@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 = {},
doi = {10.3390/ijms26178506},
pmid = {40943427},
issn = {1422-0067},
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},
doi = {10.1016/j.psj.2025.105777},
pmid = {40939324},
issn = {1525-3171},
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 = {2025},
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 = {},
number = {},
pages = {105527},
doi = {10.1016/j.jprot.2025.105527},
pmid = {40935016},
issn = {1876-7737},
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 = {},
number = {},
pages = {1-11},
doi = {10.1080/19390211.2025.2555015},
pmid = {40931599},
issn = {1939-022X},
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},
doi = {10.1136/bmjopen-2024-091631},
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.

METHODS AND ANALYSIS: This double-blind trial will randomise participants with AUD to a 12-week regimen of either NAC (2400 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.

ETHICS AND DISSEMINATION: Ethics approval for the study has been granted by The Sydney Local Health District Ethics Review Committee (X21-0342& HREC2021/ETH11614). There are no restrictions on publication from the sponsor or other parties.

TRIAL REGISTRATION NUMBER: NCT05408247.},
}

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

@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 = {},
number = {},
pages = {e0218025},
doi = {10.1128/mbio.02180-25},
pmid = {40919813},
issn = {2150-7511},
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 {pmid40700980,
year = {2026},
author = {Li, Y and Li, Y and Chen, H and Chen, Y and Ni, Y and Ji, J and Wang, K and Jin, Q},
title = {Self-assembled copper-amino acid nanoleaves for targeted treatment of deep-seated bacterial infections via chemodynamic therapy and cuproptosis-like death.},
journal = {Biomaterials},
volume = {325},
number = {},
pages = {123566},
doi = {10.1016/j.biomaterials.2025.123566},
pmid = {40700980},
issn = {1878-5905},
mesh = {*Copper/chemistry/therapeutic use/pharmacology ; Animals ; *Anti-Bacterial Agents/pharmacology/therapeutic use/chemistry ; Mice ; Biofilms/drug effects ; Reactive Oxygen Species/metabolism ; Humans ; Hyaluronic Acid/chemistry ; *Bacterial Infections/drug therapy ; *Amino Acids/chemistry ; Acetylcysteine/chemistry ; Female ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; },
abstract = {Transition metal ions such as Cu[2+] are promising broad-spectrum bactericidal agents. However, transition metal ions are not used to treat deep-seated bacterial infections in clinic owing to easy deactivation by proteins and lack of targeting ability. Herein, hyaluronic acid (HA)-modified copper-N-acetyl-l-cysteine (NAC) nanoleaves (CNH NLs) are developed to treat deep-seated bacterial infections by targeted delivery of Cu[2+] to infection sites. Cu-NAC nanoleaves (CN NLs) can be synthesized by coordinate assembly of Cu[2+] and NAC, which are further coated with HA to obtained CNH NLs with targeting ability. CNH NLs are stable in neutral physiological environment, while can be easily decomposed in acidic infection sites, leading to rapid release of Cu[2+]. The released Cu[2+] disrupts bacterial membranes, depletes glutathione, generates reactive oxygen species (ROS), and induces cuproptosis-like bacterial death, exhibiting potent activity against both planktonic bacteria and biofilms. The targeted accumulation and excellent therapeutic efficacy of CNH NLs is further confirmed on murine bacterial keratitis and pneumonia models, highlighting their therapeutic potential for deep-seated infections.},
}

*Copper/chemistry/therapeutic use/pharmacology
Animals
*Anti-Bacterial Agents/pharmacology/therapeutic use/chemistry
Mice
Biofilms/drug effects
Reactive Oxygen Species/metabolism
Humans
Hyaluronic Acid/chemistry
*Bacterial Infections/drug therapy
*Amino Acids/chemistry
Acetylcysteine/chemistry
Female
Mice, Inbred BALB C
Microbial Sensitivity Tests

@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},
doi = {10.3748/wjg.v31.i31.109630},
pmid = {40901687},
issn = {2219-2840},
mesh = {Humans ; *Carcinoma, Hepatocellular/therapy/pathology ; *Liver Neoplasms/therapy/pathology ; *Acetylcysteine/therapeutic use/administration & dosage ; Middle Aged ; Male ; *Chemoembolization, Therapeutic/adverse effects/methods ; Female ; Adult ; Double-Blind Method ; *Dexamethasone/therapeutic use/administration & 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.

AIM: To compare the incidence of PES between DEXA and NAC in intermediate-stage HCC patients undergoing conventional TACE (cTACE).

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.

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.

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.},
}

Humans
*Carcinoma, Hepatocellular/therapy/pathology
*Liver Neoplasms/therapy/pathology
*Acetylcysteine/therapeutic use/administration & dosage
Middle Aged
Male
*Chemoembolization, Therapeutic/adverse effects/methods
Female
Adult
Double-Blind Method
*Dexamethasone/therapeutic use/administration & dosage
Aged
Treatment Outcome
Incidence
Thailand/epidemiology
Syndrome
Young Adult
Adolescent

@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},
doi = {10.1007/s13205-025-04441-z},
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},
doi = {10.1002/jcb.70062},
pmid = {40891511},
issn = {1097-4644},
support = {//This study was supported by the following grants: National Institutes of Health R21CA259243 (Yong J. Lee), R01CA265827 (Yong J. Lee), R21CA256419 (Yi Zhang), and Department of Defense W81XWH-22-1-1095 RA210084 (Yong J. Lee)./ ; },
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.},
}

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

@article {pmid40884714,
year = {2025},
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 = {},
number = {},
pages = {},
pmid = {40884714},
issn = {1995-8218},
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 {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 = {},
doi = {10.3390/targets3010007},
pmid = {40881937},
issn = {2813-3137},
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 {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},
doi = {10.1111/adb.70051},
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 & dosage ; *Nicotine/pharmacology/administration & dosage ; Rats ; Male ; Motor Activity/drug effects ; Dose-Response Relationship, Drug ; Disease Models, Animal ; *Tobacco Use Disorder/drug therapy ; *Nicotinic Agonists/pharmacology/administration & 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.},
}

Animals
*Acetylcysteine/pharmacology/administration & dosage
*Nicotine/pharmacology/administration & dosage
Rats
Male
Motor Activity/drug effects
Dose-Response Relationship, Drug
Disease Models, Animal
*Tobacco Use Disorder/drug therapy
*Nicotinic Agonists/pharmacology/administration & dosage
Discrimination Learning/drug effects
Conditioning, Operant/drug effects
Rats, Sprague-Dawley
Behavior, Animal/drug effects

@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 & 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.},
}

Humans
*Acetylcysteine/therapeutic use/administration & 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

@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.

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 β-Aminopropionitrile (BAPN) were verified in THP-1 cell line and cells from PS-immunized lupus mice.

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.

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 {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 = {},
doi = {10.3390/pharmaceutics17081003},
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 = {},
doi = {10.3390/ijms26167661},
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.},
}

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

@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 = {},
doi = {10.3390/antiox14080982},
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 {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},
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 = {2025},
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 = {},
number = {},
pages = {},
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/ ; },
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC), a globally prevalent malignancy with high mortality rates, presents an unmet need for innovative effective therapies.

PURPOSE: This study aimed to explore the antitumour potential of compound XD, a novel oridonin derivative, on HCC and its underlying mechanism.

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.

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.

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 = {2025},
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 = {},
number = {},
pages = {},
pmid = {40858780},
issn = {1476-5578},
support = {1R01MH129833//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 1R01MH129833//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 1R01MH129833//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 1R01MH129833//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
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 {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 = {},
number = {},
pages = {e10194},
doi = {10.1002/advs.202510194},
pmid = {40853509},
issn = {2198-3844},
support = {RTI-4007//Department of Atomic Energy, Government of India/ ; },
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, İ and Öz, M and Erdal, H and Karaboğa, İ 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 = {},
number = {},
pages = {},
doi = {10.4274/tjod.galenos.2025.71654},
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.

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.

RESULTS: DOX significantly reduced serum anti-Müllerian hormone (AMH) (6.75 → 5.31 ng/mL; p<0.001) and GSH (422.64 → 280.98 mg/L; p<0.001), while increasing tumor necrosis factor alpha (TNF-α) (175.87 → 260.77 ng/L; p<0.001) and total oxidant status (TOS) (7.18 → 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-α (184.55 ng/L; p<0.001), TOS (7.88 U/mL; p=0.003). In ovarian tissue, DOX reduced GSH (123.63 → 80.64 mg/L; p=0.001) and total antioxidant status (14.88 → 10.57 U/mL; p<0.001), while elevating TOS (7.14 → 12.64 U/mL; p<0.001) and caspase-3 (2.06 → 3.14 ng/mL; p<0.001). NAC significantly improved all these parameters (p≤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.

