@article {pmid40256695,
year = {2025},
author = {Narvekar, PS and Shivanand, S and Patil, S and Raikar, S and Mallick, A and Doddwad, PK},
title = {Dentinal tubule penetration of a silicone-based endodontic sealer following N-acetyl cysteine intracanal medicament removal using ultrasonic agitation and laser activated irrigation - An in vitro study.},
journal = {Journal of conservative dentistry and endodontics},
volume = {28},
number = {3},
pages = {231-236},
pmid = {40256695},
issn = {2950-4708},
abstract = {CONTEXT: The removal of intracanal medicament is essential for sealer penetration and the success of endodontic therapy.

AIMS: To evaluate and compare the dentinal tubule penetration of a silicone-based endodontic sealer following N-acetyl cysteine (NAC) intracanal medicament removal using ultrasonic agitation and laser-activated irrigation.

MATERIALS AND METHODS: Eighty-one extracted single-rooted mandibular premolars were decoronated and prepared with ProTaper Universal rotary files up to MAF F3. To prepare medicament, NAC powder was mixed with propylene glycol in the ratio of 1:1, placed using a size #30 Lentulospiral, and specimens stored in an incubator for 14 days. The specimens were then instrumented with #30 Hedström and divided into three groups according to final irrigant activation techniques: Group I: Diode laser activation, Group II: Passive Ultrasonic agitation, Group III: No agitation (positive control). Canals were obturated with GuttaFlow bioseal sealer mixed with 0.1% Rhodamine B dye and gutta-percha cones and incubated for 7 days. The specimens were sectioned horizontally to obtain 1 mm thick sections from 2, 5, and 8 mm from the apex. Sections were examined under Confocal Laser Scanning Microscope to measure the depth of sealer penetration (in µm).

STATISTICAL ANALYSIS: One-way analysis of variance and Tukeys multiple post hoc test.

RESULTS: The highest mean depth of penetration of 728.52 µm was seen with Group I, followed by Group II and least was seen in Group III.

CONCLUSIONS: Diode laser activation group was most effective in the removal of NAC intracanal medicament from all the three regions of the root canal.},
}

@article {pmid40253238,
year = {2025},
author = {Zhou, Q and Lin, J and Li, Q},
title = {Study of high-strength, low-shrinkage dental resin composites with bifunctional polysilsesquioxane.},
journal = {Dental materials : official publication of the Academy of Dental Materials},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.dental.2025.03.012},
pmid = {40253238},
issn = {1879-0097},
abstract = {OBJECTIVES: The aim of this study was to develop a new composite resin to solve the problem of volume shrinkage of conventional dental restorative composite resins during the curing process in order to improve their mechanical properties and reduce the risk of restoration failure.

METHODS: We synthesized the mercapto-alkenyl click chemical reaction product (MN-POSS) of acrylate-based POSS (MAP-POSS) with N-Acetylcysteine (NAC) using a bifunctional polysilsesquioxane modification technique and improved its dispersion in the resin matrix by physicochemical methods. In addition, methacrylate-based epoxy POSS (ME-POSS) was further synthesized and used to modify acrylate dental resins to form a free radical-cation hybrid light-curing system.

RESULTS: The results showed that the composites modified with MN-POSS significantly improved mechanical strength, while the application of ME-POSS effectively reduced polymerization shrinkage, improved the water absorption and dissolution properties of the materials, and enhanced mechanical properties and hardness. This study provides new ideas and material solutions to improve the performance of dental restorative materials.

SIGNIFICANCE: Both of these improved solutions demonstrate the potential of bifunctional POSS as a modified filler, providing new ideas and methods for the design of future dental restorative materials.},
}

@article {pmid40252905,
year = {2025},
author = {Ricardi, LL and Zecchinati, F and Perdomo, VG and Basiglio, CL and García, F and Arana, MR and Villanueva, SSM},
title = {Oxidative stress promotes post-translational down-regulation of MRP2 in Caco-2 Cells: involvement of proteasomal degradation and toxicological implications.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {115459},
doi = {10.1016/j.fct.2025.115459},
pmid = {40252905},
issn = {1873-6351},
abstract = {The intestinal tract is highly susceptible to oxidative stress (OS), which impairs gut barrier function. Multidrug Resistance-Associated Protein 2 (MRP2) is a key efflux pump in the intestinal transcellular barrier, regulating toxicant and drug disposition. We here evaluated the effects of OS on MRP2 in Caco-2 cells treated with tert-butyl hydroperoxide (TBH). After 24 h, TBH 250 μM increased ROS production and lipid peroxidation while decreasing GSH content and SOD activity, confirming OS induction. Under these conditions, total MRP2 protein levels decreased, while P-gp levels remained unchanged. Correspondingly, MRP2 efflux activity decreased, impairing barrier function against ochratoxin A (OTA), a substrate of MRP2, and exacerbating OTA toxicity. Localization analysis revealed reduced apical MRP2 signal in TBH 250 group, with unchanged mRNA levels, indicating post-transcriptional regulation. Mechanistically, TBH induced rapid MRP2 internalization (30 min), mediated by cPKC and clathrin, without microtubule involvement, followed by proteasomal degradation at 24 h. Both processes were dependent on GSH depletion, as treatment with N-Acetyl-L-Cysteine (NAC) restored GSH levels, MRP2 localization, and activity. We provide here the first evidence that human intestinal MRP2 is post-translationally downregulated under specific OS conditions, highlighting its potential role in exacerbating xenobiotic absorption and toxicity in OS-related human diseases.},
}

