effect on the cell-cycle phases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production and apoptosis were also evaluated.<br><br>RESULTS: Among the synthesized compounds that were evaluated, 7,8-Diacetoxy-3-(4-(methylsulfonyl)phenyl)-4-phenylcoumrin (4f) showed highest cytotoxicity (CC50=13.5%&#xb1;0.15&#x3bc;M) in A549 cancer cell line. The mechanism of its cytotoxic action indicated significant cell arrest in G1/G0, S and G2 phases of the cell cycle, loss of mitochondrial membrane potential (MMP), increase in reactive oxygen species (ROS) production and induction of apoptotic cell death. The cell viability result of pretreated A549 cells with antioxidant N-acetylcysteine (NAC), followed by compound 4f treatment confirmed ROS-dependent cell death.<br><br>CONCLUSION: The presence of 3-4-methylsulfonyl and 7,8-diacetoxy groups on 3,4-Diarylcoumarin is critical in modulating higher cytotoxic activity and could serve as a valuable template for the development of novel synthetic compounds as potential anticancer agents for lung cancer treatment.},
}
@article {pmid36852734,
year = {2023},
author = {Akinlolu, A and Emojevwe, V and Uwejigho, R and Ilesanmi, J and Owolabi, R and Igandan, A},
title = {Neuro-protective potentials of N-acetylcysteine and zinc against di(2-ethylhexyl)-phthalate-induced neuro-histopathology and dys-regulations of Dopamine and Glutamate in rat brain.},
journal = {Journal of environmental science and health. Part A, Toxic/hazardous substances &amp; environmental engineering},
volume = {58},
number = {1},
pages = {81-90},
doi = {10.1080/10934529.2023.2177449},
pmid = {36852734},
issn = {1532-4117},
mesh = {Animals ; Rats ; Rats, Wistar ; Male ; *Diethylhexyl Phthalate/toxicity ; Dopamine/genetics ; Glutamic Acid/genetics ; *Gene Expression Regulation/drug effects ; *Acetylcysteine/pharmacology ; *Zinc/pharmacology ; *Brain/drug effects ; },
abstract = {This study examined neuro-protective potentials of N-acetyl-cysteine (NAC) and Zinc on expression levels of Dopamine and Glutamate in the Cerebrum, Hypothalami and Pituitary Glands in Di(2-ethylhexyl)-phthalate (DEHP)-induced neurotoxicity in rats. Thirty-six adult male Wistar rats were randomly divided into 6 groups (n = 6). Group 1 was control. Groups 2-6 received oral administrations of 100 mg/kg NAC, 0.5 mg/kg Zinc, 750 mg/kg DEHP, DEHP + NAC doses and DEHP + Zinc doses respectively for 21 days. Brain histology (Heamatoxyline and Eosine technique), histochemical and enzyme-linked-immunosorbent assays of Dopamine and Glutamate in homogenates of Cerebrum, Hypothalami and Pituitary Glands were evaluated. Data were statistically analyzed using One-way-ANOVA with Tukey-post-hoc test at p ≤ 0.05. Histo-pathological evaluations of Cerebrum, Hypothalami and Pituitary Glands showed gross histo-alterations and neurodegenerative changes (Group 4), mild histo- and neuro-degenerative changes (Groups 5 and 6) and normal histology (Group 1). Histochemical analyses showed higher Dopamine levels in Hypothalami (Group 5) and Pituitary Glands (Groups 5 and 6), compared with Group 4. Furthermore, results showed lower Glutamate levels in Cerebrum, Hypothalami and Pituitary Glands of Groups 5 and 6, compared with Group 4. Overall, NAC and Zinc conferred neuro-protection and histo-protection against DEHP-induced neuro-toxicity, neuro-histopathology, decreased Dopamine levels and increased Glutamate levels.},
}
@article {pmid36849104,
year = {2023},
author = {Wang, H and Banerjee, N and Wang, G and Firoze Khan, M},
title = {Autophagy dysregulation in trichloroethene-mediated inflammation and autoimmune response.},
journal = {Toxicology},
volume = {487},
number = {},
pages = {153468},
pmid = {36849104},
issn = {1879-3185},
support = {P30 ES030285/ES/NIEHS NIH HHS/United States ; R01 ES016302/ES/NIEHS NIH HHS/United States ; R01 ES026887/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Mice ; *Autoimmune Diseases/chemically induced ; Autoimmunity ; Autophagy ; Inflammation/chemically induced ; Solvents/toxicity ; *Trichloroethylene/toxicity ; },
abstract = {Trichloroethene (TCE), an organic solvent extensively used for degreasing metals, can cause inflammatory autoimmune disorders [i.e., systemic lupus erythematosus (SLE) and autoimmune hepatitis] from both environmental and occupational exposure. Autophagy has emerged as a pivotal pathogenic factor in various autoimmune diseases. However, role of autophagy dysregulation in TCE-mediated autoimmunity is largely unknown. Here, we investigate whether autophagy dysregulation contributes to pathogenesis of TCE-mediated autoimmune responses. Using our established mouse model, we observed TCE-treated mice had elevated MDA-protein adducts, microtubule-associated protein light chain 3 conversion (LC3-II/LC3-I), beclin-1, phosphorylation of AMP-activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) phosphorylation in the livers of MRL+ /+ mice. Suppression of oxidative stress with antioxidant N-acetylcysteine (NAC) effectively blocked TCE-mediated induction of autophagy markers. On the other hand, pharmacological autophagy induction with rapamycin significantly reduced TCE-mediated hepatic inflammation (NLRP3, ASC, Caspase1 and IL1-β mRNA levels), systemic cytokines (IL-12 and IL-17) and autoimmune responses (ANA and anti-dsDNA levels). Taken together, these results suggest that autophagy plays a protective role against TCE-mediated hepatic inflammation and autoimmunity in MRL+ /+ mice. These novel findings on the regulation of autophagy could help in designing therapeutic strategies for chemical exposure-mediated autoimmune responses.},
}
@article {pmid36842745,
year = {2023},
author = {Liu, YX and Yang, JY and Sun, JL and Wang, AC and Wang, XY and Zhu, LB and Cao, HH and Huang, ZH and Liu, SH and Xu, JP},
title = {Reactive oxygen species-mediated phosphorylation of JNK is involved in the regulation of BmFerHCH on Bombyx mori nucleopolyhedrovirus proliferation.},
journal = {International journal of biological macromolecules},
volume = {235},
number = {},
pages = {123834},
doi = {10.1016/j.ijbiomac.2023.123834},
pmid = {36842745},
issn = {1879-0003},
mesh = {Animals ; Phosphorylation ; *Nucleopolyhedroviruses/physiology ; Reactive Oxygen Species/metabolism ; Apoferritins/metabolism ; MAP Kinase Signaling System ; Cell Proliferation ; *Bombyx/metabolism ; Insect Proteins/metabolism ; },
abstract = {c-Jun N-terminal kinase (JNK) phosphorylation is widely observed during virus infection, modulating various aspects of the virus-host interaction. In our previous research, we have proved that B. mori ferritin heavy-chain homolog (BmFerHCH), an inhibitor of reactive oxygen species (ROS), facilitates B. mori nucleopolyhedrovirus (BmNPV) proliferation. However, one question remains: Which downstream signaling pathways does BmFerHCH regulate by inhibiting ROS? Here, we first determined that silencing BmFerHCH inhibits BmNPV proliferation, and this inhibition depends on ROS. Then, we substantiated that BmNPV infection activates the JNK signaling pathway. Interestingly, the JNK phosphorylation during BmNPV infection is activated by ROS. Further, we found that the enhanced nuclear translocation of phospho-JNK induced by BmNPV infection was dramatically reduced by pretreatment with the antioxidant N-acetylcysteine (NAC), whereas there was more detectable phospho-JNK in the cytoplasm. Next, we investigated how changes in BmFerHCH expression affect JNK phosphorylation. BmFerHCH overexpression suppressed the phosphorylation of JNK and nuclear translocation of phospho-JNK during BmNPV infection, whereas BmFerHCH knockdown facilitated phosphorylation of JNK and nuclear translocation of phospho-JNK. By measuring the viral load, we found the inhibitory effect of BmFerHCH knockdown on BmNPV infection depends on phosphorylated JNK. In addition, the JNK signaling pathway was involved in BmNPV-triggered apoptosis. Hence, we hypothesize that ROS-mediated JNK phosphorylation is involved in the regulation of BmFerHCH on BmNPV proliferation. These results elucidate the molecular mechanisms and signaling pathways of BmFerHCH-mediated response to BmNPV infection.},
}
@article {pmid36840032,
year = {2023},
author = {Kim, SH and Jung, DE and Song, JY and Jung, J and Jung, JK and Lee, H and Roh, E and Hong, JT and Han, SB and Kim, Y},
title = {Targeting IKKβ Activity to Limit Sterile Inflammation in Acetaminophen-Induced Hepatotoxicity in Mice.},
journal = {Pharmaceutics},
volume = {15},
number = {2},
pages = {},
pmid = {36840032},
issn = {1999-4923},
abstract = {The kinase activity of inhibitory κB kinase β (IKKβ) acts as a signal transducer in the activating pathway of nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death in the development of numerous hepatocellular injuries. However, the importance of IKKβ activity on acetaminophen (APAP)-induced hepatotoxicity remains to be defined. Here, a derivative of caffeic acid benzylamide (CABA) inhibited the kinase activity of IKKβ, as did IMD-0354 and sulfasalazine which show therapeutic efficacy against inflammatory diseases through a common mechanism: inhibiting IKKβ activity. To understand the importance of IKKβ activity in sterile inflammation during hepatotoxicity, C57BL/6 mice were treated with CABA, IMD-0354, or sulfasalazine after APAP overdose. These small-molecule inhibitors of IKKβ activity protected the APAP-challenged mice from necrotic injury around the centrilobular zone in the liver, and rescued the mice from hepatic damage-associated lethality. From a molecular perspective, IKKβ inhibitors directly interrupted sterile inflammation in the Kupffer cells of APAP-challenged mice, such as damage-associated molecular pattern (DAMP)-induced activation of NF-κB activity via IKKβ, and NF-κB-regulated expression of cytokines and chemokines. However, CABA did not affect the upstream pathogenic events, including oxidative stress with glutathione depletion in hepatocytes after APAP overdose. N-acetyl cysteine (NAC), the only FDA-approved antidote against APAP overdose, replenishes cellular levels of glutathione, but its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver. Taken together, we propose a novel hypothesis that chemical inhibition of IKKβ activity in sterile inflammation could mitigate APAP-induced hepatotoxicity in mice, and have the potential to complement NAC treatment in APAP overdoses.},
}
@article {pmid36836353,
year = {2023},
author = {Okamoto, M and Nakano, K and Takahashi-Nakaguchi, A and Sasamoto, K and Yamaguchi, M and Teixeira, MC and Chibana, H},
title = {In Candida glabrata, ERMES Component GEM1 Controls Mitochondrial Morphology, mtROS, and Drug Efflux Pump Expression, Resulting in Azole Susceptibility.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {9},
number = {2},
pages = {},
pmid = {36836353},
issn = {2309-608X},
abstract = {Mitochondrial dysfunction or morphological abnormalities in human pathogenic fungi are known to contribute to azole resistance; however, the underlying molecular mechanisms are unknown. In this study, we investigated the link between mitochondrial morphology and azole resistance in Candida glabrata, which is the second most common cause of human candidiasis worldwide. The ER-mitochondrial encounter structure (ERMES) complex is thought to play an important role in the mitochondrial dynamics necessary for mitochondria to maintain their function. Of the five components of the ERMES complex, deletion of GEM1 increased azole resistance. Gem1 is a GTPase that regulates the ERMES complex activity. Point mutations in GEM1 GTPase domains were sufficient to confer azole resistance. The cells lacking GEM1 displayed abnormalities in mitochondrial morphology, increased mtROS levels, and increased expression of azole drug efflux pumps encoded by CDR1 and CDR2. Interestingly, treatment with N-acetylcysteine (NAC), an antioxidant, reduced ROS production and the expression of CDR1 in Δgem1 cells. Altogether, the absence of Gem1 activity caused an increase in mitochondrial ROS concentration, leading to Pdr1-dependent upregulation of the drug efflux pump Cdr1, resulting in azole resistance.},
}
@article {pmid36835209,
year = {2023},
author = {Sakai, M and Yu, Z and Taniguchi, M and Picotin, R and Oyama, N and Stellwagen, D and Ono, C and Kikuchi, Y and Matsui, K and Nakanishi, M and Yoshii, H and Furuyashiki, T and Abe, T and Tomita, H},
title = {N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling.},
journal = {International journal of molecular sciences},
volume = {24},
number = {4},
pages = {},
pmid = {36835209},
issn = {1422-0067},
support = {20dm0107099h0005, JP19dm0107099, JP18ek0109183, JP22gm0910012, and JP22wm0425001//Ministry of Education, Culture, Sports, Science and Technology of Japan, the Strategic Research Program for Brain Sciences, and the Japan Agency for Medical Research and Development/ ; KAKENHI 21390329, 16K07210, 18H05429, 21H04812, and 19K16372//Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; No. 24116007//Grant-in-Aid for Scientific Research on Innovative Areas/ ; },
mesh = {Animals ; Humans ; Mice ; *Acetylcysteine/pharmacology ; *Inflammation/metabolism/pathology ; Lipopolysaccharides/pharmacology ; *Microglia/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; *Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {N-acetylcysteine (NAC) is an antioxidant that prevents tumor necrosis factor (TNF)-α-induced cell death, but it also acts as a pro-oxidant, promoting reactive oxygen species independent apoptosis. Although there is plausible preclinical evidence for the use of NAC in the treatment of psychiatric disorders, deleterious side effects are still of concern. Microglia, key innate immune cells in the brain, play an important role in inflammation in psychiatric disorders. This study aimed to investigate the beneficial and deleterious effects of NAC on microglia and stress-induced behavior abnormalities in mice, and its association with microglial TNF-α and nitric oxide (NO) production. The microglial cell line MG6 was stimulated by Escherichia coli lipopolysaccharide (LPS) using NAC at varying concentrations for 24 h. NAC inhibited LPS-induced TNF-α and NO synthesis, whereas high concentrations (≥30 mM) caused MG6 mortality. Intraperitoneal injections of NAC did not ameliorate stress-induced behavioral abnormalities in mice, but high-doses induced microglial mortality. Furthermore, NAC-induced mortality was alleviated in microglial TNF-α-deficient mice and human primary M2 microglia. Our findings provide ample evidence for the use of NAC as a modulating agent of inflammation in the brain. The risk of side effects from NAC on TNF-α remains unclear and merits further mechanistic investigations.},
}
@article {pmid36834536,
year = {2023},
author = {Li, F and Liu, H and Wu, X and Song, Z and Tang, H and Gong, M and Liu, L and Li, F},
title = {Tetrathiomolybdate Decreases the Expression of Alkaline Phosphatase in Dermal Papilla Cells by Increasing Mitochondrial ROS Production.},
journal = {International journal of molecular sciences},
volume = {24},
number = {4},
pages = {},
pmid = {36834536},
issn = {1422-0067},
support = {31972594//National Natural Science Foundation of China/ ; CARS-43-B-1//the earmarked fund for CARS/ ; ZR2021MC043//Natural Science Foundation of Shandong Province/ ; ZR2021QC108//Natural Science Foundation of Shandong Province/ ; SDAIT-21-16//Special Economic Animal Industry Technology System of Shandong Province/ ; 2021LZGC002//Agricultural Seed Improvement Project of Shandong Province/ ; },
mesh = {*Hair Follicle/metabolism ; *Dermis ; Cells, Cultured ; Alkaline Phosphatase/metabolism ; Reactive Oxygen Species/metabolism ; Proteomics ; Copper/metabolism ; Cell Proliferation ; Molybdenum ; },
abstract = {Dermal papilla cells (DPCs) play important roles in hair growth regulation. However, strategies to regrow hair are lacking. Here, global proteomic profiling identified the tetrathiomolybdate (TM)-mediated inactivation of copper (Cu) depletion-dependent mitochondrial cytochrome c oxidase (COX) as the primary metabolic defect in DPCs, leading to decreased Adenosine Triphosphate (ATP) production, mitochondrial membrane potential depolarization, increased total cellular reactive oxygen species (ROS) levels, and reduced expression of the key marker of hair growth in DPCs. By using several known mitochondrial inhibitors, we found that excessive ROS production was responsible for the impairment of DPC function. We therefore subsequently showed that two ROS scavengers, N-acetyl cysteine (NAC) and ascorbic acid (AA), partially prevented the TM- and ROS-mediated inhibition of alkaline phosphatase (ALP). Overall, these findings established a direct link between Cu and the key marker of DPCs, whereby copper depletion strongly impaired the key marker of hair growth in the DPCs by increasing excessive ROS production.},
}
@article {pmid36831011,
year = {2023},
author = {Li, H and Li, JJ and Lu, W and Yang, J and Xia, Y and Huang, P},
title = {Targeting Mitochondrial IDH2 Enhances Antitumor Activity of Cisplatin in Lung Cancer via ROS-Mediated Mechanism.},
journal = {Biomedicines},
volume = {11},
number = {2},
pages = {},
pmid = {36831011},
issn = {2227-9059},
support = {(No. 81902323, No. 81972595).//This work was supported in part by grants from the National Natural Science Foundation of China/ ; },
abstract = {Mitochondrial isocitrate dehydrogenase 2 (IDH2) is an important metabolic enzyme in the tricarboxylic acid cycle (TCA) cycle. Our previous study showed that high expression of wild-type IDH2 promotes the proliferation of lung cancer cells. This study aims to test the potential of targeting IDH2 as a therapeutic strategy to inhibit lung cancer in vitro and in vivo. First, we analyzed the available data from the databases gene expression omnibus (GEO) database to evaluate the clinical relevance of IDH2 expression in affecting lung cancer patient survival. We then generated a stable IDH2-knockdown lung cancer cell line using a lentivirus-based method for in vitro and in vivo study. Cell growth, apoptosis, cell viability, and colony formation assays were conducted to test the sensitivity of lung cancer cells with different IDH2 expression status to cisplatin or radiation treatment in vitro. For mechanistic study, Cellular oxygen consumption and extracellular acidification rates were measured using a Seahorse metabolic analyzer, and reactive oxygen species (ROS) generation was analyzed using flow cytometry. An animal study using a xenograft tumor model was performed to further evaluate the in vivo therapeutic effect on tumor growth. We found that high IDH2 expression was associated with poor survival in lung cancer patients undergoing chemotherapy. Inhibition of IDH2 significantly enhanced the anticancer activity of cisplatin and also increased the effect of radiation against lung cancer cells. IDH2 was upregulated in cisplatin-resistant lung cancer cells, which could be sensitized by targeted inhibition of IDH2. Mechanistic study showed that abrogation of IDH2 caused only minimal changes in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in lung cancer cells, but induced a significant increase in ROS, which rendered the cancer cells more sensitive to cisplatin. Pretreatment of lung cancer cells with the ROS scavenger N-acetyl-cysteine could partially rescue cells from the cytotoxic effect of cisplatin and IDH2 inhibition. Importantly, abrogation of IDH2 significantly increased the sensitivity of lung cancer cells to cisplatin in vivo.},
}
@article {pmid36830070,
year = {2023},
author = {Abu-Halaka, D and Shpaizer, A and Zeigerman, H and Kanner, J and Tirosh, O},
title = {DMF-Activated Nrf2 Ameliorates Palmitic Acid Toxicity While Potentiates Ferroptosis Mediated Cell Death: Protective Role of the NO-Donor S-Nitroso-N-Acetylcysteine.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {2},
pages = {},
pmid = {36830070},
issn = {2076-3921},
abstract = {Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that can develop into an aggressive form called nonalcoholic steatohepatitis (NASH), which ultimately progresses to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver failure. Currently, the deterioration of NAFLD is attributed to specific lipid toxicity which could be due to lipotoxicity and/or ferroptosis. In the current study, we evaluated the involvement of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf-2), which is a main activator of phase II metabolism in the two types of lipid-induced toxicity in hepatocytes, lipotoxicity by saturated fatty acids, and in ferroptosis, and the effect of NO donor treatment. AML12 cells were exposed to 600 μM palmitic acid to induce lipotoxicity or treated with 20 μM erastin or 5 μM RSL3 for ferroptosis. In SFA-lipotoxicity, pretreatment with the Nrf2 activator dimethyl fumarate (DMF) managed to ameliorate the cells and the oxidative stress level while aggravating ferroptosis due to emptying the thiol pool. On the other hand, the nitric oxide (NO)-donor, S-nitroso-N-acetylcysteine (NAC-SNO) proved to be effective in the prevention of hepatocytes ferroptosis.},
}
@article {pmid36830062,
year = {2023},
author = {Shakya, S and McGuffee, RM and Ford, DA},
title = {Characterization of N-Acetyl Cysteine Adducts with Exogenous and Neutrophil-Derived 2-Chlorofatty Aldehyde.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {2},
pages = {},
pmid = {36830062},
issn = {2076-3921},
support = {S10 OD025246/OD/NIH HHS/United States ; S10OD025246/NH/NIH HHS/United States ; R01 GM115553/GM/NIGMS NIH HHS/United States ; R01ES034383/NH/NIH HHS/United States ; R01 ES034383/ES/NIEHS NIH HHS/United States ; R01GM115553/NH/NIH HHS/United States ; },
abstract = {Hypochlorous acid is produced by leukocyte myeloperoxidase activity. 2-Chlorofatty aldehydes (2-ClFALDs) are formed when hypochlorous acid attacks the plasma membrane phospholipid plasmalogen molecular subclass and are thus produced following leukocyte activation as well as in the lungs of mice exposed to chlorine gas. The biological role of 2-ClFALD is largely unknown. Recently, we used an alkyne analog (2-ClHDyA) of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDA), to identify proteins covalently modified by 2-ClHDyA in endothelial cells and epithelial cells. Here, we demonstrate that 2-ClHDA reduces the metabolic activity of RAW 264.7 cells in a dose-dependent manner. 2-ClHDyA localizes to the mitochondria, endoplasmic reticulum and Golgi in RAW 264.7 cells and modifies many proteins. The thiol-containing precursor of glutathione, N-acetyl cysteine (NAC), was shown to produce an adduct with 2-ClHDA with the loss of Cl[-] (HDA-NAC). This adduct was characterized in both positive and negative ion modes using LC-MS/MS and electrospray ionization. NAC treatment of neutrophils reduced the 2-ClFALD levels in PMA-stimulated cells with subsequent increases in HDA-NAC. NAC treatments reduced the 2-ClHDA-elicited loss of metabolic activity in RAW 264.7 cells as well as 2-ClHDA protein modification. These studies demonstrate that 2-ClFALD toxic effects can be reduced by NAC, which reduces protein modification.},
}
@article {pmid36828949,
year = {2023},
author = {Dandekar, AA and Vora, D and Yeh, JS and Srivastava, RK and Athar, M and Banga, AK},
title = {Enhanced Transdermal Delivery of N-Acetylcysteine and 4-Phenylbutyric Acid for Potential Use as Antidotes to Lewisite.},
journal = {AAPS PharmSciTech},
volume = {24},
number = {3},
pages = {71},
pmid = {36828949},
issn = {1530-9932},
mesh = {*Skin Absorption ; Acetylcysteine/metabolism ; Antidotes ; Oleic Acid/metabolism ; Dimethyl Sulfoxide/metabolism ; Administration, Cutaneous ; Skin/metabolism ; *Arsenicals/metabolism ; Sodium Dodecyl Sulfate/metabolism ; Butylamines ; Fatty Alcohols ; Phenylbutyrates ; },
abstract = {Lewisite is a highly toxic chemical warfare agent that leads to cutaneous and systemic damage. N-acetylcysteine (NAC) and 4-phenylbutryic acid (4-PBA) are two novel antidotes developed to treat toxicity caused by lewisite and similar arsenicals. Our in vivo studies demonstrated safety and effectiveness of these agents against skin injury caused by surrogate lewisite (Phenylarsine oxide) proving their potential for the treatment of lewisite injury. We further focused on exploring various enhancement strategies for an enhanced delivery of these agents via skin. NAC did not permeate passively from propylene glycol (PG). Iontophoresis as a physical enhancement technique and chemical enhancers were investigated for transdermal delivery of NAC. Application of cathodal and anodal iontophoresis with the current density of 0.2 mA/cm[2] for 4 h followed by passive diffusion till 24 h significantly enhanced the delivery of NAC with a total delivery of 65.16 ± 1.95 µg/cm[2] and 87.23 ± 7.02 µg/cm[2], respectively. Amongst chemical enhancers, screened oleic acid, oleyl alcohol, sodium lauryl ether sulfate, and dimethyl sulfoxide (DMSO) showed significantly enhanced delivery of NAC with DMSO showing highest delivery of 28,370.2 ± 2355.4 µg/cm[2] in 24 h. Furthermore, 4-PBA permeated passively from PG with total delivery of 1745.8 ± 443.5 µg/cm[2] in 24 h. Amongst the chemical enhancers screened for 4-PBA, oleic acid, oleyl alcohol, and isopropyl myristate showed significantly enhanced delivery with isopropyl myristate showing highest total delivery of 17,788.7 ± 790.2 µg/cm[2]. These studies demonstrate feasibility of delivering these antidotes via skin and will aid in selection of excipients for the development of topical/transdermal delivery systems of these agents.},
}
@article {pmid36827603,
year = {2023},
author = {Pitha, I and Kambhampati, S and Sharma, A and Sharma, R and McCrea, L and Mozzer, A and Kannan, RM},
title = {Targeted Microglial Attenuation through Dendrimer-Drug Conjugates Improves Glaucoma Neuroprotection.},
journal = {Biomacromolecules},
volume = {24},
number = {3},
pages = {1355-1365},
pmid = {36827603},
issn = {1526-4602},
support = {P30 EY001765/EY/NEI NIH HHS/United States ; U01 NS103882/NS/NINDS NIH HHS/United States ; },
mesh = {Rats ; Animals ; Microglia ; *Dendrimers ; Neuroprotection ; *Glaucoma ; Disease Models, Animal ; Carbocyanines ; },
abstract = {Retinal microglial/macrophage activation and optic nerve (ON) microglial/macrophage activation are glaucoma biomarkers and potential therapeutic targets for this blinding disease. We report targeting of activated microglia by PAMAM dendrimers in a rat glaucoma model and neuroprotection by N-acetylcysteine-conjugated dendrimer (D-NAC) conjugates in a post-injury rescue experiment. Intravitreally delivered fluorescently labeled dendrimer (D-Cy5) conjugates targeted and were retained in Iba-1-positive cells (90% at 7 days and 55% after 28 days) in the retina following intraocular pressure (IOP) elevation, while systemically delivered D-Cy5 targeted ON cells. A single intravitreal D-NAC dose given 1 week after IOP elevation significantly reduced transcription of pro-inflammatory (IL-6, MCP-1, IL-1β) and A1 astrocyte (Serping1, Fkbp5, Amigo2) markers and increased survival of retinal ganglion cells (39 ± 12%) versus BSS- (20 ± 15%, p = 0.02) and free NAC-treated (26 ± 14%, p = 0.15) eyes. These results highlight the potential of dendrimer-targeted microglia and macrophages for early glaucoma detection and as a neuroprotective therapeutic target.},
}
@article {pmid36827384,
year = {2024},
author = {Ebrahimi, F and Zavareh, S and Nasiri, M},
title = {The Combination of Estradiol and N-Acetylcysteine Reduces Ischemia-Reperfusion Injuries of Mice Autografted Ovarian Tissue.},
journal = {Biopreservation and biobanking},
volume = {22},
number = {1},
pages = {29-37},
doi = {10.1089/bio.2022.0184},
pmid = {36827384},
issn = {1947-5543},
mesh = {Animals ; Mice ; *Estradiol/pharmacology ; Acetylcysteine/pharmacology ; Fibroblast Growth Factor 2 ; Interleukin-6 ; Vascular Endothelial Growth Factor A ; Antioxidants/pharmacology/therapeutic use ; *Reperfusion Injury/drug therapy ; Inflammation ; },
abstract = {Ischemia-reperfusion injuries are important issues after ovarian tissue transplantation (OTT). Our study examined the effects of N-acetylcysteine (NAC) and estradiol (E2) on mouse ovarian autografts. Mice (6-8 weeks) were divided into ovarian autograft as follows: Control: fresh OTT; Sham: cryopreserved/warmed OTT; NAC: cryopreserved/warmed OTT with NAC treatment; E2: cryopreserved/warmed OTT with E2 treatment; NAC+E2: cryopreserved/warmed OTT with the treatment of NAC and E2. In all groups, grafts were harvested on days 2, 7, and 28 after transplantation to evaluate histological parameters, inflammation relative to genes expression, and oxidative status. Histological analysis showed that NAC, E2, and a combination of NAC+E2 significantly increased the primordial, preantral, and antral follicular number. When NAC was used, it significantly reduced the expression of Tnf-α and Fgf-2, whereas it increased Il-1β, Il-6, and Vegf expression levels. The levels of Il-6, Fgf-2, and VEGF were dramatically increased in the E2-treated group. The combination of NAC and E2 significantly increased levels of Il-1β, Il-6, Fgf-2, and Vegf. NAC and E2 alone or in combination significantly increased total antioxidant capacity but did not affect the superoxide dismutase and glutathione peroxidase activities. In conclusion, after transplantation, NAC and E2 alone or in combination, could improve follicular development and angiogenesis as well as decline inflammation and ovarian oxidative damage.},
}
@article {pmid36820266,
year = {2022},
author = {Kielmann, J and Pucci, L and Xydis, A},
title = {Personalized Nutrition and Lifestyle Interventions in Systemic Lupus Erythematosus: A Case Report.},
journal = {Integrative medicine (Encinitas, Calif.)},
volume = {21},
number = {6},
pages = {22-27},
pmid = {36820266},
issn = {1546-993X},
abstract = {BACKGROUND: A 63-year-old male with a 4-year history of systemic lupus erythematosus (SLE) safely and successfully integrated personalized nutrition and lifestyle modifications to improve the symptomatic outcome of his illness.<br><br>CASE/INTERVENTION: The client presented to our nutritional practice with fatigue, acid reflux, joint pain, brain fog and skin rashes. During the nutritional intervention, he safely used a variety of nutritional interventions and supplementation, including dietary improvements, omega-3 fish oils, N-acetyl cysteine, prebiotics and intermittent fasting, along with stress reduction techniques. His symptoms decreased significantly, or disappeared, over 4 years of using these interventions.<br><br>CONCLUSION: This case demonstrates the safety and potential benefits of personalized nutrition, stress reduction techniques and targeted supplementation in helping to decrease symptoms of SLE. Our client's energy levels and overall performance improved, skin rashes and acid reflux resolved, joint pain and stiffness decreased and brain fog gradually lessened over the 4 years he was in our care.},
}
@article {pmid36816622,
year = {2023},
author = {Simasingha, N and Tanasoontrarat, W and Claimon, T and Sethasine, S},
title = {Efficacy of dexamethasone and N-acetylcysteine combination in preventing post-embolization syndrome after transarterial chemoembolization in hepatocellular carcinoma.},
journal = {World journal of gastroenterology},
volume = {29},
number = {5},
pages = {890-903},
pmid = {36816622},
issn = {2219-2840},
mesh = {Humans ; Acetylcysteine ; *Carcinoma, Hepatocellular/pathology ; *Chemoembolization, Therapeutic/adverse effects/methods ; Dexamethasone ; *Liver Neoplasms/pathology ; Nausea/etiology ; Treatment Outcome ; Vomiting/etiology ; Drug Combinations ; },
abstract = {BACKGROUND: Conventional transarterial chemoembolization (cTACE) is the current standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Post-embolization syndrome (PES) is complex clinical syndrome that presents as fever, abdominal pain, nausea, and vomiting. Either dexamethasone (DEXA) or N-acetylcysteine (NAC) is used to prevent PES; however, the synergistic effect of their combined therapy for preventing PES and liver decompensation has not been determined.<br><br>AIM: To evaluate the efficacy of DEXA and NAC combination in preventing PES and liver decompensation after cTACE.<br><br>METHODS: Patients with Barcelona Clinic Liver Cancer stage A or B HCC who were scheduled for TACE were prospectively enrolled. All patients were randomly stratified to receive NAC and DEXA or placebo. The dual therapy (NAC + DEXA) group received intravenous administration of 10 mg DEXA every 12 h, NAC 24 h prior to cTACE (150 mg/kg/h for 1 h followed by 12.5 mg/kg/h for 4 h), and a continuous infusion of 6.25 mg/h NAC plus 4 mg DEXA every 12 h for 48 h after cTACE. The placebo group received an infusion of 5% glucose solution until 48 h after procedure. PES was defined by South West Oncology Group toxicity code grading of more than 2 that was calculated using incidence of fever, nausea, vomiting, and pain.<br><br>RESULTS: One-hundred patients were enrolled with 50 patients in each group. Incidence of PES was significantly lower in the NAC + DEXA group compared with in the placebo group (6% vs 80%; P < 0.001). Multivariate analysis showed that the dual treatment is a protective strategic therapy against PES development [odds ratio (OR) = 0.04; 95% confidence interval (CI): 0.01-0.20; P < 0.001). Seven (14%) patients in the placebo group, but none in the NAC + DEXA group, developed post-TACE liver decompensation. A dynamic change in Albumin-Bilirubin score of more than 0.5 point was found to be a risk factor for post-TACE liver decompensation (OR = 42.77; 95%CI: 1.01-1810; P = 0.049).<br><br>CONCLUSION: Intravenous NAC + DEXA administration ameliorated the occurrence of PES event after cTACE in patients with intermediate-stage HCC.},
}
@article {pmid36813253,
year = {2023},
author = {Sasaki, S and Negishi, T and Tsuzuki, T and Yukawa, K},
title = {Methylmercury-induced reactive oxygen species-dependent and independent dysregulation of MAP kinase-related signaling pathway in cultured normal rat cerebellar astrocytes.},
journal = {Toxicology},
volume = {487},
number = {},
pages = {153463},
doi = {10.1016/j.tox.2023.153463},
pmid = {36813253},
issn = {1879-3185},
mesh = {Rats ; Animals ; Reactive Oxygen Species/metabolism ; *Antioxidants/pharmacology/metabolism ; MAP Kinase Signaling System ; *Methylmercury Compounds ; Astrocytes ; Oxidative Stress ; Glutathione/metabolism ; Acetylcysteine/pharmacology/metabolism ; Cells, Cultured ; },
abstract = {Methylmercury (MeHg), a global environmental pollutant, could seriously damage the central nervous system (CNS) and cause neurological disorders such as cerebellar symptoms. Although numerous studies have revealed detailed toxicity mechanisms of MeHg in neurons, toxicity in astrocytes is barely known. Here, we tried to shed light on the toxicity mechanisms of MeHg exposure in cultured normal rat cerebellar astrocytes (NRA), focusing on the involvement of reactive oxygen species (ROS) in MeHg toxicity by assessing the effects of major antioxidants Trolox, a free-radical scavenger, N-acetyl-L-cysteine (NAC), a potent thiol-containing antioxidant, and glutathione (GSH), an endogenous thiol-containing antioxidant. Exposure to MeHg at just approximately 2 µM for 96 h increased cell viability, which was accompanied by the increase in intracellular ROS level and at ≥ 5 µM induced significant cell death and lowered ROS level. Trolox and NAC suppressed 2 µM MeHg-induced increases in cell viability and ROS level corresponding to control, although GSH with 2 µM MeHg induced significant cell death and ROS increase. On the contrary, against 4 µM MeHg-induced cell loss and ROS decrease, NAC inhibited both cell loss and ROS decrease, Trolox inhibited cell loss and further enhanced ROS decrease, and GSH moderately inhibited cell loss and increased ROS level above the control level. MeHg-induced oxidative stress was suggested by increases in the protein expression levels of heme oxygenase-1 (HO-1), Hsp70, and Nrf2, except for the decrease in SOD-1 and no change in catalase. Furthermore, MeHg exposure dose-dependently induced increases in the phosphorylation of MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK) and phosphorylation and/or expression levels of transcription factors (CREB, c-Jun, and c-Fos) in NRA. NAC successfully suppressed 2 µM MeHg-induced alterations in all of the above-mentioned MeHg-responsive factors, whereas Trolox suppressed some MeHg-responsive factors but failed to suppress MeHg-induced increases in the protein expression levels of HO-1 and Hsp70 and increase in p38MAPK phosphorylation. Protein expression analyses in NRA exposed to 2 µM MeHg and GSH were excluded because of devastating cell death. These results suggested that MeHg could induce aberrant NRA activation, and ROS must be substantially involved in the toxicity mechanism of MeHg in NRA; however, other factors should be assumed.},
}
@article {pmid36810107,
year = {2023},
author = {Abbasifard, M and Khorramdelazad, H and Rostamian, A and Rezaian, M and Askari, PS and Sharifi, GTK and Parizi, MK and Sharifi, MTK and Najafizadeh, SR},
title = {Effects of N-acetylcysteine on systemic lupus erythematosus disease activity and its associated complications: a randomized double-blind clinical trial study.},
journal = {Trials},
volume = {24},
number = {1},
pages = {129},
pmid = {36810107},
issn = {1745-6215},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Severity of Illness Index ; *Lupus Erythematosus, Systemic/drug therapy ; Kidney ; Double-Blind Method ; Treatment Outcome ; },
abstract = {BACKGROUNDS: N-acetylcysteine (NAC) has broadly been used as an anti-oxidant agent in various types of diseases. This study aimed to assess the effect of NAC on the systemic lupus erythematosus (SLE) disease activity and outcome.<br><br>METHODS: In this randomized, double-blind clinical trial study, 80 SLE patients were recruited that were classified into two groups: 40 patients received NAC (1800 mg/day; 3 times per day with 8-h intervals) for 3 months and 40 patients as the control group received normal therapies. Laboratory measurements and disease activity based on the British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index (SLEDAI) were determined before the initiation of treatment and after the study time period.<br><br>RESULTS: A statistically significant decrease in BILAG (P= 0.023) and SLEDAI (P= 0.034) scores after receiving NAC for a 3-month period was observed. BILAG (P= 0.021) and SLEDAI (P= 0.030) scores were significantly lower in NAC-receiving patients compared to the control group after 3 months. The disease activity in each organ based on BILAG score after treatment indicated a significant decrease in the NAC group compared to the baseline level in general (P=0.018), mucocutaneous (P=0.003), neurological (P=0.015), musculoskeletal (P=0.048), cardiorespiratory (P=0.047), renal (P=0.025), and vascular (P=0.048) complications. Analysis indicated a significant increase in CH50 level in the NAC group after treatment compared to the baseline level (P=0.049). No adverse event was reported by the study subjects.<br><br>CONCLUSIONS: It appears that the administration of 1800 mg/day NAC to SLE patients can decrease the SLE disease activity and its complications.},
}
@article {pmid36809299,
year = {2023},
author = {Chen, DW and Kang, T and Xu, XZ and Xia, WJ and Ye, X and Wu, YB and Xu, YR and Liu, J and Ren, H and Deng, J and Chen, YK and Ding, HQ and Aslam, M and Zelek, WM and Morgan, BP and Kapur, R and Santoso, S and Fu, YS},
title = {Mechanism and intervention of murine transfusion-related acute lung injury caused by anti-CD36 antibodies.},
journal = {JCI insight},
volume = {8},
number = {6},
pages = {},
pmid = {36809299},
issn = {2379-3708},
mesh = {Mice ; Humans ; Male ; Animals ; *Transfusion-Related Acute Lung Injury/pathology ; Blood Platelets/pathology ; Monocytes/pathology ; Complement System Proteins ; Complement Activation ; },
abstract = {Anti-CD36 Abs have been suggested to induce transfusion-related acute lung injury (TRALI) upon blood transfusion, particularly in Asian populations. However, little is known about the pathological mechanism of anti-CD36 Ab-mediated TRALI, and potential therapies have not yet been identified. Here, we developed a murine model of anti-CD36 Ab-mediated TRALI to address these questions. Administration of mouse mAb against CD36 (mAb GZ1) or human anti-CD36 IgG, but not GZ1 F(ab')2 fragments, induced severe TRALI in Cd36+/+ male mice. Predepletion of recipient monocytes or complement, but not neutrophils or platelets, prevented the development of murine TRALI. Moreover, plasma C5a levels after TRALI induction by anti-CD36 Abs increased more than 3-fold, implying a critical role of complement C5 activation in the mechanism of Fc-dependent anti-CD36-mediated TRALI. Administration of GZ1 F(ab')2, antioxidant (N-acetyl cysteine, NAC), or C5 blocker (mAb BB5.1) before TRALI induction completely protected mice from anti-CD36-mediated TRALI. Although no significant amelioration in TRALI was observed when mice were injected with GZ1 F(ab')2 after TRALI induction, significant improvement was achieved when mice were treated postinduction with NAC or anti-C5. Importantly, anti-C5 treatment completely rescued mice from TRALI, suggesting the potential role of existing anti-C5 drugs in the treatment of patients with TRALI caused by anti-CD36.},
}
@article {pmid36808460,
year = {2023},
author = {Dwivedi, SK and Arachchige, DL and Vohs, T and Tang, J and Usimaki, K and Olowolagba, AM and Fritz, DR and Luck, RL and Werner, T and Liu, H},
title = {Near-infrared rhodol dyes bearing salicylaldehyde moieties for ratiometric pH sensing in live cells during mitophagy and under hypoxia conditions.},
journal = {Journal of materials chemistry. B},
volume = {11},
number = {13},
pages = {2852-2861},
pmid = {36808460},
issn = {2050-7518},
support = {R15 GM114751/GM/NIGMS NIH HHS/United States ; R15 GM146206/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; HeLa Cells ; *Mitophagy ; *Hydrogen Peroxide ; Fluorescent Dyes ; Hypoxia ; Hydrogen-Ion Concentration ; Xanthones ; Aldehydes ; },
abstract = {We describe a simple but efficient approach to make fluorescent probes A and B based on rhodol dyes incorporated with salicyaldehyde moiety for monitoring pH changes in mitochondria under oxidative stresses and hypoxia conditions, and for tracking mitophagy processes. Probes A and B possess pKa values (pKa ≈ 6.41 and 6.83 respectively) near physiological pH and exhibit decent mitochondria-targeted capabilities, low cytotoxicity, and useful ratiometric and reversible pH responses, which make the probes appropriate for monitoring pH fluctuations of mitochondria in living cells with built-in calibration feature for quantitative analysis. The probes have been effectively useful for the ratiometric determination of pH variations of mitochondria under the stimuli of carbonyl cyanide-4(trifluoromethoxy)phenylhydrazone (FCCP), hydrogen peroxide (H2O2), and N-acetyl cysteine (NAC), and during mitophagy triggered by cell nutrient deprivation, and under hypoxia conditions with cobalt chloride (CoCl2) treatment in living cells. In addition, probe A was efficient in visualizing pH changes in the larvae of fruit flies.},
}
@article {pmid36807852,
year = {2023},
author = {Wei, Y and Geng, W and Zhang, T and He, H and Zhai, J},
title = {N-acetylcysteine rescues meiotic arrest during spermatogenesis in mice exposed to BDE-209.},
journal = {Environmental science and pollution research international},
volume = {30},
number = {17},
pages = {50952-50968},
pmid = {36807852},
issn = {1614-7499},
support = {NO.&#xa0;82273598//the&#xa0;National&#xa0;Natural&#xa0;Science&#xa0;Foundation&#xa0;of&#xa0;China/ ; NO. 2108085MH305//the&#xa0;Nature&#xa0;Science&#xa0;Research&#xa0;Project&#xa0;of&#xa0;Anhui&#xa0;Province&#xa0;/ ; },
mesh = {Mice ; Male ; Animals ; *Acetylcysteine/pharmacology ; *Meiosis ; Semen ; Spermatogenesis ; Halogenated Diphenyl Ethers ; },
abstract = {Deca-bromodiphenyl ethers (BDE-209) has been widely used in electronic devices and textiles as additives to flame retardants. Growing evidence showed that BDE-209 exposure leads to poorer sperm quality and male reproductive dysfunction. However, the underlying mechanisms of BDE-209 exposure caused a decline in sperm quality remains unclear. This study aimed to evaluate the protective effects of N-acetylcysteine (NAC) on meiotic arrest in spermatocytes and decreased sperm quality in BDE-209-exposed mice. In the study, mice were treated with NAC (150 mg/kg BW) 2 h before administrated with BDE-209 (80 mg/kg BW) for 2 weeks. For the in vitro studies, spermatocyte cell line GC-2spd cells were pretreated with NAC (5 mM) 2 h before treated with BDE-209 (50 μM) for 24 h. We found that pretreatment with NAC attenuated the oxidative stress status induced by BDE-209 in vivo and in vitro. Moreover, pretreatment with NAC rescued the testicular histology impairment and decreased the testicular organ coefficient in BDE-209-exposed mice. In addition, NAC supplement partially promoted meiotic prophase and improved sperm quality in BDE-209-exposed mice. Furthermore, NAC pretreatment effectively improved DNA damage repair by recovering DMC1, RAD51, and MLH1. In conclusion, BDE-209 caused spermatogenesis dysfunction related to the meiotic arrest medicated by oxidative stress, decreasing sperm quality.},
}
@article {pmid36806345,
year = {2023},
author = {Zhang, X and Wang, S and Jin, Y and Wang, J and Wang, R and Yang, X and Zhang, S and Yan, T and Jia, Y},
title = {Wei-Tong-Xin ameliorated cisplatin-induced mitophagy and apoptosis in gastric antral mucosa by activating the Nrf2/HO-1 pathway.},
journal = {Journal of ethnopharmacology},
volume = {308},
number = {},
pages = {116253},
doi = {10.1016/j.jep.2023.116253},
pmid = {36806345},
issn = {1872-7573},
mesh = {Mice ; Animals ; *NF-E2-Related Factor 2/metabolism ; *Cisplatin/pharmacology ; Heme Oxygenase-1/metabolism ; Mitophagy ; Pyloric Antrum/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Apoptosis ; Mucous Membrane ; },
abstract = {Wei-Tong-Xin (WTX) originated from the famous ancient Chinese formula "Wan Ying Yuan", recorded in the ancient Chinese medicine book "Zhong Zang Jing" by Hua Tuo. As "Jun" drugs, Dahuang and Muxiang have the effects of clearing heat and expelling fire, reducing food retention, regulating Qi and relieving pain. As "Chen" drug, Qianniuzi has the effect of assisting "Jun" drugs. Zhuyazao and Gancao, as "Zuo-Shi" drugs, can reduce toxicity and modulate the medicinal properties of other herbs.<br><br>AIM OF THE STUDY: The present study aimed to investigate the effect and mechanism of WTX on the oxidative stress of gastric antrum mucosa in mice with cisplatin (CIS)-induced dyspepsia.<br><br>MATERIALS: AND.<br><br>METHODS: A variety of experimental methods, including western blot, qRT-PCR, immunofluorescence and immunohistochemistry were performed in vivo and in vitro.<br><br>RESULTS: In vivo, WTX restored the number and function of interstitial cells of Cajal (ICCs), accompanied by the inhibition of lipid peroxidation. Moreover, WTX inhibited the activation of Parkin-dependent mitophagy and apoptosis. In vitro, WTX activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway and inactivated mitophagy in GES-1&#xa0;cells. To explore the role of Nrf2 in WTX's improvement of CIS-induced cell damage, Nrf2 inhibitor ML385 was used in cell experiments. We found that ML385 counteracted the regulation of WTX on mitophagy and apoptosis. Finally, N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, was applied in our experiments, and the results suggested that WTX suppressed the CIS-induced apoptosis via mitochondrial pathway.<br><br>CONCLUSIONS: The above results, for the first time, indicated that WTX inhibited mitophagy and apoptosis of gastric antral mucosal cells induced by CIS through the Nrf2/HO-1 signaling pathway.},
}
@article {pmid36802832,
year = {2023},
author = {Turk, T and Liu, C and Fujiwara, E and Straube, S and Hagtvedt, R and Dennett, L and Abba-Aji, A and Dytoc, M},
title = {Pharmacological Interventions for Primary Psychodermatologic Disorders: An Evidence Mapping and Appraisal of Randomized Controlled Trials.},
journal = {Journal of cutaneous medicine and surgery},
volume = {27},
number = {2},
pages = {140-149},
pmid = {36802832},
issn = {1615-7109},
mesh = {Humans ; Sertraline/therapeutic use ; Fluoxetine/therapeutic use ; Clomipramine/therapeutic use ; Olanzapine ; *Antipsychotic Agents/therapeutic use ; Desipramine ; Pimozide ; Randomized Controlled Trials as Topic ; Acetylcysteine/therapeutic use ; *Dermatitis/drug therapy ; },
abstract = {BACKGROUND: The lack of clinical guidelines for the treatment of primary psychodermatologic disorders (PPDs) hinders the delivery of optimal care to patients. The review aimed to identify, appraise, and summarize the currently available evidence about the safety and effectiveness of pharmacological management of PPDs through randomized controlled trials (RCTs).<br><br>METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRIMSA) statement and the Global Evidence Mapping Initiative guidance were followed. Medline, Embase, PsycInfo, Cochrane and Scopus were searched, and two reviewers independently completed article review, data extraction, and quality assessment.<br><br>RESULTS: Among 2618 unique studies, full texts of 83 were reviewed and 21 RCTs were included. Five PDDs were identified: trichotillomania (n = 12), pathologic skin picking (n = 5), nail biting (n = 2), delusional parasitosis (n = 1), and dermatitis from compulsive hand washing (n = 1). Seven different classes of medications were investigated: SSRIs (i.e., fluoxetine, sertraline, and citalopram), tricyclic antidepressants (i.e., clomipramine and desipramine), antipsychotics (i.e., olanzapine and pimozide), anticonvulsant (i.e., lamotrigine), N-acetylcysteine, inositol, and milk thistle. RCT-derived evidence supports the use of antidepressants in trichotillomania (sertraline and clomipramine), pathologic skin picking (fluoxetine), pathologic nail biting and dermatitis from compulsive hand washing (clomipramine or desipramine); antipsychotics in trichotillomania (olanzapine) and delusional parasitosis (pimozide); N-acetyl cysteine in trichotillomania and skin picking.<br><br>CONCLUSION: Few pharmacotherapies for primary psychodermatologic disorders are assessed through controlled trials in the literature. This review serves as a roadmap for researchers and clinicians to reach informed decisions with current evidence, and to build on it to establish guidelines in the future.},
}
@article {pmid36799253,
year = {2023},
author = {Xu, K and Ma, J and Lu, R and Shao, X and Zhao, Y and Cui, L and Qiu, Z and Tian, Y and Li, J},
title = {Effective-compound combination of Bufei Yishen formula III combined with ER suppress airway mucus hypersecretion in COPD rats: via EGFR/MAPK signaling.},
journal = {Bioscience reports},
volume = {43},
number = {11},
pages = {},
pmid = {36799253},
issn = {1573-4935},
mesh = {Animals ; Rats ; ErbB Receptors/metabolism ; *Interleukin-6/metabolism ; Lung/pathology ; Mucus/metabolism ; *Pulmonary Disease, Chronic Obstructive/pathology ; Rats, Sprague-Dawley ; Drugs, Chinese Herbal ; },
abstract = {BACKGROUND: The aim of this study was to explore the combined efficacy ofeffective-component compatibility of Bufei Yishen formula III (ECC-BYF III) and exercise rehabilitation (ER) in inhibiting airway mucus hypersecretion in a chronic obstructive pulmonary disease (COPD) rat model.<br><br>METHODS: A total of 48 SD rats were divided into control, model, acetylcysteine (NAC), ECC-BYF III, ER, and ECC-BYF III + ER groups (n=8). COPD rats were exposed to cigarette smoke and bacteria for 8 weeks and administered various treatments over the next eight weeks. Rats were euthanized at week 17 after pulmonary function testing. Pathological examination of lung tissues was performed. IL-6 and IL-10 levels were measured in bronchoalveolar lavage fluid (BALF) and protein levels of MUC5AC, MUC5B, AQP-5, EGFR, ERK, JNK, and p38 were measured in lung tissues.<br><br>RESULTS: Improved pulmonary function and pathological changes were observed in ECC-BYF III, ECC-BYF III + ER, and NAC groups. ECC-BYF III and ECC-BYF III + ER had greater mean alveolar number (MAN) compared with NAC. Lung inflammation and goblet cell generation were reduced and MUC5AC, MUC5B and AQP-5 expressions were lower in all treatment groups. ECC-BYF III has more significant effect on MUC5AC than ER and NAC. ECC-BYFIII + ER had a greater effect on suppressing IL-6 in BALF compared with other treatments. ECC-BYFIII, ER, and ECC-BYF III + ER reduced EGFR, ERK, JNK, and p38 phosphorylated protein levels. ECC-BYFIII+ER had a greater effect on p-JNK and p-p38 than ECC-BYFIII and NAC.<br><br>CONCLUSION: ECC-BYF III, ER, and ECC-BYF III + ER have efficacy in inhibiting airway mucus hypersecretion with improved pulmonary function and pathological changes. ECC-BYF III had a greater effect in improving MAN and MUC5AC in lung tissue. ECC-BYF III+ER had a greater effect in alleviating pulmonary pathology and inflammation. These effects may be mediated by inhibition of the EGFR/MAPK pathway.},
}
@article {pmid36796651,
year = {2023},
author = {Yoo, JY and Lee, YJ and Kim, YJ and Baik, TK and Lee, JH and Lee, MJ and Woo, RS},
title = {Multiple low-dose radiation-induced neuronal cysteine transporter expression and oxidative stress are rescued by N-acetylcysteine in neuronal SH-SY5Y cells.},
journal = {Neurotoxicology},
volume = {95},
number = {},
pages = {205-217},
doi = {10.1016/j.neuro.2023.02.006},
pmid = {36796651},
issn = {1872-9711},
mesh = {Humans ; *Acetylcysteine/pharmacology/metabolism ; Apoptosis ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/metabolism ; Cell Line, Tumor ; *Neuroblastoma/radiotherapy/metabolism ; Oxidative Stress ; Cell Survival ; },
abstract = {Recently, several studies have demonstrated that low-dose radiation (LDR) therapy has positively impacts on the treatment of Alzheimer's disease (AD). LDR suppresses the production of pro-neuroinflammation molecules and improves cognitive function in AD. However, it is unclear whether direct exposure to LDR causes beneficial effects and what mechanism is involved in neuronal cells. In this study, we first determined the effect of high-dose radiation (HDR) alone on C6 cells and SH-SY5Y cells. We found that SH-SY5Y cells were more vulnerable than C6 cells to HDR. Moreover, in neuronal SH-SY5Y cells exposed to single or multiple LDR, N-type cells showed decreased cell viability with increasing radiation exposure time and frequency, but S-type cells were unaffected. Multiple LDR increased proapoptotic molecules such as p53, Bax and cleaved caspase-3, and decreased anti-apoptotic molecule (Bcl2). Multiple LDR also generated free radicals in neuronal SH-SY5Y cells. We detected a change in the expression of the neuronal cysteine transporter EAAC1. Pretreatment with N-acetylcysteine (NAC) rescued the increased in EAAC1 expression and the generation of ROS in neuronal SH-SY5Y cells after multiple LDR. Furthermore, we verified whether the increased in EAAC1 expression induces cell defense or cell death promotion signaling. We showed that transient overexpression of EAAC1 reduced the multiple LDR-induced p53 overexpression in neuronal SH-SY5Y cells. Our results indicate that neuronal cells can be injured by increased production of ROS not only by HDR but also by multiple LDR, which suggests that combination treatment with anti-free radical agents such as NAC may be useful in multiple LDR therapy.},