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 {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.},
}

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

@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},
doi = {10.1111/pim.70019},
pmid = {40847608},
issn = {1365-3024},
support = {//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; Brazil)/ ; //Fundação Amazônia Paraense de Amparo à Pesquisa (FAPESPA; Brazil)/ ; },
mesh = {Animals ; *Lung/pathology/drug effects ; Mice ; Lycopene ; *Brain/pathology/drug effects/metabolism ; Plasmodium berghei ; *Malaria/drug therapy/pathology ; *Antioxidants/administration & dosage ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Carotenoids/administration & 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.},
}

Animals
*Lung/pathology/drug effects
Mice
Lycopene
*Brain/pathology/drug effects/metabolism
Plasmodium berghei
*Malaria/drug therapy/pathology
*Antioxidants/administration & dosage
*Oxidative Stress/drug effects
*Reactive Oxygen Species/metabolism
*Carotenoids/administration & dosage
*Reactive Nitrogen Species/metabolism
Thiobarbituric Acid Reactive Substances/analysis
Male
Nitric Oxide/analysis
Female
Disease Models, Animal

@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 & control/metabolism ; *Acetylcysteine/pharmacology/administration & dosage ; Male ; Humans ; Neurons/drug effects/metabolism ; Neuronal Plasticity/drug effects ; Hippocampus/metabolism/drug effects ; Anxiety/prevention & control ; Disease Models, Animal ; Behavior, Animal/drug effects ; *Cognitive Dysfunction/prevention & 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.},
}

Animals
Female
*Diet, High-Fat/adverse effects
Mice
Pregnancy
*Prenatal Exposure Delayed Effects/prevention & control/metabolism
*Acetylcysteine/pharmacology/administration & dosage
Male
Humans
Neurons/drug effects/metabolism
Neuronal Plasticity/drug effects
Hippocampus/metabolism/drug effects
Anxiety/prevention & control
Disease Models, Animal
Behavior, Animal/drug effects
*Cognitive Dysfunction/prevention & control
Sex Factors
Mice, Inbred C57BL

@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 & 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.

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 Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) to induce hypertension from day 10 to 20 of gestation. Additionally, Group III received selenium (240 μg/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.

RESULTS: Selenium improved L-NAME-induced hypertension (Mean BP 107.63±5.22 mmHg vs 140.9±8.38 mmHg in disease control (DC) and proteinuria (65.5±4.09 vs 140.2±11.85 mg/day in DC) and significantly reduced the inflammatory response (IL-6 23.4±1.06 vs 50.63±3.35 pg/mL in DC) but had little effect on oxidative stress (MDA 0.21±0.02 vs 0.24±0.02 nmol/mL in DC). NAC did not lower BP (Mean BP 129.33±7.96 mmHg) but significantly reduced proteinuria (92.7±6.37mg/day), IL-6 levels (18.24±0.42 pg/mL), and oxidative stress (MDA 0.16±0.01 nmol/mL).

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 = {},
number = {},
pages = {217990},
doi = {10.1016/j.canlet.2025.217990},
pmid = {40834985},
issn = {1872-7980},
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},
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},
doi = {10.1590/acb406325},
pmid = {40834221},
issn = {1678-2674},
mesh = {Animals ; *Acetylcysteine/administration & dosage/pharmacology ; *Oxidative Stress/drug effects ; *Sucralfate/administration & 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 & 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.

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).

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.

CONCLUSION: SCF and NAC enemas alone or in combination reduced inflammation activity and OS in colon segments without fecal stream.},
}

Animals
*Acetylcysteine/administration & dosage/pharmacology
*Oxidative Stress/drug effects
*Sucralfate/administration & 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 & dosage
Antioxidants
Superoxide Dismutase/analysis
Glutathione/analysis
Treatment Outcome

@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 = {},
number = {},
pages = {},
doi = {10.1111/cas.70165},
pmid = {40833873},
issn = {1349-7006},
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},
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.

METHODS: Washed human platelets from healthy donors were pre-incubated with SFN (5, 10, or 20 μM) or vehicle control (0.05% DMSO) for 40 min at 37°C, with or without pharmacologic inhibitors (apalrestat, PP2, N-acetyl-cysteine, pifithrin-μ). 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.

RESULTS: The results demonstrated that SFN attenuated HG-induced platelet dysfunction by alleviating mitochondrial dysfunction (manifested as loss of mitochondrial membrane potential; p < 0.001), apoptosis (characterized by increased caspase-9/-3 activation and phosphatidylserine exposure; p < 0.01), and hyperreactivity (evidenced by enhanced aggregation and activation; p < 0.05). Mechanistically, SFN significantly suppressed HG-induced aldose reductase (AR) activity (p < 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.

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 {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 = {},
number = {},
pages = {},
doi = {10.1016/j.jhep.2025.07.032},
pmid = {40803576},
issn = {1600-0641},
}

@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},
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 {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 & dosage ; Animals ; *Phenylbutyrates/administration & dosage/chemistry/pharmacokinetics ; *Nanoparticles/chemistry/administration & dosage ; Skin/drug effects/metabolism ; Mice ; Delayed-Action Preparations/administration & 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.},
}

*Chitosan/chemistry/administration & dosage
Animals
*Phenylbutyrates/administration & dosage/chemistry/pharmacokinetics
*Nanoparticles/chemistry/administration & dosage
Skin/drug effects/metabolism
Mice
Delayed-Action Preparations/administration & dosage
Skin Absorption/drug effects
Humans
Drug Liberation
Decontamination/methods
Administration, Cutaneous
Particle Size
Chemical Warfare Agents/toxicity
Mice, Hairless
Drug Carriers/chemistry

@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.},
}

*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

@article {pmid40398422,
year = {2025},
author = {Sonar, SA and Bhat, R and Thompson, HL and Coplen, CP and Uhrlaub, JL and Jergovic, M and Nikolich, JŽ},
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.},
}

*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

@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 = {},
number = {},
pages = {},
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 ; R01 DK126887/DK/NIDDK NIH HHS/United States ; R35 GM119768/GM/NIGMS NIH HHS/United States ; },
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 {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 & 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.},
}

Humans
*Aldehyde Reductase/antagonists & 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

@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 ; },
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.

METHODS: The pro-inflammatory potential of 100 µg/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-1α, IL-1β) was measured by ELISA, while the expression of genes related to inflammation (COX2, CXCL8, IL-1α, IL-1β, TNF-α), 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).

RESULTS: Road tunnel PM caused time-dependent increases in expression of CXCL8, COX2, IL-1α, IL-1β, TNF-α, 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-1α 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-1α and CXCL8, and COX2 expression, but augmented expression of CYP1A1 and HO-1.

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.},
}

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

@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).},
}

Humans
Female
Neurofibromin 1/genetics/metabolism
*Breast Neoplasms/drug therapy
Phosphatidylinositol 3-Kinases/metabolism
*Biochemical Phenomena

@article {pmid35775164,
year = {2022},
author = {Tu, C and Lai, S and Huang, Z and Cai, G and Zhao, K and Gao, J and Wu, Z and Zhong, Z},
title = {Accumulation of advanced oxidation protein products contributes to age-related impairment of gap junction intercellular communication in osteocytes of male mice.},
journal = {Bone & joint research},
volume = {11},
number = {7},
pages = {413-425},
pmid = {35775164},
issn = {2046-3758},
abstract = {AIMS: Gap junction intercellular communication (GJIC) in osteocytes is impaired by oxidative stress, which is associated with age-related bone loss. Ageing is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, it is still unknown whether AOPP accumulation is involved in the impairment of osteocytes' GJIC. This study aims to investigate the effect of AOPP accumulation on osteocytes' GJIC in aged male mice and its mechanism.

METHODS: Changes in AOPP levels, expression of connexin43 (Cx43), osteocyte network, and bone mass were detected in 18-month-old and three-month-old male mice. Cx43 expression, GJIC function, mitochondria membrane potential, reactive oxygen species (ROS) levels, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation were detected in murine osteocyte-like cells (MLOY4 cells) treated with AOPPs. The Cx43 expression, osteocyte network, bone mass, and mechanical properties were detected in three-month-old mice treated with AOPPs for 12 weeks.

RESULTS: The AOPP levels were increased in aged mice and correlated with degeneration of osteocyte network, loss of bone mass, and decreased Cx43 expression. AOPP intervention induced NADPH oxidase activation and mitochondrial dysfunction, triggered ROS generation, reduced Cx43 expression, and ultimately impaired osteocytes' GJIC, which were ameliorated by NADPH oxidase inhibitor apocynin, mitochondria-targeted superoxide dismutase mimetic (mito-TEMPO), and ROS scavenger N-acetyl cysteine. Chronic AOPP loading accelerated the degradation of osteocyte networks and decreased Cx43 expression, resulting in deterioration of bone mass and mechanical properties in vivo.

CONCLUSION: Our study suggests that AOPP accumulation contributes to age-related impairment of GJIC in osteocytes of male mice, which may be part of the pathogenic mechanism responsible for bone loss during ageing. Cite this article: Bone Joint Res 2022;11(7):413-425.},
}

@article {pmid35629096,
year = {2022},
author = {Zisis, IE and Georgiadis, G and Docea, AO and Calina, D and Cercelaru, L and Tsiaoussis, J and Lazopoulos, G and Sofikitis, N and Tsatsakis, A and Mamoulakis, C},
title = {Renoprotective Effect of Vardenafil and Avanafil in Contrast-Induced Nephropathy: Emerging Evidence from an Animal Model.},
journal = {Journal of personalized medicine},
volume = {12},
number = {5},
pages = {},
pmid = {35629096},
issn = {2075-4426},
abstract = {The potential renoprotective effects of vardenafil (VAR) have been evaluated in a very limited number of studies using acute kidney injury animal models other than contrast-induced nephropathy (CIN) with promising results, while avanafil (AVA) has not been evaluated in this respect before. The purpose of this study was to evaluate for the first time the potential renoprotective effect of VAR and AVA in a rat model of CIN. Twenty-five male Wistar rats were equally assigned into five groups: control, CIN, CIN+N-acetyl cysteine (NAC) (100 mg/kg/day) as a positive control, CIN+VAR (10 mg/kg/day) and CIN+AVA (50 mg/kg/day). CIN was induced by dehydration, inhibition of prostaglandin and nitric oxide synthesis as well as exposure to the contrast medium (CM). Serum Cr (sCr) levels were measured at 24 and 48 h after CIN induction. At 48 h of CM exposure, animals were sacrificed. Matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9, kidney injury molecule 1 (KIM-1) and cystatin-C (Cys-C) were measured on renal tissue. Histopathological findings were evaluated on kidney tissue. All treatment groups had close to normal kidney appearance. sCr levels subsided in all treatment groups compared to CIN group at 48 h following CIN induction. A significant decline in the levels of MMP-2, MMP-9, KIM-1 and Cys-C compared to CIN group was observed. These results provide emerging evidence that VAR and AVA may have the potential to prevent CIN.},
}

@article {pmid34499870,
year = {2021},
author = {Baron, JM and Heaney, DL and John, A and Fantz, CR},
title = {Real evidence to assess clinical testing interference risk (REACTIR): A strategy using real world data to assess the prevalence of interfering substances in patients undergoing clinical laboratory testing.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {523},
number = {},
pages = {178-184},
doi = {10.1016/j.cca.2021.09.001},
pmid = {34499870},
issn = {1873-3492},
mesh = {*Blood Glucose ; Humans ; Laboratories, Clinical ; *Point-of-Care Systems ; Point-of-Care Testing ; Prevalence ; },
abstract = {INTRODUCTION: Laboratory test interferences can cause spurious test results and patient harm. Knowing the frequency of various interfering substances in patient populations likely to be tested with a particular laboratory assay may inform test development, test utilization and strategies to mitigate interference risk.