@article {pmid40251236,
year = {2025},
author = {Poojary, KK and Kunhiraman, JP and Madhvacharya, VV and Kumari, S and Krishna, N and S, SP and K, RG and Mutalik, S and Ghani, NK and Kabekkodu, SP and Prasad, TSK and Adiga, SK and Kalthur, G},
title = {Bromodomain and extraterminal protein inhibitor JQ1 induces maturation arrest and disrupts the cytoplasmic organization in mouse oocytes under in vitro conditions.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13448},
pmid = {40251236},
issn = {2045-2322},
mesh = {Animals ; *Oocytes/drug effects/metabolism/cytology ; Mice ; *Azepines/pharmacology ; *Triazoles/pharmacology ; Female ; Endoplasmic Reticulum Chaperone BiP ; *Cytoplasm/drug effects/metabolism ; In Vitro Oocyte Maturation Techniques ; Oxidative Stress/drug effects ; Oogenesis/drug effects ; },
abstract = {JQ1, a small cell-permeable molecule is known for its potent inhibitory action on bromodomain and extraterminal (BET) proteins. Although earlier studies have shown its inhibitory effect on male gametogenesis, limited information is available about its influence on oocyte development. Since BET genes are known to exhibit regulatory functions on oocyte development and maturation, the present study aimed to investigate the effect of JQ1 on oocyte developmental competence under in vitro conditions. Germinal vesicle (GV) stage oocytes were collected from adult Swiss albino mice and subjected to in vitro maturation (IVM) in the presence of various concentrations of JQ1 (25, 50, and 100 μM). The metaphase II (MII) stage oocytes were assessed for cytoplasmic organization and functional competence at 24 h after IVM. A significant decrease in nuclear maturation (at 50 and 100 μM), symmetric cytokinesis, altered distribution of mitochondria and cortical granules, poorly organized actin and meiotic spindle, misaligned chromosomes, and elevated endoplasmic reticulum (ER) stress and oxidative stress was observed in JQ1-exposed oocytes. Presence of N-acetyl cysteine (NAC), in IVM medium resulted in significant reduction in JQ1-induced oxidative stress and symmetric cytokinesis. Administration of JQ1 (50 mg/kg, intra peritoneal) to adult Swiss albino mice primed with pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) did not affect the ovulation. However, a high degree of oocyte degeneration, elevated intracellular reactive oxygen species (ROS), and GRP78 expression was observed in JQ1-administered mice. In conclusion, our study reveals that BET inhibitor JQ1 has detrimental effects on oocyte function and development.},
}

Animals
*Oocytes/drug effects/metabolism/cytology
Mice
*Azepines/pharmacology
*Triazoles/pharmacology
Female
Endoplasmic Reticulum Chaperone BiP
*Cytoplasm/drug effects/metabolism
In Vitro Oocyte Maturation Techniques
Oxidative Stress/drug effects
Oogenesis/drug effects

@article {pmid40243461,
year = {2025},
author = {Bilski, R and Nuszkiewicz, J},
title = {Antioxidant Therapies as Emerging Adjuncts in Rheumatoid Arthritis: Targeting Oxidative Stress to Enhance Treatment Outcomes.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
pmid = {40243461},
issn = {1422-0067},
mesh = {Humans ; *Arthritis, Rheumatoid/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *Antioxidants/therapeutic use/pharmacology ; Animals ; Reactive Oxygen Species/metabolism ; Antirheumatic Agents/therapeutic use/pharmacology ; Treatment Outcome ; },
abstract = {Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammation and progressive joint destruction. Recent data underscore oxidative stress as a primary factor in the pathophysiology of rheumatoid arthritis, intensifying inflammatory processes and tissue damage via the overproduction of reactive oxygen species (ROS) and compromised antioxidant defenses. Current therapies, including disease-modifying antirheumatic drugs (DMARDs), primarily target immune dysregulation but fail to address oxidative stress, necessitating novel adjunctive treatment strategies. This review explores the potential of antioxidant-based therapies as complementary approaches to RA management. Natural compounds such as curcumin, resveratrol, sulforaphane, and propolis exhibit strong anti-inflammatory and antioxidative properties by modulating redox-sensitive pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase (HO-1). N-acetylcysteine (NAC) replenishes intracellular glutathione, enhancing cellular resilience against oxidative stress. Additionally, molecular hydrogen (H2) selectively neutralizes harmful ROS, reducing oxidative damage and inflammation. The role of vitamin supplementation (D, B12, C, and K) in regulating immune responses and protecting joint structures is also discussed. This review aims to evaluate the efficacy and potential clinical applications of antioxidant therapies in RA, emphasizing their role in mitigating oxidative damage and improving treatment outcomes. While preliminary findings are promising, further clinical trials are needed to establish standardized dosing, long-term safety, and their integration into current RA treatment protocols.},
}

Humans
*Arthritis, Rheumatoid/drug therapy/metabolism
*Oxidative Stress/drug effects
*Antioxidants/therapeutic use/pharmacology
Animals
Reactive Oxygen Species/metabolism
Antirheumatic Agents/therapeutic use/pharmacology
Treatment Outcome