}
@article {pmid36795483,
year = {2023},
author = {Bhardwaj, M and Lee, JJ and Versace, AM and Harper, SL and Goldman, AR and Crissey, MAS and Jain, V and Singh, MP and Vernon, M and Aplin, AE and Lee, S and Morita, M and Winkler, JD and Liu, Q and Speicher, DW and Amaravadi, RK},
title = {Lysosomal lipid peroxidation regulates tumor immunity.},
journal = {The Journal of clinical investigation},
volume = {133},
number = {8},
pages = {},
pmid = {36795483},
issn = {1558-8238},
support = {R01 CA266404/CA/NCI NIH HHS/United States ; P50 CA174523/CA/NCI NIH HHS/United States ; R01 CA256945/CA/NCI NIH HHS/United States ; P30 CA016520/CA/NCI NIH HHS/United States ; S10 OD023586/OD/NIH HHS/United States ; R01 CA238237/CA/NCI NIH HHS/United States ; P30 DK050306/DK/NIDDK NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; P01 CA114046/CA/NCI NIH HHS/United States ; P50 CA261608/CA/NCI NIH HHS/United States ; },
mesh = {Mice ; Animals ; Lipid Peroxidation ; *Apoptosis ; Cell Death ; *Neoplasms/pathology ; Antioxidants/pharmacology ; Lysosomes/metabolism ; },
abstract = {Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC) but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12 was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naive T cells and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate that LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.},
}
@article {pmid36795166,
year = {2023},
author = {Hammerschmidt, TG and Guerreiro, GB and Donida, B and Raabe, M and Kessler, RG and Ferro, MB and Moura, DJ and Giugliani, R and Vargas, CR},
title = {Beneficial in vitro effect of N-acetylcysteine and coenzyme Q10 on DNA damage in neurodegenerative Niemann-Pick type C 1 disease: preliminary results.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {396},
number = {7},
pages = {1563-1569},
pmid = {36795166},
issn = {1432-1912},
support = {2018-0648//Fundo de Incentivo &#xe0; Pesquisa e Eventos (FIPE/HCPA)./ ; 430443/2018-8//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; },
mesh = {Humans ; *Niemann-Pick Disease, Type C/drug therapy/genetics/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; DNA Damage ; Ubiquinone/analogs &amp; derivatives ; },
abstract = {Niemann-Pick type C1 (NP-C1) is a lysosomal storage disease (LSD) caused by mutations in NPC1 gene that lead to defective synthesis of the respective lysosomal transporter protein and cholesterol accumulation in late endosomes/lysosomes (LE/L) compartments, as well as glycosphingolipids GM2 and GM3 in the central nervous system (CNS). Clinical presentation varies according to the age of onset and includes visceral and neurological symptoms, such as hepatosplenomegaly and psychiatric disorders. Studies have been associating the pathophysiology of NP-C1 with oxidative damage to lipids and proteins, as well as evaluating the benefits of adjuvant therapy with antioxidants for this disease. In this work, we evaluated the DNA damage in fibroblasts culture from patients with NP-C1 treated with miglustat, as well as the in vitro effect of the antioxidant compounds N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10), using the alkaline comet assay. Our preliminary results demonstrate that NP-C1 patients have increased DNA damage compared to healthy individuals and that the treatments with antioxidants can mitigate it. DNA damage may be due to an increase in reactive species since it has been described that NP-C1 patients have increased peripheral markers of damage to other biomolecules. Our study suggests that NP-C1 patients could benefit from the use of adjuvant therapy with NAC and CoQ10, which should be better evaluated in a future clinical trial.},
}
@article {pmid36791995,
year = {2023},
author = {Mukherjee, S and Gupta, P and Ghosh, S and Choudhury, S and Das, A and Ahir, M and Adhikary, A and Chattopadhyay, S},
title = {Targeted tumor killing by pomegranate polyphenols: Pro-oxidant role of a classical antioxidant.},
journal = {The Journal of nutritional biochemistry},
volume = {115},
number = {},
pages = {109283},
doi = {10.1016/j.jnutbio.2023.109283},
pmid = {36791995},
issn = {1873-4847},
mesh = {Animals ; Mice ; Antioxidants/pharmacology/therapeutic use/chemistry ; Reactive Oxygen Species/metabolism ; *Pomegranate ; Fruit/chemistry ; Ascites ; Polyphenols/pharmacology/analysis ; Epithelial-Mesenchymal Transition ; Oxidative Stress ; NF-E2-Related Factor 2/metabolism ; *Carcinoma ; NF-kappa B/metabolism ; Apoptosis ; },
abstract = {One of the key biochemical features that distinguish a cancer cell from normal cells is its persistent pro-oxidative state that leads to intrinsic oxidative stress. Malignant cells have evolved sophisticated adaptation systems that involve high dependency on antioxidant functions and upregulation of pro-survival molecules to counteract the deleterious effects of reactive species and to maintain dynamic redox balance. This situation renders them vulnerable to further oxidative challenges by exogenous agents. In the present study, we advocated that pomegranate polyphenols act as pro-oxidants and trigger ROS-mediated apoptosis in cancer cells. With the help of both in vitro and in vivo models, we have established that pomegranate fruit extract (PFE) can cause a significant reduction in tumor proliferation while leaving normal tissues and cells unharmed. Administration of PFE (0.2% v/v) in Erhlich's ascites carcinoma-bearing mice for 3 weeks, inhibited the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element signaling cascade, increased intracellular reactive oxygen species content, altered glutathione cycle thereby activating reactive oxygen species-induced apoptotic pathway in Erhlich's ascites carcinoma cells. Moreover, PFE mitigated epithelial to mesenchymal transition and migration in triple negative breast cancer cells (MDA-MB 231 cells) by down-regulating nuclear factor kappa light-chain-enhancer of activated B cells. Pre-treatment of tumor cells with N-acetyl cysteine protected these cells from undergoing PFE-induced apoptosis while siRNA-mediated silencing of Nuclear factor (erythroid-derived 2)-like 2 and nuclear factor kappa light-chain-enhancer of activated B cells in tumor cells increased the cytotoxic potential and pro-oxidative activity of PFE, indicating a clear role of these transcription factors in orchestrating the anticancer/pro-oxidative properties of PFE. The seminal findings provided may be exploited to develop potential therapeutic targets for selective killing of malignant cells.},
}
@article {pmid36791364,
year = {2023},
author = {Hong, MK and Echanique, KA and Hoffman, LF and Kita, AE},
title = {Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model.},
journal = {Otology &amp; neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology},
volume = {44},
number = {4},
pages = {373-381},
pmid = {36791364},
issn = {1537-4505},
support = {K08 DC019957/DC/NIDCD NIH HHS/United States ; },
mesh = {Rats ; Animals ; Cisplatin/toxicity ; *Antineoplastic Agents ; *Ototoxicity ; Acetylcysteine/pharmacology ; Gentamicins/toxicity ; Schwann Cells ; },
abstract = {HYPOTHESIS: The ototoxicity of gentamicin and cisplatin can be evaluated with a Schwann cell model to screen for otoprotective agents that can be encapsulated into poly (lactic-co-glycolic acid) (PLGA) microparticles for drug delivery to the inner ear.<br><br>BACKGROUND: Aminoglycosides and cisplatin are widely prescribed but known to cause ototoxicity. There is strong evidence that compromise to Schwann cells ensheathing inner ear afferent neurons results in inner ear dysfunction mimicking drug-induced ototoxicity. There is a need for a model for ototoxic demyelination to screen medications for protective potential and to subsequently target and tune the delivery of any promising agents.<br><br>METHODS: RT4-D6P2T rat schwannoma cells were used as a Schwann cell model to assess gentamicin and cisplatin toxicity and to screen for protective agents. Cell viability was evaluated with the MTT cell proliferation assay. N -acetylcysteine (NAC) was encapsulated into a PLGA microparticle, and its elution profile was determined.<br><br>RESULTS: The estimated 50% lethal concentration dose for gentamicin was 805.6 &#x3bc;M, which was 46-fold higher than that for cisplatin (17.5 &#x3bc;M). In several trials, cells dosed with NAC and cisplatin demonstrated a 22.6% (p < 0.001) increase in cell viability when compared with cisplatin alone. However, this protective effect was not consistent across all trials. NAC was encapsulated into a PLGA microparticle and elution plateaued at 5 days.<br><br>CONCLUSION: When dosed at their respective therapeutic ranges, cisplatin is more likely than gentamicin to induce damage to the Schwann cell model. Although NAC demonstrates an uncertain role in protecting against cisplatin-induced Schwann cell cytotoxicity, this study establishes a method to screen for other otoprotective medications to encapsulate into a tunable microparticle for localized drug delivery.},
}
@article {pmid36780980,
year = {2023},
author = {Siddiqui, SI and Malik, C and Ghosh, S},
title = {Voltage dependent anion channel and its interaction with N-acetyl-L-Cysteine (NAC) under oxidative stress on planar lipid bilayer.},
journal = {Biochimie},
volume = {209},
number = {},
pages = {150-160},
doi = {10.1016/j.biochi.2023.02.005},
pmid = {36780980},
issn = {1638-6183},
mesh = {*Lipid Bilayers ; *Acetylcysteine/pharmacology ; Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Hydrogen Peroxide/pharmacology/metabolism ; Voltage-Dependent Anion Channels/metabolism ; Oxidative Stress ; },
abstract = {Mitochondria are the major source of Hydrogen Peroxide (H2O2), a reactive oxygen species, in the cells. The reactive oxygen species generated by the mitochondria oxidize major proteins including Voltage Dependent Anion Channel (VDAC). We were interested to know how the effect of H2O2 is countered by antioxidants present around the mitochondria. N-Acetyl-l-Cysteine (NAC) is a naturally existing antioxidant in the cells. Keeping this in view, the modulatory effect of antioxidant NAC on H2O2 oxidized VDAC has been investigated through in vitro electrophysiological studies. First, the effect of H2O2 and NAC was studied on independently incorporated single-channel VDAC. It was observed that NAC suppresses VDAC conductance with a half-maximal inhibitory concentration (IC50) of ∼1.04 μM. In contrast, H2O2 enhances VDAC conductance. Later, oxidative stress was induced by H2O2 on VDAC increased conductance with half-maximal effective concentration (EC50) of ∼302 nM. An application of 1 μM NAC on H2O2 treated (300 nM) VDAC reversed the effect of oxidation. In the next step, NAC and H2O2 were added in reverse order. When oxidative stress was induced using H2O2, reduction in conductance by NAC was 4.5 ± 0.404 nS. The change in conductance is nearly 6.3%. However, if antioxidant NAC was incubated first followed by H2O2 treatment, the conductance of VDAC was 3.09 ± 0.27 nS. The change in conductance is near 33%. Both H2O2 and NAC also affected various conducting states of VDAC. In-silico studies indicated the binding of NAC at Lysine and Glutamic acid of VDAC. Hence, NAC was found to be effective in protection of VDAC against H2O2-induced oxidative stress due to its strong binding.},
}
@article {pmid36779633,
year = {2023},
author = {Fang, Z and Xu, Y and Liu, G and Shao, Q and Niu, X and Tai, W and Shen, T and Fan, M and Chen, M and Lei, L and Gao, W and Song, Y and Wang, Z and Du, X and Li, X},
title = {Narirutin activates TFEB (transcription factor EB) to protect against Acetaminophen-induced liver injury by targeting PPP3/calcineurin.},
journal = {Autophagy},
volume = {19},
number = {8},
pages = {2240-2256},
pmid = {36779633},
issn = {1554-8635},
mesh = {TOR Serine-Threonine Kinases/metabolism ; Autophagy/genetics ; *Calcineurin/metabolism ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Liver/metabolism ; Mice ; Glutathione/metabolism ; Acetaminophen ; Animals ; Disaccharides ; Flavanones ; Cornea/abnormalities ; Corneal Diseases ; Eye Diseases, Hereditary ; },
abstract = {Acetaminophen (APAP) overdose is the predominant cause of drug-induced liver injury worldwide. The macroautophagy/autophagy-lysosomal pathway (ALP) is involved in the APAP hepatotoxicity. TFEB (transcription factor EB) promotes the expression of genes related to autophagy and lysosomal biogenesis, thus, pharmacological activation of TFEB-mediated ALP may be an effective therapeutic approach for treating APAP-induced liver injury. We aimed to reveal the effects of narirutin (NR), the main bioactive constituents isolated from citrus peels, on APAP hepatotoxicity and to explore its underlying mechanism. Administration of NR enhanced activities of antioxidant enzymes, improved mitochondrial dysfunction and alleviated liver injury in APAP-treated mice, whereas NR did not affect APAP metabolism and MAPK/JNK activation. NR enhanced TFEB transcriptional activity and activated ALP in an MTOR complex 1 (MTORC1)-independent but PPP3/calcineurin-dependent manner. Moreover, knockout of Tfeb or knockdown of PPP3CB/CNA2 (protein phosphatase 3, catalytic subunit, beta isoform) in the liver abolished the beneficial effects of NR on APAP overdose. Mechanistically, NR bound to PPP3CB via PRO31, LYS61 and PRO347 residues and enhanced PPP3/calcineurin activity, thereby eliciting dephosphorylation of TFEB and promoting ALP, which alleviated APAP-induced oxidative stress and liver injury. Together, NR protects against APAP-induced liver injury by activating a PPP3/calcineurin-TFEB-ALP axis, indicating NR may be a potential agent for treating APAP overdose.Abbreviations: ALP: autophagy-lysosomal pathway; APAP: acetaminophen; APAP-AD: APAP-protein adducts; APAP-Cys: acetaminophen-cysteine adducts; CAT: catalase; CETSA: cellular thermal shift assay; CQ: chloroquine; CYP2E1: cytochrome P450, family 2, subfamily e, polypeptide 1; CYCS/Cyt c: cytochrome c, somatic; DARTS: drug affinity responsive target stability assay; ENGASE/NAG: endo-beta-N-acetylglucosaminidase; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; GSH: glutathione; GPX/GSH-Px: glutathione peroxidase; KD: dissociation constant; Leu: leupeptin; MCOLN1: mucolipin 1; MTORC1: MTOR complex 1; NAC: N-acetylcysteine; NAPQI: N-acetyl-p-benzoquinoneimine; NFAT: nuclear factor of activated T cells; NR: narirutin; OA: okadaic acid; RRAG: Ras related GTP binding; ROS: reactive oxygen species; PPP3CB/CNA2: protein phosphatase 3, catalytic subunit, beta isoform; PPP3R1/CNB1: protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type I); SOD: superoxide dismutase; SPR: surface plasmon resonance analysis; TFEB: transcription factor EB.},
}
@article {pmid36779379,
year = {2023},
author = {Zhang, Z and Shen, C and Zhou, F and Zhang, Y},
title = {Shikonin potentiates therapeutic efficacy of oxaliplatin through reactive oxygen species-mediated intrinsic apoptosis and endoplasmic reticulum stress in oxaliplatin-resistant colorectal cancer cells.},
journal = {Drug development research},
volume = {84},
number = {3},
pages = {542-555},
doi = {10.1002/ddr.22044},
pmid = {36779379},
issn = {1098-2299},
mesh = {Animals ; Mice ; Humans ; Oxaliplatin/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Apoptosis ; *Naphthoquinones/pharmacology/therapeutic use ; Cell Line, Tumor ; *Colorectal Neoplasms/drug therapy/metabolism ; Endoplasmic Reticulum Stress ; },
abstract = {Oxaliplatin (OXA) has been recognized as a third-generation platinum-based chemotherapeutic agent with stellar therapeutic efficacy in managing colorectal cancer (CRC). Nevertheless, resistance to OXA in CRC patients hinders its effectiveness. Shikonin (SHI), a natural naphthoquinone derived from Arnebia euchroma (Royle) Johnst., features a broad pharmacological profile and minimal toxicities. To assess the synergism of SHI and OXA towards OXA-resistant CRC cells (HCT116[R]), we employed in vitro and in vivo pharmacological assays. Our experiments provided evidence that SHI, either alone or in combination with OXA, considerably reduced cell proliferation, triggered apoptosis, and induced the generation of reactive oxygen species (ROS) in HCT116[R] cells. Furthermore, the combination of SHI and OXA dramatically curbed the extent of HCT116[R] -initiated xenograft growth in mouse models. Bioinformatics, western blot, and ROS assays highlighted that the mechanisms of SHI against OXA-resistant CRC cells may involve the induction of cellular responses to chemical stress, intrinsic apoptosis, as well as endoplasmic reticulum stress pathways mediated by ROS. Notably, the synergism of SHI+OXA was partially abrogated by an ROS inhibitor N-acetyl cysteine. Our findings imply the potential of SHI to boost the sensitivity of OXA to CRC, offering promising benefits for clinical strategies to combat OXA resistance.},
}
@article {pmid36777598,
year = {2023},
author = {Önem, AN and Sözgen Başkan, K and Apak, R},
title = {Voltammetric Measurement of Antioxidant Activity by Prevention of Cu(II)-Induced Oxidative Damage on DNA Bases Using a Modified Electrode.},
journal = {ACS omega},
volume = {8},
number = {5},
pages = {5103-5115},
pmid = {36777598},
issn = {2470-1343},
abstract = {The protective effect of antioxidants using electrochemical techniques can be evaluated by examining the oxidative changes in deoxyribonucleic acid (DNA) nucleobases. In this study, a gold nanoparticle (AuNP)-decorated and multiwalled carbon nanotube (MWCNT)-Nafion-modified glassy carbon electrode (GCE/AuNP/MWCNT-Nafion) was developed to evaluate the preventive ability of antioxidants on oxidative DNA damage. A modified working electrode was prepared and characterized by cyclic voltammetry, electrochemical impedance spectroscopy, and scanning electron microscopy. The developed electrochemical method relies on two phenomena: (i) reactive species (RS) produced by dissolved oxygen in the presence of copper(II) partially damage the DNA immobilized on the electrode surface and (ii) antioxidant compounds prevent this damage by scavenging the formed RS. Changes in guanine, adenine, and cytosine oxidation signals resulting from DNA damage were measured using differential pulse stripping voltammetry before/after the interaction of dsDNA with Cu(II) while antioxidants were absent or present. The DNA protective ability of antioxidants was assessed for a number of antioxidant compounds (i.e., ascorbic acid, gallic acid, epicatechin, catechin, epicatechin gallate, glutathione, chlorogenic acid, N-acetyl cysteine, rosmarinic acid, quercetin, and rutin). Quercetin was found to show the highest antioxidant effect, and its limit of detection was determined as 1 μM. The manufactured biosensor was put in an application for the determination of antioxidant activity of herbal teas.},
}
@article {pmid36775116,
year = {2023},
author = {Sharma, JR and Agraval, H and Yadav, UCS},
title = {Cigarette smoke induces epithelial-to-mesenchymal transition, stemness, and metastasis in lung adenocarcinoma cells via upregulated RUNX-2/galectin-3 pathway.},
journal = {Life sciences},
volume = {318},
number = {},
pages = {121480},
doi = {10.1016/j.lfs.2023.121480},
pmid = {36775116},
issn = {1879-0631},
mesh = {Humans ; Epithelial-Mesenchymal Transition ; Galectin 3 ; *Cigarette Smoking ; Reactive Oxygen Species ; *Adenocarcinoma of Lung ; *Lung Neoplasms/pathology ; Transcription Factors ; },
abstract = {AIMS: An elevated level of galectin-3, a carbohydrate-binding lectin implicated in tumorigenesis, metastasis, and epithelial-mesenchymal transition (EMT), has been found in cigarette smokers. However, the regulation of its expression and role in the pathogenesis of CS-induced EMT and lung cancer metastasis is unclear. Here, we have investigated the mechanism of CS-induced and galectin-3-mediated EMT in airway epithelial cells (AECs).<br><br>MAIN METHODS: A549 adenocarcinoma cells and primary small airway epithelial cells cultured on an air-liquid interface (ALI) were exposed to cigarette smoke extract (CSE), and MTT, trypan blue, migration, invasion, tumor spheroid and colony formation assays were performed to assess EMT phenotype. Immunoblotting was performed to assess EMT and stemness markers and other regulatory proteins.<br><br>KEY FINDINGS: CSE exposure affected cell survival and morphology, migration, invasion, and clonogenicity of AECs, which were concomitant with an increase in the expression of EMT markers, galectin-3, and runt-related transcription factor-2 (RUNX-2), an osteogenic transcription factor and upstream regulator of galectin-3. Chemical inhibition or silencing of RUNX-2 downregulated galectin-3 and modulated EMT marker expression, migration, invasion, and clonogenicity in CSE-exposed AECs. Recombinant human galectin-3 also induced EMT and stemness-associated changes in the AECs, and GB1107, a galectin-3 inhibitor, ameliorated these changes. Further, CSE-induced intracellular ROS enabled an increase in RUNX-2 and galectin-3 expression, which were reversed by n-acetyl-cysteine.<br><br>SIGNIFICANCE: These results provide a novel mechanistic insight into CSE-induced EMT via RUNX-2/galectin-3 axis mediated through ROS, which promoted EMT-associated changes, including invasion, migration, and stemness in AECs, which could be implicated in CS-induced lung cancer progression.},
}
@article {pmid36774779,
year = {2023},
author = {Kashif, M and Yao, H and Schmidt, S and Chen, X and Truong, M and Tüksammel, E and Liu, Y and Bergo, MO},
title = {ROS-lowering doses of vitamins C and A accelerate malignant melanoma metastasis.},
journal = {Redox biology},
volume = {60},
number = {},
pages = {102619},
pmid = {36774779},
issn = {2213-2317},
mesh = {Animals ; Humans ; Mice ; Acetylcysteine ; *Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; *Melanoma/drug therapy/genetics/pathology ; Reactive Oxygen Species/metabolism ; Vitamins ; Vitamin A/pharmacology ; Cutaneous Malignant Melanoma ; },
abstract = {Oxidative stress is a barrier of migration and metastasis for malignant melanoma cells. Consequently, reducing oxidative stress with the antioxidant N-acetylcysteine (NAC) stimulates melanoma cell migration in vitro and metastasis in vivo. However, it is not yet known whether the NAC effect is shared with other antioxidants. Here, we screened 104 redox-active compounds and identify 27 that increase migration of human malignant melanoma cells in two doses. Validation experiments in four cell lines and four drug doses resulted in a list of 18 compounds which were ranked based on their ability to increase migration and reduce ROS levels; vitamin C (VitC) ranked as number one, followed by the vitamin E analogue Trolox and several carotenoids and Vitamin A-related compounds. Four diet-relevant compounds from this list-VitC, β-carotene, retinyl palmitate, and canthaxanthin-were selected and found to accelerate metastasis in mice with BRAF[V600E]-driven malignant melanoma. Genomics analyses revealed that the transcription factor BACH1 is activated following antioxidant administration and knockout of Bach1 in mouse melanoma cells reduced lymph node and liver metastasis in xenograft mouse models. We conclude that a broad range of antioxidants accelerate melanoma migration and metastasis and that BACH1 is functionally linked to melanoma metastasis in vivo.},
}
@article {pmid36773561,
year = {2023},
author = {Chu, Y and Xu, Y and Yang, W and Chu, K and Li, S and Guo, L},
title = {N-acetylcysteine protects human periodontal ligament fibroblasts from pyroptosis and osteogenic differentiation dysfunction through the SIRT1/NF-κB/Caspase-1 signaling pathway.},
journal = {Archives of oral biology},
volume = {148},
number = {},
pages = {105642},
doi = {10.1016/j.archoralbio.2023.105642},
pmid = {36773561},
issn = {1879-1506},
mesh = {Humans ; *NF-kappa B/metabolism ; *Acetylcysteine/pharmacology ; Osteogenesis ; Caspase 1/metabolism ; Pyroptosis ; Reactive Oxygen Species/metabolism ; Periodontal Ligament ; Lipopolysaccharides/pharmacology ; Sirtuin 1/metabolism/pharmacology ; Cells, Cultured ; Signal Transduction ; Cell Differentiation ; Fibroblasts ; Adenosine Triphosphate/metabolism ; },
abstract = {OBJECTIVE: This study was aimed to determine whether N-acetylcysteine (NAC) could inhibit lipopolysaccharides / adenosine triphosphate (ATP)-induced pyroptosis and alleviate the damage of osteogenic differentiation in human periodontal ligament fibroblasts (hPDLFs). Furthermore, this study detected whether NAC acted effectively by modulating the silent information regulator 2 homolog 1 (SIRT1)/ the nuclear factor-κB (NF-κB)/Caspase-1 signaling pathway in hPDLFs.<br><br>DESIGN: Cell Counting Kit-8 assay was employed to determine the appropriate concentration of NAC for the follow-up experiments. To explore the effect and the underlying mechanisms of NAC on pyroptosis and osteogenic differentiation in hPDLFs, intracellular reactive oxygen species levels were detected using 2',7'-Dichlorodihydrofluorescein Diacetate kits. Moreover, SIRT1 inhibitor, SIRT1 activator, NF-&#x3ba;B inhibitor and Caspase-1 inhibitor were applied, the incidence of pyroptosis was detected by flow cytometry, the osteogenic differentiation of hPDLFs was observed using alkaline phosphatase and alizarin red staining, Real-time quantitative polymerase chain reaction and Western Blot were used to detect the expression of relevant factors, the release of interleukin-1&#x3b2;, interleukin-18 and lactate dehydrogenase were detected by Enzyme-linked immunosorbent assay.<br><br>RESULTS: The results demonstrated that NAC protected hPDLFs from lipopolysaccharides/ATP-induced damage, alleviating pyroptosis and osteogenic differentiation dysfunction. Moreover, NAC abrogated the inhibition of SIRT1 activity by scavenging reactive oxygen species, thereby reduced pyroptosis and osteogenic differentiation dysfunction by inhibiting the NF-&#x3ba;B/Caspase-1signaling pathway.<br><br>CONCLUSION: NAC could inhibit pyroptosis and osteogenic differentiation dysfunction of hPDLFs by scavenging reactive oxygen species to regulate the SIRT1/NF-&#x3ba;B/Caspase-1 signaling axis.},
}
@article {pmid36770846,
year = {2023},
author = {Eom, JW and Lim, JW and Kim, H},
title = {Lutein Induces Reactive Oxygen Species-Mediated Apoptosis in Gastric Cancer AGS Cells via NADPH Oxidase Activation.},
journal = {Molecules (Basel, Switzerland)},
volume = {28},
number = {3},
pages = {},
pmid = {36770846},
issn = {1420-3049},
support = {no number//BK21 FOUR project, Yonsei University, Republic of Korea./ ; },
mesh = {Humans ; Reactive Oxygen Species/metabolism ; *NF-kappa B/metabolism ; *Stomach Neoplasms/drug therapy ; Lutein/pharmacology ; Antioxidants/pharmacology ; bcl-2-Associated X Protein ; Apoptosis ; Caspases ; NADPH Oxidases/metabolism ; },
abstract = {Disruption of apoptosis leads to cancer cell progression; thus, anticancer agents target apoptosis of cancer cells. Reactive oxygen species (ROS) induce apoptosis by activating caspases and caspase-dependent DNase, leading to DNA fragmentation. ROS increase the expression of apoptotic protein Bax, which is mediated by activation of nuclear factor-κB (NF--κB). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important source of endogenous ROS, and its activation is involved in apoptosis. Lutein, an oxygenated carotenoid and known antioxidant, is abundant in leafy dark green vegetables, such as spinach and kale, and in yellow-colored foods, such as corn and egg yolk. High amounts of lutein increase ROS levels and exhibit anticancer activity. However, its anticancer mechanism remains unclear. This study aimed to determine whether lutein activates NADPH oxidase to produce ROS and induce apoptosis in gastric cancer AGS cells. Lutein increased ROS levels and promoted the activation of NADPH oxidase by increasing the translocation of NADPH oxidase subunit p47 [phox] to the cell membrane. It increased NF-κB activation and apoptotic indices, such as Bax, caspase-3 cleavage, and DNA fragmentation, and decreased Bcl-2, cell viability, and colony formation in AGS cells. The specific NADPH oxidase inhibitor ML171, and the known antioxidant N-acetyl cysteine reversed lutein-induced cell death, DNA fragmentation, and NF-κB DNA-binding activity in AGS cells. These results suggest that lutein-induced ROS production is dependent on NADPH oxidase, which mediates NF-κB activation and apoptosis in gastric cancer AGS cells. Therefore, lutein supplementation may be beneficial for increasing ROS-mediated apoptosis in gastric cancer cells.},
}
@article {pmid36769455,
year = {2023},
author = {Ito, K and Kise, H and Suzuki, S and Nagai, S and Hachiya, K and Takeda, H and Kawabata, S and Ikeda, D and Takubo, K and Kaneko, S and Fujita, N},
title = {Potential Involvement of Oxidative Stress in Ligamentum Flavum Hypertrophy.},
journal = {Journal of clinical medicine},
volume = {12},
number = {3},
pages = {},
pmid = {36769455},
issn = {2077-0383},
support = {19K09634//JSPS/ ; },
abstract = {Oxidative stress (OS) results in many disorders, of which degenerative musculoskeletal conditions are no exception. However, the interaction between OS and ligamentum flavum (LF) hypertrophy in lumbar spinal canal stenosis is not clearly understood. The first research question was whether OS was involved in LF hypertrophy, and the second was whether the antioxidant N-acetylcysteine (NAC) was effective on LF hypertrophy. In total, 47 LF samples were collected from patients with lumbar spinal disorders. The cross-sectional area of LF was measured on axial magnetic resonance imaging. Immunohistochemistry of 8-OHdG and TNF-α were conducted on human LF samples. A positive association was found between 8-OHdG or TNF-α expression and cross-sectional area of LF. Flow cytometry analysis showed that H2O2, buthionine sulfoximine, and TNF-α treatment significantly increased intracellular reactive oxygen species in primary LF cells. NAC inhibited the induction of LF hypertrophy markers by OS or TNF in a real-time reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Western blotting analysis indicated that p38, Erk, and p65 phosphorylation were involved in intracellular OS signaling in LF cells. In conclusion, our results indicated that OS could be a therapeutic target for LF hypertrophy. Although this study included no in vivo studies to examine the longitudinal efficacy of NAC on LF hypertrophy, NAC may have potential as a therapeutic agent against lumbar spinal canal stenosis.},
}
@article {pmid36764275,
year = {2023},
author = {Zhou, Y and Zhang, Y and Wang, H and Zhang, X and Chen, Y and Chen, G},
title = {Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway.},
journal = {International immunopharmacology},
volume = {116},
number = {},
pages = {109725},
doi = {10.1016/j.intimp.2023.109725},
pmid = {36764275},
issn = {1878-1705},
mesh = {Animals ; Mice ; Caspase 1/metabolism ; *Cognitive Dysfunction/chemically induced/metabolism ; Hippocampus/metabolism ; *Inflammasomes/metabolism ; Microglia ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Pyroptosis ; Reactive Oxygen Species/metabolism ; *Sevoflurane/adverse effects ; },
abstract = {BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication with its pathophysiological mechanisms not been fully elucidated. Pyroptosis is a novel type of pro-inflammatory cell death and considered to be associated with cognitive dysfunction. Therefore, our study aimed to examine the effect of pyroptosis on sevoflurane-induced cognitive impairment in aged mice as well as its underlying mechanism.<br><br>METHODS: A mice model of cognitive impairment was established by sevoflurane exposure and the levels of reactive oxygen species (ROS), N-GSDMD, cleaved caspase-1, ASC, IL-1&#x3b2; and IL-18, and NLRP3 in hippocampus was determined. To explore the underlying mechanism, a pyroptosis inhibitor, necrosulfonamide (NSA), and a ROS scavenger, N-acetylcysteine (NAC), were administrated before sevoflurane exposure both in vitro and in vivo. Neurobehavioral tests, western blot, transmission electron microscope (TEM) observation, and immunofluorescence staining were performed.<br><br>RESULTS: Sevoflurane induced hippocampal pyroptosis in the cognitive impairment model. NSA effectively inhibited the pyroptosis and improved cognitive function. Co-labeled immunofluorescence staining suggested sevoflurane induces microglial pyroptosis. Sevoflurane induced pyroptosis accompanied with ROS accumulation in a dose-independent manner in BV2 cells, and NAC effectively reduce the levels of ROS and pyroptosis through NLRP3 inflammasome pathway in both vitro and vivo. Furthermore, NAC could also alleviate sevoflurane-induced cognitive dysfunction.<br><br>CONCLUSIONS: Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway. Both pyroptosis inhibition and ROS scavenging might be potential approaches to ameliorate sevoflurane-induced neurocognitive dysfunction.},
}
@article {pmid36762617,
year = {2023},
author = {Zhai, L and Ruan, S and Wang, J and Guan, Q and Zha, L},
title = {NADPH oxidase 4 regulate the glycolytic metabolic reprogramming of microglial cells to promote M1 polarization.},
journal = {Journal of biochemical and molecular toxicology},
volume = {37},
number = {5},
pages = {e23318},
doi = {10.1002/jbt.23318},
pmid = {36762617},
issn = {1099-0461},
mesh = {Animals ; Mice ; *Glycolysis ; Lipopolysaccharides ; *Microglia/metabolism ; *NADPH Oxidase 4/genetics/metabolism ; *Neuroinflammatory Diseases ; Reactive Oxygen Species/metabolism ; },
abstract = {This work aimed to investigate the role and mechanism of NADPH oxidase 4 (NOX4) in the polarization of microglial cells. Microglial cells were transfected with the NOX4 overexpression plasmid (pGL3-NOX4), and later treated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) to induce its M1 polarization. Later, the F4/80 + CD86 + cell proportion was detected by flow cytometry (FCM), the inflammatory factor expression levels were analyzed through enzyme-linked immunosorbent assay (ELISA), while ionized calcium binding adapter molecule 1 (IBA-1) and PKM2 expression were measured by immunofluorescence (IF) staining. In addition, dichlorodihydrofluorescein diacetate probe was utilized to detect the reactive oxygen species (ROS) levels, glucose uptake, and glycolysis, as well as lactic acid level. The expression of glycolytic enzymes PKM2, HK2, and citrate (Si)-synthas (CS) was detected by Western-blot (WB) assay. Moreover, the polarization level of microglial cells was detected after ROS expression was suppressed by the ROS inhibitor N-acetylcysteine (NAC). In mouse experiments, LPS was applied in inducing central neuroinflammation in NOX4 knockdown mouse model (KO) and wild-type mice (WT). Thereafter, the inflammatory factor levels and lactic acid level in mouse tissues were detected; IBA-1 and CD86 expression in mice was measured by IF staining; and the expression of glycolytic enzymes PKM2, HK2, and CS in the central nervous system (CNS) was also detected. After NOX4 overexpression in microglial cells, the M1 polarization level was upregulated, the F4/80 + CD86 + cell proportion increased, and inflammatory factors were upregulated. At the same time, the expression of glycolytic enzymes PKM2, HK2, and CS was upregulated. NAC pretreatment suppressed the effects of NOX4, reduced the F4/80 + CD86 + cell proportion, and suppressed the expression of PKM2, HK2, and CS. In the mouse model, the expression levels of CD86 in KO group decreased, and the inflammatory factors were also downregulated. NOX4 promotes glycolysis of microglial cells via ROS, thus accelerating M1 polarization and inflammatory factor expression. In this regard, NOX4 is promising as a new target for the treatment of neuroinflammation.},
}
@article {pmid36759944,
year = {2022},
author = {Tan, R and Black, M and Home, J and Blackwell, J and Clark, I and Wylie, L and Vanhatalo, A and Jones, AM},
title = {Physiological and performance effects of dietary nitrate and N-acetylcysteine supplementation during prolonged heavy-intensity cycling.},
journal = {Journal of sports sciences},
volume = {40},
number = {23},
pages = {2585-2594},
doi = {10.1080/02640414.2023.2176052},
pmid = {36759944},
issn = {1466-447X},
mesh = {Humans ; Male ; *Exercise/physiology ; *Fruit and Vegetable Juices ; *Nitrates/blood ; *Acetylcysteine/administration &amp; dosage ; Antioxidants/administration &amp; dosage ; *Dietary Supplements ; Cross-Over Studies ; Reactive Oxygen Species ; Endurance Training ; Oxygen Consumption/physiology ; Nitrites/blood ; Adult ; *Plant Extracts/pharmacology ; Plant Roots ; },
abstract = {The purpose of this study was to investigate effects of concurrent and independent administration of dietary nitrate (NO3[-]), administered as NO3[-]-rich beetroot juice (BR; ~12.4 mmol of NO3[-]), and N-acetylcysteine (NAC; 70 mg·kg[-1]) on physiological responses during prolonged exercise and subsequent high-intensity exercise tolerance. Sixteen recreationally active males supplemented with NO3[-]-depleted beetroot juice (PL) or BR for 6 days and ingested an acute dose of NAC or maltodextrin (MAL) 1 h prior to performing 1 h of heavy-intensity cycling exercise immediately followed by a severe-intensity time-to-exhaustion (TTE) test in four conditions: 1) PL+MAL, 2) PL+NAC, 3) BR+MAL and 4) BR+NAC. Pre-exercise plasma [NO3[-]] and nitrite ([NO2[-]]) were elevated following BR+NAC and BR+MAL (both P < 0.01) compared with PL+NAC and PL+MAL; plasma [cysteine] was increased in PL+NAC and BR+NAC (both P < 0.01) compared to PL+MAL. Muscle excitability declined over time during the prolonged cycling bout in all conditions but was better preserved in PL+NAC compared to BR+NAC (P < 0.01) and PL+MAL (P < 0.05). There was no effect of supplementation on subsequent TTE . These findings indicate that co-ingestion of BR and NAC does not appreciably alter physiological responses during prolonged heavy-intensity cycling or enhance subsequent exercise tolerance.},
}
@article {pmid36757588,
year = {2023},
author = {Gupta, J and Rajamani, P},
title = {Size- and surface functionalization-driven molecular interaction of CdSe quantum dots with jack bean urease: multispectroscopic, thermodynamic, and AFM approach.},
journal = {Environmental science and pollution research international},
volume = {30},
number = {16},
pages = {48300-48322},
pmid = {36757588},
issn = {1614-7499},
support = {UGC ref No.: 3798/ (NET-DEC 2018)//University Grants Commission/ ; },
mesh = {Humans ; *Quantum Dots/chemistry ; Urease/metabolism ; *Cadmium Compounds/chemistry ; *Selenium Compounds/chemistry ; Glutathione ; Acetylcysteine ; Thermodynamics ; *Cysts ; Tumor Microenvironment ; },
abstract = {Quantum dots (QDs) with distinctive optical properties have been extensively researched and developed for usage in solar cells, imaging, drug delivery, cellular targeting, etc. But the inevitable production of QDs can lead to their unavoidable release and increased environmental concentration. Depending on morphological and surface properties, QDs at the nano-bio interface considerably impact the activity and structure of bio-molecules. The present study investigates the interaction of metalloenzyme jack bean urease (JBU) and bi-sized CdSe QDs (2.43 nm and 3.63 nm), surface-functionalized to mercaptopropionic acid (MPA) (-COOH), L-cysteine (CYS), L-glutathione (GSH), N-acetyl L-cysteine (NAC) (-COOH, -NH2), and cysteamine hydrochloride (CYST) (-NH2) to assess any alterations in JBU's binding, microenvironment, structure, exciton lifetime, and activity. JBU catalyzes the hydrolysis of urea to produce ammonia and carbon dioxide; any changes in its properties could threaten the survival of several microbes and plants. Spectroscopy techniques such as UV-Vis, fluorescence, circular dichroism, synchronous, time-resolved fluorescence, atomic force microscopy, and JBU activity assay were studied. Results suggested highly spontaneous and energy-favored interactions, which involved static quenching and hydrophobic forces of varied magnitude, dependent on QDs properties. The size, surface modifications, and dosage of QDs significantly impacted the secondary structure and activity of JBUs. Even though the larger sizes of the relevant modifications demonstrated stronger binding, the smaller sizes had the greatest impact on α-helicity and activity. CYST-capped QDs with an average number of the binding site (n) = 1, reduced α-helicity by 16% and activity by 22-30% at 7 nM concentration. In contrast, MPA-capped QDs with n < 1 had the least effect on α-helical structure and activity. The smaller GSH-capped QDs increased the activity by 9%, via partially restoring JBU's α-helical content. The study thus thoroughly analyzed the impact of varied-size and surface-functionalized QDs on the structure and function of JBU, which can be exploited further for several biomedical applications.},
}
@article {pmid36756299,
year = {2023},
author = {Guo, M and Chen, Q and Huang, Y and Wu, Q and Zeng, Y and Tan, X and Teng, F and Ma, X and Pu, Y and Huang, W and Gu, J and Zhang, C and Long, Y and Xu, Y},
title = {High Glucose-Induced Kidney Injury via Activation of Necroptosis in Diabetic Kidney Disease.},
journal = {Oxidative medicine and cellular longevity},
volume = {2023},
number = {},
pages = {2713864},
pmid = {36756299},
issn = {1942-0994},
mesh = {Rats ; Mice ; Animals ; *Diabetic Nephropathies ; Reactive Oxygen Species/metabolism ; Necroptosis ; *Diabetes Mellitus, Experimental/complications ; Kidney/metabolism ; Inflammation ; Glucose/toxicity ; },
abstract = {Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) and is closely associated to programmed cell death. However, the complex mechanisms of necroptosis, an alternative cell death pathway, in DKD pathogenesis are yet to be elucidated. This study indicates that necroptosis is involved in DKD induced by high glucose (HG) both in vivo and in vitro. HG intervention led to the activation of RIPK1/RIPK3/MLKL signaling, resulting in renal tissue necroptosis and proinflammatory activation in streptozotocin/high-fat diet- (STZ/HFD-) induced diabetic mice and HG-induced normal rat kidney tubular cells (NRK-52E). We further found that in HG-induced NRK-52E cell, necroptosis might, at least partly, depend on the levels of reactive oxygen species (ROS). Meanwhile, ROS participated in necroptosis via a positive feedback loop involving the RIPK1/RIPK3 pathway. In addition, blocking RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS generation, could effectively protect the kidney against HG-induced damage, decrease the release of proinflammatory cytokines, and rescue renal function in STZ/HFD-induced diabetic mice. Inhibition of RIPK1 effectively decreased the activation of RIPK1-kinase-/NF-κB-dependent inflammation. Collectively, we demonstrated that high glucose induced DKD via renal tubular epithelium necroptosis, and Nec-1 or NAC treatment downregulated the RIPK1/RIPK3/MLKL pathway and finally reduced necroptosis, oxidative stress, and inflammation. Thus, RIPK1 may be a therapeutic target for DKD.},
}
@article {pmid36756050,
year = {2023},
author = {Yu, Q and Shen, C and Wang, X and Wang, Z and Liu, L and Zhang, J},
title = {Graphene Oxide/Gelatin Nanofibrous Scaffolds Loaded with N-Acetyl Cysteine for Promoting Wound Healing.},
journal = {International journal of nanomedicine},
volume = {18},
number = {},
pages = {563-578},
pmid = {36756050},
issn = {1178-2013},
mesh = {Mice ; Animals ; *Acetylcysteine/pharmacology ; Gelatin/pharmacology ; Wound Healing ; Cicatrix ; *Nanofibers/chemistry ; Tissue Scaffolds/chemistry ; Graphite ; },
abstract = {PURPOSE: We aimed to develop an antioxidant dressing material with pro-angiogenic potential that could promote wound healing. Gelatin (Gel) was selected to improve the biocompatibility of the scaffolds, while graphene oxide (GO) was added to enhance their mechanical property. The loaded N-Acetyl cysteine (NAC) was performing the effect of scavenging reactive oxygen species (ROS) at the wound site.<br><br>MATERIALS AND METHODS: The physicochemical and mechanical properties, NAC releases, and biocompatibility of the NAC-GO-Gel scaffolds were evaluated in vitro. The regeneration capability of the scaffolds was systemically investigated in vivo using the excisional wound-splinting model in mice.<br><br>RESULTS: The NAC-GO-Gel scaffold had a stronger mechanical property and sustainer NAC release ability than the single Gel scaffold, which resulted in a better capacity for cell proliferation and migration. Mice wound-splinting models revealed that the NAC-GO-Gel scaffold effectively accelerated wound healing, promoted re-epithelialization, enhanced neovascularization, and reduced scar formation.<br><br>CONCLUSION: The NAC-GO-Gel scaffold not only promotes wound healing but also reduces scar formation, showing a great potential application for the repair of skin defects.},
}
@article {pmid36753335,
year = {2023},
author = {Gong, B and Zhang, S and Wang, X and Ran, G and Zhang, X and Xi, J and Gao, Z and Lei, Y and Pan, J and Liu, Y and Luan, Y and Zhang, X and Peng, Y and Li, W and Zheng, J},
title = {Inflammation Intensifies Monocrotaline-Induced Liver Injury.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.2c07939},
pmid = {36753335},
issn = {1520-5118},
abstract = {Pyrrolizidine alkaloids (PAs) are the most common toxins of plant origin, and it is evident that PAs pollute soil, water, nearby plants, and derived foods. Cases of human poisoning due to ingestion of PA-contaminated foods have been reported in several countries. Monocrotaline (MCT) is a pyrrolizidine alkaloid from the plants of Crotalaria genus that causes hepatic and cardiopulmonary toxicities, and the exhibition of the toxicities requires the metabolic activation by CYP3A4 to form electrophilic dehydro-monocrotaline (DHM). The present study demonstrated that myeloperoxidase (MPO) also participated in the bioactivation of MCT. N-Chloromonocrotaline was detected in both HClO/MCT incubations and MPO/H2O2/MgCl2/MCT incubations. DHM-derived N-acetylcysteine (NAC) conjugates were detected in the above incubations fortified with NAC. Lipopolysaccharide-induced inflammation in mice resulted in an elevated level of hepatic MPO activity, increased metabolic activation of MCT, and intensified elevation of serum ALT and AST activity induced by MCT. MPO inhibitor 4-aminobenzoic acid hydrazide was found to reverse these alterations. Mpo-KO mice were resistant to the observed potentiating effect of inflammation on MCT-induced liver injury. In conclusion, inflammation intensified MCT-induced liver injury. MPO participated in the observed potentiating effect of inflammation on the hepatotoxicity induced by MCT.},
}
@article {pmid36749578,
year = {2023},
author = {Abedi, B and Tayefi-Nasrabadi, H and Kianifard, D and Basaki, M and Shahbazfar, AA and Piri, A and Dolatyarieslami, M},
title = {The effect of co-administration of artemisinin and N-acetyl cysteine on antioxidant status, spermatological parameters and histopathology of testis in adult male mice.},
journal = {Hormone molecular biology and clinical investigation},
volume = {44},
number = {2},
pages = {207-214},
pmid = {36749578},
issn = {1868-1891},
mesh = {Male ; Mice ; Animals ; *Antioxidants/pharmacology ; Acetylcysteine/pharmacology/metabolism ; Testis/metabolism ; Oxidative Stress ; Semen/metabolism ; Spermatozoa/metabolism ; Glutathione/metabolism ; *Artemisinins/adverse effects/metabolism ; },
abstract = {OBJECTIVES: This in vivo study aimed to evaluate the effect of various concentrations of artemisinin (Art) alone or together with N-acetyl cysteine (NAC) on spermatological indices, antioxidant status, and histopathological parameters of testicular tissue in adult male mice.<br><br>METHODS: Six groups of five healthy male mice (25-30&#xa0;g) were randomly assigned to different experimental groups. These groups received DMSO and corn oil (0.1%) as an Art solvent (Control), 50&#xa0;mg&#xa0;kg[-1] Art (Art-50), 250&#xa0;mg&#xa0;kg[-1] Art (Art-250), 50&#xa0;mg&#xa0;kg[-1] Art&#xa0;+&#xa0;150&#xa0;mg&#xa0;kg[-1] NAC (Art-50+NAC-150), 250&#xa0;mg&#xa0;kg[-1] Art&#xa0;+&#xa0;150&#xa0;mg&#xa0;kg[-1] NAC (Art-250+NAC-150) and 150&#xa0;mg&#xa0;kg[-1] NAC (NAC-150) for a period of 7&#xa0;days. Testes and epididymis were prepared to evaluate the malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), spermatological indices, and histological parameters.<br><br>RESULTS: We showed that the high dose of Art (Art-250) significantly reduced the sperm count, motility, viability, and the activity of CAT and increased the levels of MDA compared to the control group. Also, the overdose of Art caused adverse changes in testicular tissue. Co-administration of NAC with Art (Art-250+NAC-150) corrected the adverse effects of Art.<br><br>CONCLUSIONS: The current study reports that a high dose of Art affects, spermatological parameters, antioxidant/stress oxidative status of the male reproductive system, and NAC is capable neutralize all adverse effects caused by Art.},
}
@article {pmid36740148,
year = {2023},
author = {Kandhari, K and Mishra, JPN and Agarwal, R and Singh, RP},
title = {Acacetin induces sustained ERK1/2 activation and RIP1-dependent necroptotic death in breast cancer cells.},
journal = {Toxicology and applied pharmacology},
volume = {462},
number = {},
pages = {116409},
doi = {10.1016/j.taap.2023.116409},
pmid = {36740148},
issn = {1096-0333},
mesh = {Female ; Humans ; Apoptosis ; *Breast Neoplasms/pathology ; Cell Line, Tumor ; MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/pharmacology ; Flavones ; RNA-Binding Proteins ; Nuclear Pore Complex Proteins ; },
abstract = {Acacetin (AC), a naturally occurring flavonoid has shown anticancer potential. Herein, we studied the mechanisms of cell death and growth inhibition by AC in breast carcinoma T-47D and MDA-MB-231 cells. AC (10-40 μM) significantly decreased the levels of G2/M phase cyclins and CDKs, simultaneously increasing the expression of CDK inhibitors including Cip1/p21. A concentration-dependent increase in cell death was noted in both breast cancer cell lines with no such considerable effects on MCF-10A non-tumorigenic breast cells. The cell death-inducing potential of AC was further confirmed using confocal microscopy and flow cytometry analysis. AC resulted in mitochondrial superoxide generation, DNA damage, and ROS generation. N-acetyl cysteine (NAC) pre-treatment inhibited ROS generation and partially reversed ERK1/2 activation as well as cell death by AC. Further, AC enhanced the expression of RIP1 and RIP3, which mediate necroptosis. RIP1-specific inhibitor Necrostatin-1 (NS-1) reversed the AC-induced DNA damage and cell death. Collectively, these findings, for the first time, suggested that AC exerts its antitumor potential through ROS induction and RIP1-dependent necroptosis in breast carcinoma cells.},
}
@article {pmid36738354,
year = {2023},
author = {Zhang, Y and Peng, X and Xue, M and Liu, J and Shang, G and Jiang, M and Chen, D and Liu, B and Wang, Y and Jia, X and Xu, J and Zhang, F and Hu, Y},
title = {SARS-COV-2 spike protein promotes RPE cell senescence via the ROS/P53/P21 pathway.},
journal = {Biogerontology},
volume = {24},
number = {5},
pages = {813-827},
pmid = {36738354},
issn = {1573-6768},
mesh = {Animals ; Humans ; *Spike Glycoprotein, Coronavirus/metabolism ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Tumor Suppressor Protein p53/metabolism ; Zebrafish ; *COVID-19 ; SARS-CoV-2/metabolism ; Cellular Senescence/physiology ; },
abstract = {SARS-Cov-2 infection, which has caused the COVID-19 global pandemic, triggers cellular senescence. In this study, we investigate the role of the SARS-COV-2 spike protein (S-protein) in regulating the senescence of RPE cells. The results showed that administration or overexpression of S-protein in ARPE-19 decreased cell proliferation with cell cycle arrest at the G1 phase. S-protein increased SA-β-Gal positive ARPE-19 cells with high expression of P53 and P21, senescence-associated inflammatory factors (e.g., IL-1β, IL-6, IL-8, ICAM, and VEGF), and ROS. Elimination of ROS by N-acetyl cysteine (NAC) or knocking down p21 by siRNA diminished S-protein-induced ARPE cell senescence. Both administrated and overexpressed S-protein colocalize with the ER and upregulate ER-stress-associated BIP, CHOP, ATF3, and ATF6 expression. S-protein induced P65 protein nuclear translocation. Inhibition of NF-κB by bay-11-7082 reduced S-protein-mediated expression of senescence-associated factors. Moreover, the intravitreal injection of S-protein upregulates senescence-associated inflammatory factors in the zebrafish retina. In conclusions, the S-protein of SARS-Cov-2 induces cellular senescence of ARPE-19 cells in vitro and the expression of senescence-associated cytokines in zebrafish retina in vivo likely by activating ER stress, ROS, and NF-κb. These results may uncover a potential association between SARS-cov-2 infection and development of AMD.},
}
@article {pmid36736558,
year = {2023},
author = {Hao, W and Zhao, C and Li, G and Wang, H and Li, T and Yan, P and Wei, S},
title = {Blue LED light induces cytotoxicity via ROS production and mitochondrial damage in bovine subcutaneous preadipocytes.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {322},
number = {},
pages = {121195},
doi = {10.1016/j.envpol.2023.121195},
pmid = {36736558},
issn = {1873-6424},
mesh = {Animals ; Cattle ; Reactive Oxygen Species/metabolism ; *Oxidative Stress ; *Apoptosis ; Light ; Antioxidants/metabolism ; Autophagy ; },
abstract = {The purpose of this study was to investigate the effect and mechanism of blue light irradiation on bovine subcutaneous preadipocytes. In this study, preadipocytes were divided into dark group (control) and blue light group. Results show that blue light exposure time-dependently reduced the viability of preadipocytes and induced mitochondrial damage, in accompaniment with the accumulation of intracellular reactive oxygen species (ROS). Meanwhile, blue light caused oxidative stress, as evidenced by the increased MDA level, the reduced T-AOC contents, as well as the decreased activities of antioxidant enzymes. Additionally, blue light treatment induced apoptosis and G2/M phase arrest via Bcl-2/Bax/cleaved caspase-3 pathway and P53/GADD45 pathway, respectively. Protein expressions of LC3-II/LC3-I and P62 were up-regulated under blue light exposure, indicating blue light initiated autophagy but impeded autophagic degradation. Moreover, blue light caused an increase in the secretion of pro-inflammatory factors (TNF-α, IL-1β, and IL-6). Pretreatment with N-acetylcysteine (NAC), a potent ROS scavenger, restored the loss of mitochondrial membrane potential (Δψ) and reduced excess ROS. Additionally, the above negative effects of blue light on cells were alleviated after NAC administration. In conclusion, this study demonstrates blue light induces cellular ROS overproduction and Δψ depolarization, resulting in the decrease of cell viability and the activation of apoptosis, autophagy, and inflammation, providing a reference for the application of blue light in the regulation of fat cells in the future.},
}
@article {pmid36728396,
year = {2023},
author = {Chen, CH and Hung, KF and Huang, CY and Leong, JL and Chu, YC and Chang, CY and Wang, ML and Chiou, SH and Cheng, YF},