METHODS: We developed REACTIR (Real Evidence to Assess Clinical Testing Interference Risk), an approach using real world data to assess the prevalence of various interfering substances in patients tested with a particular type of assay. REACTIR uses administrative real world data to identify and subgroup patient cohorts tested with a particular laboratory test and evaluate interference risk.

RESULTS: We demonstrate the application REACTIR to point of care (POC) blood glucose testing. We found that exposure to several substances with the potential to interfere in POC blood glucose tests, including N-acetyl cysteine (NAC) and high dose vitamin C was uncommon in most patients undergoing POC glucose tests with several key exceptions, such as burn patients receiving high dose IV-vitamin C or acetaminophen overdose patients receiving NAC.

CONCLUSIONS: Findings from REACTIR may support risk mitigation strategies including targeted clinician education and clinical decision support. Likewise, adaptations of REACTIR to premarket assay development may inform optimal assay design and assessment.},
}

*Blood Glucose
Humans
Laboratories, Clinical
*Point-of-Care Systems
Point-of-Care Testing
Prevalence

@article {pmid33553365,
year = {2021},
author = {Bai, L and Yu, E},
title = {A narrative review of risk factors and interventions for cancer-related cognitive impairment.},
journal = {Annals of translational medicine},
volume = {9},
number = {1},
pages = {72},
pmid = {33553365},
issn = {2305-5839},
abstract = {Cancer-related cognitive impairment (CRCI) refers to a series of cognitive impairment symptoms associated with alternations in brain structure and function, caused by a non-central nervous system malignant tumor and its related treatment. CRCI may present as memory loss, impaired concentration, difficulty in multitasking and word retrieval, and reduced comprehension speed. CRCI has become one of the prevalent factors that compromise the quality of life for cancer survivors. Different treatments, including surgery, chemotherapy, radiotherapy, endocrine therapy, and targeted drugs, may contribute to CRCI. Meanwhile, patients' factors, including emotional challenges and genetic makeup, also contribute to the development of CRCI. The condition can be treated with using stimulants methylphenidate and modafinil, metabolites of nicotine: cotinine, antidepressants of fluoxetine and fluvoxamine, dementia drug of donepezil, and antioxidants ZnSO4, n-acetyl cysteine, propofol, and Chinese herbal of silver leaf medicine. Psychotherapies, including meditation and relaxation, cognitive rehabilitation training, along with physical therapies, including aerobic exercise, resistance training, balance training, yoga, qigong, tai chi electroencephalogram biofeedback, and acupuncture, are also beneficial in alleviating cancer-related cognitive impairment symptoms. In recent years, researchers have focused on factors related to the condition and on the available interventions. However, most research was conducted independently, and no review has yet summarized the latest findings. This review details and discusses the status of related factors and potential treatments for CRCI. We also supply specific recommendations to facilitate future research and integration in this field.},
}

@article {pmid34909640,
year = {2020},
author = {Abdoli, N and Sadeghian, I and Mousavi, K and Azarpira, N and Ommati, MM and Heidari, R},
title = {Suppression of cirrhosis-related renal injury by N-acetyl cysteine.},
journal = {Current research in pharmacology and drug discovery},
volume = {1},
number = {},
pages = {30-38},
pmid = {34909640},
issn = {2590-2571},
abstract = {Cirrhosis-induced renal injury or cholemic nephropathy (CN) is a serious clinical complication with poor prognosis. CN could finally lead to renal failure and the need for organ transplantation. Unfortunately, there is no specific pharmacological intervention against CN to date. On the other hand, various studies mentioned the role of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to evaluate the potential protective effects of NAC as a thiol-reducing agent and antioxidant in CN. Bile duct ligation (BDL) was used as a reliable animal model of cholestasis. BDL animals received NAC (0.25% and 1% w: v) in drinking water for 28 consecutive days. Finally, urine, blood, and kidney samples were collected and analyzed. Significant elevation in serum biomarkers of renal injury, along with urine markers of kidney damage, was evident in the BDL group. Moreover, markers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, protein carbonylation, and increased oxidized glutathione (GSSG) were evident detected in the kidney of cholestatic rats. Renal tissue antioxidant capacity and reduced glutathione (GSH) were also significantly depleted in the BDL group. Significant mitochondrial depolarization, depleted ATP content, and mitochondrial permeabilization was also detected in mitochondria isolated from the kidney of cholestatic animals. Renal histopathological alterations consisted of significant tissue fibrosis, interstitial inflammation, and tubular atrophy. It was found that NAC (0.25 and 1% in drinking water for 28 consecutive days) blunted histopathological changes, decreased markers of oxidative stress, and improved mitochondrial indices in the kidney of cirrhotic rats. Moreover, serum and urine biomarkers of renal injury were also mitigated in upon NAC treatment. These data indicate a potential renoprotective role for NAC in cholestasis. The effects of NAC on cellular redox state and mitochondrial function seem to play a fundamental role in its renoprotective effects during CN.},
}

@article {pmid32622850,
year = {2020},
author = {Iordache, AM and Buga, AM and Albulescu, D and Vasile, RC and Mitrut, R and Georgiadis, G and Zisis, IE and Mamoulakis, C and Tsatsakis, A and Docea, AO and Calina, D},
title = {Phosphodiesterase-5 inhibitors ameliorate structural kidney damage in a rat model of contrast-induced nephropathy.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {143},
number = {},
pages = {111535},
doi = {10.1016/j.fct.2020.111535},
pmid = {32622850},
issn = {1873-6351},
mesh = {Animals ; Contrast Media/*adverse effects ; Kidney Diseases/*chemically induced/prevention & control ; Kidney Tubules/*drug effects/pathology ; Male ; Phosphodiesterase 5 Inhibitors/*pharmacology ; Rats ; Rats, Wistar ; Sildenafil Citrate/*therapeutic use ; Tadalafil/*therapeutic use ; },
abstract = {The aim of the study was to investigate the potential of sildenafil and tadalafil to ameliorate structural kidney damage in contrast-induced nephropathy (CIN). A rat model of CIN was developed by dehydration, administration of a nitric oxide inhibitor and a prostaglandin synthesis inhibitor (L-NAME/indomethacin) and contrast media exposure to iopromide. The effect of pre-treatment with sildenafil, tadalafil or N-acetyl cysteine (NAC) for 7 days prior to CIN induction was investigated. All animals were sacrificed at 24 h after CIN induction and both kidneys were collected. Histopathological examination was performed under light microscopy in serial tissue sections stained with hematoxylin and eosin. CIN group showed hydropic changes of the renal tubules (proximal and distal convoluted tubules and Henle's loop), an increased Bowman space with lobulated glomerulus and alteration of macula densa region of distal convolute tubules. The groups pretreated with sildenafil and tadalafil showed nearly normal histological aspects of renal tissue. The group pretreated with NAC showed similar but less intense histopathologic changes compared to CIN group. Sildenafil and tadalafil pre-treatment ameliorates CIN-related structural kidney damage and the protective potential of these agents is superior to NAC.},
}

Animals
Contrast Media/*adverse effects
Kidney Diseases/*chemically induced/prevention & control
Kidney Tubules/*drug effects/pathology
Male
Phosphodiesterase 5 Inhibitors/*pharmacology
Rats
Rats, Wistar
Sildenafil Citrate/*therapeutic use
Tadalafil/*therapeutic use

@article {pmid32020997,
year = {2019},
author = {Chacko, B and Peter, JV},
title = {Antidotes in Poisoning.},
journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine},
volume = {23},
number = {Suppl 4},
pages = {S241-S249},
pmid = {32020997},
issn = {0972-5229},
abstract = {INTRODUCTION: Antidotes are agents that negate the effect of a poison or toxin. Antidotes mediate its effect either by preventing the absorption of the toxin, by binding and neutralizing the poison, antagonizing its end-organ effect, or by inhibition of conversion of the toxin to more toxic metabolites. Antidote administration may not only result in the reduction of free or active toxin level, but also in the mitigation of end-organ effects of the toxin by mechanisms that include competitive inhibition, receptor blockade or direct antagonism of the toxin.

Reduction in free toxin level can be achieved by specific and non-specific agents that bind to the toxin. The most commonly used non-specific binding agent is activated charcoal. Specific binders include chelating agents, bioscavenger therapy and immunotherapy. In some situations, enhanced elimination can be achieved by urinary alkalization or hemadsorption. Competitive inhibition of enzymes (e.g. ethanol for methanol poisoning), enhancement of enzyme function (e.g. oximes for organophosphorus poisoning) and competitive receptor blockade (e.g. naloxone, flumazenil) are other mechanisms by which antidotes act. Drugs such as N-acetyl cysteine and sodium thiocyanate reduce the formation of toxic metabolites in paracetamol and cyanide poisoning respectively. Drugs such as atropine and magnesium are used to counteract the end-organ effects in organophosphorus poisoning. Vitamins such as vitamin K, folic acid and pyridoxine are used to antagonise the effects of warfarin, methotrexate and INH respectively in the setting of toxicity or overdose. This review provides an overview of the role of antidotes in poisoning.