@article {pmid40243112,
year = {2025},
author = {She, Z and Zeng, F and Wu, S},
title = {A zwitterionic chromophore as both a biomarker-activatable optical imaging probe and a therapeutic agent for the detection and treatment of acute lung injury with bacterial infection.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5bm00419e},
pmid = {40243112},
issn = {2047-4849},
abstract = {Acute lung injury (ALI), often complicated by bacterial infection, poses significant challenges in diagnosis and treatment. Nitric oxide (NO) plays a key role in the pathophysiology of ALI, making it an ideal biomarker for early detection. In this study, we developed a zwitterionic chromophore, ZW-N, designed as both a biomarker-activatable imaging probe and a therapeutic agent for ALI with bacterial infection. The chromophore ZW-N integrates quaternary ammonium groups for antimicrobial activity and zwitterionic sulfonate groups to enhance biocompatibility and water solubility. Built on a flexible propanyl linker that couples two heptamethine cyanine dyes, ZW-N enables biomarker-responsive dual-modal imaging via optoacoustic (OA) imaging and near-infrared second-window (NIR-II) fluorescence imaging. Moreover, the chromophore ZW-N demonstrates therapeutic efficacy when combined with the clinically used antioxidant N-acetylcysteine (NAC) to treat ALI with bacterial infection. This dual-functional chromophore offers a promising platform for non-invasive, real-time monitoring of ALI, providing significant potential for improved detection and a more effective treatment strategy.},
}

@article {pmid40240934,
year = {2025},
author = {Kim, JH and Lee, JH and Koo, YJ and Song, JW},
title = {N-actylcysteine inhibits diethyl phthalate-induced inflammation via JNK and STAT pathway in RAW264.7 macrophages.},
journal = {BMC molecular and cell biology},
volume = {26},
number = {1},
pages = {12},
pmid = {40240934},
issn = {2661-8850},
support = {2022R1I1A1A01068466//National Research Foundation of Korea/ ; 2022R1A2C1011500//National Research Foundation of Korea/ ; 2022R1F1A1075191//National Research Foundation of Korea/ ; },
mesh = {Animals ; Mice ; RAW 264.7 Cells ; *Phthalic Acids/toxicity ; *Macrophages/drug effects/metabolism ; *Inflammation/chemically induced/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; Cyclooxygenase 2/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Glutathione/metabolism ; Dinoprostone/metabolism ; *MAP Kinase Signaling System/drug effects ; Nitric Oxide/metabolism ; Signal Transduction/drug effects ; *STAT Transcription Factors/metabolism ; STAT3 Transcription Factor/metabolism ; *Acetylcysteine/pharmacology ; },
abstract = {BACKGROUND: Phthalates are plasticizers that cause inflammation in several cell types and adversely affect the health of humans and animals. Nacetylcysteine (NAC) has been shown to exert antioxidant effects in various diseases. However, the effect of NAC on diethyl phthalate (DEP)-induced toxicity in macrophages has not yet been elucidated. In this study, we investigated the effect and underlying mechanisms of NAC on DEP-induced inflammation in RAW264.7 macrophages. RAW264.7 macrophages were pretreated with NAC for 2 h followed by exposure to DEP. We investigated the effect of NAC on NO, reactive oxygen species (ROS), prostaglandin E2 (PGE2), and glutathione (GSH) levels following DEP exposure. In addition, pathway-related genes including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription (STAT) were evaluated using western blot.

RESULTS: Treatment with 100 and 300 µM DEHP, DBP, and DEP significantly increased the protein levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) compared with those in the control group. However, NAC pretreatment downregulated the levels of NO, PGE2, and ROS, elevated GSH levels, and suppressed the mRNA levels of inflammatory cytokines such as interleukin (IL)-1β, IL-6, COX-2, and iNOS compared with those in the DEP-treated group. In addition, NAC significantly reduced the levels of p-JNK and p-STAT1/3 in RAW264.7 macrophages treated with DEP.

CONCLUSIONS: NAC pretreatment inhibits DEP-induced inflammation via the MAPK/JNK and STAT1/3 pathways in macrophages.},
}

Animals
Mice
RAW 264.7 Cells
*Phthalic Acids/toxicity
*Macrophages/drug effects/metabolism
*Inflammation/chemically induced/metabolism/drug therapy
Reactive Oxygen Species/metabolism
Cyclooxygenase 2/metabolism
Nitric Oxide Synthase Type II/metabolism
Glutathione/metabolism
Dinoprostone/metabolism
*MAP Kinase Signaling System/drug effects
Nitric Oxide/metabolism
Signal Transduction/drug effects
*STAT Transcription Factors/metabolism
STAT3 Transcription Factor/metabolism
*Acetylcysteine/pharmacology

@article {pmid40236464,
year = {2024},
author = {Wu, J and Maller, B and Kaul, R and Galabow, A and Bryan, A and Neuwelt, A},
title = {High-Dose Acetaminophen as a Treatment for Cancer.},
journal = {Livers},
volume = {4},
number = {1},
pages = {84-91},
pmid = {40236464},
issn = {2673-4389},
support = {IK2 BX004914/BX/BLRD VA/United States ; },
abstract = {The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity-in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent "reverse translational" studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted.},
}

@article {pmid40235406,
year = {2025},
author = {Yildirim, B and Erturk, C and Buyukdogan, H and Saritas, TB and Yildirim Erdogan, N and Ertem, F},
title = {Effect of N-acetylcysteine on fracture healing in rat femoral diaphysis: A histopathological, radiological, and biomechanical analysis.},
journal = {Joint diseases and related surgery},
volume = {36},
number = {2},
pages = {283-292},
doi = {10.52312/jdrs.2025.1975},
pmid = {40235406},
issn = {2687-4792},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Male ; Rats, Wistar ; *Fracture Healing/drug effects ; *Femoral Fractures/diagnostic imaging/pathology/physiopathology/drug therapy/surgery ; Rats ; Diaphyses/diagnostic imaging/drug effects/pathology/injuries ; Biomechanical Phenomena ; Disease Models, Animal ; *Antioxidants/pharmacology ; *Femur/diagnostic imaging/drug effects/pathology/physiopathology ; Radiography ; },
abstract = {OBJECTIVES: The aim of this study was to examine the effect of N-acetylcysteine (NAC), which has antioxidant properties, on healing in a rat femoral diaphysis fracture model.