title = {Is N -acetylcysteine effective in treating patients with coronavirus disease 2019? A meta-analysis.},
journal = {Journal of the Chinese Medical Association : JCMA},
volume = {86},
number = {3},
pages = {274-281},
pmid = {36728396},
issn = {1728-7731},
mesh = {Humans ; *COVID-19 ; Acetylcysteine/therapeutic use ; SARS-CoV-2 ; Length of Stay ; },
abstract = {BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has brought tremendous challenges to public health and medical systems around the world. The current strategy for drug repurposing has accumulated some evidence on the use of N -acetylcysteine (NAC) in treating patients with COVID-19. However, the evidence remains debated.<br><br>METHODS: We performed the systematic review and meta-analysis that complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five databases and reference lists were searched from inception to May 14, 2022. Studies evaluating the efficacy of NAC in treating patients with COVID-19 were regarded as eligible. The review was registered prospectively on PROSPERO (CRD42022332791).<br><br>RESULTS: Of 778 records identified from the preliminary search, four studies were enrolled in the final qualitative review and quantitative meta-analysis. A total of 355 patients were allocated into the NAC group and the control group. The evaluated outcomes included intubation rate, improvement, duration of intensive unit stay and hospital stay and mortality. The pooled results showed nonsignificant differences in intubation rate (OR, 0.55; 95% CI, 0.16-1.89; p = 0.34; I2 = 75%), improvement of oxygenation ([MD], 80.84; 95% CI, -38.16 to 199.84; p = 0.18; I2 = 98%), ICU stay (MD, -0.74; 95% CI, -3.19 to 1.71; p = 0.55; I2 = 95%), hospital stay (MD, -1.05; 95% CI, -3.02 to 0.92; p = 0.30; I2 = 90%), and mortality (OR, 0.58; 95% CI, 0.23-1.45; p = 0.24; I2 = 54%). Subsequent trial sequential analysis (TSA) showed conclusive nonsignificant results for mortality, while the TSA for the other outcomes suggested that a larger sample size is essential.<br><br>CONCLUSIONS: The current evidence reveals NAC is not beneficial for treating patients with COVID- 19 with regard to respiratory outcome, mortality, duration of ICU stay and hospital stay.},
}
@article {pmid36723800,
year = {2023},
author = {Liu, H and Alhassan, N and Yoon, KT and Almutlaq, L and Lee, SS},
title = {Oxidative stress triggers hyperdynamic circulation via central neural activation in portal hypertensive rats.},
journal = {Hepatology international},
volume = {17},
number = {3},
pages = {689-697},
pmid = {36723800},
issn = {1936-0541},
mesh = {Rats ; Animals ; *Peroxidase/metabolism/pharmacology ; Rats, Sprague-Dawley ; Hydrogen Peroxide/pharmacology ; *Hypertension, Portal ; Hemodynamics ; Portal Vein ; Oxidative Stress ; },
abstract = {BACKGROUND: Hyperdynamic circulation in portal hypertension (PHT) depends on central neural activation. However, the initiating mechanism that signals PHT to the central neural cardiovascular-regulatory centers remains unclear. We aimed to test the hypothesis that oxidative stress in the gut initiates the signal that activates central cardiovascular nuclei in portal hypertensive rats.<br><br>METHODS: Two groups of rats were used. One had portal hypertension produced by partial portal vein ligation, while controls underwent sham operation. Hemodynamics including portal pressure, cardiac output, mean arterial pressure (MAP) and peripheral vascular resistance were measured. Activation of central cardiovascular nuclei was determined by immunohistochemical Fos expression in the paraventricular nucleus (PVN) of the hypothalamus. Myeloperoxidase activity, an oxidative stress marker, was measured in the jejunum. Hydrogen peroxide, the antioxidant N-acetyl-cysteine (NAC) or saline controls were administered for 12-14&#xa0;days by gavage or osmotic minipumps placed in the peritoneal cavity.<br><br>RESULTS: Compared with controls, PHT rats showed increased cardiac output (54.2&#x2009;&#xb1;&#x2009;9.5 vs 33.6&#x2009;&#xb1;&#x2009;2.4&#xa0;ml/min/100&#xa0;g BW, p&#x2009;<&#x2009;0.01), decreased MAP (96.2&#x2009;&#xb1;&#x2009;6.4&#xa0;mmHg vs 103.2&#x2009;&#xb1;&#x2009;7.8, p&#x2009;<&#x2009;0.01) and systemic vascular resistance (1.84&#x2009;&#xb1;&#x2009;0.28 vs 3.14&#x2009;&#xb1;&#x2009;0.19&#xa0;mmHg/min/ml/100&#xa0;g BW, p&#x2009;<&#x2009;0.01). PHT rats had increased jejunal myeloperoxidase and PVN Fos expression. NAC treatment eliminated the hyperdynamic circulation, decreased jejunal myeloperoxidase and PVN Fos expression in PHT rats, but had no effect on sham controls. H2O2 significantly increased PVN Fos expression and decreased MAP.<br><br>CONCLUSION: These results indicate that in PHT, mesenteric oxidative stress is the initial signal that activates chemoreceptors and triggers hyperdynamic circulation by central neural cardiovascular-regulatory centers.},
}
@article {pmid36722116,
year = {2023},
author = {Takeuchi, M and Nishisho, T and Toki, S and Kawaguchi, S and Tamaki, S and Oya, T and Uto, Y and Katagiri, T and Sairyo, K},
title = {Blue light induces apoptosis and autophagy by promoting ROS-mediated mitochondrial dysfunction in synovial sarcoma.},
journal = {Cancer medicine},
volume = {12},
number = {8},
pages = {9668-9683},
pmid = {36722116},
issn = {2045-7634},
mesh = {Humans ; Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Sarcoma, Synovial/therapy/pathology ; Apoptosis ; Autophagy ; Mitochondria ; Cell Line, Tumor ; },
abstract = {BACKGROUND: Synovial sarcoma (SS) has limited treatment options and there is an urgent need to develop a novel therapeutic strategy to treat SS. Blue light (BL) has been shown to inhibit the growth of several cancer cells. However, the efficacy of BL in soft tissue sarcomas such as SS has not been demonstrated, and the detailed mechanism underlying the antitumor activity of BL is not fully understood. In this study, we investigated the antitumor effect of BL on SS.<br><br>METHODS: Human SS cell lines were continuously irradiated with BL using light-emitting diodes (LEDs) in an incubator for in vitro analysis. The chicken chorioallantoic membrane (CAM) tumors and xenograft tumors in mice were subjected to daily BL irradiation with LEDs.<br><br>RESULTS: BL caused growth inhibition of SS cells and histological changes in CAM tumors. BL also suppressed the migration and invasion abilities of SS cells. The type of cell death in SS cells was revealed to be apoptosis. Furthermore, BL induced excessive production of reactive oxygen species (ROS) in mitochondria, resulting in oxidative stress and malfunctioned mitochondria. Reducing the production of ROS using N-acetylcysteine (NAC), a ROS scavenger, attenuated the inhibitory effect of BL on SS cells and mitochondrial dysfunction. In addition, BL induced autophagy, which was suppressed by the administration of NAC. The autophagy inhibitor of 3-methyladenine and small interfering RNA against the autophagy marker light chain 3B facilitated apoptotic cell death. Moreover, BL suppressed tumor growth in a mouse xenograft model.<br><br>CONCLUSION: Taken together, our results revealed that BL induced apoptosis via the ROS-mitochondrial signaling pathway, and autophagy was activated in response to the production of ROS, which protected SS cells from apoptosis. Therefore, BL is a promising candidate for the development of an antitumor therapeutic strategy targeting SS.},
}
@article {pmid36716335,
year = {2023},
author = {Gaymon, DO and Barndt, R and Stires, H and Riggins, RB and Johnson, MD},
title = {ROS is a master regulator of in vitro matriptase activation.},
journal = {PloS one},
volume = {18},
number = {1},
pages = {e0267492},
pmid = {36716335},
issn = {1932-6203},
support = {R01 CA123223/CA/NCI NIH HHS/United States ; T32 CA009686/CA/NCI NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; },
mesh = {Reactive Oxygen Species/metabolism ; Lapatinib ; Etoposide ; *Phosphatidylinositol 3-Kinases ; *Mitogen-Activated Protein Kinase Kinases ; Serine Endopeptidases ; },
abstract = {Matriptase is a type II transmembrane serine protease that is widely expressed in normal epithelial cells and epithelial cancers. Studies have shown that regulation of matriptase expression and activation becomes deranged in several cancers and is associated with poor disease-free survival. Although the central mechanism of its activation has remained unknown, our lab has previously demonstrated that inflammatory conditions such as intracellular pH decrease strongly induces matriptase activation. In this investigation, we first demonstrate clear matriptase activation following Fulvestrant (ICI) and Tykerb (Lapatinib) treatment in HER2-amplified, estrogen receptor (ER)-positive BT474, MDA-MB-361 and ZR-75-30 or single ER-positive MCF7 cells, respectively. This activation modestly involved Phosphoinositide 3-kinase (PI3K) activation and occurred as quickly as six hours post treatment. We also demonstrate that matriptase activation is not a universal hallmark of stress, with Etoposide treated cells showing a larger degree of matriptase activation than Lapatinib and ICI-treated cells. While etoposide toxicity has been shown to be mediated through reactive oxygen species (ROS) and MAPK/ERK kinase (MEK) activity, MEK activity showed no correlation with matriptase activation. Novelly, we demonstrate that endogenous and exogenous matriptase activation are ROS-mediated in vitro and inhibited by N-acetylcysteine (NAC). Lastly, we demonstrate matriptase-directed NAC treatment results in apoptosis of several breast cancer cell lines either alone or in combination with clinically used therapeutics. These data demonstrate the contribution of ROS-mediated survival, its independence of kinase-mediated survival, and the plausibility of using matriptase activation to indicate the potential success of antioxidant therapy.},
}
@article {pmid36713695,
year = {2023},
author = {Mukherjee, S and Sawant, AV and Prassanawar, SS and Panda, D},
title = {Copper-Plumbagin Complex Produces Potent Anticancer Effects by Depolymerizing Microtubules and Inducing Reactive Oxygen Species and DNA Damage.},
journal = {ACS omega},
volume = {8},
number = {3},
pages = {3221-3235},
pmid = {36713695},
issn = {2470-1343},
abstract = {Here, we have synthesized a copper complex of plumbagin (Cu-PLN) and investigated its antiproliferative activities in different cancer cells. The crystal structure of Cu-PLN showed that the complex was square planar with a binding stoichiometry of 1:2 (Cu/Plumbagin). Cu-PLN inhibited the proliferation of human cervical carcinoma (HeLa), human breast cancer (MCF-7), and murine melanoma (B16F10) cells with half-maximal inhibitory concentrations (IC50) of 0.85 ± 0.05, 2.3 ± 0.1, and 1.1 ± 0.1 μM, respectively. Plumbagin inhibited the proliferation of HeLa, MCF-7, and B16F10 cells with IC50 of 7 ± 0.1, 8.2 ± 0.2, and 6.2 ± 0.4 μM, respectively, showing that Cu-PLN is a stronger antiproliferative agent than plumbagin. Interestingly, Cu-PLN showed much stronger toxicity against breast carcinoma and skin melanoma cells than noncancerous breast epithelial and skin fibroblast cells, indicating its specific cytotoxicity toward cancer cells. A short exposure of Cu-PLN triggered microtubule disassembly in cultured cancer cells, and the complex also inhibited the polymerization of purified tubulin much more strongly than plumbagin. Furthermore, Cu-PLN inhibited the binding of colchicine to tubulin. In addition to microtubule depolymerization, the antiproliferative mechanism of Cu-PLN involved induction of reactive oxygen species, reduction of the mitochondrial membrane potential, and DNA damage. Moreover, the cytotoxic effects of Cu-PLN reduced significantly in cells pre-treated with N-acetyl cysteine, suggesting that reactive oxygen species generation is crucial in Cu-PLN's mode of action. Thus, the complexation of plumbagin with copper yields a promising antitumor agent having a stronger antiproliferative activity than cisplatin, a widely used anticancer drug.},
}
@article {pmid36713582,
year = {2022},
author = {Brown, K and Jenkins, LMM and Crooks, DR and Surman, DR and Mazur, SJ and Xu, Y and Arimilli, BS and Yang, Y and Lane, AN and Fan, TW and Schrump, DS and Linehan, WM and Ripley, RT and Appella, E},
title = {Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile.},
journal = {Frontiers in oncology},
volume = {12},
number = {},
pages = {1094210},
pmid = {36713582},
issn = {2234-943X},
support = {P30 CA177558/CA/NCI NIH HHS/United States ; },
abstract = {TP53 is the most commonly mutated gene in cancer, and gain-of-function mutations have wide-ranging effects. Efforts to reactivate wild-type p53 function and inhibit mutant functions have been complicated by the variety of TP53 mutations. Identified from a screen, the NSC59984 compound has been shown to restore activity to mutant p53 in colorectal cancer cells. Here, we investigated its effects on esophageal adenocarcinoma cells with specific p53 hot-spot mutations. NSC59984 treatment of cells reactivated p53 transcriptional regulation, inducing mitochondrial intrinsic apoptosis. Analysis of its effects on cellular metabolism demonstrated increased utilization of the pentose phosphate pathway and inhibition of glycolysis at the fructose-1,6-bisphosphate to fructose 6-phosphate junction. Furthermore, treatment of cells with NSC59984 increased reactive oxygen species production and decreased glutathione levels; these effects were enhanced by the addition of buthionine sulfoximine and inhibited by N-acetyl cysteine. We found that the effects of NSC59984 were substantially greater in cells harboring the p53 R248W mutation. Overall, these findings demonstrate p53-dependent effects of NSC59984 on cellular metabolism, with increased activity in cells harboring the p53 R248W mutation. This research highlights the importance of defining the mutational status of a particular cancer to create a patient-centric strategy for the treatment of p53-driven cancers.},
}
@article {pmid36708988,
year = {2023},
author = {Ono, S and Ogura, J and Sugiura, H and Yamauchi, M and Tanaka, A and Sato, T and Maekawa, M and Yamaguchi, H and Mano, N},
title = {Glutathione depletion results in S-nitrosylation of protein disulfide isomerase in neuroblastoma cells.},
journal = {Life sciences},
volume = {316},
number = {},
pages = {121442},
doi = {10.1016/j.lfs.2023.121442},
pmid = {36708988},
issn = {1879-0631},
mesh = {Humans ; Protein Disulfide-Isomerases/metabolism ; *Alzheimer Disease ; Endoribonucleases ; *Neuroblastoma/pathology ; Protein Serine-Threonine Kinases ; Glutathione ; Glutamates ; },
abstract = {AIMS: Protein disulfide isomerase (PDI) is an essential enzyme involved in oxidative protein folding. PDI is S-nitrosylated in the brains of Alzheimer's disease patients, and S-nitrosylated PDI is considered one of main causes of Alzheimer's disease. However, the mechanisms underlying PDI S-nitrosylation have not yet been elucidated. Because glutathione (GSH) depletion is a pathological feature of Alzheimer's disease, we investigated the effect of GSH depletion on the S-nitrosylation level of PDI.<br><br>MAIN METHODS: SH-SY5Y cells, which is a human derived neuroblastoma cells, were used in this study. Glutamate and buthionine sulfoximine (BSO) were used as GSH depletors. S-nitrosylated PDI was detected by biotin-switch assay.<br><br>KEY FINDINGS: GSH depletion by glutamate, a cystine/glutamate antiporter xCT inhibitor, increased S-nitrosylated PDI at C343 in SH-SY5Y cells, and induced IRE1&#x3b1; phosphorylation. BSO, a &#x3b3;-glutamylcysteine synthetase inhibitor, also increased S-nitrosylated PDI and phosphorylated IRE1&#x3b1; upon GSH depletion. Because S-nitrosylated PDI at C343 is stable in neuro cells, S-nitrosylated PDI by GSH depletion progresses to neurodegeneration by the induction of endoplasmic reticulum stress via phosphorylated IRE1&#x3b1; signaling from the early to late stage. Furthermore, treatment with neohesperidin, but not N-acetylcysteine (NAC), improved PDI S-nitrosylation level in GSH-depleted SH-SY5Y cells because nitrosylated compound of NAC induces PDI S-nitrosylation.<br><br>SIGNIFICANCE: The results of our study provide a new insight into the mechanisms of neurodegeneration, and may be useful for the development of drugs for Alzheimer's diseases.},
}
@article {pmid36708663,
year = {2023},
author = {Liu, X and Xi, H and Han, S and Zhang, H and Hu, J},
title = {Zearalenone induces oxidative stress and autophagy in goat Sertoli cells.},
journal = {Ecotoxicology and environmental safety},
volume = {252},
number = {},
pages = {114571},
doi = {10.1016/j.ecoenv.2023.114571},
pmid = {36708663},
issn = {1090-2414},
mesh = {Animals ; Male ; *Zearalenone/toxicity ; Sertoli Cells/metabolism ; Reactive Oxygen Species/metabolism ; Goats/metabolism ; Oxidative Stress ; Apoptosis ; Autophagy ; },
abstract = {Zearalenone (ZEA), one of the non-steroidal estrogen mycotoxin, can cause male reproductive damage and genotoxicity in mammals. Testicular oxidative injury is an important factor causing male sterility. Testicular Sertoli cells are essential for spermatogenesis and male fertility. At present, the mechanism of oxidative injury in dairy goat Sertoli cells after exposure to ZEA remains unclear. This study explored the effects of ZEA on oxidative stress and autophagy in dairy goat Sertoli cells. It was found that treatment of primary Sertoli cells with 25, 50 and 100 μmol/L ZEA for 24 h can promote ROS production, decrease cell viability, antioxidant enzyme activity and mitochondrial membrane potential, induce caspase-dependent cell apoptosis and autophagy activity. ZEA-induced autophagy was confirmed by LC3-I/LC3-II transformation. More importantly, N-acetylcysteine (NAC) pretreatment can remarkably inhibit ZEA-induced oxidative stress, apoptosis and autophagy in Sertoli cells by eliminating ROS. In conclusion, this study indicates that ZEA induces oxidative stress and autophagy in dairy goat Sertoli cells by promoting ROS production.},
}
@article {pmid36708386,
year = {2023},
author = {Fernández-Rodríguez, S and Cano-Cebrián, MJ and Esposito-Zapero, C and Pérez, S and Guerri, C and Zornoza, T and Polache, A},
title = {N-Acetylcysteine normalizes brain oxidative stress and neuroinflammation observed after protracted ethanol abstinence: a preclinical study in long-term ethanol-experienced male rats.},
journal = {Psychopharmacology},
volume = {240},
number = {4},
pages = {725-738},
pmid = {36708386},
issn = {1432-2072},
support = {GVA2016-096//Conselleria de Cultura, Educaci&#xf3;n y Ciencia, Generalitat Valenciana/ ; ACIF/2018/039//Conselleria de Cultura, Educaci&#xf3;n y Ciencia, Generalitat Valenciana/ ; UV-INV_AE18-785117//Universitat de Val&#xe8;ncia/ ; },
mesh = {Rats ; Male ; Animals ; *Ethanol ; Rats, Wistar ; *Acetylcysteine/pharmacology ; Alcohol Abstinence ; Neuroinflammatory Diseases ; Brain ; Chronic Disease ; Oxidative Stress ; Glutamates/metabolism ; Alcohol Drinking/drug therapy ; },
abstract = {RATIONALE: Using a preclinical model based on the Alcohol Deprivation Effect (ADE), we have reported that N-Acetylcysteine (NAC) can prevent the relapse-like drinking behaviour in long-term ethanol-experienced male rats.<br><br>OBJECTIVES: To investigate if chronic ethanol intake and protracted abstinence affect several glutamate transporters and whether NAC, administered during the withdrawal period, could restore the ethanol-induced brain potential dysfunctions. Furthermore, the antioxidant and anti-inflammatory effects of NAC during abstinence in rats under the ADE paradigm were also explored.<br><br>METHODS: The expression of GLT1, GLAST and xCT in nucleus accumbens (Nacc) and dorsal striatum (DS) of male Wistar was analysed after water and chronic ethanol intake. We used the model based on the ADE within another cohort of male Wistar rats. During the fourth abstinence period, rats were treated for 9&#xa0;days with vehicle or NAC (60, 100&#xa0;mg/kg; s.c.). The effects of NAC treatment on (i) glutamate transporters expression in the Nacc and DS, (ii) the oxidative status in the hippocampus (Hip) and amygdala (AMG) and (iii) some neuroinflammatory markers in prefrontal cortex (PFC) were tested.<br><br>RESULTS: NAC chronic administration during protracted abstinence restored oxidative stress markers (GSSG and GGSH/GSH) in the Hip. Furthermore, NAC was able to normalize some neuroinflammation markers in PFC without normalizing the observed downregulation of GLT1 and GLAST in Nacc.<br><br>CONCLUSIONS: NAC restores brain oxidative stress and neuroinflammation that we previously observed after protracted ethanol abstinence in long-term ethanol-experienced male rats. This NAC effect could be a plausible mechanism for its anti-relapse effect. Also, brain oxidative stress and neuroinflammation could represent and identify plausible targets for searching new anti-relapse pharmacotherapies.},
}
@article {pmid36708242,
year = {2022},
author = {yingBai, Y and meiCheng, Y and Wang, W and Yang, L and Yang, Y},
title = {In vivo and in vitro studies of Alloimperatorin induced autophagy in cervical cancer cells via reactive oxygen species pathway.},
journal = {Bioengineered},
volume = {13},
number = {6},
pages = {14299-14314},
pmid = {36708242},
issn = {2165-5987},
mesh = {Mice ; Animals ; Female ; Humans ; *Uterine Cervical Neoplasms/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Nude ; Autophagy ; Apoptosis ; Cell Line, Tumor ; },
abstract = {Alloimperatorin (Alloi) has been shown to have anti-proliferative effects in our previous studies. we aimed to investigate whether Alloimperatorin induces autophagy through the reactive oxygen species (ROS) pathway and anticancer activity in vivo. The anti-proliferative effect of Alloimperatorin was evaluated using a cell counting kit (CCK-8 kit). Apoptosis was detected using flow cytometry. Confocal microscopy, immunofluorescence, and mRFP-GFP-LC3 lentivirus transfection were used to verify autophagy. Electron microscopy detection of autophagosomes was induced by Alloimperatorin. Western blotting was used to detect autophagy proteins in HeLa and SiHa cells. A xenograft model was used to monitor the inhibitory effect of Alloimperatorin on tumor growth in nude mice. The results showed that Alloimperatorin induced ROS production and inhibited the proliferation of HeLa and SiHa cells. Furthermore, Alloimperatorin increased the apoptosis rate in HeLa and SiHa cells. Confocal microscopy fluorescence indicated that Alloimperatorin increased autophagy fluorescence of HeLa and SiHa cells. mRFP-GFP-LC3 lentivirus transfection and electron microscopy demonstrated that Alloimperatorin increased autophagy in HeLa and SiHa cells. Western blotting showed that Alloimperatorin induced the expression of autophagy proteins in HeLa and SiHa cells. However, N-acetylcysteine reversed the autophagy. These results demonstrate that Alloimperatorin can induce autophagy in HeLa and SiHa cells through the ROS pathway. In vivo xenograft experiments showed that Alloimperatorin could inhibit tumor growth in nude mice. Alloimperatorin is expected to be an effective new drug for cervical cancer treatment.Abbreviations: ROS, reactive oxygen species; Alloi, Alloimperatorin; CCK-8, Cell Counting Kit-8; NAC, N-acetyl-L-cysteine; DCFH-DA, 2,7-dichlorodihydrofluorescein diacetate; OD, optical density; PBS, phosphate buffer solution; BCA, bicinchoninic acid; DAPI, 4,6-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide.},
}
@article {pmid36707135,
year = {2023},
author = {Sahoo, DK and Chainy, GBN},
title = {Hormone-linked redox status and its modulation by antioxidants.},
journal = {Vitamins and hormones},
volume = {121},
number = {},
pages = {197-246},
doi = {10.1016/bs.vh.2022.10.007},
pmid = {36707135},
issn = {0083-6729},
mesh = {Humans ; Animals ; *Antioxidants/pharmacology/therapeutic use ; Reactive Oxygen Species/pharmacology ; Oxidative Stress/physiology ; Oxidation-Reduction ; *Melatonin/pharmacology ; },
abstract = {Hormones have been considered as key factors involved in the maintenance of the redox status of the body. We are making considerable progress in understanding interactions between the endocrine system, redox status, and oxidative stress with the dynamics of life, which encompasses fertilization, development, growth, aging, and various pathophysiological states. One of the reasons for changes in redox states of vertebrates leading to oxidative stress scenario is the disruption of the endocrine system. Comprehending the dynamics of hormonal status to redox state and oxidative stress in living systems is challenging. It is more difficult to come to a unifying conclusion when some hormones exhibit oxidant properties while others have antioxidant features. There is a very limited approach to correlate alteration in titers of hormones with redox status and oxidative stress with growth, development, aging, and pathophysiological stress. The situation is further complicated when considering various tissues and sexes in vertebrates. This chapter discusses the beneficial impacts of hormones with antioxidative properties, such as melatonin, glucagon, insulin, estrogens, and progesterone, which protect cells from oxidative damage and reduce pathophysiological effects. Additionally, we discuss the protective effects of antioxidants like vitamins A, E, and C, curcumin, tempol, N-acetyl cysteine, α-lipoic acid, date palm pollen extract, resveratrol, and flavonoids on oxidative stress triggered by hormones such as aldosterone, glucocorticoids, thyroid hormones, and catecholamines. Inflammation, pathophysiology, and the aging process can all be controlled by understanding how antioxidants and hormones operate together to maintain cellular redox status. Identifying the hormonal changes and the action of antioxidants may help in developing new therapeutic strategies for hormonal imbalance-related disorders.},
}
@article {pmid36705628,
year = {2023},
author = {Zhao, Y and Huang, H and Lv, N and Huang, C and Chen, H and Xing, H and Guo, C and Li, N and Zhao, D and Chen, X and Zhang, Y},
title = {Glutathione S-Transferases Mediate In Vitro and In Vivo Inactivation of Genipin: Implications for an Underlying Detoxification Mechanism.},
journal = {Journal of agricultural and food chemistry},
volume = {71},
number = {5},
pages = {2399-2410},
doi = {10.1021/acs.jafc.2c08175},
pmid = {36705628},
issn = {1520-5118},
mesh = {Rats ; Animals ; *Liver/metabolism ; Glutathione Transferase/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism ; Glutathione/metabolism ; Sulfhydryl Compounds/metabolism ; Iridoids ; },
abstract = {Genipin (GP), the reactive metabolite of geniposide (GE), is responsible for GE-induced hepatotoxicity. As a potential detoxification pathway, the inactivation of GP by glutathione S-transferases (GSTs) has not yet been characterized. In this study, the thiol-GSH conjugates of GP, M532-1 and M532-2 were first identified and the catalytic activities of GSTs were investigated both in vitro and in vivo. GSTA1-1 and GSTA4-4 showed high activity in the formation of both thiol-GSH conjugates, whereas GSTA4-4 specifically catalyzed M532-2 formation in vitro. The active GST isoforms protect against alkylation of N-acetylcysteine (NAC), a classic model nucleophile. GST inhibition attenuated M532-1 formation in rat bile, confirming the in vivo catalytic role of GSTs. In conclusion, this study demonstrated the inactivation of GP by GSTs and implied that interindividual variability of GSTs may be a risk factor for susceptibility to GE-induced hepatotoxicity.},
}
@article {pmid36703750,
year = {2022},
author = {Huang, Z and Wang, H and Chun, C and Li, X and Xu, S and Zhao, Y},
title = {Self-assembled FGF21 nanoparticles alleviate drug-induced acute liver injury.},
journal = {Frontiers in pharmacology},
volume = {13},
number = {},
pages = {1084799},
pmid = {36703750},
issn = {1663-9812},
abstract = {Acetaminophen (N-acetyl-p-aminophenol, APAP) is a common antipyretic agent and analgesic. An overdose of APAP can result in acute liver injury (ALI). Oxidative stress and inflammation are central to liver injury. N-acetylcysteine (NAC), a precursor of glutathione, is used commonly in clinical settings. However, the window of NAC treatment is limited, and more efficacious alternatives must be found. Endogenous cytokines such as fibroblast growth factor (FGF) 21 can improve mitochondrial function while decreasing intracellular oxidative stress and inflammatory responses, thereby exhibiting antioxidant-like effects. In this study, self-assembled nanoparticles comprising chitosan and heparin (CH) were developed to deliver FGF21 (CH-FGF21) to achieve the sustained release of FGF21 and optimize the in vivo distribution of FGF21. CH-FGF21 attenuated the oxidative damage and intracellular inflammation caused by APAP to hepatocytes effectively. In a murine model of APAP-induced hepatotoxicity, CH-FGF21 could alleviate ALI progression and promote the recovery of liver function. These findings demonstrated that a simple assembly of CH nanoparticles carrying FGF21 could be applied for the treatment of liver diseases.},
}
@article {pmid36700765,
year = {2023},
author = {Jiang, X and Li, Y and Fu, D and You, T and Wu, S and Xin, J and Wen, J and Huang, Y and Hu, C},
title = {Caveolin-1 ameliorates acetaminophen-aggravated inflammatory damage and lipid deposition in non-alcoholic fatty liver disease via the ROS/TXNIP/NLRP3 pathway.},
journal = {International immunopharmacology},
volume = {114},
number = {},
pages = {109558},
doi = {10.1016/j.intimp.2022.109558},
pmid = {36700765},
issn = {1878-1705},
mesh = {Mice ; Animals ; *Non-alcoholic Fatty Liver Disease/drug therapy/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Acetaminophen ; Reactive Oxygen Species/metabolism ; Caveolin 1/metabolism ; Inflammasomes/metabolism ; Pyroptosis ; Thioredoxins/genetics/metabolism ; RNA, Small Interfering ; *Chemical and Drug Induced Liver Injury/drug therapy ; Lipids ; Carrier Proteins/genetics ; },
abstract = {The overuse of acetaminophen (APAP) may cause more severe hepatotoxicity in patients with non-alcoholic fatty liver disease (NAFLD). Caveolin-1 (CAV1), is an essential regulator of metabolic function, which can alleviate liver damage by scavenging reactive oxygen species (ROS). Evidence suggests that the NOD-like receptor family pyrin domain-containing 3 (NLRP3) -mediated pyroptosis is involved in the development of NAFLD. Moreover, thioredoxin-interactive protein (TXNIP) activation is a key event linking ROS to NLRP3 inflammasome. However, whether CAV1 alleviates APAP-aggravated hepatotoxicity in NAFLD via the ROS/TXNIP/NLRP3 pathway remains unclear. An in vivo fatty liver model was established by feeding mice a high-fat diet for 56 days. Additionally, using in vitro approach, AML-12 cells were incubated with free fatty acids for 48 h and APAP was added during the last 24 h. We found that the overuse of APAP in NAFLD not only induced oxidative stress, but also increased TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition. In addition to inhibiting ROS generation and lipid deposition, overexpression of CAV1 reduced the elevated levels of TXNIP expression and NLRP3-mediated pyroptosis. However, the effect of CAV1 on TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition was reversed by CAV1 small interfering RNA (siRNA) intervention. Finally, N-acetyl cysteine (NAC) treatment reduced CAV1 siRNA-mediated changes in TXNIP expression and NLRP3-mediated pyroptosis levels. These results demonstrate that the inhibitory effect of CAV1 on NLRP3-mediated pyroptosis may be mediated through the ROS/TXNIP axis. Moreover, the current study provides novel mechanistic insights into the protective effects of CAV1 on APAP-aggravated hepatotoxicity in NAFLD.},
}
@article {pmid36700727,
year = {2023},
author = {Grant, JE and Chamberlain, SR},
title = {Monoamine Oxidase Inhibitors for Trichotillomania: A Case Series.},
journal = {Journal of clinical psychopharmacology},
volume = {43},
number = {2},
pages = {149-151},
doi = {10.1097/JCP.0000000000001654},
pmid = {36700727},
issn = {1533-712X},
mesh = {United States ; Humans ; Monoamine Oxidase Inhibitors/therapeutic use ; *Trichotillomania/drug therapy ; Phenelzine ; *Obsessive-Compulsive Disorder/drug therapy ; Selective Serotonin Reuptake Inhibitors ; },
abstract = {PURPOSE/BACKGROUND: Despite several decades of research, there are no US Food and Drug Administration-approved medications for trichotillomania or medications generally approved in other geographical jurisdictions. Monoamine oxidase inhibitors show efficacy in the treatment of depression and some possible promise for obsessive compulsive disorder.<br><br>METHODS/PROCEDURES: We present new data from a case series collected in a specialty clinical practice over a 4-year period.<br><br>FINDINGS/RESULTS: In 5 treatment-resistant patients whose trichotillomania had not improved with at least 1 course of cognitive behavior therapy and trials of n -acetyl cysteine, an antipsychotic, and a serotonin selective reuptake inhibitor, 2 had marked clinical improvement (>40% improvement) on phenelzine, 1 improved on tranylcypromine, and 2 showed no improvement (<10%) on phenelzine. In 2 of the 3 patients who experienced improvement, there was co-occurring depression.<br><br>IMPLICATIONS/CONCLUSIONS: Monoamine oxidase inhibitors in trichotillomania may deserve large-scale randomized controlled trials, particularly in specialist settings where first-line interventions have proven inadequate to manage severe symptoms.},
}
@article {pmid36700278,
year = {2023},
author = {Özdemir, M and Birinci, B and Haberal, B and Ok Atılgan, A and Demirkale, &#x130;},
title = {In vivo study of the role of hyaluronic acid, N-acetyl cysteine, and deproteinized calf serum on injury-induced cartilage degeneration.},
journal = {Joint diseases and related surgery},
volume = {34},
number = {1},
pages = {158-165},
pmid = {36700278},
issn = {2687-4792},
mesh = {Animals ; Rats ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; *Cartilage, Articular/injuries ; *Hyaluronic Acid/pharmacology/therapeutic use ; },
abstract = {OBJECTIVES: The aim of this study was to compare the effects of hyaluronic acid (HA), N-acetyl cysteine (NAC), and deproteinized calf serum on cartilage healing after the creation of traumatic cartilage injury in a rat model.<br><br>MATERIALS AND METHODS: A total of 48 rats, each weighing an average of 350 g, were randomly separated into four groups of 12. An osteochondral defect was created, 2-mm-wide and 3-mm deep in each rat. Injections were made to the knees of the rats as saline solution in Group 1, deproteinized calf serum in Group 2, NAC in Group 3, and HA in Group 4. At the end of 12 weeks, all rats were sacrificed and tissues were evaluated histologically.<br><br>RESULTS: The HA group had a better cell morphology, tissue morphology, surface architecture, and vascularity than the other groups (p<0.001). Matrix staining, chondrocyte clustering, and the assessment scores of the mid, deep, superficial zones, and overall were higher in the HA group than in the other groups (p<0.001). The NAC showed a better tissue morphology, cell morphology, and vascularity than the control group (p=0.003, p<0.001, and p<0.001, respectively).<br><br>CONCLUSION: Hyaluronic acid was the most effective agent in cartilage healing compared to NAC and deproteinized calf serum. In addition, the NAC was more effective compared to the control group.},
}
@article {pmid36689858,
year = {2023},
author = {Lin, CL and Yu, CI and Lee, TH and Chuang, JM and Han, KF and Lin, CS and Huang, WP and Chen, JY and Chen, CY and Lin, MY and Lee, CH},
title = {Plumbagin induces the apoptosis of drug-resistant oral cancer in vitro and in vivo through ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {111},
number = {},
pages = {154655},
doi = {10.1016/j.phymed.2023.154655},
pmid = {36689858},
issn = {1618-095X},
mesh = {Animals ; Mice ; Reactive Oxygen Species/metabolism ; *Zebrafish/metabolism ; Apoptosis ; Cell Line, Tumor ; Mitochondria ; *Mouth Neoplasms/drug therapy/metabolism ; Endoplasmic Reticulum Stress ; Naphthoquinones ; },
abstract = {BACKGROUND: Oral cancer is one of the leading causes of cancer-related deaths worldwide. Chemotherapy is widely used in the treatment of oral cancer, but its clinical efficacy is limited by drug resistance. Hence, novel compounds capable of overcoming drug-resistance are urgently needed.<br><br>PURPOSE: Plumbagin (PG), a natural compound isolated from Plumbago zeylanica L, has been used to treat various cancers. In this study, we investigated the anticancer effects of PG on drug-resistant oral cancer (CR-SAS) cells, as well as the underlying mechanism.<br><br>METHODS: MTT assays were used to evaluate the effect of PG on the viability of CR-SAS cells. Apoptosis and reactive oxygen species (ROS) production by the cells were determined using flow cytometry. Protein expression levels were detected by western blotting.<br><br>RESULTS: The results show that PG reduces the viability and causes the apoptosis of CR-SAS cells. PG is able to induce intracellular and mitochondrial ROS generation that leads to mitochondrial dysfunction. Furthermore, endoplasmic reticulum (ER) stress was triggered in PG-treated CR-SAS cells. The inhibition of ROS using&#xa0;N-acetylcysteine (NAC) abrogated the PG-induced ER stress and apoptosis, as well as the reduction in cell viability.&#xa0;Meanwhile, similar results were observed both in zebrafish and in murine models of drug-resistant oral cancer.<br><br>CONCLUSION: Our results indicate that PG induces the apoptosis of CR-SAS cells via the ROS-mediated ER stress pathway and mitochondrial dysfunction. It will be interesting to develop the natural compound PG for the treatment of drug-resistant oral cancer.},
}
@article {pmid36687698,
year = {2022},
author = {Wang, W and Guan, J and Feng, Y and Nie, L and Xu, Y and Xu, H and Fu, F},
title = {Polystyrene microplastics induced nephrotoxicity associated with oxidative stress, inflammation, and endoplasmic reticulum stress in juvenile rats.},
journal = {Frontiers in nutrition},
volume = {9},
number = {},
pages = {1059660},
pmid = {36687698},
issn = {2296-861X},
abstract = {INTRODUCTION: Unintended intake of microplastic particles has been demonstrated to exert adverse health effects, however, studies on relevant nephrotoxicity in juvenile mammals are lacking.<br><br>METHODS: Therefore, we investigated the potential nephrotoxicity of oral-exposed polystyrene microplastics (PSMPs) (1,000 nm, 2.0 mg/kg/d) for 28 days in juvenile rats. Levels of oxidative stress, inflammation, and endoplasmic reticulum (ER) stress in kidneys were analyzed.<br><br>RESULTS AND DISCUSSION: Results revealed that PSMPs noticeably decreased the growth rate of bodyweight, and organ index of the kidney, cardiac, and ovary. The intestinal injury caused by PSMPs exposure was also observed, which was distinctly alleviated with N-acetyl-cysteine (NAC) and Salubrinal (Sal) treatment compared with the single PSMPs group. PSMPs caused histological lesions of the kidney via disrupting the serum blood urea nitrogen (BUN), creatinine (CRE), and pro-inflammatory mediators IL-1&#x3b2;, IL-6, and TNF-&#x3b1;. Furthermore, PSMPs exposure induced ER stress and inflammation presumably potentially mediated by oxidative stress in kidneys of rats. Eventually, PSMPs also promoted renal cells apoptosis, manifested as an obvious increase in the number of positive cells for the dUTP nick end labeling of Terminal deoxynucleotidyl transferase, which also can be confirmed by the elevated expression of genes associated with apoptosis Bcl-2, Bax, Caspase-12, Caspase-9, Caspase-3, and IHC score of Caspase-12 in the PSMPs group. Supplementation of NAC and Sal not only ameliorated the PSMPs-induced oxidative stress and ER stress but also the inflammation and apoptosis in the kidney. Collectively, this study suggested that PSMPs caused nephrotoxicity in juvenile rats potentially through oxidative damage and ER stress, which call for greater efforts to be taken on regulating the PSMPs ingestion in children.},
}
@article {pmid36686028,
year = {2023},
author = {Dalai, MK and Singh, GK and Bairwa, Y and Chauhan, SS and Ingle, M},
title = {Premedication with simethicone and N-acetyl cysteine in esophagogastroduodenoscopy: Is it time to use it in practice?.},
journal = {Endoscopy international open},
volume = {11},
number = {1},
pages = {E81},
pmid = {36686028},
issn = {2364-3722},
}
@article {pmid36678548,
year = {2022},
author = {Song, F and Lin, J and Zhang, H and Guo, Y and Mao, Y and Liu, Z and Li, G and Wang, Y},
title = {Long-Term Sleep Deprivation-Induced Myocardial Remodeling and Mitochondrial Dysfunction in Mice Were Attenuated by Lipoic Acid and N-Acetylcysteine.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {16},
number = {1},
pages = {},
pmid = {36678548},
issn = {1424-8247},
support = {82270417;81970283;81870627//National Natural Science Foundation of China/ ; 2018YFA0107304//the National Key R&amp;D Program of China/ ; 20720202013//Fundamental Research Funds for the Central Universities/ ; },
abstract = {The impact of long-term sleep deprivation on the heart and its underlying mechanisms are poorly understood. The present study aimed to investigate the impact of chronic sleep deprivation (CSD) on the heart and mitochondrial function and explore an effective drug for treating CSD-induced heart dysfunction. We used a modified method to induce CSD in mice; lipoic acid (LA) and N-acetylcysteine (NAC) were used to treat CSD mice. Echocardiography, hematoxylin-eosin (H&amp;E) staining, Sirius red staining, and immunohistochemistry were used to determine heart function and cardiac fibrosis. The serum levels of brain natriuretic peptide (BNP), superoxide Dismutase (SOD), micro malondialdehyde (MDA), and glutathione (GSH) were measured to determine cardiovascular and oxidative stress-related damage. Transmission electron microscopy was used to investigate mitochondrial damage. RNA-seq and Western blotting were used to explore related pathways. We found that the left ventricular ejection fraction (LVEF) and fraction shortening (LVFS) values were significantly decreased and myocardial hypertrophy was induced, accompanied by damaged mitochondria, elevated reactive oxygen species (ROS), and reduced SOD levels. RNA-sequence analysis of the heart tissue showed that various differentially expressed genes in the metabolic pathway were enriched. Sirtuin 1 (Sirt1) and Glutathione S-transferase A3 (Gsta3) may be responsible for CSD-induced heart and mitochondrial dysfunction. Pharmacological inhibition of ROS by treating CSD mice with LA and NAC effectively reduced heart damage and mitochondrial dysfunction by regulating Sirt1 and Gsta3 expression. Our data contribute to understanding the pathways of CSD-induced heart dysfunction, and pharmacological targeting to ROS may represent a strategy to prevent CSD-induced heart damage.},
}
@article {pmid36672522,
year = {2022},
author = {Teschke, R},
title = {Treatment of Drug-Induced Liver Injury.},
journal = {Biomedicines},
volume = {11},
number = {1},
pages = {},
pmid = {36672522},
issn = {2227-9059},
abstract = {Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.},
}
@article {pmid36672389,
year = {2023},
author = {Schlörmann, W and Horlebein, C and Hübner, SM and Wittwer, E and Glei, M},
title = {Potential Role of ROS in Butyrate- and Dietary Fiber-Mediated Growth Inhibition and Modulation of Cell Cycle-, Apoptosis- and Antioxidant-Relevant Proteins in LT97 Colon Adenoma and HT29 Colon Carcinoma Cells.},
journal = {Cancers},
volume = {15},
number = {2},
pages = {},
pmid = {36672389},
issn = {2072-6694},
abstract = {The aim of the present study was to examine whether reactive oxygen species (ROS) contribute to chemopreventive effects of fermentation supernatants (FS) of different dietary fibers (Synergy1[®], oat-, barley-, yeast β-glucan, Curdlan) and butyrate as a fermentation metabolite. LT97 and HT29 cells were treated with butyrate and FS alone or with N-acetyl-cysteine (NAC) and their impact on ROS formation, cell growth, and protein expression (Cyclin D2, p21, PARP, Bid, GPx2) was investigated. Butyrate and FS significantly decreased cell growth. ROS levels were significantly increased, particularly in LT97 cells, while co-treatment with NAC decreased ROS formation and growth inhibitory effects in both cell lines. After treatment with butyrate and FS, Cyclin D2 expression was reduced in LT97 cells and p21 expression was increased in both cell lines. Levels of full-length PARP and Bid were decreased, while levels of cleaved PARP were enhanced. GPx2 expression was significantly reduced by fiber FS in HT29 cells. A notable effect of NAC on butyrate- and FS-modulated protein expression was observed exclusively for PARP and Bid in HT29 cells. From the present results, a contribution of ROS to growth inhibitory and apoptotic effects of butyrate and FS on LT97 and HT29 cells cannot be excluded.},
}
@article {pmid36671018,
year = {2023},
author = {Kim, JE and Park, H and Kang, TC},
title = {Peroxiredoxin 6 Regulates Glutathione Peroxidase 1-Medited Glutamine Synthase Preservation in the Hippocampus of Chronic Epilepsy Rats.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {1},
pages = {},
pmid = {36671018},
issn = {2076-3921},
support = {No. 2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; },
abstract = {Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats, although the underlying mechanisms of its anti-convulsive effects are not fully understood. To elucidate this, the present study was designed to investigate whether NAC affects astroglial glutamine synthase (GS) expression mediated by GSH peroxidase 1 (GPx1) and/or peroxiredoxin 6 (Prdx6) in the epileptic hippocampus. As compared to control animals, GS and GPx1 expressions were upregulated in reactive CA1 astrocytes of chronic epilepsy rats, while their expressions were significantly decreased in clasmatodendritic CA1 astrocytes and reactive astrocytes within the molecular layer of the dentate gyrus. Prdx6 expression was increased in reactive CA1 astrocytes as well as clasmatodendritic CA1 astrocytes. In the molecular layer of the dentate gyrus, Prdx6 expression levels were similar to those in control animals. NAC ameliorated clasmatodendrosis through the increment of GS and GPx1 expressions, while it abolished Prdx6 upregulation. 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) alleviated clasmatodendrosis by enhancing GPx1 and GS expressions in clasmatodendritic CA1 astrocytes without changing the Prdx6 level. NAC or MJ33 did not affect GS, GPx1 and Prdx6 expression in astrocytes within the molecular layer of the dentate gyrus. These findings indicate that upregulated aiPLA2 activity of Prdx6 may abolish GPx1-mediated GS preservation and lead to clasmatodendrosis in CA1 astrocytes, which would extend spontaneous seizure duration due to impaired glutamate-glutamine conversion regulated by GS. Therefore, the present data suggest that aiPLA2 activity of Prdx6 in astrocytes may be one of the upstream effectors of seizure duration in the epileptic hippocampus.},
}
@article {pmid36671002,
year = {2023},
author = {Chhunchha, B and Kubo, E and Krueger, RR and Singh, DP},
title = {Hydralazine Revives Cellular and Ocular Lens Health-Span by Ameliorating the Aging and Oxidative-Dependent Loss of the Nrf2-Activated Cellular Stress Response.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {1},
pages = {},
pmid = {36671002},
issn = {2076-3921},
support = {R01 EY024589/EY/NEI NIH HHS/United States ; EY024589/EY/NEI NIH HHS/United States ; UNMC//UNMC/ ; },
abstract = {A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2's activation has been identified as a therapeutic target to restore antioxidant defense in aging. Here, we demonstrated that FDA-approved drug, hydralazine (Hyd), was a reactivator of the Nrf2/ARE (antioxidant response element) pathway in various ages and types of mouse (m) or human (h) lens epithelial cells (LECs) and mice lenses in-vitro/in-vivo. This led to Hyd-driven abatement of carbonyls, reduced reactive oxygen species (ROS), and reduced 4-HNE/MDA-adducts with cytoprotection, and extended lens healthspan by delaying/preventing lens opacity against aging/oxidative stress. We elucidated that Hyd activated the protective signaling by inducing Nrf2 to traverse from the cytoplasm to the nucleus and potentiated the ARE response by direct interaction of Nrf2 and ARE sequences of the promoter. Loss-of-function study and cotreatment of Hyd and antioxidant, N-acetyl cysteine (NAC) or Peroxiredoxin (Prdx)6, specified that Nrf2/ARE-driven increase in the promoter activity was Hyd-dependent. Our study provides proof-of concept evidence and, thereby, paves the way to repurposing Hyd as a therapeutic agent to delay/prevent aging and oxidative-related disorders.},
}
@article {pmid36670992,
year = {2023},
author = {Mursaleen, L and Chan, SHY and Noble, B and Somavarapu, S and Zariwala, MG},
title = {Curcumin and N-Acetylcysteine Nanocarriers Alone or Combined with Deferoxamine Target the Mitochondria and Protect against Neurotoxicity and Oxidative Stress in a Co-Culture Model of Parkinson's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {1},
pages = {},
pmid = {36670992},
issn = {2076-3921},
abstract = {As the blood-brain barrier (BBB) prevents most compounds from entering the brain, nanocarrier delivery systems are frequently being explored to potentially enhance the passage of drugs due to their nanometer sizes and functional characteristics. This study aims to investigate whether Pluronic® F68 (P68) and dequalinium (DQA) nanocarriers can improve the ability of curcumin, n-acetylcysteine (NAC) and/or deferoxamine (DFO), to access the brain, specifically target mitochondria and protect against rotenone by evaluating their effects in a combined Transwell® hCMEC/D3 BBB and SH-SY5Y based cellular Parkinson’s disease (PD) model. P68 + DQA nanoformulations enhanced the mean passage across the BBB model of curcumin, NAC and DFO by 49%, 28% and 49%, respectively (p < 0.01, n = 6). Live cell mitochondrial staining analysis showed consistent co-location of the nanocarriers within the mitochondria. P68 + DQA nanocarriers also increased the ability of curcumin and NAC, alone or combined with DFO, to protect against rotenone induced cytotoxicity and oxidative stress by up to 19% and 14% (p < 0.01, n = 6), as measured by the MTT and mitochondrial hydroxyl radical assays respectively. These results indicate that the P68 + DQA nanocarriers were successful at enhancing the protective effects of curcumin, NAC and/or DFO by increasing the brain penetrance and targeted delivery of the associated bioactives to the mitochondria in this model. This study thus emphasises the potential effectiveness of this nanocarrier strategy in fully utilising the therapeutic benefit of these antioxidants and lays the foundation for further studies in more advanced models of PD.},
}
@article {pmid36670939,
year = {2022},
author = {Campesi, I and Brunetti, A and Capobianco, G and Galistu, A and Montella, A and Ieri, F and Franconi, F},
title = {Sex Differences in X-ray-Induced Endothelial Damage: Effect of Taurine and N-Acetylcysteine.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {1},
pages = {},
pmid = {36670939},
issn = {2076-3921},
abstract = {Ionizing radiation (IR) can induce some associated pathological conditions due to numerous cell damages. The influence of sex is scarcely known, and even less known is whether the effect of antioxidants is sex-dependent. Given the increased use of IR, we investigated whether male human umbilical vein endothelial cells (MHUVECs) and female human umbilical vein endothelial cells (FHUVECs) respond differently to IR exposure and whether the antioxidants 10 mM taurine (TAU) and 5 mM N-acetylcysteine (NAC) can prevent IR-induced damage in a sex-dependent way. In untreated cells, sex differences were observed only during autophagy, which was higher in FHUVECs. In non-irradiated cells, preincubation with TAU and NAC did not modify viability, lactate dehydrogenase (LDH) release, migration, or autophagy, whereas only NAC increased malondialdehyde (MDA) levels in FHUVECs. X-ray irradiation increased LDH release and reduced viability and migration in a sex-independent manner. TAU and NAC did not affect viability while reduced LDH release in irradiated cells: they have the same protective effect in FHUVECs, while, TAU was more protective than NAC in male cells.. Moreover, TAU and NAC significantly promoted the closure of wounds in both sexes in irradiated cells, but NAC was more effective at doing this in FHUVECs. In irradiated cells, TAU did not change autophagy, while NAC attenuated the differences between the sexes. Finally, NAC significantly decreased MDA in MHUVECs and increased MDA in FHUVECs. In conclusion, FHUVECs appear to be more susceptible to IR damage, and the effects of the two antioxidants present some sex differences, suggesting the need to study the influence of sex in radiation mitigators.},
}
@article {pmid36670915,
year = {2022},
author = {Lemminger, AK and Fiorenza, M and Eibye, K and Bangsbo, J and Hostrup, M},
title = {High-Intensity Exercise Training Alters the Effect of N-Acetylcysteine on Exercise-Related Muscle Ionic Shifts in Men.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {12},
number = {1},
pages = {},
pmid = {36670915},
issn = {2076-3921},
abstract = {This study investigated whether high-intensity exercise training alters the effect of N-acetylcysteine (a precursor of antioxidant glutathione) on exercise-related muscle ionic shifts. We assigned 20 recreationally-active men to 6 weeks of high-intensity exercise training, comprising three weekly sessions of 4-10 × 20-s all-out bouts interspersed by 2 min recovery (SET, n = 10), or habitual lifestyle maintenance (n = 10). Before and after SET, we measured ionic shifts across the working muscle, using leg arteriovenous balance technique, during one-legged knee-extensor exercise to exhaustion with and without N-acetylcysteine infusion. Furthermore, we sampled vastus lateralis muscle biopsies for analyses of metabolites, mitochondrial respiratory function, and proteins regulating ion transport and antioxidant defense. SET lowered exercise-related H[+], K[+], lactate[-], and Na[+] shifts and enhanced exercise performance by ≈45%. While N-acetylcysteine did not affect exercise-related ionic shifts before SET, it lowered H[+], HCO3[-], and Na[+] shifts after SET. SET enhanced muscle mitochondrial respiratory capacity and augmented the abundance of Na[+]/K[+]-ATPase subunits (α1 and β1), ATP-sensitive K[+] channel subunit (Kir6.2), and monocarboxylate transporter-1, as well as superoxide dismutase-2 and glutathione peroxidase-1. Collectively, these findings demonstrate that high-intensity exercise training not only induces multiple adaptations that enhance the ability to counter exercise-related ionic shifts but also potentiates the effect of N-acetylcysteine on ionic shifts during exercise.},
}
@article {pmid36670802,
year = {2023},
author = {Zhang, Y and Tian, J and Wang, C and Wu, T and Yi, D and Wang, L and Zhao, D and Hou, Y},
title = {N-Acetylcysteine Administration Improves the Redox and Functional Gene Expression Levels in Spleen, Mesenteric Lymph Node and Gastrocnemius Muscle in Piglets Infected with Porcine Epidemic Diarrhea Virus.},