HOW TO CITE THIS ARTICLE: Chacko B, Peter JV. Antidotes in Poisoning. Indian J Crit Care Med 2019;23(Suppl 4):S241-S249.},
}

@article {pmid31531084,
year = {2019},
author = {Barzi, F and Miri, R and Sadeghi, R and Sistanizad, M and Sadeghi, M and Mahjoob, MP and Chehrazi, M},
title = {A Randomized Double Blind Placebo Controlled Trial Examining the Effects of Pentoxifylline on Contrast Induced Nephropathy Reduction after Percutaneous Coronary Intervention in High Risk Candidates.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {18},
number = {2},
pages = {1040-1046},
pmid = {31531084},
issn = {1735-0328},
abstract = {Contrast-induced nephropathy (CIN) (known as contrast-induced acute kidney injury) occurs as a result of acute worsening of renal function following a procedure with administration of iodine contrasts agent and remains a substantial concern in clinical practices. The purpose of this study is to investigate the preventive effect of Pentoxifylline supplementation on reduction of CIN occurrence after percutaneous coronary intervention among patients who were high risk of CIN according to Mehran score. In randomized, double-blind clinical trial patients who undergo coronary angiography with Mehran Score ≥ 11 consisted of our population. Patients in a ratio 1:1, divided into two groups received saline 0.9% plus N-acetyl cysteine and Pentoxifylline 400 mg three times per day 24 h before angiography until 48 h after angiography. In control group, the patients received placebo instead of PTX in a same manner as the control group. The endpoint was the incidence of CIN defined as creatinine increase of 0.5 mg/dL within 2 days after contrast. There were no significant differences in baseline characteristics. CIN occurred in 3 (5.5%) and 4 (7.3%) patients of the both groups (Pentoxifylline and control), respectively (p = 0.69; incidence odds ratio 1.36; 95% CI 0.29-6.38). No significant differences were seen in secondary outcome measures and changes in the level of creatinine (p = 0.54). In high-risk patients undergoing coronary angiography pentoxifylline supplementation had protection effect against contrast-induced nephropathy greater than placebo based hydration, but, not supported by our data.},
}

@article {pmid31212064,
year = {2019},
author = {García-Arroyo, FE and Gonzaga, G and Muñoz-Jiménez, I and Osorio-Alonso, H and Iroz, A and Vecchio, M and Tapia, E and Roncal-Jiménez, CA and Johnson, RJ and Sánchez-Lozada, LG},
title = {Antioxidant supplements as a novel mean for blocking recurrent heat stress-induced kidney damage following rehydration with fructose-containing beverages.},
journal = {Free radical biology & medicine},
volume = {141},
number = {},
pages = {182-191},
doi = {10.1016/j.freeradbiomed.2019.06.016},
pmid = {31212064},
issn = {1873-4596},
mesh = {Active Transport, Cell Nucleus ; Aldehyde Reductase/metabolism ; Animals ; Antioxidants/administration & dosage/*pharmacology ; *Beverages ; Blood Pressure ; Cell Nucleus/metabolism ; Dehydration ; Fluid Therapy ; Fructokinases/metabolism ; Fructose/*adverse effects ; Glutathione/metabolism ; *Heat-Shock Response ; Kidney Diseases/*metabolism ; Male ; Nitric Oxide Synthase Type III/metabolism ; Polymers/metabolism ; Protein Transport ; Rats ; Rats, Wistar ; },
abstract = {Recently repeated heat stress and dehydration have been reported to cause oxidative stress and kidney damage that is enhanced by rehydrating with fructose solutions. We hypothesized that antioxidants might provide a novel way to prevent kidney damage. To test this hypothesis, mild heat stress was induced by exposing rats to 37 °C during 1 h in a closed chamber. The supplementation with water-soluble antioxidants (Antiox), ascorbic acid 1% plus N-acetyl cysteine 600 mg/L was done either in the 10% fructose 2 h rehydration fluid immediately after heat stress (Fructose 10% + Antiox), and/or in the tap water (Water + Antiox) for the remainder of the day, or in both fluids. After 4 weeks, control rats exposed to heat with fructose rehydration developed impaired renal function, tubular injury, intrarenal oxidative stress, a reduction in Nrf2-Keap1 antioxidant pathway, stimulation of vasopressin and the intrarenal polyol-fructokinase pathway. In contrast, dosing the antioxidants in the tap water (i.e., before the heat exposure and rehydration with fructose) preserved renal function, prevented renal tubule dysfunction and avoided the increase in systemic blood pressure. These effects were likely due to the amplification of the antioxidant defenses through increased Nrf2 nuclear translocation stimulated by the antioxidants and by the prevention of polyol fructokinase pathway overactivation. More studies to understand the mechanisms implicated in this pathology are warranted as there is recent evidence that they may be operating in humans as well.},
}

Active Transport, Cell Nucleus
Aldehyde Reductase/metabolism
Animals
Antioxidants/administration & dosage/*pharmacology
*Beverages
Blood Pressure
Cell Nucleus/metabolism
Dehydration
Fluid Therapy
Fructokinases/metabolism
Fructose/*adverse effects
Glutathione/metabolism
*Heat-Shock Response
Kidney Diseases/*metabolism
Male
Nitric Oxide Synthase Type III/metabolism
Polymers/metabolism
Protein Transport
Rats
Rats, Wistar

@article {pmid30829731,
year = {2019},
author = {Bellos, I and Iliopoulos, DC and Perrea, DN},
title = {Allopurinol Administration for the Prevention of Contrast-Induced Nephropathy: A Network Meta-analysis With Trial Sequential Analysis.},
journal = {Journal of cardiovascular pharmacology},
volume = {73},
number = {5},
pages = {307-315},
doi = {10.1097/FJC.0000000000000663},
pmid = {30829731},
issn = {1533-4023},
mesh = {Acute Kidney Injury/chemically induced/epidemiology/physiopathology/*prevention & control ; Allopurinol/adverse effects/*therapeutic use ; Contrast Media/*adverse effects ; Cytoprotection ; Fluid Therapy ; Gout Suppressants/adverse effects/*therapeutic use ; Humans ; Incidence ; Kidney/*drug effects/physiopathology ; Randomized Controlled Trials as Topic ; Risk Factors ; Treatment Outcome ; },
abstract = {Contrast-induced nephropathy represents a major source of morbidity in patients undergoing coronary angiography. Various preventive measures have been proposed, although the optimal one remains still unknown. The aim of the present meta-analysis is to accumulate current literature knowledge and evaluate the renoprotective effects of allopurinol administration before contrast medium exposure. To achieve this, MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and Google Scholar databases were searched from inception to November 8, 2018. Statistical meta-analysis was conducted with Review Manager 5.3, TSA 0.9.5.5 and R-3.4.3. Six studies were included with a total of 918 patients. Quantitative synthesis revealed that allopurinol leads to significantly reduced incidence of contrast-induced nephropathy compared with hydration alone [odds ratio: 0.29, 95% confidence interval: (0.09-0.90)]. Trial sequential analysis suggested that Z-curve crossed the O'Brien-Fleming significance boundaries, although required information size was not reached. Network meta-analysis indicated that allopurinol had the highest probability (81.2%) to rank as the most effective intervention compared with hydration and N-acetyl cysteine; however, significant overlap with the rest treatments was noted. In conclusion, the present meta-analysis suggests that allopurinol may represent a promising measure for the prevention of acute kidney injury after coronary angiography. Future large-scale randomized controlled trials should verify this finding, while combinations of allopurinol with other novel interventions should be evaluated to define the most effective strategy to be implemented in the clinical setting.},
}

Acute Kidney Injury/chemically induced/epidemiology/physiopathology/*prevention & control
Allopurinol/adverse effects/*therapeutic use
Contrast Media/*adverse effects
Cytoprotection
Fluid Therapy
Gout Suppressants/adverse effects/*therapeutic use
Humans
Incidence
Kidney/*drug effects/physiopathology
Randomized Controlled Trials as Topic
Risk Factors
Treatment Outcome