MATERIALS AND METHODS: Twenty-four male Wistar-Hannover rats were randomly divided into two groups: experimental (n=12) and control groups (n=12). An open femur fracture model (osteotomy) was applied to the right femora of both groups. Fixation was performed with Kirschner wire. While intraperitoneal NAC treatment was given to the experimental group for 21 days after surgery, an equal volume of intraperitoneal saline injection was administered to the control group. At the end of this period, the femurs obtained from the sacrificed animals were examined histopathologically, radiologically, and biomechanically. Huo scoring was used for histopathological examination. The samples were examined radiologically according to the Radiographic Union Scale in Tibial Fractures (RUST) scoring system. The three-point bending test was used for the biomechanical examination.

RESULTS: According to the third-week results, NAC could histopathologically contribute positively to fracture healing in rats (p=0.003 and p<0.05, respectively). Considering radiological and biomechanical parameters, no significant difference was observed between the groups in terms of healing (p>0.05). However, a positive significant correlation (67.7%) was found between histopathological results and radiological findings (p=0.016 and p<0.05, respectively).

CONCLUSION: Our study results indicate that NAC may have a histopathologically positive effect on the healing process in rat traumatic fractures. Based on these findings, NAC preparations may be used as a supportive agent in the treatment of fractures. Further clinical studies are needed.},
}

Animals
*Acetylcysteine/pharmacology
Male
Rats, Wistar
*Fracture Healing/drug effects
*Femoral Fractures/diagnostic imaging/pathology/physiopathology/drug therapy/surgery
Rats
Diaphyses/diagnostic imaging/drug effects/pathology/injuries
Biomechanical Phenomena
Disease Models, Animal
*Antioxidants/pharmacology
*Femur/diagnostic imaging/drug effects/pathology/physiopathology
Radiography

@article {pmid40229128,
year = {2025},
author = {Li, P and Meng, X and Lu, T and Sun, C and Song, G},
title = {Synergistic Effect of ROS and p38 MAPK in Apoptosis of TM4 Cells Induced by Titanium Dioxide Nanoparticles.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.4789},
pmid = {40229128},
issn = {1099-1263},
support = {82460651//National Natural Science Foundation of China/ ; 21966027//National Natural Science Foundation of China/ ; 2023AB049//Science and Technology Planning Project of Xinjiang Production and Construction Corps/ ; },
abstract = {The adverse effects of titanium dioxide nanoparticles (TiO2 NPs) on the integrity of the blood-testis barrier (BTB) are widely recognized. However, the underlying mechanisms remain incompletely understood. The integrity of the BTB is imperative for the preservation of male reproductive health. TM4 cells, which are major component of the BTB, play a critical role in its integrity. The apoptosis of TM4 cells is closely associated with the disruption of the BTB. Therefore, we selected TM4 cells as experimental models to investigate the apoptosis induced by TiO2 NPs and the underlying mechanisms. Cell viability, excessive production of reactive oxygen species (ROS), activation of p38 mitogen-activated protein kinase (MAPK) pathway, and apoptosis-related protein expression levels were determined under various concentrations (50, 100, 150, and 200 μg/mL) of TiO2 NPs exposure. The results indicate that TiO2 NPs induced the overproduction of ROS and activated the p38 MAPK signaling pathway, which subsequently led to apoptosis. The ROS scavenger N-acetylcysteine (NAC) was able to suppress the activation of p38 MAPK pathway induced by TiO2 NPs, while the p38 MAPK inhibitor SB203580 mitigated TiO2 NPs-induced ROS overproduction and subsequent apoptosis, suggesting an interplay between ROS overproduction and p38 MAPK pathway activation. In summary, TiO2 NPs induced mitochondrial apoptosis via the ROS-p38 MAPK axis. A positive feedback regulatory mechanism exists between the two processes, promoting apoptosis in TM4 cells through a synergistic effect.},
}