journal = {Animals : an open access journal from MDPI},
volume = {13},
number = {2},
pages = {},
pmid = {36670802},
issn = {2076-2615},
support = {32172763//National Natural Science Foundation of China/ ; 32072762//National Natural Science Foundation of China/ ; },
abstract = {Our previous study reported that N-acetylcysteine (NAC) administration improved the function of intestinal absorption in piglets infected with porcine epidemic diarrhea virus (PEDV). However, the effects of NAC administration on the functions of other tissues and organs in PEDV-infected piglets have not been reported. In this study, the effects of NAC on the liver, spleen, lung, lymph node, and gastrocnemius muscle in PEDV-infected piglets were investigated. Thirty-two 7-day-old piglets with similar body weights were randomly divided into one of four groups: Control group, NAC group, PEDV group, and PEDV+NAC group (eight replicates per group and one pig per replicate). The trial had a 2 × 2 factorial design consisting of oral administration of 0 or 25 mg/kg body weight NAC and oral administration of 0 or 1.0 × 10[4.5] TCID50 PEDV. The trial lasted 12 days. All piglets were fed a milk replacer. On days 5-9 of the trial, piglets in the NAC and PEDV + NAC groups were orally administered NAC once a day; piglets in the control and PEDV groups were orally administered the same volume of saline. On day 9 of trial, piglets in the PEDV and PEDV+NAC groups were orally administrated 1.0 × 10[4.5] TCID50 PEDV, and the piglets in the control and NAC groups were orally administrated the same volume of saline. On day 12 of trial, samples, including of the liver, spleen, lung, lymph node, and gastrocnemius muscle, were collected. PEDV infection significantly increased catalase activity but significantly decreased the mRNA levels of Keap1, Nrf2, HMOX2, IFN-α, MX1, IL-10, TNF-α, S100A12, MMP3, MMP13, TGF-β, and GJA1 in the spleens of piglets. NAC administration ameliorated abnormal changes in measured variables in the spleens of PEDV-infected piglets. In addition, NAC administration also enhanced the antioxidant capacity of the mesenteric lymph nodes and gastrocnemius muscles in PEDV-infected piglets. Collectively, these novel results revealed that NAC administration improved the redox and functional gene expression levels in the spleen, mesenteric lymph nodes, and gastrocnemius muscle in PEDV-infected piglets.},
}
@article {pmid36670547,
year = {2023},
author = {Luo, G and Huang, L and Zhang, Z},
title = {The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {248},
number = {5},
pages = {412-424},
pmid = {36670547},
issn = {1535-3699},
mesh = {Humans ; *Acetaminophen/adverse effects ; Oxidative Stress ; *Chemical and Drug Induced Liver Injury/drug therapy ; Acetylcysteine/therapeutic use ; },
abstract = {Acetaminophen (APAP), a widely used antipyretic and analgesic drug in clinics, is relatively safe at therapeutic doses; however, APAP overdose may lead to fatal acute liver injury. Currently, N-acetylcysteine (NAC) is clinically used as the main antidote for APAP poisoning, but its therapeutic effect remains limited owing to rapid disease progression and the general diagnosis of advanced poisoning. As is well known, APAP-induced hepatotoxicity (AIH) is mainly caused by the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), and the toxic mechanisms of AIH are complicated. Several cellular processes are involved in the pathogenesis of AIH, including liver metabolism, mitochondrial oxidative stress and dysfunction, sterile inflammation, endoplasmic reticulum stress, autophagy, and microcirculation dysfunction. Mitochondrial oxidative stress and dysfunction are the major cellular events associated with APAP-induced liver injury. Many biomolecules involved in these biological processes are potential therapeutic targets for AIH. Therefore, there is an urgent need to comprehensively clarify the molecular mechanisms underlying AIH and to explore novel therapeutic strategies. This review summarizes the various cellular events involved in AIH and discusses their potential therapeutic targets, with the aim of providing new ideas for the treatment of AIH.},
}
@article {pmid36662362,
year = {2023},
author = {Zhang, Q and Wang, M and Hu, X and Yan, A and Ho, PL and Li, H and Sun, H},
title = {Gold drugs as colistin adjuvants in the fight against MCR-1 producing bacteria.},
journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry},
volume = {28},
number = {2},
pages = {225-234},
pmid = {36662362},
issn = {1432-1327},
support = {R7070-18//Research Grants Council, University Grants Committee/ ; 17308921//Research Grants Council, University Grants Committee/ ; F-HKU704/19//Research Grants Council, University Grants Committee/ ; 2122-7S04//Research Grants Council, University Grants Committee/ ; Norman//The University of Hong Kong/ ; Cecilia Yip Foundation//The University of Hong Kong/ ; CID-HKU-1-13//Health and Medical Research Fund/ ; 18171042//Health and Medical Research Fund/ ; },
mesh = {*Colistin/pharmacology ; Anti-Bacterial Agents/pharmacology ; Bacteria ; Gold/pharmacology ; Drug Resistance, Bacterial/genetics ; Plasmids ; *Escherichia coli Proteins/chemistry ; Microbial Sensitivity Tests ; },
abstract = {The emergence and rapid spread of the mobile colistin resistance gene mcr-1 among bacterial species and hosts significantly challenge the efficacy of "last-line" antibiotic colistin. Previously, we reported silver nitrate and auranofin serve as colistin adjuvants for combating mcr-1-positive bacteria. Herein, we uncovered more gold-based drugs and nanoparticles, and found that they exhibited varying degree of synergisms with colistin on killing mcr-1-positive bacteria. However, pre-activation of the drugs by either glutathione or N-acetyl cysteine, thus releasing and accumulating gold ions, is perquisite for their abilities to substitute zinc cofactor from MCR-1 enzyme. X-ray crystallography and biophysical studies further supported the proposed mechanism. This study not only provides basis for combining gold-based drugs and colistin for combating mcr-1-positive bacterial infections, but also undoubtedly opens a new horizon for metabolism details of gold-based drugs in overcoming antimicrobial resistance.},
}
@article {pmid36652130,
year = {2023},
author = {Xu, H and Shen, X and Li, X and Yang, X and Chen, C and Luo, D},
title = {The natural product dehydrocurvularin induces apoptosis of gastric cancer cells by activating PARP-1 and caspase-3.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {28},
number = {3-4},
pages = {525-538},
pmid = {36652130},
issn = {1573-675X},
mesh = {Humans ; Apoptosis ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; *Stomach Neoplasms/drug therapy/genetics ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Caspase 3/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Apoptosis Inducing Factor/genetics/metabolism ; *Antineoplastic Agents/pharmacology ; Zearalenone/analogs &amp; derivatives ; },
abstract = {The natural product dehydrocurvularin (DSE2) is a fungal-derived macrolide with potent anticancer activity, but the mechanism is still unclear. We found that DSE2 effectively inhibited the growth of gastric cancer cells and induced the apoptosis by activating Poly(ADP-ribose) polymerase 1 (PARP-1) and caspase-3. Pharmacological inhibition and genetic knockdown with PARP-1 or caspase-3 suppressed DSE2-induced apoptosis. PARP-1 was previously reported to be cleaved into fragments during apoptosis. However, PARP-1 was barely cleaved in DSE2-induced apoptosis. DSE2 induced PARP-1 activation as indicated by rapid depletion of NAD[+] and the concomitant formation of poly(ADP-ribosylated) proteins (PARs). Interestingly, the PARP-1 inhibitor (Olaparib) attenuated the cytotoxicity of DSE2. Moreover, the combination of Olaparib and Z-DEVD-FMK (caspase-3 inhibitor) further reduced the cytotoxicity. It has been shown that PARP-1 activation triggers cytoplasm-nucleus translocation of apoptosis-inducing factor (AIF). Caspase-3 inhibitors inhibited PARP-1 activation and suppressed PARP-1-induced AIF nuclear translocation. These results indicated that DSE2-induced caspase-3 activation may occur before PARP-1 activation. The ROS inhibitor, N-acetyl-cysteine, significantly inhibited the activation of caspase-3 and PARP-1, indicating that ROS overproduction contributed to DSE2-induced apoptosis. Using an in vivo approach, we further found that DSE2 significantly inhibited gastric tumor growth and promoted translocation of AIF to the nucleus. In conclusion, DSE2 induces gastric cell apoptosis by activating caspase-3 and PARP-1, and shows potent antitumor activity against human gastric carcinoma in vitro and in vivo.},
}
@article {pmid36651429,
year = {2023},
author = {Costa, RIDD and Fischer, JMDS and Rasslan, R and Koike, MK and Utiyama, EM and Montero, EFS},
title = {Effects of N-acetylcysteine on the inflammatory response and bacterial translocation in a model of intestinal obstruction and ischemia in rats.},
journal = {Acta cirurgica brasileira},
volume = {37},
number = {12},
pages = {e371204},
pmid = {36651429},
issn = {1678-2674},
mesh = {Rats ; Animals ; Rats, Wistar ; Interleukin-10 ; Acetylcysteine/pharmacology/therapeutic use ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Bacterial Translocation ; Saline Solution, Hypertonic/pharmacology ; Ischemia ; Inflammation/drug therapy ; *Intestinal Obstruction ; Resuscitation/methods ; *Shock, Hemorrhagic ; },
abstract = {PURPOSE: To evaluate effect of N-acetylcysteine (NAC) associated with Ringer lactate or hypertonic saline in inflammation and bacterial translocation on experimental intestinal obstruction (IO).<br><br>METHODS: Wistar rats was subjected to IO. Six or 24 hours after, rats were subjected to enterectomy and fluid resuscitation: IO, RL (subjected to the same procedures but with fluid resuscitation using Ringer's lactate solution); RLNAC (added NAC to Ringer's solution); and HSNAC (surgical procedure + fluid reposition with 7.5% hypertonic saline and NAC). After 24 h, tissues were collected to cytokines, bacterial translocation, and histological assessments.<br><br>RESULTS: In kidney, interleukin-1beta (IL-1beta) was lower in the groups with fluid resuscitation compared to IO group. The RLNAC showed lower levels compared to the RL. Interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and (IFN-gamma) were lower in the treatment groups than in IO. In lung, IL-1beta and IL-6 were lower in RLNAC compared to IO. IL-10 was lower in RL, RLNAC and HSNAC compared to IO. TNF-alpha was higher in HSNAC compared to both RL and RLNAC. Bacterial translocation was observed in all animals of IO group. In kidneys, inflammation and congestion degrees were lower in HSNAC compared to RL. In lungs, inflammation levels were higher in RLNAC compared with the sham group.<br><br>CONCLUSIONS: The data indicates that NAC associated with RL can promote a decrease in the inflammatory process in the kidneys and lungs in rats, following intestinal obstruction and ischemia in rats.},
}
@article {pmid36647403,
year = {2023},
author = {Wakil, A and Niazi, M and Meybodi, MA and Pyrsopoulos, NT},
title = {Emerging Pharmacotherapies in Alcohol-Associated Hepatitis.},
journal = {Journal of clinical and experimental hepatology},
volume = {13},
number = {1},
pages = {116-126},
pmid = {36647403},
issn = {0973-6883},
abstract = {UNLABELLED: The incidence of alcoholic-associated hepatitis (AH) is increasing. The treatment options for severe AH (sAH) are scarce and limited to corticosteroid therapy which showed limited mortality benefit in short-term use only. Therefore, there is a dire need for developing safe and effective therapies for patients with sAH and to improve their high mortality rates.This review article focuses on the current novel therapeutics targeting various mechanisms in the pathogenesis of alcohol-related hepatitis. Anti-inflammatory agents such as IL-1 inhibitor, Pan-caspase inhibitor, Apoptosis signal-regulating kinase-1, and CCL2 inhibitors are under investigation. Other group of agents include gut-liver axis modulators, hepatic regeneration, antioxidants, and Epigenic modulators. We describe the ongoing clinical trials of some of the new agents for alcohol-related hepatitis.<br><br>CONCLUSION: A combination of therapies was investigated, possibly providing a synergistic effect of drugs with different mechanisms. Multiple clinical trials of novel therapies in AH remain ongoing. Their result could potentially make a difference in the clinical course of the disease. DUR-928 and granulocyte colony-stimulating factor had promising results and further trials are ongoing to evaluate their efficacy in the large patient sample.},
}
@article {pmid36647192,
year = {2023},
author = {Chen, M and Qian, C and Jin, B and Hu, C and Zhang, L and Wang, M and Zhou, B and Zuo, W and Huang, L and Wang, Y},
title = {Curcumin analog WZ26 induces ROS and cell death via inhibition of STAT3 in cholangiocarcinoma.},
journal = {Cancer biology &amp; therapy},
volume = {24},
number = {1},
pages = {2162807},
pmid = {36647192},
issn = {1555-8576},
mesh = {Humans ; Animals ; Mice ; *Curcumin/pharmacology/therapeutic use/analogs &amp; derivatives ; *Antineoplastic Agents/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Cell Line, Tumor ; Cell Death ; Apoptosis ; *Cholangiocarcinoma/drug therapy ; Cell Proliferation ; G2 Phase Cell Cycle Checkpoints ; Bile Ducts, Intrahepatic/metabolism/pathology ; *Bile Duct Neoplasms/drug therapy/pathology ; },
abstract = {Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound with several anti-cancer properties, though its clinical uses remain hindered due to its poor bioavailability. We recently synthesized curcumin analogs with multifunctional pharmacological and bioactivities with enhanced bioavailability. Among these novel curcumin analogs, WZ26 is a representative molecule. However, the anti-tumor effect of WZ26 against CCA is unclear. In this study, we evaluated the anti-tumor effect of WZ26 in both CCA cells and CCA xenograft mouse model. The underlying molecular anti-cancer mechanism of WZ26 was also studied. Our results show that WZ26 significantly inhibited cell growth and induced mitochondrial apoptosis in CCA cell lines, leading to significant inhibition of tumor growth in xenograft tumor mouse model. Treatment of WZ26 increased reactive oxygen species (ROS) generation, subsequently decreased mitochondrial membrane potential and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inducing G2/M cell cycle arrest and cell apoptosis. Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells. Our findings provide experimental evidence that curcumin analog WZ26 could be a potential candidate against CCA via enhancing ROS induction and inhibition of STAT3 activation.},
}
@article {pmid36639145,
year = {2023},
author = {Moosa, MS and Russomanno, G and Dorfman, JR and Gunter, H and Patel, C and Costello, E and Carr, D and Maartens, G and Pirmohamed, M and Goldring, C and Cohen, K},
title = {Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury.},
journal = {British journal of clinical pharmacology},
volume = {89},
number = {6},
pages = {1844-1851},
pmid = {36639145},
issn = {1365-2125},
support = {MR/L006758/1/MRC_/Medical Research Council/United Kingdom ; MR/M009114/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*MicroRNAs/blood ; *Acetylcysteine/administration &amp; dosage ; *Chemical and Drug Induced Liver Injury/drug therapy ; Administration, Intravenous ; *Acetaminophen/adverse effects ; *Antibiotics, Antitubercular/adverse effects ; Alanine Transaminase/blood ; Humans ; Male ; Female ; Adult ; Placebos ; },
abstract = {AIM: Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations.<br><br>METHODS: We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions.<br><br>RESULTS: We included 45 participants; mean age (&#xb1;&#x2009;standard deviation) 38 (&#xb1;10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68&#x2009;h (47-77&#x2009;h). The median pre-infusion ALT and miR-122 concentrations were 420&#x2009;U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's &#x3c1;&#xa0;=&#x2009;.54, P&#xa0;=&#x2009;.0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P&#xa0;=&#x2009;.40 and P&#xa0;=&#x2009;.68 respectively).<br><br>CONCLUSIONS: miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.},
}
@article {pmid36638648,
year = {2023},
author = {Silva, BR and Silva, JRV},
title = {Mechanisms of action of non-enzymatic antioxidants to control oxidative stress during in vitro follicle growth, oocyte maturation, and embryo development.},
journal = {Animal reproduction science},
volume = {249},
number = {},
pages = {107186},
doi = {10.1016/j.anireprosci.2022.107186},
pmid = {36638648},
issn = {1873-2232},
mesh = {Animals ; *Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; *Melatonin/pharmacology ; Resveratrol/pharmacology ; Lycopene/pharmacology ; Quercetin/pharmacology ; Cysteamine/metabolism/pharmacology ; Phycocyanin/metabolism/pharmacology ; In Vitro Oocyte Maturation Techniques/veterinary ; Oxidative Stress ; Oocytes/physiology ; Glutathione/pharmacology ; Acetylcysteine/pharmacology ; Carnitine/metabolism/pharmacology ; Ascorbic Acid/pharmacology ; Embryonic Development ; Glucosides ; Polyphenols ; },
abstract = {In vitro follicle growth and oocyte maturation still has a series of limitations, since not all oocytes matured in vitro have the potential to develop in viable embryos. One of the factors associated with low oocyte quality is the generation of reactive oxygen species (ROS) during in vitro culture. Therefore, this review aims to discuss the role of non-enzymatic antioxidants in the control of oxidative stress during in vitro follicular growth, oocyte maturation and embryonic development. A wide variety of non-enzymatic antioxidants (melatonin, resveratrol, L-ascorbic acid, L-carnitine, N-acetyl-cysteine, cysteamine, quercetin, nobiletin, lycopene, acteoside, mogroside V, phycocyanin and laminarin) have been used to supplement culture media. Some of them, like N-acetyl-cysteine, cysteamine, nobiletin and quercetin act by increasing the levels of glutathione (GSH), while melatonin and resveratrol increase the expression of antioxidant enzymes and minimize oocyte oxidative stress. L-ascorbic acid reduces free radicals and reactive oxygen species. Lycopene positively regulates the expression of many antioxidant genes. Additionally, L-carnitine protects DNA against ROS-induced damage, while acteoside and laminarin reduces the expression of proapoptotic genes. Mogrosides increases mitochondrial function and reduces intracellular ROS levels, phycocyanin reduces lipid peroxidation, and lycopene neutralizes the adverse effects of ROS. Thus, it is very important to know their mechanisms of actions, because the combination of two or more antioxidants with different activities has great potential to improve in vitro culture systems.},
}
@article {pmid36636887,
year = {2023},
author = {Tanabe, P and Schlenk, D},
title = {Role of Aryl Hydrocarbon Receptor and Oxidative Stress in the Regioselective Toxicities of Hydroxychrysenes in Embryonic Japanese Medaka (Oryzias latipes).},
journal = {Environmental toxicology and chemistry},
volume = {42},
number = {3},
pages = {698-706},
doi = {10.1002/etc.5560},
pmid = {36636887},
issn = {1552-8618},
mesh = {Animals ; Cytochrome P-450 CYP1A1/metabolism ; *Oryzias/metabolism ; Oxidative Stress ; *Polycyclic Aromatic Hydrocarbons/toxicity ; Reactive Oxygen Species ; Receptors, Aryl Hydrocarbon/metabolism ; Chrysenes ; },
abstract = {Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are environmental contaminants that can be created through oxidation of parent PAHs. Previous studies have found that 2-hydroxychrysene (2-OHCHR) caused anemia in embryonic Japanese medaka whereas 6-hydroxychrysene (6-OHCHR) did not, an example of regioselective toxicity. Anemia was prevented by cytochrome P450 (CYP) inhibition, which reduced the formation of the potential oxidatively active metabolite, 1,2-catechol, from 2-OHCHR. 2-OHCHR has also been found to be a four-fold more potent aryl hydrocarbon receptor (AhR) agonist compared with 6-OHCHR. These findings led us to hypothesize that AhR activation and/or oxidative stress play an important role in 2-OHCHR toxicity. Although treatments with the AhR agonists polychlorinated biphenyl (PCB)126 and 2-methoxychrysene (2-MeOCHR) did not cause significant toxicity, pretreatments with the AhR antagonist, CH-223191, reduced anemia by 97.2 ± 0.84% and mortality by 96.6 ± 0.69%. Aryl hydrocarbon receptor inhibition by the antagonist was confirmed by significant reductions (91.0 ± 9.94%) in induced ethoxyresorufin-O-deethylase activity. Thiobarbituric acid reactive substances concentrations were 32.9 ± 3.56% higher (p < 0.05) in 2-OHCHR treatments at 100 hours postfertilization compared with controls. Staining 2-OHCHR-treated embryos with the reactive oxygen species (ROS) scavenger 2',7'-dichlorofluorescin diacetate revealed 32.6 ± 2.69% of 2-OHCHR-treated embryos exhibiting high concentrations of ROS in caudal tissues, which is a site for embryonic hematopoiesis in medaka. Pretreatment with antioxidants, N-acetylcysteine (NAC) or vitamin E (Vit E) significantly reduced 2-OHCHR-induced anemia (NAC: 80.7 ± 1.12% and Vit E: 99.1 ± 0.43%) and mortality (NAC: 67.1 ± 1.69% and Vit E: 98.9 ± 0.66%). These results indicate that AhR may mediate 2-OHCHR toxicity through canonical signaling by up-regulating CYP1, enhancing the formation of reactive metabolites of 2-OHCHR that generate ROS within caudal hematopoietic tissues, potentially disrupting hematopoiesis, leading to anemia and subsequent mortality. Environ Toxicol Chem 2023;42:698-706. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.},
}
@article {pmid36634885,
year = {2023},
author = {Tang, Y and Jin, L and Qi, W and Gao, Y and Xie, Y and Xie, X and Lv, J and Jiang, Z and Jiang, H and Fan, C and Yan, J},
title = {N-acetyl-L-cysteine attenuated the toxicity of ZIF-8 on EA.hy926 endothelial cells by wnt/β-catenin pathway.},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {88},
number = {},
pages = {105553},
doi = {10.1016/j.tiv.2023.105553},
pmid = {36634885},
issn = {1879-3177},
mesh = {Humans ; *Acetylcysteine/pharmacology ; *beta Catenin/metabolism ; *Endothelial Cells/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Wnt Signaling Pathway ; Imidazoles ; Zeolites ; },
abstract = {As kinds of porous crystalline compounds, zeolitic imidazolate frameworks (ZIFs) have been developed quickly and attracted considerable attention for use in nano drug delivery systems, which raised concerns about cardiovascular disorders. At the present, the cytotoxic mechanism of ZIFs in cardiovascular disorders was still unclear. Our experiment explored the toxicity of ZIF-8, a typical kind of ZIFs, on human EA.hy926 vascular endothelial cells. The cell viability, ROS formation, apoptosis level, inflammatory response level, wound healing ability and atherosclerosis-related indicators of EA.hy926 endothelial cells were analyzed after ZIF-8 treatment. Meanwhile, we evaluated the ability of antioxidant N-Acetyl-L-cysteine (NAC) to attenuate the toxicity of ZIF-8 on EA.hy926 endothelial cells. As results, NAC attenuated ROS formation, cell apoptosis, LDH formation and endothelial dysfunction caused by ZIF-8. As the Wnt/β-catenin pathway was involved in endothelial cell dysfunction, we also studied the expression level of β-catenin and LEF1 in ZIF-8 and/or NAC treated EA.hy926 cells. As expected, ZIF-8 increased the protein expressions of β-catenin and LEF1in the IC50 group, which was significantly inhibited by co-treatment with NAC. Taken together, this study could help improve our understanding about the mechanism of ZIF-8-induced endothelial cells injury and NAC had therapeutic potential in preventing ZIF-8-associated endothelial dysfunction by wnt/β-catenin pathway.},
}
@article {pmid36627753,
year = {2023},
author = {Paraskevas, T and Kantanis, A and Karalis, I and Michailides, C and Karamouzos, V and Koniari, I and Pierrakos, C and Velissaris, D},
title = {N-acetylcysteine efficacy in patients hospitalized with COVID-19 pneumonia: a systematic review and meta-analysis.},
journal = {Romanian journal of internal medicine = Revue roumaine de medecine interne},
volume = {61},
number = {1},
pages = {41-52},
doi = {10.2478/rjim-2023-0001},
pmid = {36627753},
issn = {2501-062X},
mesh = {Humans ; *COVID-19 ; Acetylcysteine/therapeutic use ; SARS-CoV-2 ; Hospitalization ; },
abstract = {BACKGROUND: N-acetylcysteine (NAC) is a mucolytic agents with anti-inflammatory properties that has been suggested as an adjunctive therapy in patients with COVID-19 pneumonia.<br><br>OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate available evidence on the possible beneficial effects of NAC on SARS-CoV-2 infection.<br><br>METHODS: In September 2022, we conducted a comprehensive search on Pubmed/Medline and Embase on randomized controlled trials (RCTs) and observational studies on NAC in patients with COVID-19 pneumonia. Study selection, data extraction and risk of bias assessment was performed by two independent authors. RCTs and observational studies were analyzed separately.<br><br>RESULTS: We included 3 RCTs and 5 non-randomized studies on the efficacy of NAC in patients with COVID-19, enrolling 315 and 20826 patients respectively. Regarding in-hospital mortality, the summary effect of all RCTs was OR: 0.85 (95% CI: 0.43 to 1.67, I[2]=0%) and for non-randomized studies OR: 1.02 (95% CI: 0.47 to 2.23, I[2]=91%). Need for ICU admission was only reported by 1 RCT (OR: 0.86, 95% CI:0.44-1.69, p=0.66), while all included RCTs reported need for invasive ventilation (OR:0.91, 95% CI:0.54 to 1.53, I[2]=0). Risk of bias was low for all included RCTs, but certainty of evidence was very low for all outcomes due to serious imprecision and indirectness.<br><br>CONCLUSION: The certainty of evidence in the included studies was very low, thus recommendations for clinical practice cannot be yet made. For all hard clinical outcomes point estimates in RCTs are close to the line of no effect, while observational studies have a high degree of heterogeneity with some of them suggesting favorable results in patients receiving NAC. More research is warranted to insure that NAC is both effective and safe in patients with COVID-19 pneumonia.},
}
@article {pmid36626340,
year = {2023},
author = {Safarinejad, MR and Safarinejad, S},
title = {Expression of Concern: Efficacy of Selenium and/or N-Acetyl-Cysteine for Improving Semen Parameters in Infertile Men: A Double-Blind, Placebo Controlled, Randomized Study.},
journal = {The Journal of urology},
volume = {},
number = {},
pages = {101097JU0000000000003113},
doi = {10.1097/JU.0000000000003113},
pmid = {36626340},
issn = {1527-3792},
}
@article {pmid36619199,
year = {2022},
author = {Ma, J and Liu, X and Wei, Y and Lu, R and Xu, K and Tian, Y and Li, J},
title = {Effective Component Compatibility of Bufei Yishen Formula III Which Regulates the Mucus Hypersecretion of COPD Rats via the miR-146a-5p/EGFR/MEK/ERK Pathway.},
journal = {Evidence-based complementary and alternative medicine : eCAM},
volume = {2022},
number = {},
pages = {9423435},
pmid = {36619199},
issn = {1741-427X},
abstract = {BACKGROUND: The effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) with 5 ingredients (ginsenoside Rh1, astragaloside, icariin, nobiletin, and paeonol) has been shown to protect against chronic obstructive pulmonary disease (COPD). The present study aimed to observe the effects of ECC-BYF III in a COPD rat model and dissect its potential mechanisms in regulating mucus hypersecretion via the miR-146a-5p/epidermal growth factor receptor (EGFR)/MEK/ERK pathway.<br><br>METHODS: COPD model rats were treated with normal saline, ECC-BYF III, or N-acetylcysteine (NAC). Pulmonary function, lung tissue histology with H &amp; E and AB-PAS staining, expression levels of interleukin (IL)-4, IL-6, IL-1&#x3b2;, MUC5AC, MUC5B, and FOXA2 in lung tissues and the mRNA and proteins involved in the miR-146a-5p/EGFR/MEK/ERK pathway were evaluated.<br><br>RESULTS: The COPD rats showed a significant decrease in the pulmonary function and serious pathological damage to the lung tissue. ECC-BYF III and NAC significantly improved the ventilation function and small airway pathological damage in the COPD rats. The goblet cells and the expression levels of IL-1&#x3b2;, IL-6, MUC5AC, and MUC5B were increased in the COPD rats and were significantly decreased after ECC-BYF III or NAC intervention. The expression levels of IL-4 and FOXA2 in the COPD rats were markedly decreased and were improved in the ECC-BYF III and NAC groups. ECC-BYF III appeared to have a potent effect in restoring the reduced expression of miR-146a-5p. The increased phosphorylation levels of EGFR, MEK, and ERK1/2 and the protein expression levels of SPDEF in the lungs of COPD rats could be significantly reduced by ECC-BYF III.<br><br>CONCLUSIONS: ECC-BYF III has a significant effect in improving the airway mucus hypersecretion in COPD model rats, as well as a protective effect against limited pulmonary function and injured lung histopathology. The protective effect of ECC-BYF III in reducing airway mucus hypersecretion in COPD may involve the miR-146a-5p/EGFR/MEK/ERK pathway.},
}
@article {pmid36615764,
year = {2022},
author = {Alwadani, AH and Almasri, SA and Aloud, AA and Albadr, NA and Alshammari, GM and Yahya, MA},
title = {The Synergistic Protective Effect of γ-Oryzanol (OZ) and N-Acetylcysteine (NAC) against Experimentally Induced NAFLD in Rats Entails Hypoglycemic, Antioxidant, and PPARα Stimulatory Effects.},
journal = {Nutrients},
volume = {15},
number = {1},
pages = {},
pmid = {36615764},
issn = {2072-6643},
support = {GSR//This research was funded by Deanship of scientific research in King Saud University through the initiative of DSR Graduate Students Research Support/ ; },
mesh = {Rats ; Male ; Animals ; *Non-alcoholic Fatty Liver Disease/drug therapy/etiology/prevention &amp; control ; Antioxidants/metabolism ; Acetylcysteine/metabolism ; PPAR alpha/genetics/metabolism ; Hypoglycemic Agents/pharmacology ; Liver/metabolism ; Diet, High-Fat/adverse effects ; Glucose/metabolism ; Phenylpropionates ; },
abstract = {This study estimated that the combined effect of γ-Oryzanol and N-acetylcysteine (NAC) against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats also estimated some of their mechanisms of action. Adult male rats were divided into seven groups (n = 8 each) as control, control + NAC, control + γ-Oryzanol, HFD, HFD + NAC, HFD + γ-Oryzanol, and HFD + NAC + γ-Oryzanol. NAC was administered orally at a final concentration of 200 mg/kg, whereas γ-Oryzanol was added to diets at a concentration of 0.16. All treatments were conducted for 17 weeks and daily. Both NAC and γ-Oryzanol were able to reduce final body weights, fat weights, fasting glucose, fasting insulin, serum, and serum levels of liver function enzymes as well as the inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6), and leptin in HFD-fed rats. They also improved hepatic structure and glucose tolerance, increased adiponectin levels, and reduced serum and hepatic levels of triglycerides (TGs) and cholesterol (CHOL) in these rats. These effects were concomitant with a reduction in the hepatic levels of lipid peroxides (MDA) and serum levels of LDL-C, but also with an increment in the hepatic levels of superoxide dismutase (SOD) and glutathione (GSH). Interestingly, only treatment with γ-Oryzanol stimulated the mRNA levels of proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) in the liver and white adipose tissue (WAT) of rats. Of note, the combination therapy of both drugs resulted in maximum effects and restored almost normal liver structure and basal levels of all the above-mentioned metabolic parameters. In conclusion, a combination therapy of γ-Oryzanol and NAC is an effective therapy to treat NAFLD, which can act via several mechanisms on the liver and adipose tissue.},
}
@article {pmid36611912,
year = {2022},
author = {Tam, E and Sung, HK and Lam, NH and You, S and Cho, S and Ahmed, SM and Abdul-Sater, AA and Sweeney, G},
title = {Role of Mitochondrial Iron Overload in Mediating Cell Death in H9c2 Cells.},
journal = {Cells},
volume = {12},
number = {1},
pages = {},
pmid = {36611912},
issn = {2073-4409},
mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Antioxidants/metabolism ; Cell Death ; Mitochondria/metabolism ; Iron/metabolism ; *Iron Overload/metabolism ; },
abstract = {Iron overload (IO) is associated with cardiovascular diseases, including heart failure. Our study's aim was to examine the mechanism by which IO triggers cell death in H9c2 cells. IO caused accumulation of intracellular and mitochondrial iron as shown by the use of iron-binding fluorescent reporters, FerroOrange and MitoFerroFluor. Expression of cytosolic and mitochondrial isoforms of Ferritin was also induced by IO. IO-induced iron accumulation and cellular ROS was rapid and temporally linked. ROS accumulation was detected in the cytosol and mitochondrial compartments with CellROX, DCF-DA and MitoSOX fluorescent dyes and partly reversed by the general antioxidant N-acetyl cysteine or the mitochondrial antioxidant SkQ1. Antioxidants also reduced the downstream activation of apoptosis and lytic cell death quantified by Caspase 3 cleavage/activation, mitochondrial Cytochrome c release, Annexin V/Propidium iodide staining and LDH release of IO-treated cells. Finally, overexpression of MitoNEET, an outer mitochondrial membrane protein involved in the transfer of Fe-S clusters between mitochondrial and cytosol, was observed to lower iron and ROS accumulation in the mitochondria. These alterations were correlated with reduced IO-induced cell death by apoptosis in MitoNEET-overexpressing cells. In conclusion, IO mediates H9c2 cell death by causing mitochondrial iron accumulation and subsequent general and mitochondrial ROS upregulation.},
}
@article {pmid36611209,
year = {2023},
author = {Liu, Y and She, W and Li, Y and Wang, M and Liu, Y and Ning, B and Xu, T and Huang, T and Wei, Y},
title = {Aa-Z2 triggers ROS-induced apoptosis of osteosarcoma by targeting PDK-1.},
journal = {Journal of translational medicine},
volume = {21},
number = {1},
pages = {7},
pmid = {36611209},
issn = {1479-5876},
mesh = {Humans ; Apoptosis ; *Bone Neoplasms/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; *Osteosarcoma/drug therapy/pathology ; Phosphatidylinositol 3-Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism ; },
abstract = {BACKGROUND: Osteosarcoma (OS) is the most frequent cancer derived from bone, and the prognosis of OS is poor. Metabolic alterations have been previously reported to contribute to the development of OS, and arsenic compounds have been suggested to exhibit strong anti-OS effects. However, few studies have described the therapeutic efficiency of arsenic compounds by targeting metabolism in OS.<br><br>METHODS: Here, we presented a novel organo-arsenic compound, Aa-Z2, and its antitumour efficacy against OS both in vitro and in vivo.<br><br>RESULTS: Aa-Z2 induced OS cell apoptosis, G2/M phase arrest, and autophagy through the accumulation of reactive oxygen species (ROS). Elevated ROS functioned by promoting the mitochondrial-dependent caspase cascade and attenuating the PI3K/Akt/mTOR signalling pathway. N-acetylcysteine (NAC), a kind of ROS scavenger, could reverse the effects of Aa-Z2 treatment on 143B and HOS cells. Specifically, by targeting pyruvate dehydrogenase kinase 1 (PDK-1), Aa-Z2 induced changes in mitochondrial membrane potential and alterations in glucose metabolism to accumulate ROS. Overexpression of PDK-1 could partially desensitize OS cells to Aa-Z2 treatment. Importantly, Aa-Z2 suppressed tumour growth in our xenograft osteosarcoma model.<br><br>CONCLUSION: The study provides new insights into the mechanism of Aa-Z2-related metabolic alterations in OS inhibition, as well as pharmacologic evidence supporting the development of metabolism-targeting therapeutics.},
}
@article {pmid36607576,
year = {2023},
author = {Wang, W and Li, S and Wang, X and Wang, J and Zhang, Y},
title = {PbO nanoparticles increase the expression of ICAM-1 and VCAM-1 by increasing reactive oxygen species production in choroid plexus.},
journal = {Environmental science and pollution research international},
volume = {30},
number = {14},
pages = {40162-40173},
pmid = {36607576},
issn = {1614-7499},
support = {ZD2020113//Science and Technology Project of Hebei Education Department/ ; H2020209250//Natural Science Foundation of Hebei Province/ ; 82073589//National Natural Science Foundation of China/ ; },
mesh = {*Vascular Cell Adhesion Molecule-1/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; Reactive Oxygen Species/metabolism ; Choroid Plexus/metabolism ; Antioxidants/metabolism ; *Nanoparticles ; },
abstract = {PbO nanoparticles (nano-PbO) are widely used in the production of electrode materials, but exposure to them can cause brain damage. The first barrier preventing nano-PbO from entering the brain is the choroid plexus. However, the effect of nano-PbO on the choroid plexus remains unclear. Thus, the purpose of this study was to investigate the effect of nano-PbO exposure on lymphocyte cells infiltration, the adhesion protein of the choroid plexus as well as the role of reactive oxygen species (ROS) during the process. Results showed that nano-PbO exposure increased the percentage of lymphocyte cells in the brain and upregulated the expression of surface adhesion proteins, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in choroid plexus. Meanwhile, nano-PbO treatment also resulted in the increase of intercellular ROS production, and significantly decrease glutathione (GSH) content, glutathione peroxidase (GSH-PX) activity, and superoxide dismutase (SOD) activity in Z310 cells beside the increase of ICAM and VCAM-1 expression. Treatment with ROS inhibitor N-acetylcysteine (NAC) significantly downregulated the expression of ICAM-1 and VCAM-1expression. In conclusion, exposure to nano-PbO increases the expression of ICAM-1 and VCAM-1 through oxidative stress, which may contribute to peripheral lymphocyte cells infiltration into the brain.},
}
@article {pmid36604630,
year = {2023},
author = {Lu, K and Zhou, M and Wang, L and Wang, Y and Tang, H and He, G and Wang, H and Tang, C and He, J and Wang, W and Tang, K and Wang, Y and Deng, Z},
title = {N-Acetyl-L-cysteine facilitates tendon repair and promotes the tenogenic differentiation of tendon stem/progenitor cells by enhancing the integrin α5/β1/PI3K/AKT signaling.},
journal = {BMC molecular and cell biology},
volume = {24},
number = {1},
pages = {1},
pmid = {36604630},
issn = {2661-8850},
support = {CQYC2021059825//Chongqing talents funding/ ; CQYC2021059825//Chongqing talents funding/ ; CQYC2021059825//Chongqing talents funding/ ; 4174DH//National Key Research of China/ ; 4174DH//National Key Research of China/ ; 4174DH//National Key Research of China/ ; 82002306//National Science Foundation for Young Scientists of China/ ; 82002306//National Science Foundation for Young Scientists of China/ ; 82002306//National Science Foundation for Young Scientists of China/ ; cstc2021jcyj-msxmX0137//Chongqing Science &amp; Technology Commission/ ; cstc2021jcyj-msxmX0137//Chongqing Science &amp; Technology Commission/ ; cstc2021jcyj-msxmX0137//Chongqing Science &amp; Technology Commission/ ; cstc2020jcyj-cxttX0004//Sports Injury Repair and Reconstruction Research Innovation Group/ ; cstc2020jcyj-cxttX0004//Sports Injury Repair and Reconstruction Research Innovation Group/ ; cstc2020jcyj-cxttX0004//Sports Injury Repair and Reconstruction Research Innovation Group/ ; },
mesh = {Rats ; Animals ; *Phosphatidylinositol 3-Kinases/metabolism ; Integrin alpha5beta1/metabolism ; Acetylcysteine/pharmacology/metabolism ; Integrin alpha5/metabolism/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinase/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Tendons ; Cell Differentiation/genetics ; Stem Cells ; *Tendon Injuries/drug therapy/metabolism ; },
abstract = {BACKGROUND: Tendon injury is associated with oxidative stress, leading to reactive oxygen species (ROS) production and inflammation. N-acetyl-L-cysteine (NAC) is a potent antioxidant. However, how NAC affects the biological functions of tendon stem/progenitor cells (TSPCs) and tendon repair has not been clarified. METHOD: The impacts of NAC on the viability, ROS production, and differentiation of TSPCs were determined with the cell counting kit-8, fluorescence staining, Western blotting, and immunofluorescence. The effect of NAC on gene transcription in TSPCs was analyzed by transcriptomes and bioinformatics and validated by Western blotting. The potential therapeutic effect of NAC on tendon repair was tested in a rat model of Achilles tendon injury.<br><br>RESULTS: Compared with the untreated control, treatment with 500 &#xb5;M NAC greatly promoted the proliferation of TSPCs and significantly mitigated hydrogen peroxide-induced ROS production and cytotoxicity in vitro. NAC treatment significantly increased the relative protein expression of collagen type 1 alpha 1 (COL1A1), tenascin C (TNC), scleraxis (SCX), and tenomodulin (TNMD) in TPSCs. Bioinformatics analyses revealed that NAC modulated transcriptomes, particularly in the integrin-related phosphoinositide 3-kinase (PI3K)/AKT signaling, and Western blotting revealed that NAC enhanced integrin &#x3b1;5&#x3b2;1 expression and PI3K/AKT activation in TSPCs. Finally, NAC treatment mitigated the tendon injury, but enhanced the protein expression of SCX, TNC, TNMD, and COLIA1 in the injured tissue regions of the rats.<br><br>CONCLUSION: NAC treatment promoted the survival and differentiation of TSPCs to facilitate tendon repair after tendon injury in rats. Thus, NAC may be valuable for the treatment of tendon injury.},
}
@article {pmid36601378,
year = {2022},
author = {Tamagawa, S and Sakai, D and Schol, J and Sako, K and Nakamura, Y and Matsushita, E and Warita, T and Hazuki, S and Nojiri, H and Sato, M and Ishijima, M and Watanabe, M},
title = {N-acetylcysteine attenuates oxidative stress-mediated cell viability loss induced by dimethyl sulfoxide in cryopreservation of human nucleus pulposus cells: A potential solution for mass production.},
journal = {JOR spine},
volume = {5},
number = {4},
pages = {e1223},
pmid = {36601378},
issn = {2572-1143},
abstract = {BACKGROUND: Cell therapy is considered a promising strategy for intervertebral disc (IVD) regeneration. However, cell products often require long-term cryopreservation, which compromises cell viability and potency, thus potentially hindering commercialization and off-the-shelf availability. Dimethyl sulfoxide (DMSO) is a commonly used cryoprotectant, however, DMSO is associated with cytotoxicity and cell viability loss. This study aimed to investigate the effects of DMSO on human nucleus pulposus cells (NPC) and the role of oxidative stress in DMSO-induced cytotoxicity. Furthermore, we examined the potential of antioxidant N-acetylcysteine (NAC) supplementation to mitigate the negative effects of DMSO.<br><br>METHODS: NPC were exposed to various concentrations of DMSO with or without a freezing cycle. Cell viability, cell apoptosis and necrosis rates, intracellular reactive oxygen species (ROS) levels, and gene expression of major antioxidant enzymes were evaluated. In addition, NAC was added to cryopreservation medium containing 10% DMSO and its effects on ROS levels and cell viability were assessed.<br><br>RESULTS: DMSO concentrations &#x2264;1% for 24&#x2009;h did not significantly affect the NPC viability, whereas exposure to 5 and 10% DMSO (most commonly used concentration) caused cell viability loss (loss of 57% and 68% respectively after 24&#x2009;h) and cell death in a dose- and time-dependent manner. DMSO increased intracellular and mitochondrial ROS (1.9-fold and 3.6-fold respectively after 12&#x2009;h exposure to 10% DMSO) and downregulated gene expression levels of antioxidant enzymes in a dose-dependent manner. Tempering ROS through NAC treatment significantly attenuated DMSO-induced oxidative stress and supported maintenance of cell viability.<br><br>CONCLUSIONS: This study demonstrated dose- and time-dependent cytotoxic effects of DMSO on human NPC. The addition of NAC to the cryopreservation medium ameliorated cell viability loss by reducing DMSO-induced oxidative stress in the freeze-thawing cycle. These findings may be useful for future clinical applications of whole cells and cellular products.},
}
@article {pmid36597797,
year = {2023},
author = {Shahveghar Asl, Z and Parastouei, K and Eskandari, E},
title = {The effects of N-acetylcysteine on ovulation and sex hormones profile in women with polycystic ovary syndrome: a systematic review and meta-analysis.},
journal = {The British journal of nutrition},
volume = {130},
number = {2},
pages = {202-210},
doi = {10.1017/S0007114522003270},
pmid = {36597797},
issn = {1475-2662},
mesh = {Humans ; Female ; *Polycystic Ovary Syndrome/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; Gonadal Steroid Hormones ; Follicle Stimulating Hormone ; Ovulation ; },
abstract = {Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases characterised by unusual levels of sex hormones and dysfunction of the ovaries. The infertility rate is high among patients with PCOS. Unusual hormonal status can lead to the inability of ovaries to release functional and mature follicles. Clinical trials on the effects of N-acetylcysteine (NAC) supplementation on ovulation and sex hormones profile in women with PCOS have been controversial. We performed a systematic review and meta-analysis to evaluate the potential effects of NAC supplementation on ovulation and sex hormones profile. PubMed, Scopus, Embase, Web of Science and Cochrane Central library international databases were searched till September 2021. Meta-analysis was performed using a random-effects approach in case of significant between-study heterogeneity. Eighteen studies, including 2185 participants, were included in the present meta-analysis. NAC significantly reduced total testosterone (TT) levels (standardised mean difference (SMD): −0·25 ng/ml; 95 % CI (−0·39, −0·10); ‘P < 0·001’, I[2] = 53·9 %, P = 0·034) and increased follicle-stimulating hormone (FSH) levels (SMD: 0·39 mg/ml; 95 % CI (0·07, 0·71); P = 0·01, I[2] = 70·9 %, P = 0·002). Oestrogen levels also increased after correcting publication bias. However, no significant effect was observed on the number of follicles, endometrial thickness, progesterone, serum luteinising hormone levels and sex hormone-binding globulin. The results indicated that NAC supplementation decreased TT levels and increased FSH levels. Overall, NAC supplementation might be effective in the improvement of reproductive system function in patients with PCOS.},
}
@article {pmid36593372,
year = {2023},
author = {Cepaityte, D and Leivaditis, K and Varouktsi, G and Roumeliotis, A and Roumeliotis, S and Liakopoulos, V},
title = {N-Acetylcysteine: more than preventing contrast-induced nephropathy in uremic patients-focus on the antioxidant and anti-inflammatory properties.},
journal = {International urology and nephrology},
volume = {55},
number = {6},
pages = {1481-1492},
pmid = {36593372},
issn = {1573-2584},
mesh = {Humans ; Antioxidants/therapeutic use/pharmacology ; Acetylcysteine/therapeutic use ; Reactive Oxygen Species ; *Kidney Failure, Chronic/therapy/drug therapy ; Oxidative Stress ; *Renal Insufficiency, Chronic/therapy/drug therapy ; Anti-Inflammatory Agents/pharmacology ; },
abstract = {Oxidative stress (OS) has been recognized as a pathophysiologic mechanism underlying the development and progression of chronic kidney disease (CKD). OS, which results from the disturbance of balance among pro-oxidants and antioxidants favoring the pro-oxidants, is present even in early CKD and increases progressively along with deterioration of kidney function to end-stage kidney disease (ESKD). In ESKD, OS is further exacerbated mainly due to dialysis procedures per se and predisposes to increased cardiovascular morbidity and mortality. Therefore, since OS plays a pivotal role in the pathogenesis and progression of atherosclerosis in uremic patients, several strategies aiming to ameliorate OS in these patients have been proposed. Among those, N-acetylcysteine (NAC), a thiol-containing antioxidant agent, has attracted special attention due to its pleiotropic functions and beneficial effect in various OS-related entities including paracetamol overdose and prevention of contrast-induced nephropathy. In this review, we present the currently available literature on the antioxidant and anti-inflammatory properties of NAC in CKD, including hemodialysis and peritoneal dialysis.},
}
@article {pmid36592900,
year = {2023},
author = {Wang, YH and Wang, YQ and Yu, XG and Lin, Y and Liu, JX and Wang, WY and Yan, CH},
title = {Chronic environmental inorganic arsenic exposure causes social behavioral changes in juvenile zebrafish (Danio rerio).},
journal = {The Science of the total environment},
volume = {867},
number = {},
pages = {161296},
doi = {10.1016/j.scitotenv.2022.161296},
pmid = {36592900},
issn = {1879-1026},
mesh = {Humans ; Animals ; Zebrafish/metabolism ; *Arsenic/toxicity/metabolism ; *Arsenicals/metabolism ; Oxidative Stress ; Zebrafish Proteins/metabolism ; *Water Pollutants, Chemical/metabolism ; },
abstract = {Arsenic (As) is a metalloid commonly found worldwide. Environmental As exposure may cause potential health hazards and behavioral changes in humans and animals. However, the effects of environmental As concentrations on social behavior, especially during the juvenile stage, are unclear. In this study, we observed behavioral changes in juvenile zebrafish after 28 days of exposure to inorganic As (NaAsO2 100 and 500 ppb) in water, especially anxiety and social deficits. Additionally, the level of oxidative stress in the zebrafish brain after As treatment increased, the content of dopamine (DA) decreased, and the transcription level of genes involved in DA metabolism with the activity of monoamine oxidase (MAO) increased. Oxidative stress is a recognized mechanism of nerve damage induced by As exposure. The zebrafish were exposed to N-acetylcysteine (NAC) to reduce As exposure-induced oxidative stress. The results showed improvements in social behavior, DA content, MAO activity, and gene transcription in zebrafish. In conclusion, environmental As exposure can induce behavioral abnormalities, such as anxiety and social deficits in zebrafish, which may be caused by As-induced oxidative stress altering gene transcription levels, causing an increase in MAO activity and a decrease in DA.},
}
@article {pmid36591540,
year = {2022},
author = {LoBianco, FV and Krager, KJ and Johnson, E and Godwin, CO and Allen, AR and Crooks, PA and Compadre, CM and Borrelli, MJ and Aykin-Burns, N},
title = {Parthenolide induces rapid thiol oxidation that leads to ferroptosis in hepatocellular carcinoma cells.},
journal = {Frontiers in toxicology},
volume = {4},
number = {},
pages = {936149},
pmid = {36591540},
issn = {2673-3080},
support = {P20 GM109005/GM/NIGMS NIH HHS/United States ; R01 CA258673/CA/NCI NIH HHS/United States ; T32 GM106999/GM/NIGMS NIH HHS/United States ; },
abstract = {Hepatocellular carcinoma (HCC) is both a devastating and common disease. Every year in the United States, about 24,500 men and 10,000 women are diagnosed with HCC, and more than half of those diagnosed patients die from this disease. Thus far, conventional therapeutics have not been successful for patients with HCC due to various underlying comorbidities. Poor survival rate and high incidence of recurrence after therapy indicate that the differences between the redox environments of normal surrounding liver and HCC are valuable targets to improve treatment efficacy. Parthenolide (PTL) is a naturally found therapeutic with anti-cancer and anti-inflammatory properties. PTL can alter HCC's antioxidant environment through thiol modifications leaving tumor cells sensitive to elevated reactive oxygen species (ROS). Investigating the link between altered thiol mechanism and increased sensitivity to iron-mediated lipid peroxidation will allow for improved treatment of HCC. HepG2 (human) and McARH7777 (rat) HCC cells treated with PTL with increasing concentrations decrease cell viability and clonogenic efficiency in vitro. PTL increases glutathione (GSH) oxidation rescued by the addition of a GSH precursor, N-acetylcysteine (NAC). In addition, this elevation in thiol oxidation results in an overall increase in mitochondrial dysfunction. To elucidate if cell death is through lipid peroxidation, using a lipid peroxidation sensor indicated PTL increases lipid oxidation levels after 6 h. Additionally, western blotting reveals glutathione peroxidase 4 (GPx4) protein levels decrease after treatment with PTL suggesting cells are incapable of preventing lipid peroxidation after exposure to PTL. An elevation in lipid peroxidation will lead to a form of cell death known as ferroptosis. To further establish ferroptosis as a critical mechanism of death for HCC in vitro, the addition of ferrostatin-1 combined with PTL demonstrates a partial recovery in a colony survival assay. This study reveals that PTL can induce tumor cell death through elevations in intracellular oxidation, leaving cells sensitive to ferroptosis.},
}
@article {pmid36590525,
year = {2022},
author = {Prylutskyy, Y and Nozdrenko, D and Gonchar, O and Prylutska, S and Bogutska, K and Franskevych, D and Hromovyk, B and Scharff, P and Ritter, U},
title = {C60 fullerene attenuates muscle force reduction in a rat during fatigue development.},
journal = {Heliyon},
volume = {8},
number = {12},
pages = {e12449},
pmid = {36590525},
issn = {2405-8440},
abstract = {C60 fullerene (C60) as a nanocarbon particle, compatible with biological structures, capable of penetrating through cell membranes and effectively scavenging free radicals, is widely used in biomedicine. A protective effect of C60 on the biomechanics of fast (m. gastrocnemius) and slow (m. soleus) muscle contraction in rats and the pro- and antioxidant balance of muscle tissue during the development of muscle fatigue was studied compared to the same effect of the known antioxidant N-acetylcysteine (NAC). C60 and NAC were administered intraperitoneally at doses of 1 and 150 mg kg[-1], respectively, daily for 5 days and 1 h before the start of the experiment. The following quantitative markers of muscle fatigue were used: the force of muscle contraction, the level of accumulation of secondary products of lipid peroxidation (TBARS) and the oxygen metabolite H2O2, the activity of first-line antioxidant defense enzymes (superoxide dismutase (SOD) and catalase (CAT)), and the condition of the glutathione system (reduced glutathione (GSH) content and the activity of the glutathione peroxidase (GPx) enzyme). The analysis of the muscle contraction force dynamics in rats against the background of induced muscle fatigue showed, that the effect of C60, 1 h after drug administration, was (15-17)% more effective on fast muscles than on slow muscles. A further slight increase in the effect of C60 was revealed after 2 h of drug injection, (7-9)% in the case of m. gastrocnemius and (5-6)% in the case of m. soleus. An increase in the effect of using C60 occurred within 4 days (the difference between 4 and 5 days did not exceed (3-5)%) and exceeded the effect of NAC by (32-34)%. The analysis of biochemical parameters in rat muscle tissues showed that long-term application of C60 contributed to their decrease by (10-30)% and (5-20)% in fast and slow muscles, respectively, on the 5th day of the experiment. At the same time, the protective effect of C60 was higher compared to NAC by (28-44)%. The obtained results indicate the prospect of using C60 as a potential protective nano agent to improve the efficiency of skeletal muscle function by modifying the reactive oxygen species-dependent mechanisms that play an important role in the processes of muscle fatigue development.},