@article {pmid30021379,
year = {2018},
author = {Yan, J and Li, M and Wang, XD and Lu, ZY and Ni, XL},
title = {Peperomin E (PepE) protects against high fat diet-induced atherosclerosis in Apolipoprotein E deficient (ApoE[-/-]) mice through reducing inflammation via the suppression of NLRP3 signaling pathway.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {105},
number = {},
pages = {862-869},
doi = {10.1016/j.biopha.2018.04.140},
pmid = {30021379},
issn = {1950-6007},
mesh = {Animals ; Apolipoproteins E/*deficiency ; Atherosclerosis/metabolism/*prevention & control ; Benzodioxoles/pharmacology/*therapeutic use ; Cell Survival/drug effects/physiology ; Diet, High-Fat/*adverse effects ; Inflammation/drug therapy/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists & inhibitors/metabolism ; Reactive Oxygen Species/antagonists & inhibitors/metabolism ; Signal Transduction/*drug effects/physiology ; },
abstract = {Peperomin E (PepE) is a type of secolignan, a major component of the plant Peperomia dindygulensis. It has been shown to exert anti-inflammatory effects; however, the effects of PepE on human atherosclerosis remain unexplored. In the study, we investigated the role of PepE in high fat diet (HFD) induced atherosclerosis using apolipoprotein E defcient (ApoE[-/-]) mice. Elevated serum homocyteine, cholesterol, and triglyceride levels, accelerated progression of atherosclerosis and exacerbated macrophage infiltration into atherosclerotic lesions were observed in HFD-fed ApoE[-/-] mice, which were attenuated by PepE treatment. ApoE[-/-] mice fed with HFD exhibited significantly high levels of inflammation-associated regulators in artery tissues, accompanied with an increased expression of p-inhibitor of κBα (IκBα) and p-nuclear factor-kappa B (NF-κB), and the process was blocked by PepE administration. Further, we found NOD-like receptor pyrin 3 (NLRP3) inflammasome activation in artery tissues of HFD-fed ApoE[-/-] mice. In vitro, silencing NLRP3 using small interfering RNA efficiently inhibited oxidized-low-density lipoprotein (oxLDL)-induced ASC and Caspase-1 expressions, interleukin (IL)-1β and IL-18 production in human aortic endothelial cells (HAECs). Further experiments indicated that NLRP3-ASC pathway was activated by reactive oxygen species (ROS), since ROS scavenger of N-acetyl-cysteine (NAC) prevented, which was further reduced by PepE addition. However, the anti-inflammatory effects of PepE on oxLDL-incubated HAECs were abolished by over-expression NLRP3. Together, our study revealed that PepE inhibited atherosclerosis development in HFD-fed ApoE[-/-] mice by suppressing NLRP3 inflammatory signaling pathway, and suggested that PepE might be a potential therapeutic strategy in the prevention of atherosclerosis.},
}

Animals
Apolipoproteins E/*deficiency
Atherosclerosis/metabolism/*prevention & control
Benzodioxoles/pharmacology/*therapeutic use
Cell Survival/drug effects/physiology
Diet, High-Fat/*adverse effects
Inflammation/drug therapy/metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists & inhibitors/metabolism
Reactive Oxygen Species/antagonists & inhibitors/metabolism
Signal Transduction/*drug effects/physiology

@article {pmid28410397,
year = {2017},
author = {Visagie, MH and van den Bout, I and Joubert, AM},
title = {A bis-sulphamoylated estradiol derivative induces ROS-dependent cell cycle abnormalities and subsequent apoptosis.},
journal = {PloS one},
volume = {12},
number = {4},
pages = {e0176006},
pmid = {28410397},
issn = {1932-6203},
mesh = {2-Methoxyestradiol ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Autophagy/drug effects ; Cell Line, Tumor ; DNA Breaks, Double-Stranded/drug effects ; Estradiol/*analogs & derivatives/*toxicity ; G2 Phase Cell Cycle Checkpoints/drug effects ; Histones/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; M Phase Cell Cycle Checkpoints/drug effects ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; },
abstract = {Clinical trials have revealed that the potential anticancer agent, 2-methoxyestradiol (2ME2) has limitations due to its low bioavailability. Subsequently, 2ME2 derivatives including (8R,13S,14S,17S)-2-ethyl-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrane-3,17-diyl bis(sulphamate) (EMBS) have shown improved efficacies in inducing apoptosis. However, no conclusive data exist to explain the mode of action exerted by these drugs. This study investigated the mode of action used by EMBS as a representative of the sulphamoylated 2ME2 derivatives. Hydrogen peroxide and superoxide production was quantified using dichlorofluorescein diacetate and hydroethidine. Cell proliferation and mitochondrial metabolism were investigated using crystal violet and Alamar Blue. Apoptosis was assessed using Annexin V-FITC while mitochondrial integrity was assessed using Mitocapture. Autophagy was visualised using LC3B II antibodies. The effects of EMBS on H2A phosphorylation and nuclei were visualised using phospho H2A antibody and 4',6-diamidino-2-phenylindole, dihydrochloride. Data showed that EMBS exposure leads to increased reactive oxygen species (ROS) production which is correlated with loss of cell proliferation, mitochondrial membrane damage, decreased metabolic activity, G2/M arrest, endoreduplication, DNA double stranded breaks, micronuclei and apoptosis induction. Treatment of EMBS-exposed cells with the ROS scavenger, N-acetyl cysteine, abrogated ROS production, cell cycle arrest and apoptosis implying an essential role for ROS production in EMBS signaling. The inhibition of c-Jun N-terminal kinase (JNK) activity also inhibited EMBS-induced apoptosis suggesting that EMBS triggers apoptosis via the JNK pathway. Lastly, evaluation of LC3IIB protein levels indicated that autophagy is not activated in EMBS-exposed cells. Our data shows that EMBS targets a pathway that leads to increased ROS production as an early event that culminates in G2/M arrest and apoptosis by means of JNK-signaling in cancer cells. This study suggests a novel oxidative stress-dependent mode of action for sulphamoylated derivatives.},
}

2-Methoxyestradiol
Acetylcysteine/pharmacology
Apoptosis/*drug effects
Autophagy/drug effects
Cell Line, Tumor
DNA Breaks, Double-Stranded/drug effects
Estradiol/*analogs & derivatives/*toxicity
G2 Phase Cell Cycle Checkpoints/drug effects
Histones/metabolism
Humans
JNK Mitogen-Activated Protein Kinases/metabolism
M Phase Cell Cycle Checkpoints/drug effects
MCF-7 Cells
Membrane Potential, Mitochondrial/drug effects
Oxidative Stress/drug effects
Phosphorylation/drug effects
Reactive Oxygen Species/metabolism

@article {pmid25715308,
year = {2015},
author = {Nadkarni, GN and Konstantinidis, I and Patel, A and Yacoub, R and Kumbala, D and Patel, RA and Annapureddy, N and Pakanati, KC and Simoes, PK and Javed, F and Benjo, AM},
title = {Trimetazidine Decreases Risk of Contrast-Induced Nephropathy in Patients With Chronic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials.},
journal = {Journal of cardiovascular pharmacology and therapeutics},
volume = {20},
number = {6},
pages = {539-546},
doi = {10.1177/1074248415573320},
pmid = {25715308},
issn = {1940-4034},
mesh = {Aged ; Contrast Media/*adverse effects ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention & control ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; Renal Insufficiency, Chronic/*complications ; Trimetazidine/*therapeutic use ; Vasodilator Agents/*therapeutic use ; },
abstract = {OBJECTIVES: We sought to synthesize and analyze the available data from randomized controlled trials (RCTs) for trimetazidine (TMZ) in the prevention of contrast-induced nephropathy (CIN).

BACKGROUND: Contrast-induced nephropathy after coronary angiography is associated with poor outcomes. Trimetazidine is an anti-ischemic drug that might reduce incidence of CIN, but current data are inconclusive.

METHODS: We searched MEDLINE/PubMed, EMBASE, Scopus, Cochrane Library, Web of Science, and ScienceDirect electronic databases for RCTs comparing intravenous hydration with normal saline (NS) and/or N-acetyl cysteine (NAC) versus TMZ plus NS ± NAC for prevention of CIN. We used RevMan 5.2 for statistical analysis with the fixed effects model.

RESULTS: Of the 808 studies, 3 RCTs met criteria with 290 patients in the TMZ plus NS ± NAC group and 292 patients in the NS ± NAC group. The mean age of patients was 59.5 years, and baseline serum creatinine ranged from 1.3 to 2 mg/dL. Trimetazidine significantly reduced the incidence of CIN by 11% (risk difference 0.11; 95% confidence interval, 0.16-0.06; P < .01). There was no significant heterogeneity between the studies (I(2) statistic = 0). The number needed to treat to prevent 1 episode of CIN was 9.

CONCLUSIONS: The addition of TMZ to NS ± NAC significantly decreased the incidence of CIN in patients undergoing coronary angiography. In conclusion, TMZ could be considered as a potential tool for prevention of CIN in patients with renal dysfunction.},
}

Aged
Contrast Media/*adverse effects
Female
Humans
Kidney Diseases/*chemically induced/*prevention & control
Male
Middle Aged
Randomized Controlled Trials as Topic
Renal Insufficiency, Chronic/*complications
Trimetazidine/*therapeutic use
Vasodilator Agents/*therapeutic use

@article {pmid25352760,
year = {2014},
author = {Yoo, HJ and Im, CN and Youn, DY and Yun, HH and Lee, JH},
title = {Bis is Induced by Oxidative Stress via Activation of HSF1.},
journal = {The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology},
volume = {18},
number = {5},
pages = {403-409},
pmid = {25352760},
issn = {1226-4512},
abstract = {The Bis protein is known to be involved in a variety of cellular processes including apoptosis, migration, autophagy as well as protein quality control. Bis expression is induced in response to a number of types of stress, such as heat shock or a proteasome inhibitor via the activation of heat shock factor (HSF)1. We report herein that Bis expression is increased at the transcriptional level in HK-2 kidney tubular cells and A172 glioma cells by exposure to oxidative stress such as H2O2 treatment and oxygen-glucose deprivation, respectively. The pretreatment of HK-2 cells with N-acetyl cysteine, suppressed Bis induction. Furthermore, HSF1 silencing attenuated Bis expression that was induced by H2O2, accompaniedby increase in reactive oxygen species (ROS) accumulation. Using a series of deletion constructs of the bis gene promoter, two putative heat shock elements located in the proximal region of the bis gene promoter were found to be essential for the constitutive expression is as well as the inducible expression of Bis. Taken together, our results indicate that oxidative stress induces Bis expression at the transcriptional levels via activation of HSF1, which might confer an expansion of antioxidant capacity against pro-oxidant milieu. However, the possible role of the other cis-element in the induction of Bis remains to be determined.},
}