@article {pmid40227392,
year = {2025},
author = {Amador-Martínez, I and Aparicio-Trejo, OE and Aranda-Rivera, AK and Bernabe-Yepes, B and Medina-Campos, ON and Tapia, E and Cortés-González, CC and Silva-Palacios, A and Roldán, FJ and León-Contreras, JC and Hernández-Pando, R and Saavedra, E and Gonzaga-Sánchez, JG and Ceja-Galicia, ZA and Sánchez-Lozada, LG and Pedraza-Chaverri, J},
title = {Effect of N-Acetylcysteine in Mitochondrial Function, Redox Signaling, and Sirtuin 3 Levels in the Heart During Cardiorenal Syndrome Type 4 Development.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {3},
pages = {},
pmid = {40227392},
issn = {2076-3921},
support = {CBF2023-2024-190//CONAHCYT/ ; IN200922 and IN202725//PAPIIT-UNAM/ ; 21-1250//Instituto Nacional de Cardiología Ignacio Chávez/ ; },
abstract = {Type 4 cardiorenal syndrome (CRS-4) is a pathology in which chronic kidney disease (CKD) triggers the development of cardiovascular disease. CKD pathophysiology produces alterations that can affect the bioenergetics of heart mitochondria, causing oxidative stress and reducing antioxidant glutathione (GSH) levels. GSH depletion alters protein function by affecting post-translational modifications such as S-glutathionylation (RS-SG), exacerbating oxidative stress, and mitochondrial dysfunction. On the other hand, N-acetylcysteine (NAC) is an antioxidant GSH precursor that modulates oxidative stress and RS-SG. Moreover, recent studies have found that NAC can activate the Sirtuin 3 (SIRT3) deacetylase in diseases. However, the role of NAC and its effects on mitochondrial function, redox signaling, and SIRT3 modifications in the heart during CRS-4 have not been studied. This study aimed to investigate the role of NAC in mitochondrial function, redox signaling, and SIRT3 in the hearts of animals with CRS-4 at two months of follow-up. Our results showed that the oral administration of NAC (600 mg/kg/day) improved blood pressure and reduced cardiac fibrosis. NACs' protective effect was associated with preserving cardiac mitochondrial bioenergetics and decreasing these organelles' hydrogen peroxide (H2O2) production. Additionally, NAC increased GSH levels in heart mitochondria and regulated the redox state, which coincided with an increase in nicotinamide adenine dinucleotide oxidized (NAD[+]) levels and a decrease in mitochondrial acetylated lysines. Finally, NAC increased SIRT3 levels and the activity of superoxide dismutase 2 (SOD-2) in the heart. Thus, treatment with NAC decreases mitochondrial alterations, restores redox signaling, and decreases SIRT3 disturbances during CRS-4 through an antioxidant defense mechanism.},
}

@article {pmid40220949,
year = {2025},
author = {Sztolsztener, K and Michalak, D and Chabowski, A},
title = {N-acetylcysteine influence on PI3K/Akt/mTOR and sphingolipid pathways in rats with MASLD induced by HFD: a promising new therapeutic purpose.},
journal = {Molecular and cellular endocrinology},
volume = {603},
number = {},
pages = {112545},
doi = {10.1016/j.mce.2025.112545},
pmid = {40220949},
issn = {1872-8057},
abstract = {Sphingolipid and glucose metabolism play important roles in the induction and progression of severe liver disorders like metabolic dysfunction-associated steatotic liver disease (MASLD). The perturbation in sphingolipid formation may improve the liver structure and functioning and may constitute the potential therapeutic options for the development of simple steatosis and its progression to steatohepatitis. This study aims to assess the influence of N-acetylcysteine (NAC) on the sphingolipid and insulin signaling pathways in rats subjected to standard or high-fat diets. Sphingolipid level was measured using high-performance liquid chromatography (HPLC). A multiplex assay kit determined the level of phosphorylated form of proteins included in the PI3K/Akt/mTOR pathway. The immunoblotting estimated the expression of proteins from sphingolipid and insulin transduction pathways. A histological Oil red O staining was used to assess the hepatic accumulation of lipid droplets. Molecular docking was applied to showcase NAC interaction with PI3K/Akt/mTOR pathway proteins. NAC decreased dihydroceramide and ceramide levels and increased phosphorylation of sphingosine and sphinganine. This antioxidant also enhanced phosphorylated Akt, GSK3α/β, and P70 S6 kinase and decreased phosphorylated S6RP. In silico docking analysis of insulin signaling molecules evidenced the higher binding affinity of NAC with all tested proteins, i.e., IRS1, PTEN, Akt, GSK3α/β, P70 S6 kinase, and S6RP, suggesting a potential protective influence on insulin resistance development, which is one of the criteria for MASLD diagnosing. Based on these data, NAC improved the hepatic insulin sensitivity and sphingolipid synthesis and storage, improving and restoring glucose homeostasis.},
}

@article {pmid40220169,
year = {2025},
author = {Ciftel, E and Mercantepe, T and Ciftel, S and Karakas, SM and Aktepe, R and Yilmaz, A and Mercantepe, F},
title = {Somatostatin and N-acetylcysteine on testicular damage triggered by ischemia reperfusion: cellular protection and antioxidant effects.},
journal = {Hormones (Athens, Greece)},
volume = {},
number = {},
pages = {},
pmid = {40220169},
issn = {2520-8721},
abstract = {Ischemia-reperfusion (I/R) injury is a significant cause of testicular damage, leading to infertility and other reproductive dysfunctions. Antioxidant therapies have emerged as a potential intervention to mitigate oxidative stress and cellular damage. This study investigates the effects of somatostatin (SST) and N-acetylcysteine (NAC) on testicular damage induced by I/R, focusing on their antioxidant and cellular protective effects. Twenty-four male rats were divided into four groups, as follows: sham operated, I/R injury, I/R + somatostatin treatment, and I/R + NAC treatment. A testicular I/R injury was induced surgically, followed by either SST or NAC administration. Testicular tissues were assessed histopathologically using hematoxylin and eosin staining and employing Johnson's biopsy scoring. Immunohistochemical analyses were performed for caspase- 3, 8-hydroxy- 2'-deoxyguanosine (8-OHdG), testis-specific histone 2B, and testosterone to evaluate apoptosis, oxidative DNA damage, cellular proliferation, and steroidogenesis, respectively. Serum levels of testosterone and follicle-stimulating hormone (FSH) were measured by biochemical analysis. The results showed that both SST and NAC treatments significantly ameliorated histopathological damage and reduced the levels of caspase- 3 and 8-OHdG, indicating reduced apoptosis and oxidative DNA damage. Furthermore, increased testis-specific histone 2B positivity suggested enhanced cellular proliferation. Notably, administration of SST decreased testosterone positivity in the testis, whereas NAC treatment increased it. However, no significant differences in serum testosterone levels were observed between the NAC and SST groups. In addition, serum FSH levels of the I/R + SST group were found to be significantly higher than those of the control group. SST and NAC exhibit protective effects against testicular damage induced by I/R, as evidenced by their antioxidant and anti-apoptotic properties. The differential impact on testosterone positivity in the testis tissue highlights distinct underlying mechanisms, warranting further investigation. Despite these promising findings, the lack of significant changes in serum hormone levels calls for additional studies to fully elucidate the therapeutic potential and mechanistic pathways of SST and NAC in the context of testicular I/R injury.},
}