}
@article {pmid36589610,
year = {2022},
author = {Heo, YR and Son, CN and Baek, WK and Kim, SH},
title = {Grape seed proanthocyanidin extract induces apoptotic and autophagic cell death in rheumatoid arthritis fibroblast-like synoviocytes.},
journal = {Archives of rheumatology},
volume = {37},
number = {3},
pages = {393-403},
pmid = {36589610},
issn = {2618-6500},
abstract = {OBJECTIVES: In this study, we aimed to evaluate the association between grape seed proanthocyanidin extract (GSPE) and rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLSs) and to investigate whether GSPE induces cell death in RA-FLSs.<br><br>MATERIALS AND METHODS: The FLSs were isolated from RA synovial tissues. Cell viability and cell cycle staging were analyzed using a hemocytometer and flow cytometry. Caspase 3 and poly (ADP-ribose) polymerase (PARP) proteins were analyzed using Western blotting with z-VAD-fmk. Protein LC3 and polyubiquitin-binding protein p62 that were degraded by autophagy were evaluated using Western blotting with 3-methyladenine and chloroquine. Reactive oxygen species (ROS) were also evaluated.<br><br>RESULTS: When RA-FLSs were treated with GSPE, cell viability decreased, the number of cells in sub-G1 and G2/M phases increased, and the expression of pro-PARP and pro-caspase 3 proteins decreased in a concentration-dependent manner. This result was offset, when the cells were co-treated with the pan-caspase inhibitor z-VAD-fmk. The reduced cell viability, increased expression of LC3-II protein, and reduced expression of p62 protein with GSPE treatment were offset, when RA-FLSs were co-treated with GSPE and autophagy inhibitors 3-methyladenine and chloroquine. The level of ROS in RA-FLSs treated with GSPE was significantly lower than treatment with N-acetyl-cysteine, a ROS inhibitor.<br><br>CONCLUSION: Our study results show that GSPE induces apoptotic and autophagic cell death and inhibites reactive oxygen species in RA-FLSs.},
}
@article {pmid36587882,
year = {2023},
author = {Behera, J and Pitchiah Kumar, M and Ireen Femela, A and Senguttuvan, G and Ramasamy, MS},
title = {miRNA-15/IL-10Rα axis promotes Kabasura Kudineer (Indian traditional Siddha formulation) induced immunomodulation by suppressing oxidative stress.},
journal = {Journal of ethnopharmacology},
volume = {305},
number = {},
pages = {116032},
doi = {10.1016/j.jep.2022.116032},
pmid = {36587882},
issn = {1872-7573},
mesh = {Humans ; *MicroRNAs/genetics/metabolism ; Antioxidants/pharmacology/metabolism ; Interleukin-6/metabolism ; Lipopolysaccharides/pharmacology ; Nitric Oxide/metabolism ; Inflammation ; Oxidative Stress ; Anti-Inflammatory Agents/pharmacology ; Glutathione/metabolism ; Superoxide Dismutase/metabolism ; },
abstract = {Kabasura Kudineer (KK), the traditional Indian medicine of Siddha, effectively manages common respiratory symptoms such as flu, cold, and fever. However, there is no evidence of the immunomodulatory capacity of KK in the cultured Jurkat T-lymphocytes under the LPS insult studied.<br><br>AIM OF THE STUDY: Assess the effect of the traditional Indian medicine of Siddha, Kabasura Kudineer (KK) on immunomodulation by suppressing oxidative damage in cultured Jurkat T cells in vitro. The miRNA activity on anti-inflammatory gene receptors and cellular nitric oxide levels also was studied.<br><br>MATERIALS AND METHODS: Jurkat T cells were exposed to LPS treatment in the presence or absence of KK. Cell viability and nitric oxide (NO) were measured with MTT and Griess assay. Cellular antioxidant systems (glutathione and SOD) were determined using glutathione and SOD assay. Lipid peroxidation was measured using an MDA assay. MiRNA-15a-5p expression was performed using microRNA qPCR Assays. Both inflammatory and anti-inflammatory genes (IL-6, IL-1, IL-10, IL-13) were performed using a qPCR and ELISA assay.<br><br>RESULTS: The data showed that reduced cell proliferation and exaggerated NO production was observed in LPS treated condition compared to the control condition. Further, LPS treatment increased lipid peroxidation and reduced antioxidant enzyme activities (SOD and glutathione) in cultured Jurkat T cells. However, treatment with KK or N-acetyl cysteine (NAC; antioxidant) treatment mitigates the above effect. Mechanistically, LPS-induced oxidative stress upregulated miR- 15-5p expression and suppressed IL-10 Receptor alpha (IL-10R&#x3b1;) by binding to its 3'-UTR region. The deregulated expression of IL-10R&#x3b1; expression leads to increased IL-6 and IL-1&#x3b2; expression in LPS-induced Jurkat T cells; however, treatment with KK or NAC reversed the above effects.<br><br>CONCLUSION: Collectively, our study revealed the previously undefined mechanistic role of Kabasura Kudineer (KK) that alleviates the LPS-induced oxidative damage associated with inflammation by inhibiting the miRNA-15-5p/IL-10R&#x3b1; axis.},
}
@article {pmid38313355,
year = {2023},
author = {Hatami, B and Abdi, S and Pourhoseingholi, MA and Eghlimi, H and Rabbani, AH and Masoumi, M and Hajimohammadebrahim-Ketabforoush, M},
title = {The effects of N-acetylcysteine on hepatic, hematologic, and renal parameters in cirrhotic patients: a randomized controlled trial.},
journal = {Gastroenterology and hepatology from bed to bench},
volume = {16},
number = {4},
pages = {432-440},
pmid = {38313355},
issn = {2008-2258},
abstract = {AIM: To evaluate the effects of N-acetylcysteine (NAC) supplementation in cirrhotic patients.<br><br>BACKGROUND: Chronic hepatic inflammation leads to fibrosis and cirrhosis through various mechanisms such as oxidative stress. NAC is one of the intracellular precursors of glutathione that can degrade most reactive oxygen species. Recently, the beneficial effects of NAC in animal and human studies on preventing liver injury progression and improving liver function have been examined. However, more studies on human subjects are still required.<br><br>METHODS: Well-known cirrhotic patients with a specific etiology and aged 18 to 70 years who referred to the gastrointestinal clinic of Ayatollah Taleghani Hospital from December 2018 to December 2019 were enrolled in the present randomized double-blind controlled trial. Patients in the intervention group received NAC tablets at a dose of 600 mg daily, and the control group received a placebo. Demographic data, medical characteristics, and Child-Pugh and MELD scores evaluated at baseline and after 6 months.<br><br>RESULTS: Totally, 60 patients completed the present study (30 patients in the intervention group, and 30 patients in the control group). Hematological and biochemical parameters were normal in both groups with no significant differences at baseline and 6 months after intervention values. Moreover, the renal function indicators including serum creatinine (Cr) and urea (BUN) decreased significantly after intervention. Hepatic parameters also decreased significantly 6 months after intervention. Decreases in the renal and hepatic parameters 6 months after baseline in the control group were not statistically significant.<br><br>CONCLUSION: The results of this study showed that NAC improved hepatic and renal function by decreasing serum urea and creatinine levels but had no significant effect on hematological and biochemical parameters. Furthermore, NAC significantly improved hepatic profiles by decreasing ALT, AST, and ALP in the liver enzymes between the intervention and control groups. Moreover, NAC caused a significant decrease in Child-Pugh and MELD scores.},
}
@article {pmid36586713,
year = {2023},
author = {Huang, D and Wang, Y and Xiao, J and Wang, Y and Zhu, X and Xu, B and Wang, M},
title = {Scavenging of reactive oxygen species effectively reduces Pseudomonas aeruginosa biofilms through disrupting policing.},
journal = {Environmental research},
volume = {220},
number = {},
pages = {115182},
doi = {10.1016/j.envres.2022.115182},
pmid = {36586713},
issn = {1096-0953},
mesh = {Reactive Oxygen Species/metabolism ; *Anti-Bacterial Agents/pharmacology ; *Pseudomonas aeruginosa/genetics ; Biofilms ; Drug Resistance, Microbial ; Acetylcysteine/pharmacology ; },
abstract = {Biofilm formation is likely to contribute greatly to antibiotic resistance in bacteria and therefore the efficient removal of bacterial biofilms needs addressing urgently. Here, we reported that the supplement of non-inhibitory concentration of N-acetyl-L-cysteine (NAC), a common reactive oxygen species (ROS) scavenger, can significantly reduce the biomass of mature Pseudomonas aeruginosa biofilms (corroborated by crystal violet assay and laser scanning confocal microscopy). 1 mM NAC increased the cheater (ΔlasR mutant) frequency to 89.4 ± 1.5% in the evolved PAO1 after the 15-day treatment. Scavenging of ROS by NAC induced the collapse of P. aeruginosa biofilms, but it did not alter quorum sensing-regulated genes expression (e.g., hcnC and cioAB) and hydrogen cyanide production. The replenishment of public good protease contributed to the recovery of biofilm biomass, indicating the role of disrupting policing in biofilm inhibition. Furthermore, 7 typical ROS scavengers (e.g., superoxide dismutase, catalase and peroxidase, etc.) also effectively inhibited mature P. aeruginosa biofilms. This study demonstrates that scavenging of ROS can promote the selective control of P. aeruginosa biofilms through policing disruption as a targeted biofilm control strategy in complex water environments.},
}
@article {pmid36582212,
year = {2022},
author = {Chen, X and Malaeb, SN and Pan, J and Wang, L and Scafidi, J},
title = {Editorial: Perinatal hypoxic-ischemic brain injury: Mechanisms, pathogenesis, and potential therapeutic strategies.},
journal = {Frontiers in cellular neuroscience},
volume = {16},
number = {},
pages = {1086692},
pmid = {36582212},
issn = {1662-5102},
support = {P50 HD103538/HD/NICHD NIH HHS/United States ; R01 NS099461/NS/NINDS NIH HHS/United States ; R01 NS125653/NS/NINDS NIH HHS/United States ; },
}
@article {pmid36577481,
year = {2023},
author = {Mancini, L and Paolantoni, M and Schoubben, A and Ricci, M},
title = {Development of spray-dried N-acetylcysteine dry powder for inhalation.},
journal = {International journal of pharmaceutics},
volume = {631},
number = {},
pages = {122550},
doi = {10.1016/j.ijpharm.2022.122550},
pmid = {36577481},
issn = {1873-3476},
mesh = {*Acetylcysteine ; Powders/chemistry ; Leucine/chemistry ; Administration, Inhalation ; Aerosols/chemistry ; *Mannitol/chemistry ; Particle Size ; Dry Powder Inhalers ; },
abstract = {N-acetylcysteine (NAC) has both antioxidant and immunomodulatory activities and has been used as adjuvant therapy in several viral infections. Recently, NAC attracted attention for its possible role in reducing the affinity of the spike protein receptor binding domain to angiotensin-converting enzyme (ACE2) receptors. Since only NAC solutions are available for inhalation, the purpose of the work was to develop a NAC dry powder for inhalation using mannitol or leucine as excipient. The powder was successfully produced using co-spray-drying with leucine. ATR-FTIR analyses evidenced spectral variations ascribed to the formation of specific interactions between NAC and leucine. This effect on the NAC environment was not evident for NAC-mannitol powders, but mannitol was in a different polymorphic form compared to the supplied material. Both the feedstock concentration and the leucine content have an impact on the powder aerodynamic features. In particular, to maximize the respirable fraction, it is preferable to produce the powder starting from a 0.5 % w/v feedstock solution using 33 to 50 % w/w leucine content. The NAC-leucine powder was stable for ten months maintaining NAC content of 50 % (w/w) and about 200 μg of NAC was able to deposit on a transwell insert, useful for future in vitro studies.},
}
@article {pmid36567856,
year = {2022},
author = {Wei, B and Hao, Z and Zheng, H and Qin, Y and Zhao, F and Shi, L},
title = {Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction.},
journal = {Oxidative medicine and cellular longevity},
volume = {2022},
number = {},
pages = {5888636},
pmid = {36567856},
issn = {1942-0994},
mesh = {Humans ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; *Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Superoxides/metabolism ; *Vascular Endothelial Growth Factor A/metabolism ; *Neovascularization, Pathologic/metabolism ; *Angiogenesis Inhibitors/pharmacology ; Crotonates ; Sesquiterpenes ; },
abstract = {Brevilin A (BA), a sesquiterpene lactone isolated from Centipeda minima herb, has been identified to exhibit potent anticancer activity. However, the potential pharmacological effect and mechanism of BA in regulating endothelial cell (EC) angiogenesis, a key event in tumor growth, is poorly understood. In this study, BA was shown to significantly prevent vascular endothelial growth factor (VEGF) induced EC angiogenic capacities in vitro, ex vivo, and in vivo. Subsequent functional assays revealed that BA dose dependently inhibited VEGF-stimulated survival, proliferation, migration, and triggered apoptosis activity in human umbilical vein endothelial cells (HUVECs), as well as suppressed the expression of antiapoptotic protein Bcl-2, increased the expression of proapoptotic protein caspase-3 and Bax, and suppressed PI3K/AKT pathway. Meanwhile, BA was also able to depolarize mitochondrial membranal permeability (MMP), accelerate mitochondrial superoxide accumulation, induce intracellular reactive oxygen species (ROS) production, and decreased intracellular glutathione (GSH) in HUVECs. Furthermore, both mitochondria-specific superoxide scavenger Mito-TEMPOL and broad-spectrum antioxidant N-acetyl-cysteine (NAC) dramatically abolished BA-induced mitochondrial dysfunction and mitochondrial ROS production, causing the reversion of PI3K/AKT pathway and repression of apoptosis, eventually correcting the impaired endothelial behavior in survival, growth, migration, and angiogenesis. Collectively, our data for the first time identified a new mechanism for antiangiogenic effect of BA in vascular EC, one that is based on the regulation of mitochondrial-dependent ROS overproduction.},
}
@article {pmid36564154,
year = {2023},
author = {Wilkinson, MGL and Moulding, D and McDonnell, TCR and Orford, M and Wincup, C and Ting, JYJ and Otto, GW and Restuadi, R and Kelberman, D and Papadopoulou, C and Castellano, S and Eaton, S and Deakin, CT and Rosser, EC and Wedderburn, LR},
title = {Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis.},
journal = {Annals of the rheumatic diseases},
volume = {82},
number = {5},
pages = {658-669},
pmid = {36564154},
issn = {1468-2060},
support = {18DS03/DH_/Department of Health/United Kingdom ; 20164/VAC_/Versus Arthritis/United Kingdom ; 085860/WT_/Wellcome Trust/United Kingdom ; 22936/DH_/Department of Health/United Kingdom ; 21992/VAC_/Versus Arthritis/United Kingdom ; MRF-057-0001-RG-ROSS-C0797/MRF_/MRF_/United Kingdom ; 21593/VAC_/Versus Arthritis/United Kingdom ; 14518/VAC_/Versus Arthritis/United Kingdom ; MR/N003322/1/MRC_/Medical Research Council/United Kingdom ; GOSH BRC 18IR33/DH_/Department of Health/United Kingdom ; MRF-159-0006-ELP-MCDO-C0954/MRF_/MRF_/United Kingdom ; 21552/VAC_/Versus Arthritis/United Kingdom ; },
mesh = {Child ; Humans ; *Dermatomyositis ; Leukocytes, Mononuclear/metabolism ; Monocytes/metabolism ; DNA, Mitochondrial ; *Interferon Type I/metabolism ; Nucleotidyltransferases ; },
abstract = {OBJECTIVES: To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM).<br><br>METHODS: RNA-sequencing was performed on CD4[+], CD8[+], CD14[+] and CD19[+] cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by [13]C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-&#x3b1;, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/or n-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35.<br><br>RESULTS: Dysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including 'megamitochondria', cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC.<br><br>CONCLUSIONS: These results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.},
}
@article {pmid36563924,
year = {2023},
author = {Yang, HL and Lin, YA and Pandey, S and Liao, JW and Way, TD and Yeh, YL and Chen, SJ and Hseu, YC},
title = {In vitro and in vivo anti-tumor activity of Antrodia salmonea against twist-overexpressing HNSCC cells: Induction of ROS-mediated autophagic and apoptotic cell death.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {172},
number = {},
pages = {113564},
doi = {10.1016/j.fct.2022.113564},
pmid = {36563924},
issn = {1873-6351},
mesh = {*Head and Neck Neoplasms/drug therapy ; *Apoptosis ; Reactive Oxygen Species/metabolism ; Polyporales ; Autophagy ; Mice ; Animals ; Cell Line, Tumor ; Mice, Nude ; Squamous Cell Carcinoma of Head and Neck/drug therapy ; },
abstract = {Head and neck squamous cell carcinoma (HNSCC) is a relatively common malignancy, characterized by lethal morbidity. Herein, we attempted to investigate the autophagy/apoptosis activities of the submerged fermented broths of Antrodia salmonea (AS) in HNSCC Twist-overexpressing (OECM-1 and FaDu-Twist) cells. AS (0-150 μg/mL) effectively reduced cell viability, colony formation, and downregulated Twist expression in OECM-1 and FaDu-Twist cells compared to FaDu cells. AS- induced apoptosis was mainly associated with activation of caspase-3, PARP cleavage, increased expression of VDAC-1 and disproportionation of Bax/Bcl-2. Annexin V/PI staining suggested late apoptosis induction by AS treatment. AS exhibits enhanced autophagy process mediated via LC3-I/II accumulation, increased acidic vesicular organelles (AVOs) formation and p62/SQSTM1 expression feeding into the apoptotic program. However, pre-treatment with autophagy blockers 3-MA and CQ significantly diminished AS-induced cell death. Additionally, suppression of AS-induced ROS release by treatment with antioxidant N-acetylcysteine (NAC) resulted in reduction of apoptotic and autophagic cell death. In vivo studies strengthened the above observations and showed that AS effectively reduced the tumor volume and tumor weight in OECM-1-xenografted nude mice. This study discovered that Antrodia salmonea exhibits a novel anti-cancer mechanism which could be harnessed as a new potent drug for HNSCC treatment.},
}
@article {pmid36563904,
year = {2023},
author = {Mohammadi, E and Nikbakht, F and Vazifekhah, S and Babae, JF and Jogataei, MT},
title = {Evaluation the cognition-improvement effects of N-acetyl cysteine in experimental temporal lobe epilepsy in rat.},
journal = {Behavioural brain research},
volume = {440},
number = {},
pages = {114263},
doi = {10.1016/j.bbr.2022.114263},
pmid = {36563904},
issn = {1872-7549},
mesh = {Rats ; Animals ; *Epilepsy, Temporal Lobe/drug therapy/metabolism ; Acetylcysteine/pharmacology/metabolism ; Maze Learning ; Hippocampus/metabolism ; Cognition ; *Epilepsy/metabolism ; Kainic Acid/pharmacology ; Memory Disorders/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Disease Models, Animal ; },
abstract = {Memory impairment is a critical issue in patients with temporal lobe epilepsy (TLE). Neuronal loss within the hippocampus and recurrent seizures may cause cognitive impairment in TLE. N -acetyl cysteine (NAC) is a sulfur-containing amino acid cysteine that is currently being investigated due to its protective effects on neurodegenerative disorders. NAC was orally administrated at a dose of 100 mg/kg for 8 days (7-day pretreatment and 1-day post-surgery). Neuronal viability, mTOR protein level, and spatial memory were detected in the kainite temporal epilepsy model via Nissl staining, western blot method, and Morris water maze task, respectively. Results showed that NAC delayed seizure activity and ameliorated memory deficit induced by Kainic acid. Histological analysis showed that NAC significantly increased the number of intact neurons in CA3 and hilar areas of the hippocampus following the induction of epilepsy. NAC also modulated the mTOR protein level 5 days after epilepsy compared to the KA-induced group. CONCLUSION: These results suggest that NAC improved memory impairment via anticonvulsant and neuroprotective activity and, in all probability, by lowering the level of mTOR.},
}
@article {pmid36558992,
year = {2022},
author = {Zhang, T and Xiu, YH and Xue, H and Li, YN and Cao, JL and Hou, WS and Liu, J and Cui, YH and Xu, T and Wang, Y and Jin, CH},
title = {A Mechanism of Isoorientin-Induced Apoptosis and Migration Inhibition in Gastric Cancer AGS Cells.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
pmid = {36558992},
issn = {1424-8247},
support = {2020YFD1001400//National Key Research and Development Project of China/ ; 2019HTY078//Heilongjiang Touyan Innovation Team Program/ ; 2020GSP16//Central Government Supports Local College Reform and Development Fund Talent Training Projects/ ; },
abstract = {Isoorientin (ISO) is a flavonoid compound containing a luteolin structure, which can induce autophagy in some tumor cells. This study investigated the impact of ISO in gastric cancer AGS cells, and performed an experimental analysis on the main signaling pathways and transduction pathways it regulates. CCK-8 assay results showed that ISO reduced the survival rate of gastric cancer AGS cells, but the toxicity to normal cells was minimal. Hoechst 33342/PI double staining assay results showed that ISO induced apoptosis in gastric cancer AGS cells. Further analysis by flow cytometry and Western blot showed that ISO induced apoptosis via a mitochondria-dependent pathway. In addition, the level of reactive oxygen species (ROS) in gastric cancer AGS cells also increased with the extension of the ISO treatment time. However, cell apoptosis was inhibited by preconditioning cells with N-acetylcysteine (NAC). Moreover, ISO arrested the cell cycle at the G2/M phase by increasing intracellular ROS levels. Cell migration assay results showed that ISO inhibited cell migration by inhibiting the expression of p-AKT, p-GSK-3β, and β-catenin and was also related to the accumulation of ROS. These results suggest that ISO-induced cell apoptosis by ROS-mediated MAPK/STAT3/NF-κB signaling pathways inhibited cell migration by regulating the AKT/GSK-3β/β-catenin signaling pathway in gastric cancer AGS cells.},
}
@article {pmid36557977,
year = {2022},
author = {Huang, J and Wang, J and Song, G and Hu, C and Xu, Z and Chen, Z and Xu, C and Yang, D},
title = {Antiproliferative Evaluation of Novel 4-Imidazolidinone Derivatives as Anticancer Agent Which Triggers ROS-Dependent Apoptosis in Colorectal Cancer Cell.},
journal = {Molecules (Basel, Switzerland)},
volume = {27},
number = {24},
pages = {},
pmid = {36557977},
issn = {1420-3049},
support = {cstc2020jcyj-msxmX0595//Natural Science Foundation of Chongqing/ ; KJQN201901331//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; KJZD-K202001302//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; P2021YX05//Scientific Research Foundation of the Chongqing University of Arts and Sciences/ ; KJQN202201330//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; },
mesh = {Humans ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Apoptosis ; *Antineoplastic Agents/pharmacology/therapeutic use ; *Colorectal Neoplasms/drug therapy/metabolism ; },
abstract = {Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide, and more therapies are needed to treat CRC. To discover novel CRC chemotherapeutic molecules, we used a series of previously synthesized novel imidazolidin-4-one derivatives to study their anticancer role in several cancer cell lines. Among these compounds, compound 9r exhibited the best anticancer activity in CRC cell lines HCT116 and SW620. We further investigated the anticancer molecular mechanism of compound 9r. We found that compound 9r induced mitochondrial pathway apoptosis in HCT116 and SW620 cells by inducing reactive oxygen species (ROS) production. Moreover, the elevated ROS generation activated the c-Jun N-terminal kinase (JNK) pathway, which further accelerated apoptosis. N-acetylcysteine (NAC), an antioxidant reagent, suppressed compound 9r-induced ROS production, JNK pathway activation, and apoptosis. Collectively, this research synthesized a series of imidazolidin-4-one derivatives, evaluated their anticancer activity, and explored the molecular mechanism of compound 9r-induced apoptosis in CRC cells. The present results suggest that compound 9r has a potential therapeutic role in CRC. Hence, it deserves further exploration as a lead compound for CRC treatment.},
}
@article {pmid36555816,
year = {2022},
author = {Kesidou, E and Bitsina, C and Chatzisotiriou, A and Theotokis, P and Dandi, E and Tata, DA and Spandou, E},
title = {N-Acetylcysteine Administration Attenuates Sensorimotor Impairments Following Neonatal Hypoxic-Ischemic Brain Injury in Rats.},
journal = {International journal of molecular sciences},
volume = {23},
number = {24},
pages = {},
pmid = {36555816},
issn = {1422-0067},
mesh = {Animals ; Rats ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; Animals, Newborn ; Rats, Sprague-Dawley ; *Hypoxia-Ischemia, Brain/metabolism ; *Brain Injuries/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use/metabolism ; Brain/metabolism ; },
abstract = {Hypoxic ischemic (HI) brain injury that occurs during neonatal period has been correlated with severe neuronal damage, behavioral deficits and infant mortality. Previous evidence indicates that N-acetylcysteine (NAC), a compound with antioxidant action, exerts a potential neuroprotective effect in various neurological disorders including injury induced by brain ischemia. The aim of the present study was to investigate the role of NAC as a potential therapeutic agent in a rat model of neonatal HI brain injury and explore its long-term behavioral effects. To this end, NAC (50 mg/kg/dose, i.p.) was administered prior to and instantly after HI, in order to evaluate hippocampal and cerebral cortex damage as well as long-term functional outcome. Immunohistochemistry was used to detect inducible nitric oxide synthase (iNOS) expression. The results revealed that NAC significantly alleviated sensorimotor deficits and this effect was maintained up to adulthood. These improvements in functional outcome were associated with a significant decrease in the severity of brain damage. Moreover, NAC decreased the short-term expression of iNOS, a finding implying that iNOS activity may be suppressed and that through this action NAC may exert its therapeutic action against neonatal HI brain injury.},
}
@article {pmid36555541,
year = {2022},
author = {Matsuura, T and Komatsu, K and Ogawa, T},
title = {N-Acetyl Cysteine-Mediated Improvements in Dental Restorative Material Biocompatibility.},
journal = {International journal of molecular sciences},
volume = {23},
number = {24},
pages = {},
pmid = {36555541},
issn = {1422-0067},
mesh = {Humans ; *Acetylcysteine/metabolism ; *Antioxidants/pharmacology ; Glutathione/metabolism ; Gingiva/metabolism ; Polymers ; Composite Resins/pharmacology ; Materials Testing ; Dental Materials/pharmacology ; },
abstract = {The fibroblast-rich gingival tissue is usually in contact with or adjacent to cytotoxic polymer-based dental restoration materials. The objective of this study was to determine whether the antioxidant amino acid, N-acetyl cysteine (NAC), reduces the toxicity of dental restorative materials. Human oral fibroblasts were cultured with bis-acrylic, flowable composite, bulk-fill composite, self-curing acrylic, and titanium alloy test specimens. Cellular behavior and function were analyzed on and around the materials. Impregnation of the bulk-fill composite and self-curing acrylic with NAC reduced their toxicity, improving the attachment, growth, and function of human oral fibroblasts on and around the materials. These mitigating effects were NAC dose dependent. However, NAC impregnation of the bis-acrylic and flowable composite was ineffective, with no cells attaching to nor around the materials. Although supplementing the culture medium with NAC also effectively improved fibroblast behaviors, direct impregnation of materials with NAC was more effective than supplementing the cultures. NAC-mediated improvements in fibroblast behavior were associated with reduced production of reactive oxygen species and oxidized glutathione together with increased glutathione reserves, indicating that NAC effectively directly scavenged ROS from materials and reinforced the cellular antioxidant defense system. These results establish a proof of concept of NAC-mediated improvements in biocompatibility in the selected dental restorative materials.},
}
@article {pmid36553574,
year = {2022},
author = {Ji, T and Chen, X and Zhang, Y and Fu, K and Zou, Y and Wang, W and Zhao, J},
title = {Effects of N-Acetylcysteine on the Proliferation, Hormone Secretion Level, and Gene Expression Profiles of Goat Ovarian Granulosa Cells.},
journal = {Genes},
volume = {13},
number = {12},
pages = {},
pmid = {36553574},
issn = {2073-4425},
mesh = {Female ; Animals ; Sheep ; *Transcriptome ; *Acetylcysteine/metabolism ; Goats/genetics ; Granulosa Cells/metabolism ; Cell Proliferation ; Hormones ; RNA, Messenger/metabolism ; },
abstract = {The purpose of this paper was to investigate the effects of N-acetylcysteine (NAC) on the proliferation, hormone secretion, and mRNA expression profiles of ovarian granulosa cells (GCs) in vitro. A total of 12 ovaries from 6 follicular-stage goats were collected for granulosa cell extraction. The optimum concentration of NAC addition was determined to be 200 μM via the Cell Counting Kit 8 (CCK-8) method. Next, GCs were cultured in a medium supplemented with 200 μM NAC (200 μM NAC group) and 0 μ M NAC (control group) for 48 h. The effects of 200 μM NAC on the proliferation of granulosa cells and hormones were studied by 5-ethynyl-2'-deoxyuridine (EdU) assay and enzyme-linked immunosorbent assay (ELISA). mRNA expression was analyzed by transcriptome sequencing. The results indicate that 200 μM NAC significantly increased cell viability and the proportion of cells in the S phase but promoted hormone secretion to a lesser degree. Overall, 122 differentially expressed genes (DEGs) were identified. A total of 51 upregulated and 71 downregulated genes were included. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that the most DEGs were enriched in terms of cell growth regulation, cell growth, neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, the cAMP-signaling pathway, and the Wnt-signaling pathway. Seven genes related to granulosa cell proliferation were screened, IGFBP4, HTRA4, SST, SSTR1, WISP1, DAAM2, and RSPO2. The above results provide molecular theoretical support for NAC as a feed additive to improve follicle development and improve reproductive performance in ewes.},
}
@article {pmid36550944,
year = {2022},
author = {Lee, JH and Park, HJ and Kim, YA and Lee, DH and Noh, JK and Jung, JG and Yoon, HH and Lee, SK and Lee, S},
title = {Establishment of a Serum-Free Hepatocyte Cryopreservation Process for the Development of an "Off-the-Shelf" Bioartificial Liver System.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {9},
number = {12},
pages = {},
pmid = {36550944},
issn = {2306-5354},
support = {Technology Innovation Program (10078349)//the Ministry of Trade, Industry &amp; Energy (MOTIE; Korea)/ ; SMO1220041//Future Medicine 2030 Project of the Samsung Medical center/ ; },
abstract = {To use hepatocytes immediately when necessary for hepatocyte transplantation and bioartificial liver (BAL) systems, a serum-free cryopreservation protocol ensuring the high survival of hepatocytes and maintenance of their functions should be developed. We established a serum-free protocol for the cryopreservation of primary hepatocytes, hepatocyte spheroids, and hepatocyte spheroid beads in liquid nitrogen. The serum-free cryopreservation solutions showed a significantly higher performance in maintaining enhanced viability and ammonia removal, urea secretion, and the albumin synthesis of hepatocyte spheroids and spheroid beads. The serum-free thawing medium, containing human serum albumin (HSA) and N-acetylcysteine (NAC), was compared with a fetal bovine serum-containing thawing medium for the development of a serum-free thawing medium. Our results show that hepatocyte spheroids and spheroid beads thawed using a serum-free thawing medium containing HSA and NAC exhibited increased hepatocyte viability, ammonia removal, urea secretion, and albumin synthesis compared to those thawed using the serum-containing medium. Finally, we evaluated the liver functions of the cryopreserved BAL system-applied serum-free cryopreservation process compared to the fresh BAL system. The ammonia removal efficiency of the cryopreserved hepatocyte spheroids BAL was lower than or similar to that of the fresh BAL system. Additionally, the urea concentrations in the media of all three BAL systems were not significantly different during BAL system operation. This cryopreserved spheroid-based BAL system using a serum-free process will be a good candidate for the treatment of patients.},
}
@article {pmid36549672,
year = {2023},
author = {Kim, NH and Lee, AY},
title = {Growth Factors Upregulated by Uric Acid Affect Guanine Deaminase-Induced Melanogenesis.},
journal = {Biomolecules &amp; therapeutics},
volume = {31},
number = {1},
pages = {89-96},
pmid = {36549672},
issn = {1976-9148},
abstract = {Uric acid produced by guanine deaminase (GDA) is involved in photoaging and hyperpigmentation. Reactive oxygen species (ROS) generated by uric acid plays a role in photoaging. However, the mechanism by which uric acid stimulates melanogenesis in GDA-overexpressing keratinocytes is unclear. Keratinocyte-derived paracrine factors have been identified as important mechanisms of ultraviolet-induced melanogenesis. Therefore, the role of paracrine melanogenic growth factors in GDA-induced hypermelanosis mediated by uric acid was examined. The relationships between ROS and these growth factors were examined. Primary cultured normal keratinocytes overexpressed with wild type or mutant GDA and those treated with xanthine or uric acid in the presence or absence of allopurinol, H2O2, or N-acetylcysteine (NAC) were used in this study. Intracellular and extracellular bFGF and SCF levels were increased in keratinocytes by wild type, but not by loss-of-function mutants of GDA overexpression. Culture supernatants from GDA-overexpressing keratinocytes stimulated melanogenesis, which was restored by anti-bFGF and anti-SCF antibodies. Allopurinol treatment reduced the expression levels of bFGF and SCF in both GDA-overexpressing and normal keratinocytes exposed to exogenous xanthine; the exogenous uric acid increased their expression levels. H2O2-stimulated tyrosinase expression and melanogenesis were restored by NAC pretreatment. However, H2O2 or NAC did not upregulate or downregulate bFGF or SCF, respectively. Overall, uric acid could be involved in melanogenesis induced by GDA overexpression in keratinocytes via bFGF and SCF upregulation not via ROS generation.},
}
@article {pmid36541703,
year = {2023},
author = {Demers, ND and Riccio, V and Jo, DS and Bhandari, S and Law, KB and Liao, W and Kim, C and McQuibban, GA and Choe, SK and Cho, DH and Kim, PK},
title = {PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal ROS.},
journal = {Autophagy},
volume = {19},
number = {6},
pages = {1781-1802},
pmid = {36541703},
issn = {1554-8635},
support = {PJT#156196//CIHR/Canada ; },
mesh = {Animals ; Humans ; Mice ; *Macroautophagy ; *Autophagy/physiology ; Reactive Oxygen Species/metabolism ; Leucine/metabolism ; Lysine/metabolism ; Actins/metabolism ; Zebrafish/metabolism ; Fibroblasts/metabolism ; Ubiquitin/metabolism ; Peroxisomes/metabolism ; Amino Acids/metabolism ; Oxygen/metabolism ; Sirolimus ; Membrane Proteins/metabolism ; },
abstract = {Peroxisomes are rapidly degraded during amino acid and oxygen deprivation by a type of selective autophagy called pexophagy. However, how damaged peroxisomes are detected and removed from the cell is poorly understood. Recent studies suggest that the peroxisomal matrix protein import machinery may serve double duty as a quality control machinery, where they are directly involved in activating pexophagy. Here, we explored whether any matrix import factors are required to prevent pexophagy, such that their loss designates peroxisomes for degradation. Using gene editing and quantitative fluorescence microscopy on culture cells and a zebrafish model system, we found that PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes. The loss of PEX13 caused an accumulation of ubiquitinated PEX5 on peroxisomes and an increase in peroxisome-dependent reactive oxygen species that coalesce to induce pexophagy. We also found that PEX13 protein level is downregulated to aid in the induction of pexophagy during amino acid starvation. Together, our study points to PEX13 as a novel pexophagy regulator that is modulated to maintain peroxisome homeostasis.Abbreviations: AAA ATPases: ATPases associated with diverse cellular activities; ABCD3: ATP binding cassette subfamily D member; 3ACOX1: acyl-CoA oxidase; 1ACTA1: actin alpha 1, skeletal muscle; ACTB: actin beta; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; CAT: catalase; CQ: chloroquine; Dpf: days post fertilization: FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; H2O2: hydrogen peroxide; HA - human influenza hemagglutinin; HBSS: Hanks' Balanced Salt Solution; HCQ; hydroxychloroquine; KANL: lysine alanine asparagine leucine; KO: knockout; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYC: MYC proto-oncogene, bHLH transcription factor; MZ: maternal and zygotic; NAC: N-acetyl cysteine; NBR1 - NBR1 autophagy cargo receptor; PBD: peroxisome biogenesis disorder; PBS: phosphate-buffered saline; PEX: peroxisomal biogenesis factor; PTS1: peroxisome targeting sequence 1; RFP: red fluorescent protein; ROS: reactive oxygen speciess; iRNA: short interfering RNA; SKL: serine lysine leucine; SLC25A17/PMP34: solute carrier family 25 member 17; Ub: ubiquitin; USP30: ubiquitin specific peptidase 30.},
}
@article {pmid36539667,
year = {2023},
author = {Newman, SA and Short, JL and Nicolazzo, JA},
title = {Reduction in ABCG2 mRNA Expression in Human Immortalised Brain Microvascular Endothelial Cells by Ferric Ammonium Citrate is Mediated by Reactive Oxygen Species and Activation of ERK1/2 Signalling.},
journal = {Pharmaceutical research},
volume = {40},
number = {3},
pages = {651-660},
pmid = {36539667},
issn = {1573-904X},
mesh = {Humans ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics/metabolism ; ATP-Binding Cassette Transporters/metabolism ; Brain/metabolism ; *Endothelial Cells/metabolism ; *MAP Kinase Signaling System ; Neoplasm Proteins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; RNA, Messenger/genetics/metabolism ; Quaternary Ammonium Compounds ; Ferric Compounds ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinase 1 ; },
abstract = {PURPOSE: The ATP-binding cassette (ABC) transport protein ABCG2 (also known as breast cancer resistance protein (BCRP)) is expressed at the luminal face of the blood-brain barrier (BBB), where it limits the brain uptake of a number of therapeutic drugs. We recently reported that the ABC efflux transporter P-glycoprotein (P-gp) was downregulated in human immortalised brain endothelial (hCMEC/D3) cells treated with ferric ammonium citrate (FAC). The aim of the present study, therefore, was to assess whether BCRP expression is also affected by FAC and identify any signalling mechanisms involved.<br><br>METHODS: ABCG2 mRNA was assessed by RT-qPCR. Protein levels of BCRP, phosphorylated extracellular-regulated kinases 1 and 2 (p-ERK1/2) and total ERK 1/2 were assessed by Western blot. Reactive oxygen species (ROS) levels were determined using 2',7'-dichlorofluorescin diacetate.<br><br>RESULTS: Treatment of hCMEC/D3 cells with FAC (250 &#xb5;M, 72 h) significantly reduced ABCG2 mRNA levels (32.2 &#xb1; 3.7%) without a concomitant reduction in BCRP protein expression. ABCG2 mRNA levels were restored to control levels when co-treated with the antioxidant N-acetylcysteine (NAC), suggesting the effect of FAC was mediated by a ROS-sensitive pathway. We also found that FAC-treatment was associated with increased levels of p-ERK1/2, suggesting involvement of the ERK1/2 signalling pathway in the observed ABCG2 mRNA downregulation. The ERK1/2 signalling pathway inhibitor U0126 restored p-ERK1/2 levels and partially attenuated the FAC-induced reduction in ABCG2 mRNA.<br><br>CONCLUSIONS: This study suggests that FAC-induced downregulation of ABCG2 mRNA is&#xa0;driven by&#xa0;ROS and ERK1/2 signalling, mechanisms which may be exploited to modulate BCRP expression at the BBB.},
}
@article {pmid36533744,
year = {2022},
author = {Abdelrazik, E and Hassan, HM and Abdallah, Z and Magdy, A and Farrag, EA},
title = {Renoprotective effect of N-acetylcystein and vitamin E in bisphenol A-induced rat nephrotoxicity; Modulators of Nrf2/ NF-κB and ROS signaling pathway.},
journal = {Acta bio-medica : Atenei Parmensis},
volume = {93},
number = {6},
pages = {e2022301},
pmid = {36533744},
issn = {2531-6745},
mesh = {Animals ; Rats ; Male ; *NF-kappa B/metabolism/pharmacology/therapeutic use ; *NF-E2-Related Factor 2/metabolism/pharmacology/therapeutic use ; Reactive Oxygen Species/adverse effects/metabolism ; Vitamin E/adverse effects ; Oxidative Stress ; Signal Transduction ; Inflammation/drug therapy ; Bisphenol A Compounds ; },
abstract = {Bisphenol A (BPA) is a chemical product that is widely used as a plastic precursor. It acts directly on the kidney mitochondria, causing renal dysfunction. N-acetylcysteine is effective in protecting the kidneys from chemical-induced damage. Vitamin E is an antioxidant that protects cells from the damaging effects of free radicals. The aim of this study is to further evaluate and compare NAC and vitamin E to oppose the nephrotoxicity caused by BPA.<br><br>RESEARCH DESIGN AND METHODS: Forty-two adult male rats were divided into 7 groups:&#xa0; control, BPA, NAC, vitamin E, BPA plus NAC, BPA plus vitamin E, and combined BPA, NAC and vitamin E. BPA, NAC, vitamin E were given orally at doses of 50 mg/kg, 200 mg/kg, and 1000 mg/kg respectively, for 5 weeks.<br><br>RESULTS: NAC and vitamin E groups showed improved kidney function tests and alleviated BPA-induced oxidative stress; increased GSH and decreased MDA, NO and iNOS levels. NAC and vitamin E significantly attenuated inflammation; decreased NF-&#x3ba;B and increased IL-4, and Nrf2, in addition there was alleviation of renal histopathology. To some extent, vitamin E administration showed significant improvement. Moreover, combined NAC and vitamin E treatment showed more significance than either NAC or vitamin E separate groups.<br><br>CONCLUSIONS: This study determined the substantial protective effects of NAC and/or vitamin E in BPA-induced nephrotoxicity through modulation of Nrf2 with subsequent improvement of oxidative stress and inflammation. The alleviation was more significant in combined NAC and vitamin E treatment mainly through their synergistic effect on Nrf2.},
}
@article {pmid36528076,
year = {2023},
author = {Haugsten Hansen, M and Sadredini, M and Hasic, A and Anderson, ME and Sjaastad, I and Korseberg Stokke, M},
title = {CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIδ at methionines 281/282 is not a determining factor.},
journal = {Journal of molecular and cellular cardiology},
volume = {175},
number = {},
pages = {49-61},
doi = {10.1016/j.yjmcc.2022.12.002},
pmid = {36528076},
issn = {1095-8584},
support = {R35 HL140034/HL/NHLBI NIH HHS/United States ; },
mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; *Methionine/metabolism ; Mice, Inbred C57BL ; Arrhythmias, Cardiac/metabolism ; Myocytes, Cardiac/metabolism ; Racemethionine/metabolism ; Reperfusion/adverse effects ; Phosphorylation ; Benzylamines ; Benzenesulfonamides ; },
abstract = {BACKGROUND: Available evidence suggest that Ca[2+]/calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing.<br><br>METHODS: We exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion. Hearts were collected for immunoblotting of key phosphoproteins. We evaluated the effects of beta-adrenoceptor stimulation, inhibition of CaMKII, and reduced ROS levels with isoprenaline, KN93/AIP and N-acetylcysteine (NAC), respectively. We further tested the importance of Ox-CaMKII&#x3b4; by using hearts and cardiomyocytes from mice with CaMKII&#x3b4; resistant to oxidation of methionines 281 and 282 (MMVV).<br><br>RESULTS: Hearts treated with KN93, AIP or NAC had lower incidence of early IRA, and NAC-treated cardiomyocytes had lower incidence of arrhythmogenic events. However, hearts from MMVV mice had a similar incidence of early IRA to wild type mice (WT), and MMVV and WT cardiomyocytes had a similar frequency of Ca[2+] waves and Ca[2+] sparks. Immunoblotting confirmed high levels of oxidation in early reperfusion, but revealed no significant differences in the phosphorylation levels of Ca[2+]-handling proteins in MMVV and WT hearts.<br><br>CONCLUSIONS: Although CaMKII and ROS both contribute to early IRA, hearts from mice with CaMKII resistant to oxidation at methionines 281/282 were not protected from such arrhythmias, suggesting that oxidation at these sites is not a determining factor.},
}
@article {pmid36526177,
year = {2023},
author = {Shi, X and Xu, T and Cui, W and Qi, X and Xu, S},
title = {Combined negative effects of microplastics and plasticizer DEHP: The increased release of Nets delays wound healing in mice.},
journal = {The Science of the total environment},
volume = {862},
number = {},
pages = {160861},
doi = {10.1016/j.scitotenv.2022.160861},
pmid = {36526177},
issn = {1879-1026},
mesh = {Animals ; Mice ; *Diethylhexyl Phthalate/metabolism/toxicity ; Ecosystem ; *Extracellular Traps/metabolism ; Fibrosis ; Microplastics/metabolism ; *Plasticizers/toxicity/metabolism ; Plastics/metabolism ; *Wound Healing ; },
abstract = {Environmental harmful pollutants microplastics (MPs) and di (2-ethyl) hexyl phthalate (DEHP) are widely residual in the environment, which may cause lesion to multiple apparatus by inducing oxidative stress, threatening the health of human and animals. Neutrophil extracellular traps (Nets) are involved in skin wound healing. Most studies focused on the individual effects of different poisons on animals and ecosystems, but there are few studies on the accumulation and interaction of multiple poisons. The purpose of this study is to explore the effect of DEHP and MPs co-exposure on skin wound healing and the formation of Nets. For this purpose, we detected this hypothesis by replicating the DEHP and MPs-exposed skin wound model in mice, as well as the co-culture system of neutrophil and fibroblast. The results displayed that MPs and DEHP exposure delayed skin healing, which was more pronounced in the combined exposure group. In vitro and in vivo experiments confirmed that compared with the DEHP or MPs group, the DEHP+MPs group had more significant oxidative stress, increased Nets release and inflammatory factors, and inhibited the Wnt/β-catenin pathway and fibrosis-related factors. N-acetylcysteine (NAC) attenuated these phenomena. Through the co-culture system, we confirmed that the overproduction of Nets induced fibroblasts to exacerbate inflammatory responses and inhibit Wnt pathway and fibrosis. Overall, DEHP and MPs can produce synergistic toxic injury in mice skin wounds, and the excessive activation of ROS/Nets can aggravate inflammatory and inhibit fibrosis, resulting in delayed wound healing.},
}
@article {pmid36525766,
year = {2023},
author = {Xu, H and Du, Y and Wang, Q and Chen, L and Huang, J and Liu, Y and Zhou, C and Du, B},
title = {Comparative efficacy, acceptability, and tolerability of adjunctive anti-inflammatory agents on bipolar disorder: A systemic review and network meta-analysis.},
journal = {Asian journal of psychiatry},
volume = {80},
number = {},
pages = {103394},
doi = {10.1016/j.ajp.2022.103394},
pmid = {36525766},
issn = {1876-2026},
mesh = {Humans ; *Bipolar Disorder/drug therapy ; Anti-Inflammatory Agents/therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal ; Combined Modality Therapy ; },
abstract = {OBJECTIVES: We performed a network meta-analysis (NMA) with up-to-date evidence to compare different anti-inflammatory agents to improve the treatment of bipolar disorder (BD) patients.<br><br>METHODS: Four databases (i.e., the Cochrane Library, Web of Science, PubMed, and Embase) were searched for randomized controlled trials (RCTs) published between 1995 and 2022 on the use of anti-inflammatory agents in the treatment of BD. A systematic review and NMA were conducted.<br><br>RESULTS: Adjunctive N-acetylcysteine (NAC) was superior to placebo for the treatment of BD according to the endpoint scale score (SMD -0.65, 95% confidence interval (CI): -&#xa0;0.99 to -&#xa0;0.31), response rate (odds ratio (OR) 3.42, 95% CI: 1.23-9.52), remission rate (OR 4.94, 95% CI: 1.03-41.38) and surface under the cumulative ranking curve (SUCRA) value of the endpoint scale score (0.84). Adjunctive nonsteroidal anti-inflammatory drugs (NSAIDs) were more favorable than placebo based on the remission rate (OR 3.93, 95% CI: 1.15-13.43) and were significantly more acceptable than other treatments (OR 0.60, 95% CI: 0.36-0.99). Adjunctive coenzyme Q10 (CoQ10) was superior to other agents in terms of the response rate (OR 18.85, 95% CI: 2.63-135.00), with a SUCRA value for the response rate of 0.90 and that for the remission rate of 0.71.<br><br>CONCLUSION: Adjunctive NAC is recommended for the treatment of BD. Adjunctive NSAIDs and CoQ10 are still seen as effective, but more high-quality clinical studies are needed to verify their efficacy. Other anti-inflammatory agents may not be recommended for clinical use at present. All anti-inflammatory agents demonstrated a good safety profile. We call for further research on the combined treatment of BD with different anti-inflammatory agents to be included in future trials.},
}
@article {pmid36521547,
year = {2023},
author = {Ma, F and Li, H and Huo, H and Han, Q and Liao, J and Zhang, H and Li, Y and Pan, J and Hu, L and Guo, J and Tang, Z},
title = {N-acetyl-L-cysteine alleviates FUNDC1-mediated mitophagy by regulating mitochondrial dynamics in type 1 diabetic nephropathy canine.},
journal = {Life sciences},
volume = {313},
number = {},
pages = {121278},
doi = {10.1016/j.lfs.2022.121278},
pmid = {36521547},
issn = {1879-0631},
mesh = {Animals ; Dogs ; Acetylcysteine/pharmacology ; *Diabetes Mellitus ; *Diabetic Nephropathies/pathology ; *Insulins/pharmacology ; Mitochondrial Dynamics ; Mitochondrial Proteins/metabolism ; Mitophagy ; },
abstract = {Diabetic nephropathy (DN) is a major complication of type 1 diabetes mellitus, and hyperglycemia and hypertension are the main risk factors for the development of DN. N-Acetyl-Cysteine (NAC) has a variety of effects, interfering with the production and scavenging of free radicals and regulating the metabolic activity of tissue cells. However, the efficacy of NAC on DN treatment is unclear. Thus, this study investigated the protective mechanism of NAC combined with insulin on renal injury in dogs with DN. The forty dogs were selected and divided into control group, DM group, INS group, INS + NAC group and NAC group to establish the model for a trial period of 4 months. The results revealed that INS + NAC was effective in reducing and stabilizing blood glucose levels. Biochemical results showed that INS + NAC treatment significantly regulated the stability of UREA, CREA and fructosamine indicators. Meanwhile, histopathology staining showed significant glomerular wrinkling and fibrosis in the DM group, which could be reversed after INS + NAC treatment. In addition, INS + NAC could restore mitochondria homeostasis by upregulating the levels of mitochondrial fission (MFN1, MFN2 and OPA1) and inhibiting of mitochondrial fusion (DRP1, FIS1 and MFF) related indicators. Further studies revealed that INS + NAC regulated the expression levels of renal BNIP3, NIX and FUNDC1 in the DM group, thereby alleviating mitophagy. Collectively, these results suggested that NAC combined with insulin protects DN by regulating the mitochondrial dynamics and FUNDC1-mediated mitophagy.},
}
@article {pmid36518453,
year = {2022},
author = {Henneh, IT and Ahlidja, W and Alake, J and Kwabil, A and Ahmed, MA and Kyei-Asante, B and Adinortey, MB and Ekor, M and Armah, FA},
title = {Ziziphus abyssinica root bark extract ameliorates paracetamol-induced liver toxicity in rats possibly via the attenuation of oxidative stress.},
journal = {Toxicology reports},
volume = {9},
number = {},
pages = {1929-1937},
pmid = {36518453},
issn = {2214-7500},
abstract = {Ziziphus abyssinica root bark is widely used in folk medicine to manage liver diseases, particularly, jaundice but its effect on paracetamol-induced liver toxicity (PILT) has not yet been validated. This study explored the ameliorative effect of ethanolic root bark extract of Ziziphus abyssinica (ZAE) against PILT in rats. The flavonoid and phenolic content of ZAE was evaluated using Folin-Ciocalteau and aluminium trichloride colorimetric methods, respectively. Antioxidant activity of ZAE was determined in vitro by evaluating its ferrous reducing antioxidant capacity (FRAC) as well as DPPH and nitic oxide (NO) radicals scavenging activities. Sprague-Dawley rats were assigned to six groups (n = 6) and administered with normal saline (10 mL/kg, p.o.), N-acetylcysteine (50 mg/kg, i.p.) and ZAE (30, 100, and 300 mg/kg, p.o.) respectively for seven days after which they received paracetamol (PCM, 3000 mg/kg, p.o.). Animals were sacrificed 48 h after paracetamol administration under light anaesthesia and assessed for liver toxicity and oxidative stress. Total flavonoid and phenolic contents of ZAE were 1313.425 µg/mL quercetin equivalence and 268.31 µg/mL gallic acid equivalence respectively. ZAE exhibited marked FRAC as well as DPPH and NO radical scavenging activities with IC50s of 80.41 ± 1.56, 67.56 ± 1.11 and 7.11 ± 1.48 μg/mL respectively. ZAE and N-acetylcysteine significantly (p < 0.05) reduced the paracetamol-mediated elevation of serum total bilirubin, proteins and activity of liver enzymes (AST, ALP, and ALT). Similarly, ZAE increased hepatic glutathione, total thiols and catalase activity of the paracetamol intoxicated rats. Morphological changes associated with the paracetamol hepatotoxicity were also ameliorated by ZAE. Overall, the hepatoprotective effect of ZAE may be related to its antioxidant property.},
}
@article {pmid36517965,