@article {pmid24932583,
year = {2014},
author = {Thakur, P and Lamoke, F and Chaffin, JM and Bartoli, M and Lee, JR and Duncan, MB},
title = {Dysplastic hepatocytes develop nuclear inclusions in a mouse model of viral hepatitis.},
journal = {PloS one},
volume = {9},
number = {6},
pages = {e99872},
pmid = {24932583},
issn = {1932-6203},
mesh = {Aldehydes/metabolism ; Animals ; Biomarkers/metabolism ; Cell Death ; Cell Nucleus/metabolism ; Cell Nucleus Size ; Cellular Senescence ; Disease Models, Animal ; Endoplasmic Reticulum/metabolism ; Glycogen/metabolism ; Hepatitis/immunology/*pathology/*virology ; Hepatitis B Surface Antigens/immunology ; Hepatocytes/metabolism/*pathology/*virology ; Intranuclear Inclusion Bodies/*pathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Oxidative Stress ; Proliferating Cell Nuclear Antigen/metabolism ; Vacuoles/metabolism ; },
abstract = {Viral hepatitis resulting in chronic liver disease is an important clinical challenge and insight into the cellular processes that drive pathogenesis will be critical in order to develop new diagnostic and therapeutic options. Nuclear inclusions in viral and non-viral hepatitis are well documented and have diagnostic significance in some disease contexts. However, the origins and functional consequences of these nuclear inclusions remain elusive. To date the clinical observation of nuclear inclusions in viral and non-viral hepatitis has not been explored at depth in murine models of liver disease. Herein, we report that in a transgenic model of hepatitis B surface antigen mediated hepatitis, murine hepatocytes exhibit nuclear inclusions. Cells bearing nuclear inclusions were more likely to express markers of cell proliferation. We also established a correlation between these inclusions and oxidative stress. N-acetyl cysteine treatment effectively reduced oxidative stress levels, relieved endoplasmic reticulum (ER) stress, and the number of nuclear inclusions we observed in the transgenic mice. Our results suggest that the presence of nuclear inclusions in hepatocytes correlates with oxidative stress and cellular proliferation in a model of antigen mediated hepatitis.},
}

Aldehydes/metabolism
Animals
Biomarkers/metabolism
Cell Death
Cell Nucleus/metabolism
Cell Nucleus Size
Cellular Senescence
Disease Models, Animal
Endoplasmic Reticulum/metabolism
Glycogen/metabolism
Hepatitis/immunology/*pathology/*virology
Hepatitis B Surface Antigens/immunology
Hepatocytes/metabolism/*pathology/*virology
Intranuclear Inclusion Bodies/*pathology
Mice, Inbred C57BL
Mice, Transgenic
Oxidative Stress
Proliferating Cell Nuclear Antigen/metabolism
Vacuoles/metabolism

@article {pmid23723505,
year = {2013},
author = {Vikramkumar, AG and Kuruvila, S and Ganguly, S},
title = {Monilethrix: a rare hereditary condition.},
journal = {Indian journal of dermatology},
volume = {58},
number = {3},
pages = {243},
pmid = {23723505},
issn = {1998-3611},
abstract = {Monilethrix is a rare hereditary condition generally considered to be an autosomal-dominant disorder with variable penetrance. Here, we report a case of monilethrix in a 13-year-old boy with an affected sibling. A therapeutic trial with oral N-acetyl cysteine was attempted. There was slight improvement after 2 months of therapy. The hair density, however, did not show any further improvement subsequently. Monilethrix remains as a therapeutic challenge for dermatologists.},
}

@article {pmid19955665,
year = {2009},
author = {Thomson, VS and Narayanan, K and Singh, JC},
title = {Contrast induced nephropathy in urology.},
journal = {Indian journal of urology : IJU : journal of the Urological Society of India},
volume = {25},
number = {4},
pages = {437-445},
pmid = {19955665},
issn = {1998-3824},
abstract = {Intravenous contrast agents have a distinct role in urological imaging: to study precise anatomical delineation, vascularity, and to assess the function of the renal unit. Contrast induced nephropathy (CIN) is a known adverse effect of intravenous contrast administration. The literature on incidence, pathophysiology, clinical features, and current preventive strategies available for CIN relevant to urologists was reviewed. A search of the PubMed database was done using the keywords nephropathy and media, prevention and control or prevention Contrast media (explode), all adverse effects, and kidney diseases (explode). An online search of the EMBASE database for the time ranging from 1977 to February 2009 was performed using the keywords ionic contrast medium, adverse drug reaction, major or controlled clinical study, human, nephrotoxicity, and kidney disease. Current publications and data most relevant to urologists were examined. CIN was the third most common cause of hospital-acquired renal failure. The incidence is less common with intravenous contrast administration as compared with intra-arterial administration. The pathogenesis of contrast mediated nephropathy is due to a combination of toxic injury to renal tubules and medullary ischemic injury mediated by reactive oxygen species. CIN most commonly manifests as a nonoliguric and asymptomatic transient decline in renal function. Patients who developed CIN were found to have increased mortality, longer hospital stay, and complicated clinical course. An overview of risk factors and risk prediction score for prognostication of CIN are elaborated. Preventive strategies including choice of contrast agents, maximum tolerated dose, role of hydration, hydration regime, etc. are discussed. The role of N- acetyl cysteine, Theophylline, Fenoldapam, Endothelin receptor antagonists, iloprost, atrial natriuretic peptide, and newer therapies such as targeted renal therapy (TRT) are discussed. A working algorithm based on current evidence is proposed. No current treatment can reverse or ameliorate CIN once it occurs, but prophylaxis is possible.},
}

@article {pmid16614485,
year = {2006},
author = {Mizuguchi, S and Takemura, S and Minamiyama, Y and Kodai, S and Tsukioka, T and Inoue, K and Okada, S and Suehiro, S},
title = {S-allyl cysteine attenuated CCl4-induced oxidative stress and pulmonary fibrosis in rats.},
journal = {BioFactors (Oxford, England)},
volume = {26},
number = {1},
pages = {81-92},
doi = {10.1002/biof.5520260108},
pmid = {16614485},
issn = {0951-6433},
mesh = {Animals ; Bronchoalveolar Lavage Fluid/cytology ; Carbon Tetrachloride/*pharmacology ; Cysteine/*analogs & derivatives/pharmacology ; Enzyme Precursors/analysis ; Glutathione/analysis ; Hydroxyproline/analysis ; Liver/pathology ; Lung/chemistry ; Male ; Matrix Metalloproteinase 9/analysis ; Nitric Oxide/urine ; Nitric Oxide Synthase Type II/analysis ; Oxidative Stress/*drug effects ; Pulmonary Fibrosis/*chemically induced/*prevention & control ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/blood ; Transforming Growth Factor beta ; Transforming Growth Factor beta1 ; },
abstract = {This study examined effects of S-allyl cysteine (SAC) on carbon tetrachloride (CCl4)-induced interstitial pulmonary fibrosis in Wistar rats. CCl4 (0.5 ml/kg) was intraperitoneally injected into rats twice a week for 8 weeks, and SAC (50, 100, or 200 mg/kg), N-acetyl cysteine (NAC, 200 or 600 mg/kg), or L-cysteine (CYS, 600 mg/kg) were orally administrated to rats everyday for 8 weeks. SAC significantly reduced the increases of transforming growth factor beta, lipid peroxides, AST, and ALT in plasma, induced by CCl4. Although CCl4 is mainly metabolized by hepatic cytochrome P450, CCl4 induced systemic inflammation and some organ fibrosis. SAC dose-dependently and significantly attenuated CCl4-induced systemic inflammation and fibrosis of lung. SAC also inhibited the decrease of thiol levels, the increase of inducible nitric oxide synthase expression, the infiltration of leukocytes, and the generation of reactive oxygen species in lungs. Although NAC and CYS attenuated CCl4-induced pulmonary inflammation and fibrosis, the order of preventive potency was SAC > NAC > CYS according to their applied doses. These results indicate that SAC is more effective than other cysteine compounds in reducing CCl4-induced lung injury, and might be useful in prevention of interstitial pulmonary fibrosis.},
}

Animals
Bronchoalveolar Lavage Fluid/cytology
Carbon Tetrachloride/*pharmacology
Cysteine/*analogs & derivatives/pharmacology
Enzyme Precursors/analysis
Glutathione/analysis
Hydroxyproline/analysis
Liver/pathology
Lung/chemistry
Male
Matrix Metalloproteinase 9/analysis
Nitric Oxide/urine
Nitric Oxide Synthase Type II/analysis
Oxidative Stress/*drug effects
Pulmonary Fibrosis/*chemically induced/*prevention & control
Rats
Rats, Wistar
Reactive Oxygen Species/metabolism
Sulfhydryl Compounds/blood
Transforming Growth Factor beta
Transforming Growth Factor beta1