@article {pmid40218498,
year = {2025},
author = {Jensch, H and Setford, S and Thomé, N and Srikanthamoorthy, G and Weingärtner, L and Grady, M and Holt, E and Pfützner, A},
title = {Dynamic Interference Testing-Unexpected Results Obtained with the Abbott Libre 2 and Dexcom G6 Continuous Glucose Monitoring Devices.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {7},
pages = {},
pmid = {40218498},
issn = {1424-8220},
support = {951933 (ForgetDiabetes)//European Union's Horizon 2020 research and innovation program/ ; Unrestricted grant//Lifescan Global Corp./ ; },
mesh = {*Blood Glucose Self-Monitoring/instrumentation/methods ; Humans ; *Blood Glucose/analysis ; *Biosensing Techniques/methods ; Continuous Glucose Monitoring ; },
abstract = {BACKGROUND: Sensors for continuous glucose monitoring (CGM) are now commonly used by people with type 1 and type 2 diabetes. However, the response of these devices to potentially interfering nutritional, pharmaceutical, or endogenous substances is barely explored. We previously developed an in vitro test method for continuous and dynamic CGM interference testing and herein explore the sensitivity of the Abbott Libre2 (L2) and Dexcom G6 (G6) sensors to a panel of 68 individual substances.

METHODS: In each interference experiment, L2 and G6 sensors were exposed in triplicate to substance gradients from zero to supraphysiological concentrations at a stable glucose concentration of 200 mg/dL. YSI Stat 2300 Plus was used as the glucose reference method. Interference was presumed if the CGM sensors showed a mean bias of at least ±10% from baseline with a tested substance at any given substance concentration.

RESULTS: Both L2 and G6 sensors showed interference with the following substances: dithiothreitol (maximal bias from baseline: L2/G6: +46%/-18%), galactose (>+100%/+17%), mannose (>+100%/+20%), and N-acetyl-cysteine (+11%/+18%). The following substances were found to interfere with L2 sensors only: ascorbic acid (+48%), ibuprofen (+14%), icodextrin (+10%), methyldopa (+16%), red wine (+12%), and xylose (>+100%). On the other hand, the following substances were found to interfere with G6 sensors only: acetaminophen (>+100%), ethyl alcohol (+12%), gentisic acid (+18%), hydroxyurea (>+100%), l-cysteine (-25%), l-Dopa (+11%), and uric acid (+33%). Additionally, G6 sensors could subsequently not be calibrated for use after exposure to dithiothreitol, gentisic acid, l-cysteine, and mesalazine (sensor fouling).

CONCLUSIONS: Our standardized dynamic interference testing protocol identified several nutritional, pharmaceutical and endogenous substances that substantially influenced L2 and G6 sensor signals. Clinical trials are now necessary to investigate whether our findings are of relevance during routine care.},
}

*Blood Glucose Self-Monitoring/instrumentation/methods
Humans
*Blood Glucose/analysis
*Biosensing Techniques/methods
Continuous Glucose Monitoring

@article {pmid40207512,
year = {2025},
author = {Zhou, Y and Sha, J and Xu, B and Zhang, K and Wang, Y and Jiang, S and Zhang, H and Xu, S},
title = {Identification and Characterization of Dacomitinib Metabolites in Rats by Liquid Chromatography Combined With Q-Exactive-Orbitrap High Resolution Mass Spectrometry.},
journal = {Biomedical chromatography : BMC},
volume = {39},
number = {5},
pages = {e70075},
doi = {10.1002/bmc.70075},
pmid = {40207512},
issn = {1099-0801},
mesh = {Animals ; Rats ; Microsomes, Liver/metabolism ; Rats, Sprague-Dawley ; Chromatography, Liquid/methods ; *Quinazolinones/metabolism/analysis/chemistry/urine/pharmacokinetics ; Male ; *Mass Spectrometry/methods ; Tandem Mass Spectrometry/methods ; },
abstract = {Dacomitinib is an irreversible inhibitor targeting epidermal growth factor receptor, which has been developed for the treatment of metastatic non-small cell lung cancer (NSCLC). The aim of this study was to establish a reliable liquid chromatography combined with high resolution mass spectrometric method to identify and characterize the metabolites of dacomitinib in rats. In vitro metabolism was investigated through 60-min incubation with rat liver microsomes, while in vivo analysis involved bile and urine sample collection following a single oral 10 mg/kg dose. A total of 18 metabolites, were structurally elucidated through accurate MS measurements, MS[2] spectral interpretation, and fragmentation pattern analysis, including two GSH conjugates and two N-acetyl-cysteine conjugates. Among these metabolites, a total of 12 metabolites were first reported, i.e., M1, M2, M3, M7, M9, M10, M11, M13, M14, M15, M16, and M17. The parent drug remained the predominant species across all metrices. The primary metabolic pathways included: oxidative defluorination, O-demethylation, N-dealkylation, oxidative deamination, piperidin ring opening, N-oxygenation, lactam formation, dehydrogenation, and hydroxylation. Phase II biotransformation pathways included GSH conjugation and N-acetyl-cysteine conjugation. These findings enhance understanding of dacomitinib's metabolic fate, providing critical insights into its elimination mechanisms, and supporting subsequent evaluation of therapeutic efficacy and safety profiles.},
}