year = {2023},
author = {Wang, P and Ma, H and Hou, X and Song, L and Feng, M},
title = {N-acetyl-L-cysteine ameliorates gestational diabetes mellitus by inhibiting oxidative stress.},
journal = {Biotechnology and applied biochemistry},
volume = {70},
number = {3},
pages = {1128-1136},
doi = {10.1002/bab.2426},
pmid = {36517965},
issn = {1470-8744},
mesh = {Pregnancy ; Humans ; Female ; Mice ; Animals ; *Diabetes, Gestational/drug therapy/metabolism ; Acetylcysteine/pharmacology/metabolism/therapeutic use ; Oxidative Stress ; Antioxidants/metabolism ; Inflammation ; },
abstract = {Gestational diabetes mellitus (GDM) is a common pregnant disorder that needs careful medical attention. N-acetyl-L-cysteine (NAC) is a well-recognized antioxidant to treat oxidative stress-induced diseases. Although its role in GDM has been reported, the mechanism remains largely unknown. Therefore, our current study further explored its protective role against GDM. An 8-week-old, db/+, female mice were injected with a single dose of 100 mg/kg streptozotocin (STZ) to induce diabetes. Pregnant mice were randomly treated with 1200 mg/kg NAC or water daily. On gestational day 19, oral glucose tolerance test was performed, and visceral fat tissue and blood samples were collected. After delivery, litter size and weight were recorded. NAC could effectively improve GDM-induced glucose intolerance, hyperlipidemia, activated inflammation, and oxidative stress in GDM mice. Moreover, NAC reduced the litter size and weight of GDM mice. NAC also activated the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in the liver of GDM mice. NAC effectively ameliorated GDM symptoms and the reproductive outcome of GDM mice through inhibiting oxidative stress, inflammation, and hyperlipidemia. Therefore, NAC might serve as a potential candidate drug against GDM.},
}
@article {pmid36517743,
year = {2022},
author = {Liu, F and Zhang, Y and Shi, Y and Xiong, K and Wang, F and Yang, J},
title = {Ceramide induces pyroptosis through TXNIP/NLRP3/GSDMD pathway in HUVECs.},
journal = {BMC molecular and cell biology},
volume = {23},
number = {1},
pages = {54},
pmid = {36517743},
issn = {2661-8850},
support = {81400058//Jin Yang/ ; },
mesh = {Humans ; *Pyroptosis/genetics ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Ceramides/pharmacology ; Caspase 1/genetics/metabolism/pharmacology ; Human Umbilical Vein Endothelial Cells ; RNA, Messenger/genetics ; Lactate Dehydrogenases/metabolism ; Carrier Proteins ; Phosphate-Binding Proteins/metabolism/pharmacology ; Pore Forming Cytotoxic Proteins/metabolism ; Gasdermins ; },
abstract = {BACKGROUND: Pyroptosis of endothelial cells is a new cause of endothelial dysfunction in multiple diseases. Ceramide acts as a potential bioactive mediator of inflammation and increases vascular endothelial permeability in many diseases, whether it can aggravate vascular endothelial injury by inducing cell pyroptosis remains unknown. This study was established to explore the effects of C8-ceramide (C8-Cer) on human umbilical vein vascular endothelial cells (HUVECs) and its possible underlying mechanism.<br><br>METHODS: HUVECs were exposed to various concentrations of C8-Cer for 12&#x2009;h, 24&#x2009;h, 48&#x2009;h. The cell survival rate was measured using the cell counting kit-8 assay. Western blotting and Real-time polymerase chain reaction (RT-PCR) were used to detect the pyroptosis-releated protein and mRNA expressions, respectively. Caspase-1 activity assay was used to detect caspase-1 activity. Hoechst 33342/propidium iodide double staining and flow cytometry were adopted to measure positive staining of cells. Lactate dehydrogenase release assay and enzyme-linked immunosorbent assay were adopted to measure leakage of cellular contents. FITC method was used to detect the permeability of endothelial cells. ROS fluorescence intensity were detected by flow cytometry.<br><br>RESULTS: The viability of HUVECs decreased gradually with the increase in ceramide concentration and time. Ceramide upregulated the expression of thioredoxin interacting protein (TXNIP), NLRP3, GSDMD, GSDMD-NT, caspase-1 and Casp1 p20 at the protein and mRNA level in a dose-dependent manner. It also enhanced the PI uptake in HUVECs and upregulated caspase-1 activity. Moreover, it promoted the release of lactate dehydrogenase, interleukin-1&#x3b2;, and interleukin-18. Meanwhile, we found that ceramide led to increased vascular permeability. The inhibitor of NLRP3 inflammasome assembly, MCC950, was able to disrupt the aforementioned positive loop, thus alleviating vascular endothelial cell damage. Interestingly, inhibition of TXNIP either chemically using verapamil or genetically using small interfering RNA (siRNA) can effectively inhibit ceramide-induced pyroptosis and improved cell permeability. In addition, ceramide stimulated reactive oxygen species (ROS) generation. The pretreatment of antioxidant N-acetylcysteine (NAC), ROS scavenger, blocked the expression of pyroptosis markers induced by C8-cer in HUVECs.<br><br>CONCLUSION: The current study demonstrated that C8-Cer could aggravate vascular endothelial cell damage and increased cell permeability by inducing cell pyroptosis. The results documented that the ROS-dependent TXNIP/NLRP3/GSDMD signalling pathway plays an essential role in the ceramide-induced pyroptosis in HUVECs.},
}
@article {pmid36514019,
year = {2022},
author = {Podolanczuk, AJ and Kim, JS and Cooper, CB and Lasky, JA and Murray, S and Oldham, JM and Raghu, G and Flaherty, KR and Spino, C and Noth, I and Martinez, FJ and , },
title = {Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial.},
journal = {BMC pulmonary medicine},
volume = {22},
number = {1},
pages = {475},
pmid = {36514019},
issn = {1471-2466},
support = {R61 HL158540/HL/NHLBI NIH HHS/United States ; U24 HL145265/HL/NHLBI NIH HHS/United States ; UH3 HL145266/HL/NHLBI NIH HHS/United States ; UH3HL145266/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Double-Blind Method ; Genotype ; *Idiopathic Pulmonary Fibrosis/drug therapy/genetics ; Treatment Outcome ; Vital Capacity ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; Clinical Trials, Phase III as Topic ; },
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial.<br><br>METHODS: The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600&#xa0;mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC.<br><br>DISCUSSION: The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920.},
}
@article {pmid36509450,
year = {2023},
author = {Ramesh, R and Skog, S and Örkenby, L and Kugelberg, U and Nätt, D and Öst, A},
title = {Dietary Sugar Shifts Mitochondrial Metabolism and Small RNA Biogenesis in Sperm.},
journal = {Antioxidants &amp; redox signaling},
volume = {38},
number = {16-18},
pages = {1167-1183},
pmid = {36509450},
issn = {1557-7716},
mesh = {Male ; Humans ; Animals ; Reactive Oxygen Species/metabolism ; Dietary Sugars/metabolism ; Hydrogen Peroxide/metabolism ; Proteomics ; Semen/metabolism ; Spermatozoa/metabolism ; Mitochondria/metabolism ; *MicroRNAs/genetics/metabolism ; Drosophila/metabolism ; *RNA, Small Untranslated/metabolism ; },
abstract = {Aims: Increasing concentrations of dietary sugar results in a linear accumulation of triglycerides in male Drosophila, while inducing a U-shaped obesity response in their offspring. Here, using a combination of proteomics and small RNA (sRNA) sequencing, we aimed at understanding the molecular underpinning in sperm for such plasticity. Results: Proteomic analysis of seminal vesicles revealed that increasing concentrations of dietary sugar resulted in a bell-shaped induction of proteins involved in metabolic/redox regulation. Using stains and in vivo redox reporter flies, this pattern could be explained by changes in sperm production of reactive oxygen species (ROS), more exactly mitochondria-derived H2O2. By quenching ROS with the antioxidant N-acetyl cysteine and performing sRNA-seq on sperm, we found that sperm miRNA is increased in response to ROS. Moreover, we found sperm mitosRNA to be increased in high-sugar diet conditions (independent of ROS). Reanalyzing our previously published data revealed a similar global upregulation of human sperm mitosRNA in response to a high-sugar diet, suggesting evolutionary conserved mechanisms. Innovation: This work highlights a fast response to dietary sugar in mitochondria-produced H2O2 in Drosophila sperm and identifies redox-sensitive miRNA downstream of this event. Conclusions: Our data support a model where changes in the sperm mitochondria in response to dietary sugar are the primary event, and changes in redox homoeostasis are secondary to mitochondrial ROS production. These data provide multiple candidates for paternal intergenerational metabolic responses as well as potential biomarkers for human male fertility. Antioxid. Redox Signal. 38, 1167-1183.},
}
@article {pmid36506010,
year = {2022},
author = {Magalhães, LS and Melo, EV and Damascena, NP and Albuquerque, ACB and Santos, CNO and Rebouças, MC and Bezerra, MO and Louzada da Silva, R and de Oliveira, FA and Santos, PL and da Silva, JS and Lipscomb, MW and da Silva, &#xc2;M and de Jesus, AR and de Almeida, RP},
title = {Use of N-acetylcysteine as treatment adjuvant regulates immune response in visceral leishmaniasis: Pilot clinical trial and in vitro experiments.},
journal = {Frontiers in cellular and infection microbiology},
volume = {12},
number = {},
pages = {1045668},
pmid = {36506010},
issn = {2235-2988},
mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; Adjuvants, Immunologic/therapeutic use ; Immunity ; Interleukin-10 ; *Leishmania infantum ; *Leishmaniasis, Visceral/drug therapy ; Leukocytes, Mononuclear ; },
abstract = {This investigation aimed to assess the effect of N-acetylcysteine (NAC) as an adjuvant treatment to alleviate visceral leishmaniasis (VL). The present work includes both blinded randomized clinical intervention and experimental in vitro studies. The clinical trial included 60 patients with VL randomly allocated into two groups: a test group (n = 30) treated with meglumine antimoniate plus NAC (SbV + NAC) and a control group (n = 30) treated with meglumine antimoniate only (SbV). The primary outcome was clinical cure (absence of fever, spleen and liver sizes reduction, and hematological improvement) in 180 days. The cure rate did not differ between the groups; both groups had similar results in all readout indices. The immunological parameters of the patients treated with SbV + NAC showed higher sCD40L in sera during treatment, and the levels of sCD40L were negatively correlated with Interleukin-10 (IL-10) serum levels. In addition, data estimation showed a negative correlation between the sCD40L levels and the spleen size in patients with VL. For the in vitro experiments, peripheral blood mononuclear cells (PBMCs) or PBMC-derived macrophages from healthy donors were exposed to soluble Leishmania antigen (SLA) or infected with stationary promastigotes of Leishmania infantum in the presence or absence of NAC. Results revealed that NAC treatment of SLA-stimulated PBMCs reduces the frequency of monocytes producing IL-10 and lowers the frequency of CD4+ and CD8+ T cells expressing (pro-)inflammatory cytokines. Together, these results suggest that NAC treatment may modulate the immune response in patients with VL, thus warranting additional investigations to support its case use as an adjuvant to antimony therapy for VL.},
}
@article {pmid36502431,
year = {2023},
author = {Tüfekci, KK and Bakirhan, EG and Terzi, F},
title = {A Maternal High-Fat Diet Causes Anxiety-Related Behaviors by Altering Neuropeptide Y1 Receptor and Hippocampal Volumes in Rat Offspring: the Potential Effect of N-Acetylcysteine.},
journal = {Molecular neurobiology},
volume = {60},
number = {3},
pages = {1499-1514},
pmid = {36502431},
issn = {1559-1182},
support = {KUBAP01/2021-03//Kastamonu &#xdc;niversitesi/ ; },
mesh = {Humans ; Rats ; Animals ; Male ; Female ; Pregnancy ; *Acetylcysteine/pharmacology/therapeutic use ; Diet, High-Fat/adverse effects ; *Pregnancy in Obesity/metabolism ; Hippocampus/metabolism ; Obesity/complications/drug therapy/metabolism ; Anxiety/complications ; },
abstract = {The children of obese mothers are known to have a high risk of obesity and metabolic disease and are prone to developing cognitive deficits, although the underlying mechanism is not yet fully understood. This study investigated the relationship between neuropeptide Y1 receptor (NPY1R) and anxiety-like behaviors in the hippocampi of male rat offspring exposed to maternal obesity and the potential neuroprotective effects of N-acetylcysteine (NAC). A maternal obesity model was created using a high-fat (60% k/cal) diet. NAC (150 mg/kg) was administered by intragastric gavage for 25 days in both the NAC and obesity + NAC (ObNAC) groups. All male rat offspring were subjected to behavioral testing on postnatal day 28, the end of the experiment. Stereological analysis was performed on hippocampal sections, while NPY1R expression was determined using immunohistochemical methods. Stereological data indicated significant decreases in the total volume of the hippocampus and CA1 and dentate gyrus (DG) regions in the obese (Ob) group (p < 0.01). Decreased NPY1R expression was observed in the Ob group hippocampus (p < 0.01). At behavioral assessments, the Ob group rats exhibited increased anxiety and less social interaction, although the ObNAC group rats exhibited stronger responses than the Ob group (p < 0.01). The study results show that NAC attenuated anxiety-like behaviors and NPY1R expression and also protected hippocampal volume against maternal obesity. The findings indicate that a decrease in NPY1R-positive neurons in the hippocampus of male rats due to maternal conditions may be associated with increased levels of anxiety and a lower hippocampal volume. Additionally, although there is no direct evidence, maintenance of NPY1R expression by NAC may be critical for regulating maternal obesity-induced anxiety-related behaviors and hippocampal structure.},
}
@article {pmid36500398,
year = {2022},
author = {Słowiński, D and Świerczyńska, M and Romański, J and Podsiadły, R},
title = {HPLC Study of Product Formed in the Reaction of NBD-Derived Fluorescent Probe with Hydrogen Sulfide, Cysteine, N-acetylcysteine, and Glutathione.},
journal = {Molecules (Basel, Switzerland)},
volume = {27},
number = {23},
pages = {},
pmid = {36500398},
issn = {1420-3049},
support = {POWR.03.02.00-00-I029/16//National Center for Research and Development (Warsaw, Poland)/ ; },
mesh = {Humans ; *Cysteine ; Fluorescent Dyes ; *Hydrogen Sulfide ; Acetylcysteine ; Optical Imaging ; Glutathione ; Sulfhydryl Compounds ; Homocysteine ; HeLa Cells ; },
abstract = {Hydrogen sulfide (H2S) and its bioderivatives analogs, such as L-cysteine (L-Cys) and glutathione (GSH), are ubiquitous biological thiols in the physiological and pathological processes of living systems. Their aberrant concentration levels are associated with many diseases. Although several NBD-based fluorescence probes have been developed to detect biological thiols, the HPLC-detection of H2S, GSH, L-Cys, and N-acetylcysteine-specific products has not been described. Herein, a novel NBD-derived pro-coumarin probe has been synthesized and used to develop a new strategy for the triple mode detection of H2S and such thiols as GSH, L-Cys, and NAC. Hydrogen sulfide and those biothiols at physiological pH release fluorescent coumarin from the probe and cause a significant fluorescence enhancement at 473 nm. The appropriate NBD-derived product for H2S, L-Cys, GSH, and NAC has a different color and retention time that allows distinguishing these biological thiols meaning the probe has a great possibility in the biological application. Fluorescent imaging combined with colorimetric and HPLC detection of H2S/biothiol-specific product(s) brings a potential tool for confirming the presence of biological thiols and determining concentrations in various aqueous biological samples.},
}
@article {pmid36499332,
year = {2022},
author = {Feriotto, G and Tagliati, F and Brunello, A and Beninati, S and Tabolacci, C and Mischiati, C},
title = {A Central Contribution of TG2 Activity to the Antiproliferative and Pro-Apoptotic Effects of Caffeic Acid in K562 Cells of Human Chronic Myeloid Leukemia.},
journal = {International journal of molecular sciences},
volume = {23},
number = {23},
pages = {},
pmid = {36499332},
issn = {1422-0067},
mesh = {Humans ; K562 Cells ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics/metabolism ; Imatinib Mesylate/pharmacology/therapeutic use ; Caffeic Acids/pharmacology/therapeutic use ; Apoptosis ; Drug Resistance, Neoplasm ; },
abstract = {Caffeic acid (CA) has shown antitumor activity in numerous solid and blood cancers. We have recently reported that CA is active in reducing proliferation and triggering apoptosis in both Imatinib-sensitive and resistant Chronic Myeloid Leukemia (CML) cells. Tissue transglutaminase type 2 (TG2) enzyme is involved in cell proliferation and apoptosis of numerous types of cancer. However, its activity has different effects depending on the type of tumor. This work investigated the possible involvement of TG2 activation in the triggering of CA-dependent anticancer effects on the K562 cell line, which was studied as a model of CML. CA-dependent changes in TG2 activity were compared with the effects on cell proliferation and apoptosis. The use of N-acetylcysteine (NAC), an antioxidant molecule, suggested that the antiproliferative effect of CA was due to the increase in reactive oxygen species (ROS). The use of a TG2 inhibitor showed that TG2 activity was responsible for the increase in ROS generated by CA and reduced both caspase activation and triggering of CA-dependent apoptosis. The knocking-down of TGM2 transcripts confirmed the crucial involvement of TG2 activation in CML cell death. In conclusion, the data reported, in addition to ascertaining the important role of TG2 activation in the antiproliferative and pro-apoptotic mechanism of CA allowed us to hypothesize a possible therapeutic utility of the molecules capable of triggering the activation pathways of TG2 in the treatment of CML.},
}
@article {pmid36498845,
year = {2022},
author = {Milara, J and Martínez-Expósito, F and Montero, P and Roger, I and Bayarri, MA and Ribera, P and Oishi-Konari, MN and Alba-García, JR and Zapater, E and Cortijo, J},
title = {N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro.},
journal = {International journal of molecular sciences},
volume = {23},
number = {23},
pages = {},
pmid = {36498845},
issn = {1422-0067},
support = {PI20/01363//Instituto de Salud Carlos III/ ; PID2020-114871RB-I00//Instituto de Salud Carlos III/ ; CB06/06/0027//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red/ ; 2017/023/UV//Generalitat Valenciana/ ; },
mesh = {Humans ; *SARS-CoV-2/metabolism ; Inflammasomes/metabolism ; Acetylcysteine/pharmacology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *COVID-19 ; Cytokines ; Recombinant Proteins/pharmacology ; },
abstract = {Inflammasome activation is one of the first steps in initiating innate immune responses. In this work, we studied the activation of inflammasomes in the airways of critically ill COVID-19 patients and the effects of N-acetylcysteine (NAC) on inflammasomes. Tracheal biopsies were obtained from critically ill patients without COVID-19 and no respiratory disease (control, n = 32), SARS-CoV-2 B.1 variant (n = 31), and B.1.1.7 VOC alpha variant (n = 20) patients. Gene expression and protein expression were measured by RT-qPCR and immunohistochemistry. Macrophages and bronchial epithelial cells were stimulated with different S, E, M, and N SARS-CoV-2 recombinant proteins in the presence or absence of NAC. NLRP3 inflammasome complex was over-expressed and activated in the COVID-19 B.1.1.7 VOC variant and associated with systemic inflammation and 28-day mortality. TLR2/MyD88 and redox NOX4/Nrf2 ratio were also over-expressed in the COVID-19 B.1.1.7 VOC variant. The combination of S-E-M SARS-CoV-2 recombinant proteins increased cytokine release in macrophages and bronchial epithelial cells through the activation of TLR2. NAC inhibited SARS-CoV-2 mosaic (S-E-M)-induced cytokine release and inflammasome activation. In summary, inflammasome is over-activated in severe COVID-19 and increased in B.1.1.7 VOC variant. In addition, NAC can reduce inflammasome activation induced by SARS-CoV-2 in vitro, which may be of potential translational value in COVID-19 patients.},
}
@article {pmid36498831,
year = {2022},
author = {Lee, JW and Cho, JY and Thuy, PX and Moon, EY},
title = {HeLa Cervical Cancer Cells Are Maintained by Nephronophthisis 3-Associated Primary Cilium Formation via ROS-Induced ERK and HIF-1α Activation under Serum-Deprived Normoxic Condition.},
journal = {International journal of molecular sciences},
volume = {23},
number = {23},
pages = {},
pmid = {36498831},
issn = {1422-0067},
support = {Basic Research Program 2021R1A4A5033289//National Research Foundation of Korea/ ; },
mesh = {Female ; Humans ; Cell Hypoxia ; *Cilia/metabolism ; HeLa Cells ; Hydrogen Peroxide/metabolism ; *Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Kinesins/genetics/metabolism ; },
abstract = {The primary cilium (PC) is a microtubule-based antenna-like organelle projecting from the surface of the cell membrane. We previously reported that PC formation could be regulated by nephronophthisis 3 (NPHP3) expression followed by its interaction with thymosin β4. Here, we investigated whether cancer cell viability is regulated by NPHP3-mediated PC formation. The total and viable cell number were reduced by incubating cells under serum deprivation (SD) without fetal bovine serum (-FBS). PC frequency was increased by SD which enhanced NPHP3 expression and hypoxia inducible factor (HIF)-1α. The role of HIF-1α on NPHP3 expression and PC formation was confirmed by the binding of HIF-1α to the NPHP3 promoter and siRNA-based inhibition of HIF-1α (siHIF-1α), respectively. HIF-1α-stabilizing dimethyloxallyl glycine (DMOG) and hypoxic conditions increased NPHP3 expression and PC formation. In addition, as SD elevated the reactive oxygen species (ROS), PC frequency and NPHP3 expression were inhibited by a treatment with N-acetylcysteine (NAC), a ROS scavenger. PC formation was increased by H2O2 treatment, which was inhibited by siHIF-1α. The inhibition of ERK with P98059 decreased the frequency of PC formation and NPHP3 expression. Cell viability was reduced by a treatment with ciliobrevin A (CilioA) to inhibit PC formation, which was re-affirmed by using PC-deficient IFT88[-/-] cells. Taken together, the results imply that PC formation in cancer cells could be controlled by NPHP3 expression through ROS-induced HIF-1α and ERK activation under SD conditions. It suggests that cancer cell viability under SD conditions could be maintained by NPHP3 expression to regulate PC formation.},
}
@article {pmid36497648,
year = {2022},
author = {Gorbachev, V and Nikulchev, E and Kosenkov, AN and Sokolov, A and Zavalishin, I and Nikitin, I},
title = {Estimating the Mass of Food Components Necessary for the Utilization of Free Radical Particles in the Human Body.},
journal = {International journal of environmental research and public health},
volume = {19},
number = {23},
pages = {},
pmid = {36497648},
issn = {1660-4601},
mesh = {Humans ; *Human Body ; Free Radicals ; *Diet ; Vitamins ; Ascorbic Acid ; },
abstract = {The article proposes an algorithm for an approximate assessment of the molar volume of free radicals generated in the human body per day. It takes into account the act of breathing, physical activity, food consumption, the influence of unfavorable environmental conditions, exposure to xenobiotics, as well as bad habits (alcohol and tobacco smoking). A calculation of the required set of the most commonly used food products for the disposal of free radicals was made. The calculation is a structure of four blocks with the possibility of adding optional data from human population genetic studies, environmental conditions, etc. In the proposed algorithm, the results of antiradical activity (ARA) of food products are used as input, including the results of predicting antiradical activity using artificial neural networks (ANN), which we published earlier. Based on the accepted values of one equivalent (in terms of the activity of 1 μmol of ascorbic acid), it was shown (for our data) that for the utilization of all free radicals produced in the human body per day, it will take an average of ≈260 to ≈540 g of food components in terms of dry mass (including proteins, fats, carbohydrates, etc.). At the same time, for the utilization of consumed xenobiotics, from 220 mg (in terms of vitamin C) to 260 mg (in terms of acetylcysteine -NAC) of additional plastic components or 11.5-13.0 g of essential amino acids will be required, which must be taken into account when calculating diets. This approach will be useful in the development of new functional foods, as well as in assessing the possible impact of diets on human health. Another applied point of this study is related to the possibility of using these data for better detailing and selection of food products for people working in conditions of increased radiation (in space conditions), in contact with harmful substances (chemical synthesis and production), for people practicing increased physical activity (bodybuilding and sports), and for the purposes of medical nutritional therapy.},
}
@article {pmid36497051,
year = {2022},
author = {Liu, B and Ding, C and Tang, W and Zhang, C and Gu, Y and Wang, Z and Yu, T and Li, Z},
title = {Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury.},
journal = {Cells},
volume = {11},
number = {23},
pages = {},
pmid = {36497051},
issn = {2073-4409},
support = {81974458, 82170607//National Natural Science Foundation of China/ ; 2021JJ30463, 2022JJ10037//Hunan Provincial Natural Science Foundation of China/ ; 2019RS1042, 2019TP1035//China Hunan Provincial Science/Technology Department/ ; 2022XKQ0205 and KF2022001//Hunan Normal University/ ; },
mesh = {Mice ; Animals ; Macrophage Activation ; Irinotecan/pharmacology ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Hepatocytes/metabolism ; *Fatty Liver/metabolism ; Acetylcysteine/pharmacology ; },
abstract = {Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury remain elusive. In this study, we found that irinotecan treatment caused significant elevation of ALT, inflammation, and fat accumulation in the liver, which are associated with hepatic macrophage activation. Depletion of macrophages by clodronate liposome improved irinotecan induced liver injury and inflammatory response in mice. In vitro data indicated that irinotecan induced intracellular ROS production in primary hepatocyte and upregulating of toll-like receptor (TLRs) family expression in macrophages. Supernatant from irinotecan treated hepatocyte triggered macrophage activation and upregulation of TLRs in macrophage, and N-acetylcysteine (NAC) abolished these effects. By using co-culture system, we further revealed that irinotecan activated macrophage induced impairment of lipid metabolism and promoted apoptosis in hepatocyte and NAC prevented macrophage-induced cell death and partially revered impaired lipid metabolism in hepatocytes. By using the irinotecan liver injury model, we demonstrated that combining NAC with irinotecan prevented irinotecan-induced macrophage activation, TLR upregulation, liver injury, and partially prevented the accumulation of triglycerides in liver. Our results thus indicated that macrophages play a critical role in irinotecan-induced liver injury, and targeting ROS provides new options for development of hepatoprotective drugs in clinical practice.},
}
@article {pmid36495185,
year = {2023},
author = {Panahi, Y and Ghanei, M and Rahimi, M and Samim, A and Vahedian-Azimi, A and Atkin, SL and Sahebkar, A},
title = {Evaluation the efficacy and safety of N-acetylcysteine inhalation spray in controlling the symptoms of patients with COVID-19: An open-label randomized controlled clinical trial.},
journal = {Journal of medical virology},
volume = {95},
number = {1},
pages = {e28393},
pmid = {36495185},
issn = {1096-9071},
mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/adverse effects ; *COVID-19/therapy ; Length of Stay ; SARS-CoV-2 ; Treatment Outcome ; Administration, Inhalation ; *Oral Sprays ; Nebulizers and Vaporizers ; },
abstract = {The aim of this study was to evaluate the effect and safety of N-acetylcysteine (NAC) inhalation spray in the treatment of patients with coronavirus disease 2019 (COVID-19). This randomized controlled clinical trial study was conducted on patients with COVID-19. Eligible patients (n = 250) were randomly allocated into the intervention group (routine treatment + NAC inhaler spray one puff per 12 h, for 7 days) or the control group who received routine treatment alone. Clinical features, hemodynamic, hematological, biochemical parameters and patient outcomes were assessed and compared before and after treatment. The mortality rate was significantly higher in the control group than in the intervention group (39.2% vs. 3.2%, p < 0.001). Significant differences were found between the two groups (intervention and control, respectively) for white blood cell count (6.2 vs. 7.8, p < 0.001), hemoglobin (12.3 vs. 13.3, p = 0.002), C-reactive protein (CRP: 6 vs. 11.5, p < 0.0001) and aspartate aminotransferase (AST: 32 vs. 25.5, p < 0.0001). No differences were seen for hospital length of stay (11.98 ± 3.61 vs. 11.81 ± 3.52, p = 0.814) or the requirement for intensive care unit (ICU) admission (7.2% vs. 11.2%, p = 0.274). NAC was beneficial in reducing the mortality rate in patients with COVID-19 and inflammatory parameters, and a reduction in the development of severe respiratory failure; however, it did not affect the length of hospital stay or the need for ICU admission. Data on the effectiveness of NAC for Severe Acute Respiratory Syndrome Coronavirus-2 is limited and further research is required.},
}
@article {pmid36493885,
year = {2023},
author = {Dong, W and Zhang, K and Gong, Z and Luo, T and Li, J and Wang, X and Zou, H and Song, R and Zhu, J and Ma, Y and Liu, G and Liu, Z},
title = {N-acetylcysteine delayed cadmium-induced chronic kidney injury by activating the sirtuin 1-P53 signaling pathway.},
journal = {Chemico-biological interactions},
volume = {369},
number = {},
pages = {110299},
doi = {10.1016/j.cbi.2022.110299},
pmid = {36493885},
issn = {1872-7786},
mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Cadmium/toxicity ; Sirtuin 1/metabolism ; Tumor Suppressor Protein p53/metabolism ; Kidney/metabolism ; *Renal Insufficiency, Chronic/chemically induced/drug therapy ; Signal Transduction ; Fibrosis ; Cellular Senescence ; },
abstract = {With the development of modern industrial civilization, cadmium (Cd), a known nephrotoxic metal, has become a growing public safety issue due to its ability to induce various types of kidney disease. Maladaptive proximal tubule repair is a significant cause of Cd-induced chronic kidney disease (CKD), which is characterized by premature senescence and pro-fibrosis. Previously, we demonstrated that cadmium causes DNA damage and cycle arrest in renal tubular epithelial cells, which may be relevant to premature senescence regulated by sirtuin 1 (SIRT1). In this study, in vivo and in vitro studies were conducted to elucidate the role of SIRT1-mediated premature renal senescence in Cd-induced CKD. As oxidative stress is a significant cause of aging, we evaluated whether N-acetylcysteine (NAC) would inhibit Cd-induced premature aging and dysfunction in rat renal tubular epithelial cells. Cadmium induced premature renal senescence and fibrosis, and NAC inhibited premature renal senescence and fibrosis through the SIRT1-P53 pathway and delayed CKD progression. Overall, the results suggested that the SIRT1-P53 pathway mediates oxidative stress, premature renal senescence, and renal fibrosis during cadmium exposure, which may be a potential therapeutic target for Cd-induced CKD.},
}
@article {pmid36481977,
year = {2022},
author = {Ye, Z and Wang, Q and Dai, S and Ji, X and Cao, P and Xu, C and Bao, G},
title = {The Berberis vulgaris L. extract berberine exerts its anti-oxidant effects to ameliorate cholesterol overloading-induced cell apoptosis in the primary mice hepatocytes: an in vitro study.},
journal = {In vitro cellular &amp; developmental biology. Animal},
volume = {58},
number = {10},
pages = {855-866},
pmid = {36481977},
issn = {1543-706X},
support = {202101AY070001-085//Basic Research Program of Yunnan Science and Technology Department/ ; 2018BS006//The Doctoral Research Fund of First Affiliated Hospital of Kunming Medical University/ ; },
mesh = {Animals ; Mice ; *Antioxidants/pharmacology/metabolism ; *Apoptosis/drug effects ; *Berberine/pharmacology/therapeutic use ; *Berberis/metabolism ; Cardiovascular Diseases/drug therapy ; Cholesterol/metabolism/pharmacology ; Hepatocytes/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; },
abstract = {Cholesterol overloading stress damages normal cellular functions in hepatocytes and induces metabolic disorders to facilitate the development of multiple diseases, including cardiovascular diseases, which seriously degrades the life quality of human beings. Recent data suggest that the Berberis vulgaris L. extract berberine is capable of regulating cholesterol homeostasis, which is deemed as potential therapeutic drug for the treatment of cholesterol overloading-associated diseases, but its detailed functions and molecular mechanisms are still largely unknown. In the present study, we evidenced that berberine suppressed cell apoptosis in high-cholesterol-diet mice liver and cholesterol-overloaded mice hepatocytes. Also, cholesterol overloading promoted reactive oxygen species (ROS) generation to trigger oxidative damages in hepatocytes, which were reversed by co-treating cells with both berberine and the ROS scavenger N-acetylcysteine (NAC). Moreover, the underlying mechanisms were uncovered, and we validated that berberine downregulated Keap1, and upregulated Nrf2 to activate the anti-oxidant Nrf2/HO-1 signaling pathway in cholesterol overloading-treated hepatocytes, and both Keap1 upregulation and Nrf2 downregulation abrogated the suppressing effects of berberine on cell apoptosis in the hepatocytes with cholesterol exposure. Taken together, we concluded that berberine activated the anti-oxidant Keap1/Nrf2/HO-1 pathway to eliminate cholesterol overloading-induced oxidative stress and apoptotic cell death in mice hepatocytes, and those evidences hinted that berberine might be used as putative therapeutic drug for the treatment of cholesterol overloading-associated cardiovascular diseases.},
}
@article {pmid36471531,
year = {2023},
author = {Guo, M and Zhang, W and Niu, S and Shang, M and Chang, X and Wu, T and Zhang, T and Tang, M and Xue, Y},
title = {Adaptive regulations of Nrf2 alleviates silver nanoparticles-induced oxidative stress-related liver cells injury.},
journal = {Chemico-biological interactions},
volume = {369},
number = {},
pages = {110287},
doi = {10.1016/j.cbi.2022.110287},
pmid = {36471531},
issn = {1872-7786},
mesh = {Humans ; Reactive Oxygen Species/metabolism ; Silver/toxicity ; NF-E2-Related Factor 2/metabolism ; *Metal Nanoparticles/toxicity ; Oxidative Stress ; Acetylcysteine/pharmacology ; Hep G2 Cells ; *Chemical and Drug Induced Liver Injury ; },
abstract = {Silver nanoparticles (AgNPs) are widely used in various fields such as industry, agriculture, and medical care because of their excellent broad-spectrum antibacterial activity. However, their extensive use has raised concerns about their health risks. Liver is one of the main target organs for the accumulation and action of AgNPs. Therefore, evaluating the toxic effects of AgNPs on liver cells and its mechanisms of action is crucial for the safe application of AgNPs. In the study, polyvinylpyrrolidone (PVP)-coated AgNPs were characterized. The human hepatoma cell line (HepG2) and the normal hepatic cell line (L02) were exposed to different concentrations of AgNPs (20-160 μg/mL) and pretreated with the addition of N-acetylcysteine (NAC) or by Nrf2 siRNA transfection. NAC was able to inhibit the concentration-dependent increase in the level of apoptosis induced by AgNPs in HepG2 cells and L02 cells. Interestingly, HepG2 cells were more sensitive to AgNPs than L02 cells, and this may be related to the different ROS generation and responses to AgNPs by cancer cells and normal cells. In addition, NAC also alleviated the imbalance of antioxidant system and cell cycle arrest, which may be related to AgNPs-induced DNA damage and autophagy. The knockdown of nuclear factor erythroid-derived factor 2-related factor (Nrf2) found that AgNPs-induced ROS and apoptosis levels were further upregulated, but the cell cycle arrest was alleviated. On the whole, Nrf2 exerts a protective role in AgNPs-induced hepatotoxicity. This study complements the hepatotoxicity mechanisms of AgNPs and provides data for a future exploration of AgNPs-related anti-hepatocellular carcinoma drugs.},
}
@article {pmid36467056,
year = {2022},
author = {Elsayed, S and Elsaid, KA},
title = {Protein phosphatase 2A regulates xanthine oxidase-derived ROS production in macrophages and influx of inflammatory monocytes in a murine gout model.},
journal = {Frontiers in pharmacology},
volume = {13},
number = {},
pages = {1033520},
pmid = {36467056},
issn = {1663-9812},
abstract = {Background: Gout is a common arthritis, due to deposition of monosodium urate (MSU) crystals which results in IL-1β secretion by tissue-resident macrophages. Xanthine oxidase (XO) catalyzes uric acid (UA) production and in the process, reactive oxygen species (ROS) are generated which contributes to NLRP3 inflammasome activation. Protein phosphatase 2A (PP2A) may be involved in regulating inflammatory pathways in macrophages. The objective of this study was to investigate whether PP2A regulates gout inflammation, mediated by XO activity modulation. We studied UA and ROS generations in MSU stimulated murine bone marrow derived macrophages (BMDMs) in response to fingolimod phosphate, a PP2A activator, and compared its anti-inflammatory efficacy to that of an XO inhibitor, febuxostat. Methods: BMDMs were stimulated with MSU, GM-CSF/IL-1β or nigericin ± fingolimod (2.5 μM) or febuxostat (200 μM) and UA levels, ROS, XO, and PP2A activities, Xdh (XO) expression and secreted IL-1β levels were determined. PP2A activity and IL-1β in MSU stimulated BMDMs ± N-acetylcysteine (NAC) (10 μM) ± okadaic acid (a PP2A inhibitor) were also determined. M1 polarization of BMDMs in response to MSU ± fingolimod treatment was assessed by a combination of iNOS expression and multiplex cytokine assay. The in vivo efficacy of fingolimod was assessed in a murine peritoneal model of acute gout where peritoneal lavages were studied for pro-inflammatory classical monocytes (CMs), anti-inflammatory nonclassical monocytes (NCMs) and neutrophils by flow cytometry and IL-1β by ELISA. Results: Fingolimod reduced intracellular and secreted UA levels (p < 0.05), Xdh expression (p < 0.001), XO activity (p < 0.001), ROS generation (p < 0.0001) and IL-1β secretion (p < 0.0001), whereas febuxostat enhanced PP2A activity (p < 0.05). NAC treatment enhanced PP2A activity and reduced XO activity and PP2A restoration mediated NAC's efficacy as co-treatment with okadaic acid increased IL-1β secretion (p < 0.05). Nigericin activated caspase-1 and reduced PP2A activity (p < 0.001) and fingolimod reduced caspase-1 activity in BMDMs (p < 0.001). Fingolimod reduced iNOS expression (p < 0.0001) and secretion of IL-6 and TNF-α (p < 0.05). Fingolimod reduced CMs (p < 0.0001), neutrophil (p < 0.001) and IL-1β (p < 0.05) lavage levels while increasing NCMs (p < 0.001). Conclusion: Macrophage PP2A is inactivated in acute gout by ROS and a PP2A activator exhibited a broad anti-inflammatory effect in acute gout in vitro and in vivo.},
}
@article {pmid36467051,
year = {2022},
author = {Liu, M and Hu, T and Gou, W and Chang, H and Li, Y and Li, Y and Zuo, D and Hou, W and Jiao, S},
title = {Exploring the pharmacological mechanisms of icaritin against nasopharyngeal carcinoma via network pharmacology and experimental validation.},
journal = {Frontiers in pharmacology},
volume = {13},
number = {},
pages = {993022},
pmid = {36467051},
issn = {1663-9812},
abstract = {Background: Icaritin is a natural product with a wide range of anti-tumor effects. However, its anti-tumor mechanism has not been thoroughly studied. This study examined the inhibitory effect of icaritin on nasopharyngeal cancer and its underlying mechanism using network pharmacology along with in vivo and in vitro experiments. Methods: MTT and clone formation assays were used to detect the effects of icaritin on the viability and proliferation of nasopharyngeal carcinoma cells, followed by the construction of a HONE1 xenograft tumor model to evaluate the anti-tumor efficacy of icaritin in vivo. A public database was used to predict prospective targets, built a protein-protein interaction (PPI) network, and analyze gene enrichment and biological processes. Based on network pharmacological data, cell cycle-related proteins were identified using western blotting. Besides, cell cycle distribution, apoptosis, and intracellular reactive oxygen species (ROS) generation were identified using flow cytometry. In addition, SA-β-Gal staining was performed to detect cellular senescence, and western blotting was performed to detect the expression of P53, P21, and other proteins to verify key signaling pathways. Results: Icaritin effectively inhibited the viability and proliferation of nasopharyngeal carcinoma cell lines and showed good anti-tumor activity against HONE1 nasopharyngeal carcinoma cells in vivo. Key protein targets, including AKT1, HSP90AA1, CDK4, CCND1, and EGFR, were screened using PPI network topology analysis. GO and KEGG analysis revealed that the cell cycle, p53 signaling, and cell senescence pathways may be the main regulatory pathways. Flow cytometry and western blot experiments showed that icaritin caused S-phase arrest and promoted an increase in ROS. SA-β-Gal staining showed that icaritin significantly induced cellular senescence, and western blotting showed that the expression of senescence-related proteins p53 and P21 increased significantly. Moreover, inhibition of ROS levels by N-Acetylcysteine (NAC) enhanced cell viability, reversed cellular senescence and reduced cellular senescence-associated protein expression. Conclusion: The results of network pharmacological analysis and in vivo and in vitro experiments showed that icaritin effectively inhibited the growth of nasopharyngeal carcinoma cells, promoted ROS production, induced cellular senescence, and inhibited tumor cells, which are related to the regulation of P53/P21 signal pathway.},
}
@article {pmid36464114,
year = {2023},
author = {Abdallah, S and Jampy, A and Moison, D and Wieckowski, M and Messiaen, S and Martini, E and Campalans, A and Radicella, JP and Rouiller-Fabre, V and Livera, G and Guerquin, MJ},
title = {Foetal exposure to the bisphenols BADGE and BPAF impairs meiosis through DNA oxidation in mouse ovaries.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {317},
number = {},
pages = {120791},
doi = {10.1016/j.envpol.2022.120791},
pmid = {36464114},
issn = {1873-6424},
mesh = {Female ; Mice ; Animals ; *Meiosis ; *Ovary ; Benzhydryl Compounds/toxicity ; DNA ; Aneuploidy ; Epoxy Compounds ; Bisphenol A Compounds ; Fluorocarbons ; },
abstract = {Many endocrine disruptors have been proven to impair the meiotic process which is required for the production of healthy gametes. Bisphenol A is emblematic of such disruptors, as it impairs meiotic prophase I and causes oocyte aneuploidy following in utero exposure. However, the mechanisms underlying these deleterious effects remain poorly understood. Furthermore, the increasing use of BPA alternatives raises concerns for public health. Here, we investigated the effects of foetal exposure to two BPA alternatives, bisphenol A Diglycidyl Ether (BADGE) and bisphenol AF (BPAF), on oogenesis in mice. These compounds delay meiosis initiation, increase the number of MLH1 foci per cell and induce oocyte aneuploidy. We further demonstrate that these defects are accompanied by changes in gene expression in foetal premeiotic germ cells and aberrant mRNA splicing of meiotic genes. We observed an increase in DNA oxidation after exposure to BPA alternatives. Specific induction of oxidative DNA damage during foetal germ cell differentiation causes similar defects during oogenesis, as observed in 8-oxoguanine DNA Glycosylase (OGG1)-deficient mice or after in utero exposure to potassium bromate (KBrO3), an inducer of oxidative DNA damage. The supplementation of BPA alternatives with N-acetylcysteine (NAC) counteracts the effects of bisphenols on meiosis. Together, our results propose oxidative DNA lesion as an event that negatively impacts female meiosis with major consequences on oocyte quality. This could be a common mechanism of action for numerous environmental pro-oxidant pollutants, and its discovery, could lead to reconsider the adverse effect of bisphenol mixtures that are simultaneously present in our environment.},
}
@article {pmid36459039,
year = {2022},
author = {Santus, P and Danzo, F and Zuffi, A and Pini, S and Saad, M and Visconti, A and Radovanovic, D},
title = {Oxidative stress and viral Infections: rationale, experiences, and perspectives on N-acetylcysteine.},
journal = {European review for medical and pharmacological sciences},
volume = {26},
number = {22},
pages = {8582-8590},
doi = {10.26355/eurrev_202211_30395},
pmid = {36459039},
issn = {2284-0729},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress ; *Virus Diseases/drug therapy ; Inflammation ; },
abstract = {This article explores current evidence on the role of oxidative stress in viral infections, and on the use of antioxidant drugs as adjunctive treatment. MEDLINE/PubMed was searched for appropriate keywords, and preclinical and clinical studies with reviews were retrieved and examined by authors. Old and current evidence shows that GSH content reduction is the main mechanism of redox imbalance in viral-infected cells. Clinical studies found that GSH levels are depleted in patients with viral infections such as HIV and SARS-CoV. Viral infections activate inflammation through different pathways, and several of these mechanisms are related to oxidative stress. NAC is a precursor of GSH, and many of its intracellular effects are mediated by GSH replenishment, but it also activates some anti-inflammatory mechanisms. NAC has an excellent safety profile and better oral and topical bioavailability than GSH. These characteristics make NAC a suitable option as a repurposed drug. Adjunctive antioxidant treatment may improve the outcomes of antiviral therapies. Current evidence supports the rationale for this practice and some clinical experience showed encouraging results.},
}
@article {pmid36458919,
year = {2023},
author = {Amar, SK and Donohue, KB and Gust, KA},
title = {Cellular and molecular responses to ethyl-parathion in undifferentiated SH-SY5Y cells provide neurotoxicity pathway indicators for organophosphorus impacts.},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {191},
number = {2},
pages = {285-295},
pmid = {36458919},
issn = {1096-0929},
mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Parathion/toxicity ; Cell Line, Tumor ; *Neuroblastoma/metabolism ; Apoptosis ; *Neurotoxicity Syndromes/etiology ; Cell Survival ; },
abstract = {High-fidelity nonanimal screening methods are needed that can rapidly and accurately characterize organophosphorus compound (OP)-induced neurotoxicity. Herein, the efficacy of human neuroblastoma cell line (SH-SY5Y) to provide molecular and cellular responses characteristic of the OP neurotoxicity pathway was investigated in response to the OP-model compound, ethyl-parathion. Undifferentiated SH-SY5Y cells were exposed to ethyl-parathion for 30 min at 0 (control), 0.5, 2.5, 5, 10, and 25 µg/ml. Dose-responsive reductions in cell viability were observed with significant reductions at ≥10 µg/ml. From these results, ethyl-parathion exposures of 0 (control), 5, and 10 µg/ml were selected to examine bioindicators underlying the OP neurotoxicity pathway including: reactive oxygen species (ROS), cell membrane peroxidation, mitochondrial membrane potential (MMP), and apoptosis. Ethyl-parathion elicited highly significant increases in ROS relative to controls (p < .01) at both exposure concentrations, confirmed using N-acetyl cysteine (NAC) as a ROS quencher which alleviated ROS increases. A response characteristic of increased ROS exposure, cell membrane-lipid peroxidation, significantly increased (p < .05) at the highest ethyl-parathion exposure (10 µg/ml). As a likely consequence of membrane-lipid peroxidation, ethyl-parathion-induced reductions in MMP were observed with significant effects at 10 µg/ml, reducing MMP by 58.2%. As a culmination of these cellular-damage indicators, apoptosis progression was investigated by phosphatidylserine translocation where ethyl-parathion-induced dose-responsive, highly significant (p < .01) increases at both 5 and 10 µg/ml. Overall, the mechanistic responses observed in undifferentiated SH-SY5Y cells corresponded with in vivo mammalian results demonstrating potential for this nonanimal model to provide accurate OP neurotoxicology screening.},
}
@article {pmid36454053,
year = {2022},
author = {Palsdottir, A and Snorradottir, AO and Hakonarson, H},
title = {[Did ketogenic diet in past centuries protect against the consequence of the cystatin L68Q mutation in carriers of HCCAA?].},
journal = {Laeknabladid},
volume = {108},
number = {12},
pages = {553-557},
doi = {10.17992/lbl.2022.12.721},
pmid = {36454053},
issn = {1670-4959},
mesh = {Humans ; *Cystatin C/genetics ; *Diet, Ketogenic ; Food ; Glutathione ; Mutation ; *Cerebral Amyloid Angiopathy, Familial/genetics ; },
abstract = {Hereditary cystatin C amyloid angiopathy (HCCAA) is a dominantly inherited disease caused by a mutation (L68Q) in the cystatin C gene, CST3. Mutant cystatin C protein accumulates as amyloid in arterioles in the brain leading to repeated brain hemorrhages and death of young carriers. Recently a possible treatment option was reported for HCCAA carriers involving an oral treatment with N-acetyl-cysteine in order to increase glutathione which was found to dissolve aggregates of mutant cystatin C. An earlier study described how the life span of carriers of the L68Q mutation shortened in the latter half of the 19th century. During the same decades a drastic change occured in the diet in Iceland. In the beginning of the century the diet was simple and low in carbohydrates, which mostly came from milk products. Import of grains and sugar was limited, but increased greatly according to import records. Due to lack of salt, food was preserved in acid whey, but gradually salt replaced whey as means of preserving food. This study aims to explore if changes in the diet of Icelanders during the same decades could possibly affect the amount of glutathione in people.},
}
@article {pmid36453778,
year = {2022},
author = {Erol, K and Y Sozmen, E and Küçük, &#xdc; and Kucuk, L},
title = {Effect of pheniramine maleate on rat skeletal muscle ischemia-reperfusion injury.},
journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma &amp; emergency surgery : TJTES},
volume = {28},
number = {12},
pages = {1667-1673},
pmid = {36453778},
issn = {1307-7945},
mesh = {Male ; Animals ; Rats ; *Pheniramine ; Rats, Sprague-Dawley ; Poly(ADP-ribose) Polymerase Inhibitors ; Thiobarbituric Acid Reactive Substances ; *Reperfusion Injury/drug therapy ; Acetylcysteine ; Superoxide Dismutase ; Femoral Artery ; Muscle, Skeletal ; Nitric Oxide ; },
abstract = {BACKGROUND: Skeletal muscle ischemia-reperfusion injury (IRI) is a common clinical problem encountered after tourniquet ap-plication or replantation. This study investigated the effect of pheniramine maleate (Ph), which is frequently used in clinical practice to reduce IRI, and compared its efficacy in IRI with N-acetylcysteine (NAC), a molecule that has been shown to be effective in IRI.<br><br>METHODS: Twenty-eight male Sprague-Dawley rats were randomly divided into four groups (sham, ischemia-reperfusion [IR], IR+Ph, IR+NAC; n=7 rats per group). Ischemia was induced in the lower right extremities of rats for 3 h using a femoral artery clamp and an elastic tourniquet. Ph and NAC were administered intraperitoneally 15 min before ischemia was terminated. At 24 h after reperfusion, levels of thiobarbituric acid reactive substance (TBARS), catalase (CAT), myeloperoxidase (MPO), superoxide dismutase (SOD), polyadenosine diphosphate ribose polymerase (PARP), and neutrophil infiltration were evaluated. Inducible nitric oxide syn-thase (iNOS) density in muscle tissue was evaluated by immunohistochemical methods after 1 week.<br><br>RESULTS: SOD, MPO, PARP, CAT, and TBARS levels in muscle tissue were significantly lower in the sham group compared with the other groups (p<0.001). All parameters except TBARS were lower in the NAC and Ph groups than in the IR group (p<0.001). Neu-trophil infiltration in the muscle tissue samples from the IR group was significantly increased compared with the NAC and Ph groups (p<0.05). iNOS staining was not observed in the sham and NAC groups.<br><br>CONCLUSION: Ph is effective at reducing experimental rat skeletal muscle IRI.},
}
@article {pmid38362235,
year = {2022},
author = {Greenberg, NR and Farhadi, F and Kazer, B and Potenza, MN and Angarita, GA},
title = {The Potential of N-acetyl Cysteine in Behavioral Addictions and Related Compulsive and Impulsive Behaviors and Disorders: a Scoping Review.},
journal = {Current addiction reports},
volume = {9},
number = {4},
pages = {660-670},
pmid = {38362235},
issn = {2196-2952},
support = {R01 AT010508/AT/NCCIH NIH HHS/United States ; R01 DA052454/DA/NIDA NIH HHS/United States ; R01 DK121551/DK/NIDDK NIH HHS/United States ; R21 DA043055/DA/NIDA NIH HHS/United States ; },
abstract = {PURPOSE OF REVIEW: Behavioral addictions (also termed disorders due to addictive behaviors) contain impulsive and compulsive features and have been shown to involve glutamate dysregulation. N-acetylcysteine (NAC), a well-tolerated cysteine pro-drug and antioxidant, may reduce addictive behaviors by restoring glutamate homeostasis. The current review details and discusses the use of NAC in behavioral addictions and related impulsive and compulsive behaviors, including gambling disorder, problematic use of the internet, problematic video gaming, compulsive sexual behavior, problematic shopping/buying, problematic stealing, repetitive self-injurious behavior, and binge eating disorder.<br><br>RECENT FINDINGS: Preliminary results have indicated the usefulness of NAC in gambling disorder, self-injurious behaviors, and compulsive sexual behaviors. Preclinical studies indicate that NAC is effective in improving binge eating behavior, but clinical trials are limited to a small open-label trial and case report. Studies are lacking on the efficacy of NAC in problematic use of the internet, problematic video gaming, problematic stealing, and problematic shopping/buying.<br><br>SUMMARY: NAC demonstrates potential for use in behavioral addictions and compulsive behaviors, particularly in gambling disorder and self-injury. However, more studies are needed to assess the effectiveness of NAC in other behavioral addictions and the mechanisms by which NAC improves these conditions.},