@article {pmid16551579,
year = {2006},
author = {Floriano-Sánchez, E and Villanueva, C and Medina-Campos, ON and Rocha, D and Sánchez-González, DJ and Cárdenas-Rodríguez, N and Pedraza-Chaverrí, J},
title = {Nordihydroguaiaretic acid is a potent in vitro scavenger of peroxynitrite, singlet oxygen, hydroxyl radical, superoxide anion and hypochlorous acid and prevents in vivo ozone-induced tyrosine nitration in lungs.},
journal = {Free radical research},
volume = {40},
number = {5},
pages = {523-533},
doi = {10.1080/10715760500419365},
pmid = {16551579},
issn = {1071-5762},
mesh = {Animals ; Antioxidants/chemistry/pharmacology ; Dose-Response Relationship, Drug ; Free Radical Scavengers/chemistry/*pharmacology ; Hydroxyl Radical/metabolism ; Hypochlorous Acid/metabolism ; Immunohistochemistry ; Lung/*drug effects/metabolism ; Male ; Masoprocol/chemistry/*pharmacology ; Ozone/*pharmacology ; Peroxynitrous Acid/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Singlet Oxygen/metabolism ; Superoxides/metabolism ; Tyrosine/metabolism ; },
abstract = {The antioxidant nordihydroguaiaretic acid (NDGA) has recently become well known as a putative anticancer drug. In this paper, it was evaluated the in vitro peroxynitrite (ONOO(-)), singlet oxygen ((1)O(2)), hydroxyl radical (OH(v)), hydrogen peroxide (H(2)O(2)), superoxide anion and hypochlorous acid (HOCl) scavenging capacity of NDGA. It was found that NDGA scavenges: (a) ONOO(-) (IC(50) = 4 +/- 0.94 microM) as efficiently as uric acid; (b) (1)O(2) (IC(50) = 151 +/- 20 microM) more efficiently than dimethyl thiourea, lipoic acid, N-acetyl-cysteine and glutathione; (c) OH(v) (IC(50) = 0.15 +/- 0.02 microM) more efficiently than dimethyl thiourea, uric acid, trolox, dimethyl sulfoxide and mannitol, (d) (IC(50) = 15 +/- 1 microM) more efficiently than N-acetyl-cysteine, glutathione, tempol and deferoxamine and (e) HOCl (IC(50) = 622 +/- 42 microM) as efficiently as lipoic acid and N-acetyl-cysteine. NDGA was unable to scavenge H(2)O(2). In an in vivo study in rats, NDGA was able to prevent ozone-induced tyrosine nitration in lungs. It is concluded that NDGA is a potent in vitro scavenger of ONOO(-), (1)O(2), OH(v), and HOCl and is able to prevent lung tyrosine nitration in vivo.},
}

Animals
Antioxidants/chemistry/pharmacology
Dose-Response Relationship, Drug
Free Radical Scavengers/chemistry/*pharmacology
Hydroxyl Radical/metabolism
Hypochlorous Acid/metabolism
Immunohistochemistry
Lung/*drug effects/metabolism
Male
Masoprocol/chemistry/*pharmacology
Ozone/*pharmacology
Peroxynitrous Acid/metabolism
Rats
Rats, Wistar
Reactive Oxygen Species/*metabolism
Singlet Oxygen/metabolism
Superoxides/metabolism
Tyrosine/metabolism

@article {pmid11562447,
year = {2001},
author = {Guermonprez, L and Ducrocq, C and Gaudry-Talarmain, YM},
title = {Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitrite are differentially prevented by antioxidants.},
journal = {Molecular pharmacology},
volume = {60},
number = {4},
pages = {838-846},
pmid = {11562447},
issn = {0026-895X},
mesh = {Acetates/metabolism ; Acetylcholine/*antagonists & inhibitors/biosynthesis ; Animals ; Antioxidants/*pharmacology ; Biological Transport/drug effects ; Carbon Radioisotopes ; Choline/metabolism ; Choline O-Acetyltransferase/antagonists & inhibitors/*metabolism ; Drug Interactions ; Molsidomine/analogs & derivatives/pharmacology ; Nitrates/*pharmacology ; Oxidants/*pharmacology ; Reducing Agents/pharmacology ; Torpedo ; Tyrosine/*analogs & derivatives/*metabolism ; Uric Acid/pharmacology ; },
abstract = {Evidence of an overload of reactive oxygen species and peroxynitrite, a derivative of nitric oxide, in sporadic amyotrophic lateral sclerosis suggests that peroxynitrite could impair cholinergic functions. Because of the impossibility of obtaining synaptosomes from vertebrate neuromuscular junctions, we used cholinergic synaptosomes purified from Torpedo marmorata electroneurons to characterize the defects triggered by peroxynitrite in more detail. Addition of peroxynitrite or its donor 3-morpholinosydnonimine abolished high-affinity choline uptake and synthesis of acetylcholine from acetate. T. marmorata choline acetyltransferase (ChAT) was impaired to the same extent as bovine brain ChAT. A hallmark of peroxynitrite action is the nitration of tyrosine residues in proteins. Peroxynitrite induced a concentration-dependent appearance of nitrotyrosines in several neuronal proteins from synaptosomes and, more readily, from synaptic vesicles. Peroxynitrite also triggered tyrosine nitrations in purified ChAT. Peroxynitrite-dependent nitrations were impaired when synaptosomes were pretreated with thioreductants (glutathione, N-acetyl cysteine, dithiothreitol) or antioxidants (uric acid, melatonin, bovine serum albumin, desferrioxamine). Deleterious effects of peroxynitrite on choline transport and ChAT activity were prevented by the thioreductants but only partially by the antioxidants, suggesting a mechanism other than tyrosine nitration, which may involve cysteine oxidation. Further development of protective agents acting on choline transport and on ChAT activity may offer interesting therapeutic possibilities with respect to cholinergic dysfunction occurring in neurodegenerative diseases.},
}

Acetates/metabolism
Acetylcholine/*antagonists & inhibitors/biosynthesis
Animals
Antioxidants/*pharmacology
Biological Transport/drug effects
Carbon Radioisotopes
Choline/metabolism
Choline O-Acetyltransferase/antagonists & inhibitors/*metabolism
Drug Interactions
Molsidomine/analogs & derivatives/pharmacology
Nitrates/*pharmacology
Oxidants/*pharmacology
Reducing Agents/pharmacology
Torpedo
Tyrosine/*analogs & derivatives/*metabolism
Uric Acid/pharmacology

@article {pmid11500943,
year = {2001},
author = {Núñez, MT and Osorio, A and Tapia, V and Vergara, A and Mura, CV},
title = {Iron-induced oxidative stress up-regulates calreticulin levels in intestinal epithelial (Caco-2) cells.},
journal = {Journal of cellular biochemistry},
volume = {82},
number = {4},
pages = {660-665},
doi = {10.1002/jcb.1194},
pmid = {11500943},
issn = {0730-2312},
mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Caco-2 Cells ; Calcium-Binding Proteins/*biosynthesis/genetics ; Calreticulin ; Humans ; Intestinal Mucosa/*metabolism ; Iron/*pharmacology ; *Oxidative Stress ; Quercetin/pharmacology ; RNA, Messenger/biosynthesis ; Ribonucleoproteins/*biosynthesis/genetics ; Thiourea/analogs & derivatives/pharmacology ; Up-Regulation ; },
abstract = {Calreticulin, a molecular chaperone involved in the folding of endoplasmic reticulum synthesized proteins, is also a shock protein induced by heat, food deprivation, and chemical stress. Mobilferrin, a cytosolic isoform of calreticulin, has been proposed to be an iron carrier for iron recently incoming into intestinal cells. To test the hypothesis that iron could affect calreticulin expression, we investigated the possible associations of calreticulin with iron metabolism. To that end, using Caco-2 cells as a model of intestinal epithelium, the mass and mRNA levels of calreticulin were evaluated as a function of the iron concentration in the culture media. Increasing the iron content in the culture from 1 to 20 microM produced an increase in calreticulin mRNA and a two-fold increase in calreticulin. Increasing iron also induced oxidative damage to proteins, as assessed by the formation of 4-hydroxy-2-nonenal adducts. Co-culture of cells with the antioxidants quercetin, dimethyltiourea and N-acetyl cysteine abolished both the iron-induced oxidative damage and the iron-induced increase in calreticulin. We postulate that the iron-induced expression of calreticulin is part of the cellular response to oxidative stress generated by iron.},
}

Acetylcysteine/pharmacology
Antioxidants/pharmacology
Caco-2 Cells
Calcium-Binding Proteins/*biosynthesis/genetics
Calreticulin
Humans
Intestinal Mucosa/*metabolism
Iron/*pharmacology
*Oxidative Stress
Quercetin/pharmacology
RNA, Messenger/biosynthesis
Ribonucleoproteins/*biosynthesis/genetics
Thiourea/analogs & derivatives/pharmacology
Up-Regulation

@article {pmid10653978,
year = {2000},
author = {Chen, KD and Lai, MT and Cho, JH and Chen, LY and Lai, YK},
title = {Activation of p38 mitogen-activated protein kinase and mitochondrial Ca(2+)-mediated oxidative stress are essential for the enhanced expression of grp78 induced by the protein phosphatase inhibitors okadaic acid and calyculin A.},
journal = {Journal of cellular biochemistry},
volume = {76},
number = {4},
pages = {585-595},
pmid = {10653978},
issn = {0730-2312},
mesh = {Acetylcysteine/pharmacology ; Animals ; Calcium/*pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Carrier Proteins/genetics/*metabolism ; Egtazic Acid/analogs & derivatives/pharmacology ; Endoplasmic Reticulum Chaperone BiP ; Enzyme Inhibitors/pharmacology ; *Heat-Shock Proteins ; Imidazoles/pharmacology ; Marine Toxins ; Mitochondria/*metabolism ; *Mitogen-Activated Protein Kinases ; Molecular Chaperones/genetics/*metabolism ; Okadaic Acid/*pharmacology ; Oxazoles/*pharmacology ; Oxidative Stress/*drug effects ; Phosphoprotein Phosphatases/*antagonists & inhibitors ; Proline/analogs & derivatives/pharmacology ; Promoter Regions, Genetic ; Pyridines/pharmacology ; RNA, Messenger/metabolism ; Rats ; Ruthenium Red/pharmacology ; Thiocarbamates/pharmacology ; Transcriptional Activation/genetics ; Tumor Cells, Cultured ; p38 Mitogen-Activated Protein Kinases ; },
abstract = {We have reported that treatment with okadaic acid, a potent protein phosphatase inhibitor, has the ability to enhance the synthesis of the 78-kDa glucose-regulated protein (GRP78). This article reports our investigation of another protein phosphatase inhibitor, calyculin A, demonstrating the signaling pathways elicited by the protein phosphatase inhibitors that lead to the induction of grp78. Our data showed that the induction process is abolished by SB203580, a specific inhibitor of p38 mitogen-activated protein kinase (p38(MAPK)). Phosphorylation-activation of p38(MAPK) in the treated cells was indicated by its own phosphorylation, as shown by double Western blotting analyses and directly confirmed by the in vitro kinase assay using MAPK-activated protein kinase-2, a well-known downstream effector of p38(MAPK), as a substrate. The involvement of p38(MAPK) in this process is further substantiated by using transient transfection assays with a plasmid, pGRP78-Luc, which contains a 0.72-kbp stretch of the grp78 promoter. By exploiting the same transfection assay, we demonstrated that the up-regulation of the grp78 promoter by the protein phosphatase inhibitors is suppressed in the presence of the cytoplasmic calcium chelator bis(aminophenoxy)ethane N,N'-tetraacetic acid, the mitochondria calcium uniporter inhibitor ruthenium red as well as the antioxidants N-acetyl cysteine and pyrrolidinedithiocarbamate. Taken together, our results lead us to conclude that treatment with the protein phosphatase inhibitors would activate the signaling pathways involving p38(MAPK) and mitochondrial calcium-mediated oxidative stress and that these pathways must act in concert in order to confer the induction of grp78 by okadaic acid and calyculin A.},
}