Animals
Rats
Microsomes, Liver/metabolism
Rats, Sprague-Dawley
Chromatography, Liquid/methods
*Quinazolinones/metabolism/analysis/chemistry/urine/pharmacokinetics
Male
*Mass Spectrometry/methods
Tandem Mass Spectrometry/methods

@article {pmid40207489,
year = {2025},
author = {Efati, M and Sahebkar, A and Tavallaei, S and Alidadi, S and Hosseini, H and Hamidi-Alamdari, D},
title = {Protective effect of Leuco-methylene blue against acetaminophen-induced liver injury: an experimental study.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/01480545.2025.2485347},
pmid = {40207489},
issn = {1525-6014},
abstract = {Acetaminophen is a commonly used drug for mild to moderate pain relief; however, acetaminophen toxicity due to the formation of toxic metabolites is a major cause of drug-induced liver injury. Methylene blue is an FDA-approved drug for the treatment of methemoglobinemia and has potential applications in the treatment of carbon monoxide and cyanide poisoning. Leuco-methylene blue, a colorless form of methylene blue, is more effective in entering cells and counteracting oxidative stress, making it a valuable option in regulating mitochondrial function and ATP production. In this study, we aimed to evaluate the effect of LMB on liver damage caused by acetaminophen toxicity. Thirty-six rats were divided into six groups: control, APAP, NAC, LMB, MB, and NAC+LMB. All groups except the control received acetaminophen (1500 mg/kg), followed by treatments with NAC (100 mg/kg), LMB (5 mg/kg), MB (5 mg/kg), and NAC+LMB after 3 hours. The rats were sacrificed 24 hours post-acetaminophen administration. LMB significantly reduced serum levels of liver enzymes (ALT, AST, and ALP) and increased the expression of genes involved in mitochondrial biogenesis and antioxidant defense (PGC-1, Nrf2, and Tfam). Additionally, LMB significantly increased total antioxidant capacity and glutathione reductase levels, decreased the prooxidant-antioxidant balance (PAB), and reduced the expression of inflammatory cytokines (IL-6 and TNF-α) in the liver tissue. LMB effectively reduced the severity of acetaminophen-induced liver damage through antioxidant and anti-inflammatory effects. LMB can effectively ameliorate APAP-induced toxicity in rats, with comparable efficacy to N-acetylcysteine with respect to most complications of acetaminophen-induced toxicity in rats.},
}

@article {pmid40205270,
year = {2025},
author = {Gouda, AR and El-Bassiouny, NA and Salahuddin, A and Hamouda, EH and Kassem, AB},
title = {Repurposing of high-dose N-acetylcysteine as anti-inflammatory, antioxidant and neuroprotective agent in moderate to severe traumatic brain injury patients: a randomized controlled trial.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40205270},
issn = {1568-5608},
abstract = {INTRODUCTION: Traumatic brain injury (TBI) refers to an impact of the brain within the skull resulting in an altered mental state. The study aim is to determine the effect of a high dose of N-acetylcysteine (NAC) on biochemical and inflammatory markers of neuronal damage and clinical outcomes in patients with moderate to severe TBI.

METHODS: A randomized open label-controlled trial was conducted on 40 patients with moderate to severe TBI patients presented to the emergency unit within < 24 h since the trauma occurred and randomized into NAC and control groups 20 patients each. Serum samples for evaluation of biomarkers: malondialdehyde (MDA), interleukin-6 (IL-6), neuron-specific enolase (NSE), and S100B were withdrawn at baseline and on day 7. The patients were followed for 7 days and evaluated clinically by the Glasgow Coma Scale (GCS).

RESULTS: There was a significant decrease in NSE and MDA levels on day 7 from baseline in NAC group (p < 0.001 and p < 0.001). Also, S100B and IL-6 decreased significantly in NAC group on day 7 from baseline (p = 0.003 and p < 0.001 consequently) compared to control group. Moreover, patients in NAC group showed a significantly shorter length of stay at intensive care unit (ICU) (p = 0.038). There was a significant increase in GCS in NAC group on day 7 from baseline (p = 0.001).

CONCLUSION: Adjunctive early use of high-dose NAC significantly reduced inflammatory and oxidative markers and had neuroprotective effect which may be a novel treatment option for moderate to severe TBI patients.