}
@article {pmid36450250,
year = {2022},
author = {Laoukili, J and van Schelven, S and Küçükköse, E and Verheem, A and Goey, K and Koopman, M and Borel Rinkes, I and Kranenburg, O},
title = {BRAF[V600E] in colorectal cancer reduces sensitivity to oxidative stress and promotes site-specific metastasis by stimulating glutathione synthesis.},
journal = {Cell reports},
volume = {41},
number = {9},
pages = {111728},
doi = {10.1016/j.celrep.2022.111728},
pmid = {36450250},
issn = {2211-1247},
mesh = {Humans ; Proto-Oncogene Proteins B-raf/genetics ; Oxidative Stress ; Glutamate-Cysteine Ligase/genetics ; Glutathione ; *Lung Neoplasms/genetics ; *Colorectal Neoplasms/genetics ; },
abstract = {The presence of BRAF[V600E] in colorectal cancer (CRC) is associated with a higher chance of distant metastasis. Oxidative stress in disseminated tumor cells limits metastatic capacity. To study the relationship between BRAF[V600E], sensitivity to oxidative stress, and metastatic capacity in CRC, we use patient-derived organoids (PDOs) and tissue samples. BRAF[V600E] tumors and PDOs express high levels of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. Deletion of GCL in BRAF[V600E] PDOs strongly reduces their capacity to form distant liver and lung metastases but does not affect peritoneal metastasis outgrowth. Vice versa, the glutathione precursor N-acetyl-cysteine promotes organ-site-specific metastasis in the liver and the lungs but not in the peritoneum. BRAF[V600E] confers resistance to pharmacologically induced oxidative stress in vitro, which is partially overcome by treatment with the BRAF-inhibitor vemurafenib. We conclude that GCL-driven glutathione synthesis protects BRAF[V600E]-expressing tumors from oxidative stress during distant metastasis to the liver and the lungs.},
}
@article {pmid36448959,
year = {2023},
author = {Padoei, F and Mamsharifi, P and Hazegh, P and Boroumand, H and Ostadmohammady, F and Abbaszadeh-Mashkani, S and Banafshe, HR and Matini, AH and Ghaderi, A and Dehkohneh, SG},
title = {The therapeutic effect of N-acetylcysteine as an add-on to methadone maintenance therapy medication in outpatients with substance use disorders: A randomized, double-blind, placebo-controlled clinical trial.},
journal = {Brain and behavior},
volume = {13},
number = {1},
pages = {e2823},
pmid = {36448959},
issn = {2162-3279},
mesh = {Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; *Acetylcysteine/pharmacology/therapeutic use ; Outpatients ; Antioxidants ; Methadone/therapeutic use ; *Substance-Related Disorders ; Double-Blind Method ; },
abstract = {OBJECTIVE: Patients with substance use disorders (SUD) under methadone maintenance therapy (MMT) are susceptible to a number of complications (psychological and metabolic disorders). Evidence studies have shown the roles of the glutamatergic system in addiction. N-Acetylcysteine (NAC) enhances extracellular glutamate, and is effective in the treatment of neuropsychiatric disorders. We assessed oral NAC as an add-on to MMT medication for the treatment of SUD.<br><br>METHODS: In the current randomized, double-blind, placebo-controlled clinical trial, outpatients with SUD under MMT who were 18-60 years old received 2400&#xa0;mg/day NAC (n&#xa0;=&#xa0;30) or placebo (n&#xa0;=&#xa0;30) for 12&#xa0;weeks. Psychological status and metabolic biomarkers were assessed at baseline and the end of the trial.<br><br>RESULTS: Compared with the placebo group, NAC treatment resulted in a significant improvement in depression score (&#x3b2; -2.36; 95% CI, -3.97, -0.76; p&#xa0;=&#xa0;.005), and anxiety score (&#x3b2; -1.82; 95% CI, -3.19, -0.44; p&#xa0;=&#xa0;.01). Furthermore, NAC treatment resulted in a significant elevation in total antioxidant capacity levels (&#x3b2; 72.28&#xa0;mmol/L; 95% CI, 11.36, 133.19; p&#xa0;=&#xa0;.02), total glutathione (GSH) levels (&#x3b2; 81.84&#xa0;&#x3bc;mol/L; 95% CI, 15.40, 148.28; p&#xa0;=&#xa0;.01), and a significant reduction in high-sensitivity C-reactive protein levels (&#x3b2; -0.89&#xa0;mg/L; 95% CI, -1.50, -0.28; p&#xa0;=&#xa0;.005), and homeostasis model of assessment-insulin resistance (&#x3b2; -0.33; 95% CI, -0.65, -0.009; p&#xa0;=&#xa0;.04), compared with the placebo group.<br><br>CONCLUSION: In the current study, improvement in depression and anxiety symptoms as well as some metabolic profiles with NAC treatment for 12&#xa0;weeks in outpatients with SUD under MMT was detected.},
}
@article {pmid36447062,
year = {2023},
author = {Hammerschmidt, TG and Donida, B and Raabe, M and Faverzani, JL and de Fátima Lopes, F and Machado, AZ and Kessler, RG and Reinhardt, LS and Poletto, F and Moura, DJ and Vargas, CR},
title = {Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and β-cyclodextrin nanoparticles.},
journal = {Metabolic brain disease},
volume = {38},
number = {2},
pages = {507-518},
pmid = {36447062},
issn = {1573-7365},
support = {430443/2018-8//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 2018-0648//Fundo de Incentivo &#xe0; Pesquisa e Eventos (FIPE/HCPA)/ ; },
mesh = {Animals ; *Niemann-Pick Disease, Type C/genetics ; Antioxidants/pharmacology/therapeutic use/metabolism ; *beta-Cyclodextrins/pharmacology/therapeutic use/metabolism ; Oxidation-Reduction ; Mitochondria/metabolism ; Cholesterol/metabolism ; },
abstract = {Niemann-Pick C disease (NPC) is an autosomal recessive genetic disorder resulting from mutation in one of two cholesterol transport genes: NPC1 or NPC2, causing accumulation of unesterified cholesterol, together with glycosphingolipids, within the endosomal/lysosomal compartment of cells. The result is a severe disease in both multiple peripheral organs and the central nervous system, causing neurodegeneration and early death. However, the pathophysiological mechanisms of NPC1 remain poorly understood. Recent studies have shown that the primary lysosomal defect found in fibroblasts from NPC1 patients is accompanied by a deregulation of mitochondrial organization and function. There is currently no cure for NPC1, but recently the potential of β-cyclodextrin (β-CD) for the treatment of the disease was discovered, which resulted in the redistribution of cholesterol from subcellular compartments to the circulation and increased longevity in an animal model of NPC1. Considering the above, the present work evaluated the in vitro therapeutic potential of β-CD to reduce cholesterol in fibroblasts from NPC1 patients. β-CD was used in its free and nanoparticulate form. We also evaluated the β-CD potential to restore mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidants N-Acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). Besides, we evaluated oxidative and nitrative stress parameters in NPC1 patients. We showed that oxidative and nitrative stress could contribute to the pathophysiology of NPC1, as the levels of lipoperoxidation and the nitrite and nitrate levels were increased in these patients when compared to healthy individuals, as well as DNA damage. The nanoparticles containing β-CD reduced the cholesterol accumulated in the NPC1 fibroblasts. This result was potentiated by the concomitant use of the nanoparticles with the antioxidants NAC and CoQ10 compared to those presented by healthy individuals cells ́. In addition, treatments combining β-CD nanoparticles and antioxidants could reduce mitochondrial oxidative stress, demonstrating advantages compared to free β-CD. The results obtained are promising regarding the combined use of β-CD loaded nanoparticles and antioxidants in the treatment of NPC1 disease.},
}
@article {pmid36445126,
year = {2022},
author = {Llamosí, M and Sempere, J and Coronel, P and Gimeno, M and Yuste, J and Domenech, M},
title = {Combination of Cefditoren and N-acetyl-l-Cysteine Shows a Synergistic Effect against Multidrug-Resistant Streptococcus pneumoniae Biofilms.},
journal = {Microbiology spectrum},
volume = {10},
number = {6},
pages = {e0341522},
pmid = {36445126},
issn = {2165-0497},
mesh = {Humans ; Animals ; Mice ; Streptococcus pneumoniae ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology ; *COVID-19 ; SARS-CoV-2 ; Cephalosporins/pharmacology/therapeutic use ; Biofilms ; Anti-Bacterial Agents/pharmacology/therapeutic use ; *Respiratory Tract Infections/microbiology ; },
abstract = {Biofilm formation by Streptococcus pneumoniae is associated with colonization of the upper respiratory tract, including the carrier state, and with chronic respiratory infections in patients suffering from chronic obstructive pulmonary disease (COPD). The use of antibiotics alone to treat recalcitrant infections caused by biofilms is insufficient in many cases, requiring novel strategies based on a combination of antibiotics with other agents, including antibodies, enzybiotics, and antioxidants. In this work, we demonstrate that the third-generation oral cephalosporin cefditoren (CDN) and the antioxidant N-acetyl-l-cysteine (NAC) are synergistic against pneumococcal biofilms. Additionally, the combination of CDN and NAC resulted in the inhibition of bacterial growth (planktonic and biofilm cells) and destruction of the biofilm biomass. This marked antimicrobial effect was also observed in terms of viability in both inhibition (prevention) and disaggregation (treatment) assays. Moreover, the use of CDN and NAC reduced bacterial adhesion to human lung epithelial cells, confirming that this strategy of combining these two compounds is effective against resistant pneumococcal strains colonizing the lung epithelium. Finally, administration of CDN and NAC in mice suffering acute pneumococcal pneumonia caused by a multidrug-resistant strain was effective in clearing the bacteria from the respiratory tract in comparison to treatment with either compound alone. Overall, these results demonstrate that the combination of oral cephalosporins and antioxidants, such as CDN and NAC, respectively, is a promising strategy against respiratory biofilms caused by S. pneumoniae. IMPORTANCE Streptococcus pneumoniae is one of the deadliest bacterial pathogens, accounting for up to 2 million deaths annually prior to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccines have decreased the burden of diseases produced by S. pneumoniae, but the rise of antibiotic-resistant strains and nonvaccine serotypes is worrisome. Pneumococcal biofilms are associated with chronic respiratory infections, and treatment is challenging, making the search for new antibiofilm therapies a priority as biofilms become resistant to traditional antibiotics. In this work, we used the combination of an antibiotic (CDN) and an antioxidant (NAC) to treat the pneumococcal biofilms of relevant clinical isolates. We demonstrated a synergy between CDN and NAC that inhibited and treated pneumococcal biofilms, impaired pneumococcal adherence to the lung epithelium, and treated pneumonia in a mouse pneumonia model. We propose the widely used cephalosporin CDN and the repurposed drug NAC as a new antibiofilm therapy against S. pneumoniae biofilms, including those formed by antibiotic-resistant clinical isolates.},
}
@article {pmid36435287,
year = {2023},
author = {Zhang, Q and Deng, C and Peng, M and Li, C and Teng, Y and Guo, S and Wu, T and Yi, D and Hou, Y},
title = {Integration of transcriptomic and proteomic analyses reveals protective mechanisms of N-acetylcysteine in indomethacin-stimulated enterocytes.},
journal = {The Journal of nutritional biochemistry},
volume = {112},
number = {},
pages = {109231},
doi = {10.1016/j.jnutbio.2022.109231},
pmid = {36435287},
issn = {1873-4847},
mesh = {Humans ; Animals ; Swine ; *Acetylcysteine/pharmacology ; *Enterocytes/metabolism ; Transcriptome ; Indomethacin/pharmacology ; Proteomics ; Apoptosis ; },
abstract = {Intestinal health is critical for the growth and development of humans and animals. Our previous study has demonstrated that indomethacin (IDMT) could induce intestinal injury in piglets, and N-acetylcysteine (NAC) supplementation contributed to alleviating intestinal injury induced by various stimuli. In this study, we investigated the mechanism of IDMT-induced cell death in IPEC-1 cell lines and explored the role of NAC by using transcriptomic and proteomic analyses. Results showed that cell viability was substantially reduced with the increasing concentrations of IDMT, whereas NAC significantly increased the survival rate of IPEC-1 cells regardless of its addition method. Transcriptomics and proteomics data indicated that terms, such as cell cycle, energy metabolism, and cell proliferation, were significantly enriched by Gene ontology and pathway analyses. Flow cytometer analysis showed that IDMT induced cell cycle arrest at G0/G1 phase. The expression of cell cycle regulatory proteins (CDK1, CCNA2, and CDC45) was decreased by IDMT stimulation. Importantly, NAC treatment repaired IDMT-induced mitochondrial dysfunction by increasing ATP production, decreasing oxygen consumption rate in non-mitochondrial O2 consumption, and increasing the red/green fluorescence ratio. IDMT stimulation significantly increased caspase-3 expression, which was partially reversed by NAC treatment. These results suggest that IDMT-induced cell death may be attributable to disturbance of the cell cycle processes, mitochondria dysfunction and apoptosis, and NAC could confer a protective effect by restoring the mitochondrial function and inhibiting the apoptosis pathway. This study provides a theoretical basis for the pathogenesis of IDMT-induced intestinal injury and guides the clinic application of NAC.},
}
@article {pmid36434296,
year = {2022},
author = {Yilmaz, FN and Hacioglu, M and Aldogan, EH},
title = {Impact of N-Acetylcysteine and Antibiotics Against Single and Dual Species Biofilms of Pseudomonas aeruginosa and Achromobacter xylosoxidans.},
journal = {Current microbiology},
volume = {80},
number = {1},
pages = {5},
pmid = {36434296},
issn = {1432-0991},
mesh = {Animals ; Humans ; Pseudomonas aeruginosa ; *Achromobacter denitrificans ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Aztreonam/pharmacology ; *Cystic Fibrosis/microbiology ; Caenorhabditis elegans ; Biofilms ; Tobramycin/pharmacology ; Ciprofloxacin/pharmacology ; },
abstract = {Lungs of cystic fibrosis patients are often colonized or infected with organisms, such as Pseudomonas aeruginosa and other emerging pathogenic bacteria such as Achromobacter xylosoxidans. Further, it is well established that infections of the cystic fibrosis lung airways are caused by polymicrobial infections, although its composition and diversity may change throughout the patient's life. In the present study, we investigated the effects of N-acetylcysteine (NAC) and amikacin, aztreonam, ciprofloxacin, and tobramycin alone and in combination against single- and dual-species biofilms of P. aeruginosa and A. xylosoxidans, in vitro and in the Caenorhabditis elegans infection model. Results showed that tobramycin and ciprofloxacin were the most effective antibiotics, while aztreonam was the least effective antibiotic against both single- and dual-species biofilms of P. aeruginosa and A. xylosoxidans. However, NAC showed little effect on both single- and dual-species, even with a combination of antibiotics. Increased survival was observed in C. elegans when treated with NAC in combination with tobramycin or ciprofloxacin, compared to no treatment or NAC alone. Tobramycin and ciprofloxacin were found effective in biofilms, but more research is needed to better understand the effects of NAC and antibiotics against single- and dual-species biofilms.},
}
@article {pmid36432632,
year = {2022},
author = {Petkova, T and Yordanova, A and Milanova, A},
title = {Population Pharmacokinetics of Doxycycline, Administered Alone or with N-Acetylcysteine, in Chickens with Experimental Mycoplasma gallisepticum Infection.},
journal = {Pharmaceutics},
volume = {14},
number = {11},
pages = {},
pmid = {36432632},
issn = {1999-4923},
support = {N/A//TRAKIA UNIVERSITY, PhD program/ ; },
abstract = {Mycoplasmosis is a bacterial infection that significantly affects poultry production, and it is often controlled with antibiotics, including doxycycline. The conducted study aimed to determine population pharmacokinetic (PopPk) parameters of doxycycline in healthy (n = 12) and in Mycoplasma gallisepticum-challenged (n = 20) chickens after its oral administration via drinking water at the registered dose rate of 20 mg/kg b.w./24 h for five days, without or with co-administration of N-acetylcysteine (NAC, a dose of 100 mg/kg b.w./24 h) via the feed. Doxycycline concentrations in plasma were analyzed with the LC-MS/MS method. The values of tvV/F and tvke were 4.73 L × kg−1 and 0.154 h−1, respectively, and they showed low BSV. A high BSV of 93.17% was calculated for the value of tlag of 0.8 h, which reflects the inter-individual differences in the water consumption. PTA was computed after Monte Carlo simulation with the registered dose for doxycycline. The target of %fT > MIC ≥ 80% and 100% can be achieved in 90% of the broiler population, after a correction for protein binding, for bacteria with MIC ≤ 0.5 mg × L−1 and 0.25 mg × L−1, respectively. The applied PopPk model did not reveal significant effect of M. gallisepticum infection and co-administration of NAC on pharmacokinetic parameters of doxycycline.},
}
@article {pmid36428416,
year = {2022},
author = {Nascimento, DR and Azevedo, VAN and Barroso, PAA and Barrozo, LG and Silva, BR and Silva, AWB and Donato, MAM and Peixoto, CA and Silva, JRV},
title = {Effects of N-acetylcysteine on Growth, Viability, and Ultrastructure of In Vitro Cultured Bovine Secondary Follicles.},
journal = {Animals : an open access journal from MDPI},
volume = {12},
number = {22},
pages = {},
pmid = {36428416},
issn = {2076-2615},
support = {308737/2018-0//National Council for Scientific and Technological Development/ ; },
abstract = {This study aimed to investigate the effects of different concentrations of N-acetylcysteine (NAC) on the growth, antrum formation, viability, and ultrastructure of bovine secondary follicles cultured in vitro for 18 days. To this end, the follicles were cultured in TCM-199+ medium alone or supplemented with 1.0, 5.0, or 25.0 mM NAC. Follicular growth, antrum formation, viability (calcein-AM and ethidium homodimer-1) and ultrastructure were evaluated at the end of culture period. The results showed that 1.0 mM NAC increased the percentage of growing follicles and the fluorescence intensity for calcein-AM when compared to other treatments (p < 0.05). On the other hand, follicles cultured with 25.0 mM NAC had higher fluorescence intensity for ethidium homodimer-1, which is a sign of degeneration. Ultrastructural analysis showed that oocytes from follicles cultured in control medium alone or with 1 mM NAC had intact zonae pellucidae in close association with oolemmae, but the ooplasm showed mitochondria with a reduced number of cristae. On the other hand, oocytes from follicles cultured with 5 or 25 mM NAC had extremely vacuolated cytoplasm and no recognizable organelles. In conclusion, 1 mM NAC increases cytoplasmic calcein staining and the growth rate in bovine secondary follicles cultured in vitro, but the presence of 5 or 25 mM NAC causes damage in cellular membranes and organelles, as well as reducing the percentages of growing follicles.},
}
@article {pmid36421484,
year = {2022},
author = {Mapamba, DA and Sauli, E and Mrema, L and Lalashowi, J and Magombola, D and Buza, J and Olomi, W and Wallis, RS and Ntinginya, NE},
title = {Impact of N-Acetyl Cysteine (NAC) on Tuberculosis (TB) Patients-A Systematic Review.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {11},
number = {11},
pages = {},
pmid = {36421484},
issn = {2076-3921},
support = {LMU-IMPH-TB Sequel-01//TB sequel project by the German Ministry of Education and Research/ ; },
abstract = {Sustained TB infection overproduces reactive oxygen species (ROS) as a host defense mechanism. Research shows ROS is destructive to lung tissue. Glutathione (GSH) neutralizes ROS, although it is consumed. NAC is a precursor of GSH synthesis, and administering an appropriate dose of NAC to patients with respiratory conditions may enhance lung recovery and replenish GSH. The present review searched for articles reporting on the effects of NAC in TB treatment from 1960 to 31 May 2022. The PICO search strategy was used in Google Scholar, PubMed, SciFinder, and Wiley online library databases. The COVIDENCE tool was used to delete inappropriate content. We eventually discovered five clinical trials, one case report, seven reviews, in vitro research, and four experimental animal studies from the twenty-four accepted articles. The use of NAC resulted in increased GSH levels, decreased treatment time, and was safe with minimal adverse events. However, the evidence is currently insufficient to estimate the overall effects of NAC, thus the study warrants more NAC clinical trials to demonstrate its effects in TB treatment.},
}
@article {pmid36421407,
year = {2022},
author = {Gençosman, S and Ceylanlı, D and Şehirli, A&#xd6; and Teralı, K and Bölükbaşı, F and Çetinel, &#x15e; and Sayıner, S},
title = {Investigation of the Possible Protective Effect of N-Acetylcysteine (NAC) against Irinotecan (CPT-11)-Induced Toxicity in Rats.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {11},
number = {11},
pages = {},
pmid = {36421407},
issn = {2076-3921},
abstract = {Irinotecan (CPT-11) is a chemotherapeutic agent involved in the treatment regimens for several malignancies such as colorectal cancer. N-acetylcysteine (NAC) is a strong antioxidant and anti-inflammatory agent used in the treatment of several diseases related to oxidative stress and inflammation. This study aimed at investigating whether NAC provides protection against hepatorenal and gastrointestinal tissue damage induced by CPT-11. Thirty-two Wistar albino rats were divided into four groups as control, NAC, CPT-11, and CPT-11+NAC. Following the experimental period, blood, and tissue samples (liver, kidney, stomach, and small intestine) were collected, and biochemical indicators, together with pro-inflammatory cytokines (TNF-α and IL-1β), matrix metalloproteinases (MMPs), malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD) levels were evaluated. Both the biochemical indicators and the pro-inflammatory cytokines, MMP, and MDA levels increased in animals treated with CPT-11, while SOD and GPx activities decreased. Histopathological evaluation revealed structural damage in all examined tissues. With NAC administration, significant improvements were observed, both biochemically and histologically. In conclusion, the results of the present study suggest that NAC treatment together with CPT-11 may have a beneficial effect on reducing CPT-11 toxicity in rats, by modulating inflammation and the oxidant-antioxidant balance. These results strongly promote further investigative studies.},
}
@article {pmid36420805,
year = {2022},
author = {Janković, SM},
title = {Acetaminophen toxicity and overdose: current understanding and future directions for NAC dosing regimens.},
journal = {Expert opinion on drug metabolism &amp; toxicology},
volume = {18},
number = {11},
pages = {745-753},
doi = {10.1080/17425255.2022.2151893},
pmid = {36420805},
issn = {1744-7607},
mesh = {Humans ; Acetylcysteine ; Acetaminophen/therapeutic use ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury/drug therapy ; },
abstract = {INTRODUCTION: Although N-acetyl-cysteine (NAC) has long been used for the treatment of acetaminophen poisoning/overdose, the optimal NAC dosing regimen for varying patterns or severity of the poisoning/overdose is still unknown.<br><br>AREAS COVERED: Relevant literature was searched for in the MEDLINE (from 1964 until August 31[st], 2022), SCOPUS (from 2004 until August 31[st], 2022) and GOOGLE SCHOLAR (from 2004 until August 31[st], 2022) databases, without restriction in terms of publication date. The inclusion criteria were: original clinical studies reporting results, and studies investigating efficacy and safety of NAC dosing regimens in case(s) of overdose or poisoning with acetaminophen.<br><br>EXPERT OPINION: For a more effective treatment of acetaminophen poisoning in the future, it will be crucial to advance the technology of measuring acetaminophen, its metabolites and NAC in the serum, preferably with the point-of-care technique, so that in real time it can be continuously assessed whether it is necessary to administer NAC, and further to increase the dose of NAC and extend the duration of its administration, or not.},
}
@article {pmid36418258,
year = {2022},
author = {Zhang, YP and Zhang, Q and Deng, F and Chen, B and Zhang, JH and Hu, J},
title = {[Effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its mechanism].},
journal = {Zhonghua shao shang yu chuang mian xiu fu za zhi},
volume = {38},
number = {11},
pages = {1014-1022},
pmid = {36418258},
issn = {2097-1109},
support = {82100889//Youth Science Foundation Project of National Natural Science Foundation of China/ ; CSTB2022BSXM-JCX0022//Chongqing Doctor "Through Train" Project/ ; XZ-2019-505-018//Science and Technology Ability Promotion Project of Army Medical University/ ; },
mesh = {Humans ; RNA, Small Interfering/genetics ; Cell Line ; *Epidermis ; *Glucose/pharmacology ; Epidermal Cells ; },
abstract = {Objective: To investigate the effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its possible molecular mechanism, so as to explore the mechanism of refractory diabetic foot wound healing. Methods: The method of experimental research was used. HaCaT cells in logarithmic growth phase was taken for experiment. The cells were collected and divided into normal control group (culture solution containing glucose with final molarity of 5.5 mmol/L) and high glucose (culture solution containing glucose with final molarity of 30.0 mmol/L) 24 h group, high glucose 48 h group, and high glucose 72 h group according to the random number table (the same grouping method below). The cells in normal control group were routinely cultured for 72 h, cells in high glucose 72 h group were cultured with high glucose for 72 h, cells in high glucose 48 h group were routinely cultured for 24 h then cultured with high glucose for 48 h, cells in high glucose 24 h group were routinely cultured for 48 h then cultured with high glucose for 24 h. Then the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal control group and high glucose group. After being correspondingly cultured for 48 h as before, the protein expression of P62 was detected by immunofluorescence method (indicated as green fluorescence). The cells were collected and divided into negative control small interfering RNA (siRNA) group, P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group, and transfected with the corresponding reagents. At post transfection hour (PTH) 72, the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group. After the corresponding treatment, the protein expression of P62 was detected by Western blotting at PTH 72 h, the cell migration rate was detected and calculated at 24 h after scratching by scratch test, with the number of samples being 9; and the range of cell movement was observed and the trajectory velocity was calculated within 3 h under the living cell workstation, with the number of samples being 76, 75, 80, and 79 in normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group, respectively. The cells were collected and divided into normal glucose+phosphate buffered solution (PBS) group, high glucose+PBS group, and high glucose+N-acetylcysteine (NAC) group. After the corresponding treatment, the protein expression of P62 at 48 h of culture was detected by Western blotting and immunofluorescence method, respectively. Except for scratch test and cell motility experiment, the number of samples was all 3 in the rest experiments. Data were statistically analyzed with one-way analysis of variance and least significant difference test. Results: Compared with the protein expression in normal control group, the protein expressions of P62 of cells in high glucose 24 h group, high glucose 48 h group, and high glucose 72 h group were significantly increased (P<0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose group was stronger than that in normal control group. At PTH 72, compared with the protein expression in negative control siRNA group, the protein expressions of P62 of cells in P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group were significantly decreased (P<0.01). At PTH 72, compared with the protein expression in normal glucose+negative control siRNA group, the protein expression of P62 of cells in normal glucose+P62-siRNA group was significantly decreased (P<0.01), while the protein expression of P62 of cells in high glucose+negative control siRNA group was significantly increased (P<0.01); compared with the protein expression in high glucose+negative control siRNA group, the protein expression of P62 of cells in high glucose+P62-siRNA group was significantly decreased (P<0.01). At 24 h after scratching, compared with (55±7)% in normal glucose+negative control siRNA group, the cell migration rate in normal glucose+P62-siRNA group was significantly increased ((72±14)%, P<0.01), while the cell migration rate in high glucose+negative control siRNA group was significantly decreased ((37±7)%, P<0.01); compared with that in high glucose+negative control siRNA group, the cell migration rate in high glucose+P62-siRNA group was significantly increased ((54±10)%, P<0.01). Within 3 h of observation, the cell movement range in high glucose+negative control siRNA group was smaller than that in normal glucose+negative control siRNA group, while the cell movement range in normal glucose+P62-siRNA group was larger than that in normal glucose+negative control siRNA group, and the cell movement range in high glucose+P62-siRNA group was larger than that in high glucose+negative control siRNA group. Compared with that in normal glucose+negative control siRNA group, the cell trajectory speed in normal glucose+P62-siRNA group was significantly increased (P<0.01), while the cell trajectory speed in high glucose+negative control siRNA group was significantly decreased (P<0.01); compared with that in high glucose+negative control siRNA group, the cell trajectory speed in high glucose+P62-siRNA group was significantly increased (P<0.01). At 48 h of culture, compared with that in normal glucose+PBS group, the protein expression of P62 of cells in high glucose+PBS group was significantly increased (P<0.01); compared with that in high glucose+PBS group, the protein expression of P62 of cells in high glucose+NAC group was significantly decreased (P<0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose+PBS group was stronger than that in normal glucose+PBS group, while the green fluorescence of P62 of cells in high glucose+NAC group was weaker than that in high glucose+PBS group. Conclusions: In HaCaT cells, high glucose microenvironment can promote the protein expression of P62; knockdown of P62 protein can promote the migration and increase the mobility of HaCaT cells; and the increase of reactive oxygen species in high glucose microenvironment may be the underlying mechanism for the increase of P62 expression.},
}
@article {pmid36414340,
year = {2022},
author = {Lee, M and McCarron, J and Balinski, A and Bower, R},
title = {Intravenous acetaminophen associated with acute liver failure.},
journal = {BMJ case reports},
volume = {15},
number = {11},
pages = {},
pmid = {36414340},
issn = {1757-790X},
mesh = {Female ; Humans ; Acetaminophen/adverse effects ; *Liver Failure, Acute/etiology ; Acetylcysteine/therapeutic use ; *Drug-Related Side Effects and Adverse Reactions ; *Brain Diseases/complications ; },
abstract = {A woman in her mid-60s, without known liver disease, was admitted to the hospital with a partial malignant colonic obstruction. Over a 6-day course, she received a total of 13 g of intravenous acetaminophen not exceeding 4 g over a 24-hour period. She developed encephalopathy and an international normalised ratio of 6.1 meeting criteria for acute liver failure (ALF). She was treated with intravenous N-acetyl cysteine and other causes of liver failure were excluded. The patient was discharged with subsequent resolution of encephalopathy and improvement of her liver chemistries. Though ALF is rare, in countries where acetaminophen is readily available, almost 50% of ALF cases are acetaminophen-induced hepatotoxicity and most have been documented as oral ingestion of acetaminophen. We present a rare case of intravenous acetaminophen-induced ALF.},
}
@article {pmid36410267,
year = {2022},
author = {Izquierdo-Alonso, JL and Pérez-Rial, S and Rivera, CG and Peces-Barba, G},
title = {N-acetylcysteine for prevention and treatment of COVID-19: Current state of evidence and future directions.},
journal = {Journal of infection and public health},
volume = {15},
number = {12},
pages = {1477-1483},
pmid = {36410267},
issn = {1876-035X},
mesh = {Humans ; Acetylcysteine/therapeutic use ; SARS-CoV-2 ; *Respiratory Distress Syndrome ; Immunotherapy ; *COVID-19 Drug Treatment ; },
abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19) and can be associated with serious complications, including acute respiratory distress syndrome. This condition is accompanied by a massive release of cytokines, also denominated cytokine storm, development of systemic oxidative stress and a prothrombotic state. In this context, it has been proposed a role for acetylcysteine (NAC) in the management of patients with COVID-19. NAC is a molecule classically known for its mucolytic effect, but it also has direct and indirect antioxidant activity as a precursor of reduced glutathione. Other effects of NAC have also been described, such as modulating the immune and inflammatory response, counteracting the thrombotic state, and having an antiviral effect. The pharmacological activities of NAC and its effects on the mechanisms of disease progression make it a potential therapeutic agent for COVID-19. NAC is safe, tolerable, affordable, and easily available. Moreover, the antioxidant effects of the molecule may even prevent infection and play an important role as a complement to vaccination. Although the clinical efficacy and dosing regimens of NAC have been evaluated in the clinical setting with small series of patients, the results are promising. In this article, we review the pathogenesis of SARS-CoV-2 infection and the current knowledge of the mechanisms of action of NAC across disease stages. We also propose NAC posology strategies to manage COVID-19 patients in different clinical scenarios.},
}
@article {pmid36409196,
year = {2023},
author = {Lopez-Mejia, IC and Pijuan, J and Navaridas, R and Santacana, M and Gatius, S and Velasco, A and Castellà, G and Panosa, A and Cabiscol, E and Pinyol, M and Coll, L and Bonifaci, N and Peña, LP and Vidal, A and Villanueva, A and Gari, E and Llobet-Navàs, D and Fajas, L and Matias-Guiu, X and Yeramian, A},
title = {Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness.},
journal = {Molecular oncology},
volume = {17},
number = {1},
pages = {98-118},
pmid = {36409196},
issn = {1878-0261},
mesh = {Humans ; *Antioxidants/metabolism ; Cell Line, Tumor ; Cell Movement ; *Cystadenocarcinoma, Serous/drug therapy/pathology ; *Focal Adhesion Kinase 1/metabolism ; Oxidative Stress ; Phosphorylation ; Reactive Oxygen Species ; Tyrosine/metabolism ; Animals ; Benzamides ; Pyrazines ; Sulfonamides ; },
abstract = {Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer (EC), characterized by its high propensity for metastases. In fact, while endometrioid endometrial carcinoma (EEC), which accounts for 85% of EC, presents a good prognosis, USC is the most frequently fatal. Herein, we used for the first time a peptide-based tyrosine-kinase-activity profiling approach to quantify the changes in tyrosine kinase activation between USC and EEC. Among the tyrosine kinases highly activated in USC, we identified focal adhesion kinase (FAK). We conducted mechanistic studies using cellular models. In a USC cell line, targeting FAK either by inhibitors PF-573228 and defactinib (VS-6063) or by gene silencing limits 3D cell growth and reduces cell migration. Moreover, results from our studies suggest that oxidative stress is increased in USC tumors compared to EEC ones. Reactive oxygen species (ROS) induce tyrosine phosphorylation of FAK and a concomitant tyrosine phosphorylation of paxillin, a mediator of FAK signal transduction. Mechanistically, by tracking hundreds of individual cells per condition, we show that ROS increased cell distance and migration velocity, highlighting the role of ROS-FAK-PAX signaling in cell migration. Both defactinib and ROS scavenger N-acetylcysteine (NAC) revert this effect, pointing toward ROS as potential culprits for the increase in USC cell motility. A proof of concept of the role of FAK in controlling cell growth was obtained in in vivo experiments using cancer-tissue-originated spheroids (CTOS) and a patient-derived orthotopic xenograft model (orthoxenograft/PDOX). Defactinib reduces cell proliferation and protein oxidation, supporting a pro-tumoral antioxidant role of FAK, whereas antioxidant NAC reverts FAK inhibitor effects. Overall, our data points to ROS-mediated FAK activation in USC as being responsible for the poor prognosis of this tumor type and emphasize the potential of FAK inhibition for USC treatment.},
}
@article {pmid36407165,
year = {2022},
author = {Santosa, Y and Harca, AD and Yuwono, A and Hermanto, A and Oliver, MS and Sukmadja, E and Soewardi, R},
title = {Is It Safe to Do Percutaneous Coronary Intervention in Moderate to Severe Chronic Kidney Disease Patients? A Prospective Cohort Study.},
journal = {Cureus},
volume = {14},
number = {10},
pages = {e30312},
pmid = {36407165},
issn = {2168-8184},
abstract = {INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is a common and potentially serious complication of percutaneous coronary intervention (PCI) procedures, as it induces acute kidney injury (AKI), especially in previously diagnosed chronic kidney disease (CKD) patients, particularly in those who also have diabetes. Adequate hydration and using a minimal volume of contrast media are the recommended measures to decrease CI-AKI in CKD patients. A combination of sodium bicarbonate and N-acetylcysteine (NAC) may be a superior strategy for preventing CI-AKI. This study is aimed to evaluate the safety of PCI in moderate to severe CKD patients.<br><br>METHOD: This was a prospective, single-center study, from 2019 to 2021. We included all chronic kidney disease who undergo PCI procedures. The kidney level was measured on admission and 24 hours after the PCI procedure. The patients received 75 meq/500 mL of sodium bicarbonate one to six hours before procedures, oral acetylcysteine 600 mg bid for three days, and rehydration with 1000 ml of normal saline infusion for eight hours in patients without congestive heart failure. SPSS Version 23.0 (IBM SPSS Statistics for Windows, Version 23.0., IBM Corp., Armonk, NY) was used to input and process the data.<br><br>RESULTS: This study included 118 subjects, with baseline characteristics of age 58.77 &#xb1; 9.08 years, 80.5% male, 47.5% diabetic, 50% hypertension, and 59.5% congestive heart failure. From the coronary angiogram, we found most of our subjects (57.6%) had three-vessel disease, 28.8% had two-vessel disease, and 15.6% had one-vessel disease. About 67.8% of subjects used <50 ml of low molecular contrast. The baseline creatinine level was 2.46 &#xb1; 1.04 mg/dL and the estimated glomerular filtration rate (eGFR) was 30 &#xb1; 12.65 mL/min. There were 19 (16.1%) patients with stage 3A CKD, 45 (38.1%) stage 3B, 41 (34.7%) stage 4, and 41 (34.7%) stage 5. The kidney function test after 24 hours of contrast admission showed a creatinine level of 2.37 &#xb1; 1.20 mg/dL (P<0.05) and the eGFR of 34.74 &#xb1; 16.10 mL/min. There was no significant difference in creatinine levels between stage 3A and stage 5 CKD. There was a significant reduction in creatinine in stage 3B CKD, from 1.917 &#xb1; 0.22 to 1.71 &#xb1; 0.37 mg/dL (P = 0.001); and stage 4 CKD, from 2.77 &#xb1; 0.55 to 2.72 &#xb1; 0.94 mg/dL (P = 0.013).<br><br>DISCUSSION: CKD is a risk factor for developing CI-AKI after PCI, which is a marker of poor long-term outcomes. The development of CI-AKI is a strong predictor of post-PCI bleeding, which aggravates hemodynamic instability. The combination of NAC and NaHCO3 exerts a better antioxidative effect, which reduces the harmful short-term and long-term consequences of contrast media. Previous studies revealed the use of low-to-zero contrast media was safer in CKD patients who had undergone PCI. By applying these measures, our study showed a good outcome of PCI with no worsening renal function in CKD patients.<br><br>CONCLUSION: With good prophylaxis measures, such as using minimal volume contrast media, adequate rehydration, and the combination of sodium bicarbonate and acetylcysteine, it is safe to do PCI in moderate to severe CKD patients.},
}
@article {pmid36406192,
year = {2022},
author = {Min, WL and Wang, BF and Liang, BB and Zhang, L and Pan, JY and Huang, Y and Zhao, Y and Lin, S and Zhao, YH and Zhang, SQ and Ma, QY},
title = {A ROS/Akt/NF-κB Signaling Cascade Mediates Epidermal Growth Factor-Induced Epithelial-Mesenchymal Transition and Invasion in Human Breast Cancer Cells.},
journal = {World journal of oncology},
volume = {13},
number = {5},
pages = {289-298},
pmid = {36406192},
issn = {1920-454X},
abstract = {BACKGROUND: As one of the most widely used anti-diabetic drugs for type II diabetes, metformin has been shown to exhibit anti-cancer activity in recent years. Epidermal growth factor (EGF) and its receptor, EGFR, play important roles in cancer metastasis in various tumors, including breast cancer. Epithelial-mesenchymal transition (EMT) is a critical process for cancer invasion and metastasis. In this study, we use EGF as a metastatic inducer to investigate the effect of metformin on cancer cell migration, invasion and EMT.<br><br>METHODS: Human breast cancer MCF-7 cells were exposed to EGF with or without metformin or N-acetyl cysteine (NAC). The effects of metformin on breast cancer cell proliferation were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The production of reactive oxygen species (ROS) was tested using 2,7-dichlorodihydrofluorecein diacetate (DCFH-DA). The migratory and invasive abilities of tumor cells were analyzed using wound healing assay and transwell invasion assay, respectively. The expressions of E-cadherin, N-cadherin and Snail were tested using real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting at mRNA and protein levels. The activation of protein kinase B (Akt) and nuclear factor kappa B (NF-&#x3ba;B) were measured by western blotting.<br><br>RESULTS: Our results showed that metformin inhibited breast cancer cell proliferation in a dose-dependent manner with or without EGF. EGF-induced alterations in cell morphology that are characteristic of EMT were reversed by metformin. Metformin also inhibited the EGF-modulated expression of E-cadherin, N-cadherin and Snail and further suppressed cell invasion and migration. In addition, metformin suppressed EGF-induced phosphorylation of Akt and NF-&#x3ba;B. ROS is involved in EGF-induced cancer invasion and activation of phosphatidylinositol 3-kinase (PI3K)/Akt/NF-&#x3ba;B pathway.<br><br>CONCLUSION: Taken together, these data indicate that metformin suppresses EGF-induced breast cancer cell migration, invasion and EMT through the inhibition of the PI3K/Akt/NF-&#x3ba;B pathway. These results provide a novel mechanism to explain the role of metformin as a potent anti-metastatic agent in breast cancer cells.},
}
@article {pmid36403891,
year = {2023},
author = {Wei, Y and Ni, L and Pan, J and Li, X and Deng, Y and Xu, B and Yang, T and Sun, J and Liu, W},
title = {Methylmercury promotes oxidative stress and autophagy in rat cerebral cortex: Involvement of PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways and attenuation by N-acetyl-L-cysteine.},
journal = {Neurotoxicology and teratology},
volume = {95},
number = {},
pages = {107137},
doi = {10.1016/j.ntt.2022.107137},
pmid = {36403891},
issn = {1872-9738},
mesh = {Animals ; Rats ; *Acetylcysteine/pharmacology ; AMP-Activated Protein Kinases/metabolism/pharmacology ; Autophagy ; Cerebral Cortex ; *Methylmercury Compounds/toxicity ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases ; Tuberous Sclerosis Complex 2 Protein ; },
abstract = {Methylmercury (MeHg) is a potent neurotoxicant that could induce oxidative stress and autophagy. However, the underlying mechanisms through which MeHg affects the central nervous system have not been fully elucidated, and little has been known of the interaction between oxidative stress and autophagy. Therefore, rats were administrated with different MeHg concentrations to evaluate the neurotoxic effects and autophagy in cerebral cortex. Moreover, we have investigated the neuroprotective role of N-acetyl-L-cysteine (NAC) against MeHg-induced neurotoxicity in order to estimate the regulation effects of oxidative stress on autophagy. A total of 64 rats, 40 of which were randomly divided into control and MeHg-treated (4, 8 and 12 μ mol/kg) groups. The remaining 24 rats were divided into control, NAC control (1 mmol/kg), 12 μ mol/kg MeHg, and NAC pretreatment. Administration of 12 μ mol/kg MeHg significantly increased behavioral and pathological abnormalities, and autophagy levels. In addition, the oxidative stress levels increased, together with abnormal expression of autophagy-related molecules. Pretreatment with NAC significantly prevented MeHg-induced oxidative stress and PI3K/AKT/mTOR or AMPK/TSC2/mTOR-mediated autophagy. In conclusion, the present study suggested that oxidative stress can regulate autophagy through PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways. This study provides a theoretical basis for the study and treatment of MeHg-induced neurotoxicity.},
}
@article {pmid36402045,
year = {2023},
author = {Cao, X and Guo, L and Zhou, C and Huang, C and Li, G and Zhuang, Y and Yang, F and Liu, P and Hu, G and Gao, X and Guo, X},
title = {Effects of N-acetyl-l-cysteine on chronic heat stress-induced oxidative stress and inflammation in the ovaries of growing pullets.},
journal = {Poultry science},
volume = {102},
number = {1},
pages = {102274},
pmid = {36402045},
issn = {1525-3171},
mesh = {Animals ; Female ; *Acetylcysteine/pharmacology/metabolism ; *Chickens/physiology ; Ovary/metabolism ; Oxidative Stress ; Antioxidants/metabolism ; Inflammation/veterinary/metabolism ; Heat-Shock Response ; Cytokines/metabolism ; },
abstract = {The aims of this study were to investigate the effects of supplemental N-acetyl-l-cysteine (NAC) on chronic heat stress-induced oxidative stress and inflammation in the ovaries of growing pullets. A total of 120, 12-wk-old, Hy-Line Brown hens were randomly separated into 4 groups with 6 replicates of 5 birds in each group for 21 d. The 4 treatments were as follows: the CON group and CN group were supplemented with basal diet or basal diet with 1 g/kg NAC, respectively; and the HS group and HSN group were heat-stressed groups supplemented with basal diet or basal diet with 1 g/kg NAC, respectively. The results indicated that the ovaries suffered pathological damage due to chronic heat stress and that NAC effectively ameliorated these changes. Compared with the HS group, antioxidant enzyme activities (including SOD, GSH-Px, CAT, and T-AOC) were enhanced, while the MDA contents and the expression levels of HSP70 were decreased in the HSN group. In addition, NAC upregulated the expression levels of HO-1, SOD2, and GST by upregulating the activity of Nrf2 at different time points to mitigate oxidative stress caused by heat exposure. Simultaneously, NAC attenuated chronic heat stress-induced NF-κB pathway activation and decreased the expression levels of the proinflammatory cytokines IL-8, IL-18, TNF-α, IKK-α, and IFN-γ. Cumulatively, our results indicated that NAC could ameliorate chronic heat stress-induced ovarian damage by upregulating the antioxidative capacity and reducing the secretion of proinflammatory cytokines.},
}
@article {pmid36400163,
year = {2023},
author = {Suresh, V and Behera, P and Parida, D and Mohapatra, AP and Das, SK and Kumari, S and Avula, K and Mohapatra, A and Syed, GH and Senapati, S},
title = {Therapeutic role of N-acetyl cysteine (NAC) for the treatment and/or management of SARS-CoV-2-induced lung damage in hamster model.},
journal = {European journal of pharmacology},
volume = {938},
number = {},
pages = {175392},
pmid = {36400163},
issn = {1879-0712},
mesh = {Animals ; Cricetinae ; *SARS-CoV-2 ; Acetylcysteine/pharmacology/therapeutic use ; *COVID-19 ; Interleukin-6 ; Reactive Oxygen Species ; Lung ; },
abstract = {Oxidative stress by reactive oxygen species (ROS) has been hypothesized to be the major mediator of SARS-CoV-2-induced pathogenesis. During infection, the redox homeostasis of cells is altered as a consequence of virus-induced cellular stress and inflammation. In such scenario, high levels of ROS bring about the production of pro-inflammatory molecules like IL-6, IL-1β, etc. that are believed to be the mediators of severe COVID-19 pathology. Based on the known antioxidant, anti-inflammatory, mucolytic and antiviral properties of NAC, it has been hypothesized that NAC will have beneficial effects in COVID-19 patients. In the current study efforts have been made to evaluate the protective effect of NAC in combination with remdesivir against SARS-CoV-2 induced lung damage in the hamster model. The SARS-CoV-2 infected animals were administered with high (500 mg/kg/day) and low (150 mg/kg/day) doses of NAC intraperitoneally with and without remdesivir. Lung viral load, pathology score and expression of inflammatory molecules were checked by using standard techniques. The findings of this study show that high doses of NAC alone can significantly suppress the SARS-CoV-2 mediated severe lung damage (2 fold), but on the contrary, it fails to restrict viral load. Moreover, high doses of NAC with and without remdesivir significantly suppressed the expression of pro-inflammatory genes including IL-6 (4.16 fold), IL-1β (1.96 fold), and TNF-α (5.55 fold) in lung tissues. Together, results of this study may guide future preclinical and clinical attempts to evaluate the efficacy of different doses and routes of NAC administration with or without other drugs against SARS-CoV-2 infection.},
}
@article {pmid36399957,
year = {2022},
author = {Yin, YL and Chen, Y and Ren, F and Wang, L and Zhu, ML and Lu, JX and Wang, QQ and Lu, CB and Liu, C and Bai, YP and Wang, SX and Wang, JZ and Li, P},
title = {Nitrosative stress induced by homocysteine thiolactone drives vascular cognitive impairments via GTP cyclohydrolase 1 S-nitrosylation in vivo.},
journal = {Redox biology},
volume = {58},
number = {},
pages = {102540},
pmid = {36399957},
issn = {2213-2317},
mesh = {Animals ; Humans ; Mice ; *Cognitive Dysfunction/etiology/metabolism ; Cysteine/metabolism ; Endothelial Cells/metabolism ; GTP Cyclohydrolase ; *Hyperhomocysteinemia/chemically induced/metabolism ; Nitric Oxide/metabolism ; Nitrosative Stress ; Homocysteine/analogs &amp; derivatives ; },
abstract = {BACKGROUND: s: Hyperhomocysteinemia (HHcy) is one of risk factors for vascular cognitive impairment (VCI). GTP cyclohydrolase 1 (GCH1) deficiency is critical to oxidative stress in vascular dysfunction. The aim of this study was designed to examine whether HHcy induces VCI through GCH1 S-nitrosylation, a redox-related post-translational modification of cysteine.<br><br>METHODS: The VCI model was induced by feeding mice homocysteine thiolactone (HTL) for 16 consecutive weeks. The cognitive functions were evaluated by step-down avoidance test, passive avoidance step-through task test, and Morris water maze (MWM) test. Protein S-nitrosylation was assayed using a biotin-switch method.<br><br>RESULTS: In cell-free system, nitric oxide (NO) donor induced GCH1 protein S-nitrosylation and decreased GCH1 activity. In endothelial cells, HTL increased GCH1 S-nitrosylation, reduced tetrahydrobiopterin, and induced oxidative stress, which were attenuated by N-acetyl-cysteine, L-N6-1-Iminoethyl-lysine, mutant of GCH1 cysteine 141 to alanine (MT-GCH1) or gene deletion of inducible NO synthase (iNOS). Further, HTL incubation or iNOS overexpression promoted endothelial cellular senescence, but abolished by exogenous expression of MT-GCH1 or pharmacological approaches including N-acetyl-cysteine, L-sepiapterin, and tempol. In wildtype mice, long-term administration of HTL induced GCH1 S-nitrosylation and vascular stiffness, decreased cerebral blood flow, and damaged the cognitive functions. However, these abnormalities induced by HTL administration were rescued by enforced expression of MT-GCH1 or gene knockout of iNOS. In human subjects, GCH1 S-nitrosylation was increased and cognitive functions were impaired in patients with HHcy.<br><br>CONCLUSION: The iNOS-mediated nitrosative stress induced by HTL drives GCH1 S-nitrosylation to induce cerebral vascular stiffness and cognitive impairments.},
}
@article {pmid36396003,
year = {2023},
author = {Elkin, ER and Su, AL and Dou, JF and Colacino, JA and Bridges, D and Padmanabhan, V and Harris, SM and Boldenow, E and Loch-Caruso, R and Bakulski, KM},
title = {Sexually concordant and dimorphic transcriptional responses to maternal trichloroethylene and/or N-acetyl cysteine exposure in Wistar rat placental tissue.},
journal = {Toxicology},
volume = {483},
number = {},
pages = {153371},
pmid = {36396003},
issn = {1879-3185},
support = {P30 AG053760/AG/NIA NIH HHS/United States ; P42 ES017198/ES/NIEHS NIH HHS/United States ; T32 DK071212/DK/NIDDK NIH HHS/United States ; R01 ES025574/ES/NIEHS NIH HHS/United States ; R01 DK107535/DK/NIDDK NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; R01 ES025531/ES/NIEHS NIH HHS/United States ; T32 HD079342/HD/NICHD NIH HHS/United States ; R01 ES028802/ES/NIEHS NIH HHS/United States ; R01 AG055406/AG/NIA NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; R01 AG067592/AG/NIA NIH HHS/United States ; },
mesh = {Female ; Male ; Rats ; Pregnancy ; Animals ; *Trichloroethylene/toxicity/metabolism ; Acetylcysteine/pharmacology ; Rats, Wistar ; Antioxidants/pharmacology ; Placenta/metabolism ; },