Acetylcysteine/pharmacology
Animals
Calcium/*pharmacology
Calcium-Calmodulin-Dependent Protein Kinases/*metabolism
Carrier Proteins/genetics/*metabolism
Egtazic Acid/analogs & derivatives/pharmacology
Endoplasmic Reticulum Chaperone BiP
Enzyme Inhibitors/pharmacology
*Heat-Shock Proteins
Imidazoles/pharmacology
Marine Toxins
Mitochondria/*metabolism
*Mitogen-Activated Protein Kinases
Molecular Chaperones/genetics/*metabolism
Okadaic Acid/*pharmacology
Oxazoles/*pharmacology
Oxidative Stress/*drug effects
Phosphoprotein Phosphatases/*antagonists & inhibitors
Proline/analogs & derivatives/pharmacology
Promoter Regions, Genetic
Pyridines/pharmacology
RNA, Messenger/metabolism
Rats
Ruthenium Red/pharmacology
Thiocarbamates/pharmacology
Transcriptional Activation/genetics
Tumor Cells, Cultured
p38 Mitogen-Activated Protein Kinases

@article {pmid10653697,
year = {2000},
author = {Schmitz, S and Clayton, J and Nongthomba, U and Prinz, H and Veigel, C and Geeves, M and Sparrow, J},
title = {Drosophila ACT88F indirect flight muscle-specific actin is not N-terminally acetylated: a mutation in N-terminal processing affects actin function.},
journal = {Journal of molecular biology},
volume = {295},
number = {5},
pages = {1201-1210},
doi = {10.1006/jmbi.1999.3407},
pmid = {10653697},
issn = {0022-2836},
mesh = {Acetylation ; Acetylcysteine/metabolism ; Actins/*chemistry/genetics/*metabolism ; Actomyosin/metabolism ; Animals ; *Drosophila melanogaster ; Electrophoresis, Gel, Two-Dimensional ; Flight, Animal ; Genes, Insect/genetics/physiology ; Isoelectric Point ; Mass Spectrometry ; Methionine/metabolism ; Methylation ; Methylcellulose/metabolism ; Mutation/*genetics ; Phenotype ; Protein Isoforms/chemistry/genetics/metabolism ; *Protein Processing, Post-Translational ; Viscosity ; },
abstract = {Many eukaryotic proteins are co and post-translationally modified at their N termini by removal of one or two amino acid residues and N(alpha)-acetylation. Actins show two different forms of N-terminal processing dependent on their N-terminal sequence. In class II actins, which include muscle actins, the common primary sequence of Met-Cys-Asp-actin is processed to acetyl-Asp-actin. The functional significance of this in vivo is unknown. We have studied the indirect flight muscle-specific actin, ACT88F, of Drosophila melanogaster. Our results show that ACT88F is N-terminally processed in vivo as a class II actin by removal of the first two amino acid residues (Met and Cys), but that uniquely the N terminus is not acetylated. In addition we show that ACT88F is methylated, probably at His73. Flies carrying the mod(-) mutation fail to complete post-translational processing of ACT88F. We propose that the mod gene product is normally responsible for removing N-acetyl-cysteine from actin. The biological significance of this process is demonstrated by observations that retention of the N-acetyl-cysteine in ACT88F affects the flight muscle function of mod(-) flies. This suggests that the extreme N terminus affects actomyosin interactions in vivo, a proposal we have examined by in vitro motility assays of ACT88F F-actin from mod(-) flies. The mod(-) actin only moves in the presence of methylcellulose, a viscosity-enhancing agent, where it moves at velocities slightly, but significantly, reduced compared to wild-type. These data confirm that N-acetyl-cysteine at the N terminus affects actomyosin interactions, probably by reducing formation of the initial actomyosin collision complex, a process known to involve the actin N terminus.},
}

Acetylation
Acetylcysteine/metabolism
Actins/*chemistry/genetics/*metabolism
Actomyosin/metabolism
Animals
*Drosophila melanogaster
Electrophoresis, Gel, Two-Dimensional
Flight, Animal
Genes, Insect/genetics/physiology
Isoelectric Point
Mass Spectrometry
Methionine/metabolism
Methylation
Methylcellulose/metabolism
Mutation/*genetics
Phenotype
Protein Isoforms/chemistry/genetics/metabolism
*Protein Processing, Post-Translational
Viscosity

@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},
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.

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).

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.

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.

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 = {},
number = {},
pages = {},
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/ ; },
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/ ; },
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.

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.

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 μg/mL) despite a negative history. Three (0.2%) patients had levels above 100 μg/mL and were treated with N-acetylcysteine (NAC).

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/ ; },
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 & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/19440049.2025.2544327},
pmid = {40803992},
issn = {1944-0057},
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 {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 ; },
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.

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 Concepción, Chile (n = 140). Participants were randomised to receive daily doses of 2400 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.

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).

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 Bricki-Nigassa, N and Desilles, JP and Tomadesso, C and Vallée, E and Legros, H and Saint-Paul, LP and Touzé, E and De Lizarrondo, SM 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 = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.08.006},
pmid = {40796083},
issn = {1873-7544},
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},
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.},
}

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

@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 & 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.

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.

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.

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.},
}

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 & derivatives/pharmacology
Dopamine/metabolism
Autophagy/drug effects
*Parkinson Disease, Secondary/chemically induced/drug therapy

@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 = {},
number = {},
pages = {},
doi = {10.1002/mc.70028},
pmid = {40794023},
issn = {1098-2744},
support = {//This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)./ ; },
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 = {2025},
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 = {},
number = {},
pages = {},
pmid = {40788469},
issn = {1573-2584},
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.

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 mg twice daily) in Group I vs. probiotics (containing Streptococcus faecalis, Clostridium butyricum, Bacillus mesentericus, and Lactic Acid Bacillus) in Group II for 5 weeks. Primary outcomes included routine urine microscopy, culture, stent culture, and biofilm detection on the stent surfaces.

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.

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.

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.

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.

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.

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},
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 & pharmacology : CBP},
volume = {298},
number = {},
pages = {110319},
doi = {10.1016/j.cbpc.2025.110319},
pmid = {40780632},
issn = {1532-0456},
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},
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.

MATERIALS AND METHODS: Twenty TKA patients were randomized into two groups, one group receiving NAC (600 mg, 6 h pre-op) and Deferiprone (1000 mg, 2 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 min (T1) and 40 min (T2) after tourniquet inflation, and 5 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.

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.

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.},
}

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

@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 = {},
number = {},
pages = {},
doi = {10.1111/bph.70157},
pmid = {40759602},
issn = {1476-5381},
support = {NMRPG3M6171//National Science Research Project/ ; CMRPG3N1271//Chang Gung Memorial Hospital Research Project/ ; },
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.

EXPERIMENTAL APPROACH: Asthmatic patients with apnoea-hypopnoea index (AHI) ≥ 5 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-1α (HIF-1α) expression were evaluated by Western blotting and flow cytometry.

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% O₂ 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-α-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-1α (CAY10585) or phosphoinositide 3-kinase (LY294002) restored HDAC2 and corticosteroid sensitivity.

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},
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 & 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.

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.

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±6.04 vs -7.17±3.99; -44.43±4.21 vs -14.02±4.05, respectively, P<0.05).

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.},
}

Humans
*Acetylcysteine/therapeutic use/administration & 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

@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.},
}

*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

@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 = {},
number = {},
pages = {},
doi = {10.1007/s13181-025-01091-8},
pmid = {40745148},
issn = {1937-6995},
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.

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 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.

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 = 5.88, aOR = 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.

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 & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jop.70018},
pmid = {40744504},
issn = {1600-0714},
support = {2023-TDU-DİŞF-0006//İzmir Katip Çelebi University Scientific Research Projects Coordinatorship/ ; },
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.

METHODS: Sixty-four Wistar rats were randomly divided into four groups. 5 mm diameter wounds were created in the hard palates of the rats. 150 mg/kg/day NAC, 100 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 (α-SMA, FGF-2) were performed on wound tissues.

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 + LC groups on Day 5, and significantly differed between the LC and NAC groups on day 10. A slight elevation in α-SMA expression was observed in the NAC group on Day 5, while NAC + LC treatment significantly reduced α-SMA levels compared to NAC alone. FGF-2 expression showed an increasing trend in the NAC + 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 + LC group versus the NAC group on Day 5, and within the NAC group between Days 5 and 10.

CONCLUSION: Our findings have shown that LC in the late stage and NAC + 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.},
}

*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

@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.},
}