abstract = {Numerous Superfund sites are contaminated with the volatile organic chemical trichloroethylene (TCE). In women, exposure to TCE in pregnancy is associated with reduced birth weight. Our previous study reported that TCE exposure in pregnant rats decreased fetal weight and elevated oxidative stress biomarkers in placentae, suggesting placental injury as a potential mechanism of TCE-induced adverse birth outcomes. In this study, we investigated if co-exposure with the antioxidant N-acetylcysteine (NAC) attenuates TCE exposure effects on RNA expression. Timed-pregnant Wistar rats were exposed orally to 480 mg TCE/kg/day on gestation days 6-16. Exposure of 200 mg NAC/kg/day alone or as a pre/co-exposure with TCE occurred on gestation days 5-16 to stimulate antioxidant genes prior to TCE exposure. Tissue was collected on gestation day 16. In male and female placentae, we evaluated TCE- and/or NAC-induced changes to gene expression and pathway enrichment analyses using false discovery rate (FDR) and fold-change criteria. In female placentae, exposure to TCE caused significant differential expression 129 genes while the TCE+NAC altered 125 genes, compared with controls (FDR< 0.05 + fold-change >1). In contrast, in male placentae TCE exposure differentially expressed 9 genes and TCE+NAC differentially expressed 35 genes, compared with controls (FDR< 0.05 + fold-change >1). NAC alone did not significantly alter gene expression in either sex. Differentially expressed genes observed with TCE exposure were enriched in mitochondrial biogenesis and oxidative phosphorylation pathways in females whereas immune system pathways and endoplasmic reticulum stress pathways were differentially expressed in both sexes (FDR<0.05). TCE treatment was differentially enriched for genes regulated by the transcription factors ATF6 (both sexes) and ATF4 (males only), indicating a cellular condition triggered by misfolded proteins during endoplasmic reticulum stress. This study demonstrates novel genes and pathways involved in TCE-induced placental injury and showed antioxidant co-treatment largely did not attenuate TCE exposure effects.},
}
@article {pmid36394765,
year = {2022},
author = {Alomar, FA},
title = {Methylglyoxal in COVID-19-induced hyperglycemia and new-onset diabetes.},
journal = {European review for medical and pharmacological sciences},
volume = {26},
number = {21},
pages = {8152-8171},
doi = {10.26355/eurrev_202211_30169},
pmid = {36394765},
issn = {2284-0729},
mesh = {Humans ; Pyruvaldehyde ; *COVID-19 ; Magnesium Oxide ; SARS-CoV-2 ; *Hyperglycemia ; *Diabetes Mellitus/drug therapy ; Insulin ; },
abstract = {Elevation in blood glucose is common in COVID-19 patients. There is also a high incidence of new-onset diabetes mellitus (DM) in COVID-19 patients following hospitalization. To date, the underlying cause(s) for the hyperglycemia and new-onset DM post-COVID-19 remain poorly understood. In this narrative review, we suggest that upregulation of the cytotoxic and diffusible glycolytic byproduct methylglyoxal (MGO) arising from increased glycolysis in infected pancreatic islets, macrophages, and peripheral cells/tissues is impairing insulin production, secretion, and signaling. This hypothesis is based on our recent discovery that MGO levels were elevated in the plasma of hospitalized COVID-19 patients without and with DM and even higher in COVID-19 patients that succumb to the disease. In pancreatic islets infected with SARS-CoV-2, elevated MGO will disrupt mitochondrial function, perturb Ca2+ homeostasis, and activate the receptors for advanced glycation end-product (RAGE) and nuclear factor kappa B (NF-kB) resulting in impaired insulin production and secretion. In macrophages, excess MG production can diffuse into the vasculature disrupting endothelial function and triggering micro/macro hemorrhage, ischemia, and tissue fibrosis. In skeletal muscle and liver cells, MGO disruption of insulin signaling can blunt glucose absorption. Metformin and N-acetyl cysteine have recently been shown to decrease morbidity and mortality in COVID-19 patients. Here we propose that these agents may be exerting their beneficial effects by chemically reacting with and lowering MGO levels. Knowledge gained from this review should provide novel mechanistic insights for hyperglycemia in COVID-19 patients and strategies to blunt the development of new-onset of DM in post-COVID patients.},
}
@article {pmid36384314,
year = {2023},
author = {Parli, GM and Gales, MA and Gales, BJ},
title = {"N-Acetylcysteine for Obsessive-Compulsive and Related Disorders in Children and Adolescents: A Review".},
journal = {The Annals of pharmacotherapy},
volume = {57},
number = {7},
pages = {847-854},
doi = {10.1177/10600280221138092},
pmid = {36384314},
issn = {1542-6270},
mesh = {Humans ; Adolescent ; Child ; Child, Preschool ; Young Adult ; Adult ; Acetylcysteine/therapeutic use ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; *Obsessive-Compulsive Disorder/drug therapy/diagnosis/psychology ; *Cognitive Behavioral Therapy ; *Drug-Related Side Effects and Adverse Reactions ; Treatment Outcome ; Randomized Controlled Trials as Topic ; },
abstract = {OBJECTIVE: To evaluate clinical data using oral n-acetylcysteine (NAC) in obsessive-compulsive and related disorders (OCDRD) treatment.<br><br>DATA SOURCES: PubMed, Ovid MEDLINE (1946-July 2022), and the Cochrane Library database were searched using the terms NAC, children, adolescent, obsessive-compulsive disorder (OCD), trichotillomania (TTM), excoriation, hoarding disorder, and body dysmorphic disorder. Bibliographies were reviewed for relevant trials and case studies.<br><br>English language, clinical trials, or case studies analyzing NAC use in patients aged 3 to 21 years old with OCDRD as determined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition.<br><br>DATA SYNTHESIS: Three randomized double-blind placebo-controlled trials of NAC in children and adolescents studied 121 patients with OCDRD. Trials assessed symptom severity from baseline to 10 to 12 weeks of NAC therapy. Two OCD trials identified statistically significant improvements, with only 1 trial demonstrating a clear clinically relevant difference from placebo. One trial in TTM found no difference between the NAC and placebo. Adverse effects were mild and included nausea, blurred vision, fatigue, tremor, and sweats. N-acetylcysteine titrated to 2400 or 2700 mg/day in divided doses was the most studied regimen.<br><br>Many OCDRD patients fail to completely respond to first-line treatment with cognitive behavioral therapy (CBT) and/or selective serotonin reuptake inhibitors (SSRIs) leaving practitioners with few additional treatment options. Preliminary efficacy and safety data are presented in this review.<br><br>CONCLUSIONS: Limited evidence suggests children and adolescents with OCD refractory to SSRIs or CBT may benefit from NAC augmentation.},
}
@article {pmid36383882,
year = {2022},
author = {Alavinejad, P and Tran, NN and Eslami, O and Shaarawy, OE and Hormati, A and Seiedian, SS and Parsi, A and Ahmed, MH and Behl, NS and Abravesh, AA and Tran, QT and Vignesh, S and Salman, S and Sakr, N and Ara, TF and Hajiani, E and Hashemi, SJ and Patai, &#xc1;V and Butt, AS and Lee, SH},
title = {ORAL N-ACETYL CYSTEINE VERSUS RECTAL INDOMETHACIN FOR PREVENTION OF POST ERCP PANCREATITIS: A MULTICENTER MULTINATIONAL RANDOMIZED CONTROLLED TRIAL.},
journal = {Arquivos de gastroenterologia},
volume = {59},
number = {4},
pages = {508-512},
doi = {10.1590/S0004-2803.202204000-90},
pmid = {36383882},
issn = {1678-4219},
abstract = {BACKGROUND: This multicenter multinational RCT designed to compare the efficacy of suppository indomethacin and NAC for prevention of PEP.<br><br>METHODS: During a 6-month period, all of the ERCP cases in seven referral centers were randomly assigned to receive either 1200 mg oral NAC, indomethacin suppository 100 mg, 1200 mg oral NAC plus indomethacin suppository 100 mg or placebo 2 hours before ERCP. The primary outcomes were the rate and severity of any PEP.<br><br>RESULTS: A total of 432 patients included (41.4% male). They were originally citizens of 6 countries (60.87% Caucasian). They were randomly allocated to receive either NAC (group A, 84 cases), rectal indomethacin (group B, 138 cases), NAC + rectal indomethacin (group C, 115 cases) or placebo (group D, 95 cases). The rate of PEP in groups A, B and C in comparison with placebo were 10.7%, 17.4%, 7.8% vs 20% (P=0.08, 0.614 &amp; 0.01 respectively). The NNT for NAC, indomethacin and NAC + indomethacin was 11, 38 and 8 respectively.<br><br>CONCLUSION: Oral NAC is more effective than rectal indomethacin when compared to placebo for prevention of PEP and the combination of NAC and Indomethacin had the lowest incidence of PEP and may have synergistic effect in preventing of PEP (IRCT20201222049798N1; 29/12/2020).},
}
@article {pmid36382021,
year = {2022},
author = {Soleymani, M and Masoudkabir, F and Shabani, M and Vasheghani-Farahani, A and Behnoush, AH and Khalaji, A},
title = {Updates on Pharmacologic Management of Microvascular Angina.},
journal = {Cardiovascular therapeutics},
volume = {2022},
number = {},
pages = {6080258},
pmid = {36382021},
issn = {1755-5922},
mesh = {Humans ; Female ; *Microvascular Angina/diagnosis/drug therapy ; *Coronary Artery Disease ; Coronary Angiography ; Angiotensin Receptor Antagonists/therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; },
abstract = {Microvascular angina (MVA), historically called cardiac syndrome X, refers to angina with nonobstructive coronary artery disease. This female-predominant cardiovascular disorder adds considerable health-related costs due to repeated diagnostic angiography and frequent hospital admissions. Despite the high prevalence of this diagnosis in patients undergoing coronary angiography, it is still a therapeutic challenge for cardiologists. Unlike obstructive coronary artery disease, with multiple evidence-based therapies and management guidelines, little is known regarding the management of MVA. During the last decade, many therapeutic interventions have been suggested for the treatment of MVA. However, there is a lack of summarization tab and update of current knowledge about pharmacologic management of MVA, mostly due to unclear pathophysiology. In this article, we have reviewed the underlying mechanisms of MVA and the outcomes of various medications in patients with this disease. Contrary to vasospastic angina in which normal angiogram is observed as well, nitrates are not effective in the treatment of MVA. Beta-blockers and calcium channel blockers have the strongest evidence of improving the symptoms. Moreover, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, estrogen, and novel antianginal drugs has had promising outcomes. Investigations are still ongoing for vitamin D, omega-3, incretins, and n-acetyl cysteine, which have resulted in beneficial initial outcomes. We believe that the employment of the available results and results of the future large-scale trials into cardiac care guidelines would help reduce the global cost of cardiac care tremendously.},
}
@article {pmid36374790,
year = {2022},
author = {Flores, A and Moyano, P and Sola, E and García, JM and García, J and Anadon, MJ and Frejo, MT and Naval, MV and Fernadez, MC and Pino, JD},
title = {Single and repeated bisphenol A treatment induces ROS, Aβ and hyperphosphorylated-tau accumulation, and insulin pathways disruption, through HDAC2 and PTP1B overexpression, leading to SN56 cholinergic apoptotic cell death.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {170},
number = {},
pages = {113500},
doi = {10.1016/j.fct.2022.113500},
pmid = {36374790},
issn = {1873-6351},
mesh = {*tau Proteins/metabolism ; Reactive Oxygen Species/metabolism ; Histone Deacetylase 2/metabolism ; Phosphoric Monoester Hydrolases/metabolism ; Amyloid beta-Peptides/metabolism ; Cholinergic Neurons/metabolism ; Apoptosis ; Cholinergic Agents/metabolism ; *Insulins/metabolism ; Bisphenol A Compounds ; },
abstract = {Bisphenol-A (BPA), a polymer component extensively used, produces memory and learning alterations after acute and long-term exposure. However, the mechanisms are not well known. Cortex and hippocampus neuronal networks control cognitive functions, which are innervated by basal forebrain cholinergic neurons (BFCN), and their neurodegeneration induces cognitive dysfunctions. Wild type or protein tyrosine phosphatase 1B (PTP1B), histone deacetylase 2 (HDAC2), tau or β amyloid precursor protein (βAPP) silenced SN56 cells treated with BPA (0.001 μM-100 μM) with or without N-acetylcysteine (NAC; 1 mM), following 1 and 14 days, were used, as a model of BFCN to determine the insulin pathway dysfunction, oxidative stress (OS) generation and amyloid-β (Aβ) and tau proteins accumulation involvement in the BCFN cell death induction, as a possible mechanism that could produce the cognitive disorders reported. BPA-induced BFCN cell death, after 24 h and 14 days of treatment, through insulin pathway dysfunction, OS generation, mediated by NRF2 pathway downregulation, and Aβ and tau proteins accumulation, which were in turn induced by HDAC2 and PTP1B overexpression. This is relevant information to explain the BFCN neurodegeneration mechanisms that could trigger the neurodegeneration in the rest of the regions innerved by them, leading to cognitive disorders.},
}
@article {pmid36374720,
year = {2023},
author = {Hsu, SS and Lin, YS and Chio, LM and Liang, WZ},
title = {Evaluation of the mycotoxin patulin on cytotoxicity and oxidative stress in human glioblastoma cells and investigation of protective effect of the antioxidant N-acetylcysteine (NAC).},
journal = {Toxicon : official journal of the International Society on Toxinology},
volume = {221},
number = {},
pages = {106957},
doi = {10.1016/j.toxicon.2022.106957},
pmid = {36374720},
issn = {1879-3150},
mesh = {Humans ; *Patulin/toxicity ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology/metabolism ; *Glioblastoma/drug therapy/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; },
abstract = {Mycotoxins are secondary metabolites produced by various kinds of fungi that can induce disease in humans. The fungal species Penicillium expansum produces patulin (C7H6O4), a polyketide lactone mycotoxin found in fruits. Patulin is classified as noncarcinogen; however, recently, it has been associated with harmful effects on the central nervous system. Patulin's toxic action has been established in various brain models; however, its effect on human glioblastoma remains elusive. This study explores whether patulin induces cytotoxicity through oxidative stress in DBTRG-05MG human glioblastoma cells. This study also evaluates whether the antioxidant N-acetylcysteine (NAC) protects against patulin-induced cytotoxicity. In DBTRG-05MG cells, patulin concentration (10-60 μM) dependently induced cytotoxicity. Concerning oxidative stress, patulin (10 and 20 μM) increased the production of intracellular reactive oxygen species (ROS) but depleted reduced glutathione (GSH) contents and regulated the expressions of antioxidant-related proteins (Nrf2 and HO-1). Furthermore, patulin induced cytotoxicity via modulation of apoptosis-related protein expressions (Bax, cleaved caspase-9, and cleaved caspase-3). These cytotoxic responses were partially reversed via pretreatment with NAC (10 μM). In summary, these data help us understand the toxicology of patulin in human glioblastoma and evaluate whether NAC could clinically reduce patulin-affected brain damage.},
}
@article {pmid36364008,
year = {2022},
author = {Zhang, Y and Tang, Y and Tang, X and Wang, Y and Zhang, Z and Yang, H},
title = {Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression.},
journal = {Molecules (Basel, Switzerland)},
volume = {27},
number = {21},
pages = {},
pmid = {36364008},
issn = {1420-3049},
support = {2020J01176, 2021J02028 and 2022J01172//Fujian Natural Science Foundation/ ; 2021G02023 and 2022G023//Key Projects of Scientific and Technological Innovation in Fujian Province/ ; 2020L3008//Special Funds of the Central Government Guilding Local Science and Technology Development/ ; I202003009 and I202102008//Innovation and Entrepreneurship Project of Fujian Normal University/ ; },
mesh = {Male ; Humans ; Reactive Oxygen Species/metabolism ; Paclitaxel/pharmacology ; Caspase 3/genetics/pharmacology ; Apoptosis ; *Prostatic Neoplasms/drug therapy/genetics/pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/pharmacology ; *Antineoplastic Agents/pharmacology ; },
abstract = {Prostate cancer (PCa) is the most common malignancy to endanger the health of male genitourinary system. Clinically, paclitaxel (PTX) (C47H51NO14), a diterpene alkaloid, is commonly used as an effective natural antineoplastic drug during the treatment of PCa. However, the mechanism and pathway involved in the function of PTX are poorly understood. In the current study, we employed the CCK-8 assay, revealing that PTX can inhibit the survival and induce the apoptosis of PC3M cells (a human prostate cancer cell line) in a concentration-dependent manner. Reactive oxygen species (ROS), as a metabolic intermediate produced by the mitochondrial respiratory chain, are highly accumulated under the PTX treatment, which results in a sharp decrease of the mitochondrial membrane potential in PC3M cells. Additionally, the migration and invasion of PC3M cells are weakened due to PTX treatment. Further analysis reveals that N-acetylcysteine (NAC), which functions as an antioxidant, not only rescues the decreased mitochondrial membrane potential induced by the abnormal ROS level, but also restores the migration and invasion of PC3M cells. In a subsequent exploration of the detailed mechanism, we found that hypoxia-inducible factor (HIF)-1α works as a downstream gene that can respond to the increased ROS in PC3M cells. Under PTX treatment, the expression levels of HIF-1α mRNA and protein are significantly increased, which stimulate the activation of JNK/caspase-3 signaling and promote the apoptosis of PC3M cells. In summary, we demonstrate that PTX regulates the expression of HIF-1α through increased ROS accumulation, thereby promoting the activation of JNK/caspase-3 pathway to induce the apoptosis of PCa cells. This study provides new insights into the mechanism of antineoplastic action of taxanes and unveils the clinical benefit of the ROS-HIF-1α signaling pathway, which may offer a potential therapeutic target to prevent the development of PCa.},
}
@article {pmid36362692,
year = {2022},
author = {Mylonas, KS and Sarantis, P and Kapelouzou, A and Karamouzis, MV and Kapetanakis, EI and Kontzoglou, K and Iliopoulos, DC and Nikiteas, N and Schizas, D},
title = {Mechanosensitive Stem-Cell Genes and Klotho in Atherosclerotic Aortas: Regulating Spatially Deranged Expression Patterns Using Colchicine Regimens.},
journal = {Journal of clinical medicine},
volume = {11},
number = {21},
pages = {},
pmid = {36362692},
issn = {2077-0383},
support = {N/A//Hellenic Atherosclerosis Society/ ; N/A//Hellenic Surgical Society/ ; },
abstract = {AIMS: Inflammatory dysregulation of mechanosensitive developmental genes may be central to atherogenesis. In the present seven-week model, we utilized colchicine regimens to curtail aortic atherogenesis in New Zealand White rabbits. We also explored the effect of colchicine regimens on atheroprotective (Klotho, HOXA5, NOTCH1, and OCT4) and proatherogenic (HIF1a, SOX2, BMP4, and NANOG) genes.<br><br>METHODS: The control (n = 6) and group A (n = 6) received standard and cholesterol-enriched chow, respectively. Groups B (n = 8) and C (n = 8) were fed hypercholesterolemic diet and were treated with colchicine plus fenofibrate or N-acetylcysteine (NAC), respectively.<br><br>RESULTS: Group A developed significantly greater thoracic and abdominal aortic atherosclerosis compared to groups B (p < 0.001) and C (p < 0.001). Combining colchicine with NAC resulted in stronger atheroprotection both in the thoracic and the abdominal aorta. In group A thoracic aortas, Klotho was downregulated compared to controls (95% CI: 1.82-15.76). Both colchicine regimens upregulated Klotho back to baseline levels (p < 0.001). Colchicine/fenofibrate also significantly upregulated thoracic NOTCH1 compared to controls (95% CI: -8.09 to -0.48). Colchicine/NAC significantly reduced thoracic NANOG expression compared to hyperlipidemic diet alone (95% CI: 0.37-8.29). In the abdominal aorta, hypercholesterolemic diet resulted in significant downregulation of HOXA5 (95% CI: 0.03-2.74) which was reversed with colchicine/NAC back to baseline (95% CI: -1.19 to 1.51). Colchicine/fenofibrate downregulated HIF1a compared to baseline (95% CI: 0.83-6.44). No significant differences were noted in terms of BMP4, SOX2, and OCT4.<br><br>CONCLUSIONS: Overall, the aortic expression pattern of mechanosensitive genes seems to be spatially influenced by a hyperlipidemic diet and can be modified using colchicine-based therapy.},
}
@article {pmid36359827,
year = {2022},
author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Chovatiya, N and Huerta-Yepez, S and Ni, W and Mackay, S and Zhou, J and Maharaj, D and Malarkannan, S and Jewett, A},
title = {The Potential Role of Cytotoxic Immune Effectors in Induction, Progression and Pathogenesis of Amyotrophic Lateral Sclerosis (ALS).},
journal = {Cells},
volume = {11},
number = {21},
pages = {},
pmid = {36359827},
issn = {2073-4409},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/metabolism/pathology ; *CD8-Positive T-Lymphocytes/metabolism ; Cytokines/metabolism ; Granzymes/metabolism ; Leukocytes, Mononuclear/metabolism ; *T-Lymphocytes, Cytotoxic/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neuron system. The causes of ALS are heterogeneous, and are only partially understood. We studied different aspects of immune pathogenesis in ALS and found several basic mechanisms which are potentially involved in the disease. Our findings demonstrated that ALS patients' peripheral blood contains higher proportions of NK and B cells in comparison to healthy individuals. Significantly increased IFN-γ secretion by anti-CD3/28 mAbs-treated peripheral blood mononuclear cells (PBMCs) were observed in ALS patients, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism for ALS progression. In addition, elevated granzyme B and perforin secretion at a single cell level, and increased cytotoxicity and secretion of IFN-γ by patients' NK cells under specific treatment conditions were also observed. Increased IFN-γ secretion by ALS patients' CD8+ T cells in the absence of IFN-γ receptor expression, and increased CD8+ T cell effector/memory phenotype as well as increased granzyme B at the single cell level points to the CD8+ T cells as potential cells in targeting motor neurons. Along with the hyper-responsiveness of cytotoxic immune cells, significantly higher levels of inflammatory cytokines including IFN-γ was observed in peripheral blood-derived serum of ALS patients. Supernatants obtained from ALS patients' CD8+ T cells induced augmented cell death and differentiation of the epithelial cells. Weekly N-acetyl cysteine (NAC) infusion in patients decreased the levels of many inflammatory cytokines in peripheral blood of ALS patient except IFN-γ, TNF-α, IL-17a and GMCSF which remained elevated. Findings of this study indicated that CD8+ T cells and NK cells are likely culprits in targeting motor neurons and therefore, strategies should be designed to decrease their function, and eliminate the aggressive nature of these cells. Analysis of genetic mutations in ALS patient in comparison to identical twin revealed a number of differences and similarities which may be important in the pathogenesis of the disease.},
}
@article {pmid36359406,
year = {2022},
author = {Aiyer, A and Das, T and Whiteley, GS and Glasbey, T and Kriel, FH and Farrell, J and Manos, J},
title = {The Efficacy of an N-Acetylcysteine-Antibiotic Combination Therapy on Achromobacter xylosoxidans in a Cystic Fibrosis Sputum/Lung Cell Model.},
journal = {Biomedicines},
volume = {10},
number = {11},
pages = {},
pmid = {36359406},
issn = {2227-9059},
support = {IMCRC/WLY/08052019.1 and CT20584//This research was funded by COMMERCIAL DEVELOPMENT &amp; INDUSTRY PARTNERSHIP, grant number CT20584-University of Sydney and Whiteley Corporation and DEPARTMENT OF IN-DUSTRY, INNOVATION AND SCIENCE (Innovative Manufacturing CRC Ltd.) and WHITELEY CORPORATION/ ; },
abstract = {Cystic fibrosis (CF) is a disorder causing dysfunctional ion transport resulting in the accumulation of viscous mucus. This environment fosters a chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans, a gram-negative aerobic bacillus, has been increasingly associated with antibiotic resistance and chronic colonisation in CF. In this study, we aimed to create a reproducible model of CF infection using an artificial sputum medium (ASMDM-1) with bronchial (BEAS-2B) and macrophage (THP-1) cells to test A. xylosoxidans infection and treatment toxicity. This study was conducted in three distinct stages. First, the tolerance of BEAS-2B cell lines and two A. xylosoxidans strains against ASMDM-1 was optimised. Secondly, the cytotoxicity of combined therapy (CT) comprising N-acetylcysteine (NAC) and the antibiotics colistin or ciprofloxacin was tested on cells alone in the sputum model in both BEAS-2B and THP-1 cells. Third, the efficacy of CT was assessed in the context of a bacterial infection within the live cell/sputum model. We found that a model using 20% ASMDM-1 in both cell populations tolerated a colistin-NAC-based CT and could significantly reduce bacterial loads in vitro (~2 log10 CFU/mL compared to untreated controls). This pilot study provides the foundation to study other bacterial opportunists that infect the CF lung to observe infection and CT kinetics. This model also acts as a springboard for more complex co-culture models.},
}
@article {pmid36357979,
year = {2023},
author = {Li, ZQ and Zhang, C and Fan, S and Wang, LL and Jiang, Y and Li, HJ},
title = {Evidence for exposure biomarkers in dictamnine-induced liver injury resulting from metabolic activation in vitro and in mice.},
journal = {Journal of applied toxicology : JAT},
volume = {43},
number = {5},
pages = {662-679},
doi = {10.1002/jat.4414},
pmid = {36357979},
issn = {1099-1263},
mesh = {Mice ; Animals ; Activation, Metabolic ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Microsomes, Liver/metabolism ; Acetylcysteine ; Glutathione/metabolism ; Quinolines ; },
abstract = {Dictamnine (DTN), a furoquinoline alkaloid isolated from Dictamni Cortex, is responsible for the liver injury caused by Dictamni Cortex and the preparations. Discovering new biomarkers with high specificity and sensitivity for diagnosis and tracing the source of DTN-induced liver injury is urgently needed. Considering that metabolic activation of DTN has been suggested as a primary trigger initiating hepatotoxicity, the present study aimed to investigate the bio-activation process of DTN in vitro and in mice and to explore whether the adducts could be developed as exposure biomarkers. When trapping with N-acetyl-cysteine (NAC) and glutathione (GSH) in mouse liver microsomes and CYP3A4 overexpressed L02 cells, two isomers of DTN-NAC adducts were detected in both systems and one DTN-GSH adduct was found in mouse liver microsomes. As expected, one DTN-NAC adduct was also found in plasma and bile of mice with liver injury after DTN exposure. Moreover, mouse liver microsomes were used to simulate the conjugation of serum albumin with metabolically activated DTN. The sole modified peptide [25] DAHKSEVAHR[34] was found, and the oxidative metabolites of DTN might bind to the side chain amino of albumin at Arg34. The above findings not only provided confirmative evidence that DTN was metabolically activated to induce liver injury but also suggested that the adducts had the potential to be developed as exposure biomarkers of DTN-induced liver injury.},
}
@article {pmid36354958,
year = {2022},
author = {Kandel, R and Singh, KP},
title = {Higher Concentrations of Folic Acid Cause Oxidative Stress, Acute Cytotoxicity, and Long-Term Fibrogenic Changes in Kidney Epithelial Cells.},
journal = {Chemical research in toxicology},
volume = {35},
number = {11},
pages = {2168-2179},
pmid = {36354958},
issn = {1520-5010},
support = {R15 DK121362/DK/NIDDK NIH HHS/United States ; },
mesh = {Humans ; Animals ; Mice ; *Folic Acid/pharmacology ; *Antioxidants ; Reactive Oxygen Species ; Oxidative Stress ; Kidney ; Acetylcysteine ; Epithelial Cells ; Fibrosis ; },
abstract = {Kidney fibrosis is a common step during chronic kidney disease (CKD), and its incidence has been increasing worldwide. Aberrant recovery after repeated acute kidney injury leads to fibrosis. The mechanism of fibrogenic changes in the kidney is not fully understood. Folic acid-induced kidney fibrosis in mice is an established in vivo model to study kidney fibrosis, but the mechanism is poorly understood. Moreover, the effect of higher concentrations of folic acid on kidney epithelial cells in vitro has not yet been studied. Oxidative stress is a common property of nephrotoxicants. Therefore, this study evaluated the role of folic acid-induced oxidative stress in fibrogenic changes by using the in vitro renal proximal tubular epithelial cell culture model. To obtain comprehensive and robust data, three different cell lines derived from human and mouse kidney epithelium were treated with higher concentrations of folic acid for both acute and long-term durations, and the effects were determined at the cellular and molecular levels. The result of cell viability by the MTT assay and the measurement of reactive oxygen species (ROS) levels by the DCF assay revealed that folic acid caused cytotoxicity and increased levels of ROS in acute exposure. The cotreatment with antioxidant N-acetyl cysteine (NAC) protected the cytotoxic effect, suggesting the role of folic acid-induced oxidative stress in cytotoxicity. In contrast, the long-term exposure to folic acid caused increased growth, DNA damage, and changes in the expression of marker genes for EMT, fibrosis, oxidative stress, and oxidative DNA damage. Some of these changes, particularly the acute effects, were abrogated by cotreatment with antioxidant NAC. In summary, the novel findings of this study suggest that higher concentrations of folic acid-induced oxidative stress act as the driver of cytotoxicity as an acute effect and of fibrotic changes as a long-term effect in kidney epithelial cells.},
}
@article {pmid36352994,
year = {2022},
author = {Parvizrad, R and Marghamlki, EG and Nikfar, S and Dermani, SK},
title = {Effects of melatonin and N-acetylcysteine on aluminum phosphide poisoning in rats.},
journal = {Journal of family medicine and primary care},
volume = {11},
number = {8},
pages = {4500-4504},
pmid = {36352994},
issn = {2249-4863},
abstract = {INTRODUCTION: Aluminum phosphide (ALP) poisoning is one of the deadliest types of poisoning in the world. The antioxidant properties of melatonin and N-acetylcysteine and their effects on reducing cell death have been identified. The aim of this study was to evaluate the effects of N-acetylcysteine and melatonin in the treatment of aluminum phosphide poisoning in rats.<br><br>MATERIALS AND METHODS: Fifty male Wistar rats weighing 200-250 g were tested in five groups of ten. The first group was the control group; the second group received (10 mg/kg) of ALP, the third group received (10 mg/kg) of ALP and (10 mg/kg) of melatonin, the fourth group received (10 mg/kg) of ALP and (10 mg/kg) of N-acetylcysteine, and the last group received (10 mg/kg) of ALP and (10 mg/kg) of melatonin and N-acetylcysteine. The plasma of samples was isolated, and the activity of antioxidant enzymes (glutathione S-transferase (GST), Superoxide dismutase (SOD), and catalase (CAT)) was analyzed.<br><br>RESULTS: The concentrations of CAT, GST, Glutathione, GSH were decreased in plasma, liver, and kidneys of mice treated with aluminum phosphide; also, the concentrations of aspartate aminotransferase (AST), ALT, and AlK were increased (P < 0.05), while the activity of SOD did not change significantly (P > 0.05). Treatment with N-acetylcysteine and melatonin led to an increase in the activity of CAT, GST, and GSH in plasma, liver, and kidney. After the administration of N-acetylcysteine and melatonin to mice, the levels of all enzymes were close to normal, and the mice survived for 12-15 hours after administration.<br><br>DISCUSSION: The administration of N-acetylcysteine (NAC) and melatonin at a dose of 10 mg/kg improves hepatic manifestations and prevents liver necrosis; also, they are considered potential therapeutic agents in the treatment of this poisoning.},
}
@article {pmid36345724,
year = {2022},
author = {Zalachoras, I and Ramos-Fernández, E and Hollis, F and Trovo, L and Rodrigues, J and Strasser, A and Zanoletti, O and Steiner, P and Preitner, N and Xin, L and Astori, S and Sandi, C},
title = {Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort.},
journal = {eLife},
volume = {11},
number = {},
pages = {},
pmid = {36345724},
issn = {2050-084X},
mesh = {Humans ; Male ; Rats ; Animals ; *Nucleus Accumbens/physiology ; *Motivation ; Antioxidants/metabolism ; Reward ; Glutathione/metabolism ; },
abstract = {Emerging evidence is implicating mitochondrial function and metabolism in the nucleus accumbens in motivated performance. However, the brain is vulnerable to excessive oxidative insults resulting from neurometabolic processes, and whether antioxidant levels in the nucleus accumbens contribute to motivated performance is not known. Here, we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation. Using proton magnetic resonance spectroscopy at ultra-high field in both male humans and rodent populations, we establish that higher accumbal GSH levels are highly predictive of better, and particularly, steady performance over time in effort-related tasks. Causality was established in in vivo experiments in rats that, first, showed that downregulating GSH levels through micro-injections of the GSH synthesis inhibitor buthionine sulfoximine in the nucleus accumbens impaired effort-based reward-incentivized performance. In addition, systemic treatment with the GSH precursor N-acetyl-cysteine increased accumbal GSH levels in rats and led to improved performance, potentially mediated by a cell-type-specific shift in glutamatergic inputs to accumbal medium spiny neurons. Our data indicate a close association between accumbal GSH levels and an individual's capacity to exert reward-incentivized effort over time. They also suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.},
}
@article {pmid36344940,
year = {2022},
author = {Liao, Y and Wu, Y and Zi, K and Shen, Y and Wang, T and Qin, J and Chen, L and Chen, M and Liu, L and Li, W and Zhou, H and Xiong, S and Wen, F and Chen, J},
title = {The effect of N-acetylcysteine in patients with non-cystic fibrosis bronchiectasis (NINCFB): study protocol for a multicentre, double-blind, randomised, placebo-controlled trial.},
journal = {BMC pulmonary medicine},
volume = {22},
number = {1},
pages = {401},
pmid = {36344940},
issn = {1471-2466},
mesh = {Humans ; Acetylcysteine/therapeutic use ; Quality of Life ; Prospective Studies ; RNA, Ribosomal, 16S ; Anti-Bacterial Agents ; *Bronchiectasis/complications ; Double-Blind Method ; *Cystic Fibrosis/complications ; Fibrosis ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; },
abstract = {BACKGROUND: N-acetylcysteine (NAC), which is specifically involved in airway mucus clearance and antioxidation, is recommended by the treatment guideline for non-cystic fibrosis bronchiectasis (NCFB). However, there is little clinical evidence of its long-term efficacy concerning quality of life (QoL) and exacerbation in patients with NCFB. In addition, the influences of NAC on airway bacterial colonization, chronic inflammation and oxidative stress in NCFB are also unclear.<br><br>METHODS: NINCFB is a prospective, multicentre, double-blind, randomised, placebo-controlled trial that will recruit 119 patients with NCFB and randomly divide them into an NAC group (n&#xa0;=&#x2009;79) and a control group (n&#xa0;=&#x2009;40). Participants in the NAC group will receive 600&#x2009;mg oral NAC twice daily for 52&#x2009;weeks, while patients in the control group will receive 600&#x2009;mg placebo twice daily for 52&#x2009;weeks. The information at baseline will be collected once participants are enrolled. The primary endpoints are the changes in St George's Respiratory Questionnaire scores and the number of exacerbations in 52&#x2009;weeks. The secondary endpoints are the 16S rRNA of sputum and the levels of inflammatory factors and oxidative stressors in sputum and serum. Other data related to radiography, lung function tests, number of oral and/or intravenous antibiotic therapies and adverse events (AEs) will also be analysed. Further subgroup analysis distinguished by the severity of disease, severity of lung function, airway bacterial colonization and exacerbation frequency will be performed.<br><br>DISCUSSION: The objective of this study is to determine the long-term efficacy of NAC on QoL and exacerbation of NCFB and to explore the effectiveness of NAC for antibiosis, anti-inflammation and antioxidation in NCFB. The study results will provide high-quality clinical proof for the revision and optimization of treatment guidelines and for expert consensus on NCFB treatment.<br><br>TRIAL REGISTRATION: The trial was registered on the Chinese Clinical Trial Register at April 11, 2020 (chictr.org.cn , ChiCTR2000031817).},
}
@article {pmid36341071,
year = {2022},
author = {Akibekov, OS and Syzdykova, AS and Lider, LA and Zhumalin, AK and Baibolin, ZK and Zhagipar, FS and Akanova, ZZ and Ibzhanova, AA and Gajimuradova, AM},
title = {Hematological, biochemical, and serological parameters of experimentally infected rabbits with Trichinella nativa and Trichinella spiralis for early identification of trichinellosis.},
journal = {Veterinary world},
volume = {15},
number = {9},
pages = {2285-2292},
pmid = {36341071},
issn = {0972-8988},
abstract = {BACKGROUND AND AIM: Trichinellosis remains a dangerous disease for humans and animals, which can lead to a lethal outcome. The study of specific body reactions in response to invasion by different types of Trichinella can help in the early diagnosis of the disease. This study aimed to investigate the hematological, biochemical, and serological characteristics of rabbits experimentally infected with trichinellosis, as well as the possibility of using changes in these parameters at various disease stages for early hematological, biochemical, and serological diagnosis of trichinellosis.<br><br>MATERIALS AND METHODS: Three groups of rabbits were orally infected with Trichinella nativa and Trichinella spiralis derived from encysted T. spirtalis larvae in pork muscle samples. The first and second groups were infected with T. nativa and T. spiralis, respectively, while the third group served as control by receiving a physiological solution. An ADVIA 2120i automatic hematology analyzer with a blood smear staining module was used to determine the hematological parameters of rabbits. Antigens were used in an enzyme-linked immunosorbent assay (ELISA) to detect antibodies in the sera of infected rabbits that were supernatants containing excretory-secretory antigens (ES-Ag) and somatic antigen (S-Ag).<br><br>RESULTS: The detection of biochemical responses to the invasion of T. nativa and T. spiralis isolates was detected and hematological parameters were featured in two cases. Trichinella nativa increased the number of erythrocytes, neutrophils, eosinophils, monocytes, basophils, and thrombocytes on day 7 in rabbits. Creatine kinase (CK) is regarded as the most important indicator for the early detection of parasite invasion. Blood biochemistry showed no active response to T. spiralis infection. However, counts of erythrocytes, neutrophils, lymphocytes, and CK rose significantly. In both color indicators, the number of thrombocytes decreased. Enzyme-linked immunosorbent assay with ES-Ag and S-Ag of these isolates demonstrated the ability to detect antibodies as early as 7 days after infection, with a significant increase in the marker up to 70 days.<br><br>CONCLUSION: On the 7[th] day after infection, blood tests of infected animals revealed CK-N-acetyl-cysteine (18.2%) and neutrophils (43%) when infected with T. nativa and neutrophils (26.7%) and lymphocytes (20%) when infected with T. spiralis. These indicators may serve as specific parameters for the early detection of Trichinella spp. invasion.},
}
@article {pmid36338342,
year = {2022},
author = {Hsu, YC and Chuang, HC and Tsai, KL and Tu, TY and Shyong, YJ and Kuo, CH and Liu, YF and Shih, SS and Lin, CL},
title = {Administration of N-Acetylcysteine to Regress the Fibrogenic and Proinflammatory Effects of Oxidative Stress in Hypertrophic Ligamentum Flavum Cells.},
journal = {Oxidative medicine and cellular longevity},
volume = {2022},
number = {},
pages = {1380353},
pmid = {36338342},
issn = {1942-0994},
mesh = {Humans ; *Ligamentum Flavum/metabolism ; Acetylcysteine/pharmacology/metabolism ; Vimentin/metabolism ; Hydrogen Peroxide/metabolism ; Hypertrophy/drug therapy/metabolism ; Transforming Growth Factor beta/metabolism ; Collagen Type I/metabolism ; Oxidative Stress ; },
abstract = {Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal stenosis (LSS). In hypertrophic ligamentum flavum (LF) cells, oxidative stress activates intracellular signaling and induces the expression of inflammatory and fibrotic markers. This study explored whether healthy and hypertrophic LF cells respond differently to oxidative stress, via examining the levels of phosphorylated p38 (p-p38), inducible nitric oxide synthase (iNOS), and α-smooth muscle actin (α-SMA). Furthermore, the efficacy of N-acetylcysteine (NAC), an antioxidant, in reversing the fibrogenic and proinflammatory effects of oxidative stress in hypertrophic LF cells was investigated by assessing the expression levels of p-p38, p-p65, iNOS, TGF-β, α-SMA, vimentin, and collagen I under H2O2 treatment with or without NAC. Under oxidative stress, p-p38 increased significantly in both hypertrophic and healthy LF cells, and iNOS was elevated in only the hypertrophic LF cells. This revealed that oxidative stress negatively affected both hypertrophic and healthy LF cells, with the hypertrophic LF cells exhibiting more active inflammation than did the healthy cells. After H2O2 treatment, p-p38, p-p65, iNOS, TGF-β, vimentin, and collagen I increased significantly, and NAC administration reversed the effects of oxidative stress. These results can form the basis of a novel therapeutic treatment for LFH using antioxidants.},
}
@article {pmid36337710,
year = {2022},
author = {Liu, LF and Hu, Y and Liu, YN and Shi, DW and Liu, C and Da, X and Zhu, SH and Zhu, QY and Zhang, JQ and Xu, GH},
title = {Reactive oxygen species contribute to delirium-like behavior by activating CypA/MMP9 signaling and inducing blood-brain barrier impairment in aged mice following anesthesia and surgery.},
journal = {Frontiers in aging neuroscience},
volume = {14},
number = {},
pages = {1021129},
pmid = {36337710},
issn = {1663-4365},
abstract = {Postoperative delirium (POD) is common in the elderly and is associated with poor clinical outcomes. Reactive oxygen species (ROS) and blood-brain barrier (BBB) damage have been implicated in the development of POD, but the association between these two factors and the potential mechanism is not clear. Cyclophilin A (CypA) is a specifically chemotactic leukocyte factor that can be secreted in response to ROS, which activates matrix metalloproteinase 9 (MMP9) and mediates BBB breakdown. We, therefore, hypothesized that ROS may contribute to anesthesia/surgery-induced BBB damage and delirium-like behavior via the CypA/MMP9 pathway. To test these hypotheses, 16-month-old mice were subjected to laparotomy under 3% sevoflurane anesthesia (anesthesia/surgery) for 3 h. ROS scavenger (N-acetyl-cysteine) and CypA inhibitor (Cyclosporin A) were used 0.5 h before anesthesia/surgery. A battery of behavior tests (buried food test, open field test, and Y maze test) was employed to evaluate behavioral changes at 24 h before and after surgery in the mice. Levels of tight junction proteins, CypA, MMP9, postsynaptic density protein (PSD)-95, and synaptophysin in the prefrontal cortex were assessed by western blotting. The amounts of ROS and IgG in the cortex of mice were observed by fluorescent staining. The concentration of S100β in the serum was detected by ELISA. ROS scavenger prevented the reduction in TJ proteins and restored the permeability of BBB as well as reduced the levels of CypA/MMP9, and further alleviated delirium-like behavior induced by anesthesia/surgery. Furthermore, the CypA inhibitor abolished the increased levels of CypA/MMP, which reversed BBB damage and ameliorated delirium-like behavior caused by ROS accumulation. Our findings demonstrated that ROS may participate in regulating BBB permeability in aged mice with POD via the CypA/MMP9 pathway, suggesting that CypA may be a potential molecular target for preventing POD.},
}
@article {pmid36332383,
year = {2023},
author = {Chilvery, S and Yelne, A and Khurana, A and Saifi, MA and Bansod, S and Anchi, P and Godugu, C},
title = {Acetaminophen induced hepatotoxicity: An overview of the promising protective effects of natural products and herbal formulations.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {108},
number = {},
pages = {154510},
doi = {10.1016/j.phymed.2022.154510},
pmid = {36332383},
issn = {1618-095X},
mesh = {Mice ; Animals ; Acetaminophen/adverse effects ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention &amp; control/metabolism ; *Biological Products/pharmacology ; Mice, Inbred C57BL ; Liver ; Plant Extracts/pharmacology/metabolism ; },
abstract = {BACKGROUND: The liver plays an important role in regulating the metabolic processes and is the most frequently targeted organ by toxic chemicals. Acetaminophen (APAP) is a well-known anti-allergic, anti-pyretic, non-steroidal anti-inflammatory drug (NSAID), which upon overdose leads to hepatotoxicity, the major adverse event of this over-the-counter drug.<br><br>PURPOSE: APAP overdose induced acute liver injury is the second most common cause that often requires liver transplantation worldwide, for which N-acetyl cysteine is the only synthetic drug clinically approved as an antidote. So, it was felt that there is a need for the novel therapeutic approach for the treatment of liver diseases with less adverse effects. This review provides detailed analysis of the different plant extracts; phytochemicals and herbal formulations for the amelioration of APAP-induced liver injury.<br><br>METHOD: The data was collected using different online resources including PubMed, ScienceDirect, Google Scholar, Springer, and Web of Science using keywords given below.<br><br>RESULTS: Over the past decades various reports have revealed that plant-based approaches may be a better treatment choice for the APAP-induced hepatotoxicity in pre-clinical experimental conditions. Moreover, herbal compounds provide several advantages over the synthetic drugs with fewer side effects, easy availability and less cost for the treatment of life-threatening diseases.<br><br>CONCLUSION: The current review summarizes the hepatoprotective effects and therapeutic mechanisms of various plant extracts, active phytoconstituents and herbal formulations with potential application against APAP induced hepatotoxicity as the numbers of hepatoprotective natural products are more without clinical relativity. Further, pre-clinical pharmacological research will contribute to the designing of natural products as medicines with encouraging prospects for clinical application.},
}
@article {pmid36322347,
year = {2023},
author = {Albeltagy, RS and Dawood, SM and Mumtaz, F and Abdel Moneim, AE and El-Habit, OH},
title = {Antioxidant capacity of N-acetylcysteine against the molecular and cytotoxic implications of cadmium chloride leading to hepatotoxicity and vital progression.},
journal = {Environmental science and pollution research international},
volume = {30},
number = {9},
pages = {23237-23247},
pmid = {36322347},
issn = {1614-7499},
mesh = {Male ; Rats ; Acetylcysteine/pharmacology ; *Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; bcl-2-Associated X Protein ; Cadmium/pharmacology ; Cadmium Chloride/pharmacology ; *Chemical and Drug Induced Liver Injury ; Glutathione/pharmacology ; Oxidative Stress ; Proto-Oncogene Proteins c-bcl-2 ; Animals ; },
abstract = {Many studies have reported that cadmium (Cd) can induce liver cell injury; however, the toxicity mechanisms of Cd on the liver have not been fully explained. Thirty-two male albino rats were divided into four groups: the control group, the N-acetylcysteine (NAC) group orally as effervescent instant sachets with a concentration of 200 mg dissolved in distilled water and dosage was 200 mg/kg body weight freshly prepared, the cadmium chloride (CdCl2) group (treated with 3 mg/kg orally), and the N-acetylcysteine (NAC) + cadmium chloride group (treated with 200 mg/kg orally post to CdCl2) for 60 days. The NAC alone did not make notable changes in most of the parameters. The CdCl2 alone, compared to control, induced significant alterations in oxidative stress markers (increment in lipid peroxidation (LPO) and nitric oxide (NO)) and antioxidant defense system (decrement in superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx)), which resulted in a downregulation of pro-apoptotic Bcl2-associated X protein (Bax) and caspase-3 and upregulation of anti-apoptotic B-cell leukemia/lymphoma 2 (Bcl2) protein as well as the survival fate of hepatic cells. Post-administration of NAC to CdCl2 resulted in a reduction in oxidative stress markers, shifting of cells from the G2/M phase to the G0/G1 inhibiting signal-regulated kinase activation, and impairment of the anti-apoptotic signaling pathway when compared to the CdCl2 group alone. Accordingly, the Bcl2/Bax ratio was reduced to 1.17-fold change, as an adaptive process to hepatic tissue injury. These findings demonstrated that NAC would attenuate the possibility of oxidative stress and cytotoxicity of hepatic tissue induced by CdCl2.},
}
@article {pmid36321532,
year = {2022},
author = {Zhang, Q and Li, P and Li, H and Yi, D and Guo, S and Wang, L and Zhao, D and Wang, C and Wu, T and Hou, Y},
title = {Multifaceted Effects and Mechanisms of N-Acetylcysteine on Intestinal Injury in a Porcine Epidemic Diarrhea Virus-Infected Porcine Model.},
journal = {Molecular nutrition &amp; food research},
volume = {66},
number = {24},
pages = {e2200369},
doi = {10.1002/mnfr.202200369},
pmid = {36321532},
issn = {1613-4133},
mesh = {Animals ; Acetylcysteine/pharmacology ; *Coronavirus Infections/drug therapy/veterinary ; Interferons ; *Porcine epidemic diarrhea virus/genetics ; Proteomics ; Swine ; *Swine Diseases/drug therapy ; },
abstract = {SCOPE: This study investigates the potential effects of N-acetylcysteine (NAC) on intestinal injury in a porcine epidemic diarrhea virus (PEDV)-infected porcine model.<br><br>METHODS AND RESULTS: Thirty-two piglets are randomly assigned to one of four groups: the control, PEDV, NAC, and NAC+PEDV. Piglets in the NAC+PEDV group are orally administrated with NAC (100&#xa0;mg&#xa0;(kg&#xb7;BW)[-1] &#xa0;day[-1]) for 4 consecutive days after 2 days of PEDV infection. The results show that NAC administration decreases the diarrhea rate and improves intestinal morphology. The concentration of diamine oxidase and intestinal fatty-acid binding protein, as well as IL-1&#x3b2;, IL-8, and TNF-&#x3b1; in the plasma, is decreased by NAC. Intriguingly, NAC administration significantly increases the viral load in the jejunum and ileum and down-regulates the expression of interferon-related genes. Microarray and proteomic analyses show that the differentially expressed genes/proteins between NAC+PEDV and PEDV groups are highly enriched in substance transport. Furthermore, aquaporin 8/10 expression is significantly increased by NAC upon PEDV infection.<br><br>CONCLUSION: NAC administration alleviates PEDV-induced intestinal injury by inhibiting inflammatory responses and improving substance transport, but promotes viral replication by inhibiting interferon signaling. These results suggest NAC exhibits multifaceted effects upon PEDV infection, and thus caution is required when using NAC as a dietary supplement to prevent viral infection.},
}
@article {pmid36321244,
year = {2022},
author = {Jannatifar, R and Asa, E and Sahraei, SS and Verdi, A and Piroozmanesh, H},
title = {N-acetyl-l-cysteine and alpha lipoic acid are protective supplement on human sperm parameters in cryopreservation of asthenoteratozoospermia patients.},
journal = {Andrologia},
volume = {54},
number = {11},
pages = {e14612},
doi = {10.1111/and.14612},
pmid = {36321244},
issn = {1439-0272},
support = {//Academic Center for Education, Culture and Research/ ; },
mesh = {Humans ; Male ; *Thioctic Acid/pharmacology/therapeutic use ; Sperm Motility ; *Semen Preservation/methods ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use/metabolism ; *Asthenozoospermia/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; Cryopreservation/methods ; Spermatozoa/metabolism ; },
abstract = {The aim of this study is to evaluate the beneficial effects of N-acetyl-cysteine (NAC), alpha lipoic acid (ALA) and combination of NAC + ALA supplement in freezing medium on Sperm structural and functional in asthenoteratozoospermia patients. Thirty freshly ejaculated semen samples were cryopreserved with sperm freezing medium (SFM) as control group and three group that SFM supplemented with NAC, ALA and their combination NAC+ ALA. The sperm samples were analysed according to WHO. Mitochondrial membrane potential (MMP), acrosome reaction (AR), antioxidant enzymes and DNA fragmentation were assessed using by Rhodamine123, PSA- FITC ELISA and TUNEL staining respectively. Expression level of NRF2 was assessed by real-time PCR assay. NAC and ALA alone significantly improved sperm motility, viability and DNA fragmentation (p < 0.05). MMP increased in NAC and ALA separately (p < 0.05). While did not affect the amount of sperm morphology and AR (p > 0.05). Antioxidant enzymes significantly difference in NAC and ALA groups (p < 0.05). In addition, NAC and ALA groups showed a significantly higher expression of NRF2 gene compared with other groups (p < 0.05). Our results revealed that the ALA and NAC supplements had a protective effect in cryopreservation process on the structural and functional characteristics of sperm.},
}
@article {pmid36315628,
year = {2023},
author = {Zhang, M and Ma, B and Yang, S and Wang, J and Chen, J},
title = {Bisphenol A (BPA) induces apoptosis of mouse Leydig cells via oxidative stress.},
journal = {Environmental toxicology},
volume = {38},
number = {2},
pages = {312-321},
doi = {10.1002/tox.23690},
pmid = {36315628},
issn = {1522-7278},
support = {81660255//National Natural Science Foundation of China/ ; 82060278//National Natural Science Foundation of China/ ; 82171591//National Natural Science Foundation of China/ ; //Major Discipline Academic and Technical Leaders Training Program of Jiangxi Province/ ; 20212ACB206036//Natural Science Foundation of Jiangxi Province/ ; 20204BCJ22031//Natural Science Foundation of Jiangxi Province/ ; },
mesh = {Animals ; Male ; Mice ; Acetylcysteine ; *Apoptosis ; Benzhydryl Compounds/toxicity/metabolism ; *Leydig Cells/metabolism ; *Oxidative Stress ; RNA, Messenger/metabolism ; *Semen/metabolism ; Testis/metabolism ; *Phenols/metabolism/toxicity ; Bisphenol A Compounds ; },
abstract = {As one of the most frequently produced synthetic compounds worldwide, bisphenol A (BPA) has been widely used in many kinds of products such as appliances, housewares, and beverage cans. BPA has been shown to caus