TRIAL REGISTRATION: Pactr.org identifier: (PACTR202209548995270) on 14 September 2022.},
}

@article {pmid40202448,
year = {2025},
author = {Ommi, NB and Mattocks, DAL and Kalecký, K and Bottiglieri, T and Nichenametla, SN},
title = {Pharmacological recapitulation of the lean phenotype induced by the lifespan-extending sulfur amino acid-restricted diet.},
journal = {Aging},
volume = {17},
number = {},
pages = {},
doi = {10.18632/aging.206237},
pmid = {40202448},
issn = {1945-4589},
abstract = {Sulfur amino acid restriction (SAAR), lowering the dietary concentration of sulfur amino acids methionine and cysteine, induces strong anti-obesity effects in rodents. Due to difficulties in formulating the SAAR diet for human consumption, its translation is challenging. Since our previous studies suggest a mechanistic role for low glutathione (GSH) in SAAR-induced anti-obesity effects, we investigated if the pharmacological lowering of GSH recapitulates the lean phenotype in mice on a sulfur amino acid-replete diet. Male obese C57BL6/NTac mice were fed high-fat diets with 0.86% methionine (CD), 0.12% methionine (SAAR), SAAR diet supplemented with a GSH biosynthetic precursor, N-acetylcysteine in water (NAC), and CD supplemented with a GSH biosynthetic inhibitor, DL-buthionine-(S, R)-sulfoximine in water (BSO). The SAAR diet lowered hepatic GSH but increased Nrf2, Phgdh, and serine. These molecular changes culminated in lower hepatic lipid droplet frequency, epididymal fat depot weights, and body fat mass; NAC reversed all these changes. BSO mice exhibited all SAAR-induced changes, with two notable differences, i.e., a smaller effect size than that of the SAAR diet and a higher predilection for molecular changes in kidneys than in the liver. Metabolomics data indicate that BSO and the SAAR diet induce similar changes in the kidney. Unaltered plasma aspartate and alanine transaminases and cystatin-C indicate that long-term continuous administration of BSO is safe. Data demonstrate that BSO recapitulates the SAAR-induced anti-obesity effects and that GSH plays a mechanistic role. BSO dose-response studies in animals and pilot studies in humans to combat obesity are highly warranted.},
}

@article {pmid40201900,
year = {2025},
author = {Hu, X and Wu, JL and He, Q and Xiong, ZQ and Li, N},
title = {Strategy for cysteine-targeting covalent inhibitors screening using in-house database based LC-MS/MS and drug repurposing.},
journal = {Journal of pharmaceutical analysis},
volume = {15},
number = {3},
pages = {101045},
pmid = {40201900},
issn = {2214-0883},
abstract = {Targeted covalent inhibitors, primarily targeting cysteine residues, have attracted great attention as potential drug candidates due to good potency and prolonged duration of action. However, their discovery is challenging. In this research, a database-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy was developed to quickly discover potential cysteine-targeting compounds. First, compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes. And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database. Second, substrate-independent product ions produced from N-acetyl-cysteine moiety were selected. Third, multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds. This strategy showed broad applicability, and covalent compounds with diverse structures were screened out, offering structural resources for covalent inhibitors development. Moreover, the screened compounds, norketamine and hydroxynorketamine, could modify synaptic transmission-related proteins in vivo, indicating their potential as covalent inhibitors. This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.},
}

@article {pmid40200382,
year = {2025},
author = {Kasai, H and Kawai, K and Fujisawa, K},
title = {Formation of the toxic furan metabolite 2-butene-1,4-dial through hemin-induced degradation of 2,4-alkadienals in fried foods.},
journal = {Genes and environment : the official journal of the Japanese Environmental Mutagen Society},
volume = {47},
number = {1},
pages = {8},
pmid = {40200382},
issn = {1880-7046},
abstract = {BACKGROUND: The mechanism of protein modification by 2,4-alkadienals (ADE), lipid peroxidation products prevalent in fried foods, was investigated through model reactions.

RESULTS: A mixture of 2,4-heptadienal (HDE) and hemin was initially incubated at pH 3.0-7.4, followed by treatment with acetyl-cysteine (AcCys) and acetyl-lysine (AcLys) at pH 7.4. Analysis via HPLC revealed a product with a characteristic UV spectrum as the primary peak. This product was identified as an AcCys-pyrrole-AcLys (CPL) crosslink derived from AcCys, 2-butene-1,4-dial (BDA), and AcLys. Increasing the HDE concentration in the initial reaction led to maximum CPL formation at pH 3.5 in the presence of hemin. Lowering the HDE concentration with a higher Cys/HDE ratio resulted in CPL formation, which was observed at pH 7.4 and 3.5 in the presence of hemin. Upon incubation of ADE and hemin at pH 3.0-3.5, BDA was directly identified as 2,4-dinitrophenylhydrazone. BDA was also detected in the 2,4-decadienal reaction mixture. Additionally, a notable propensity for high BDA-dC adduct formation with hemin under acidic conditions was observed, consistent with the results of CPL assay and BDA-2,4-dinitrophenylhydrazone analysis.

CONCLUSIONS: 1) BDA is efficiently generated from ADE in the presence of hemin under gastric conditions, and 2) BDA-derived CPL can also form under physiological conditions (pH 7.4) through the interaction of ADE, hemin, Cys, and Lys. BDA is recognized as the primary reactive metabolite of the suspected carcinogen furan (IARC, 2B). Given that human intake of ADE exceeds that of furan and acrylamide (IARC 2A) by several orders of magnitude, and the estimated hemin concentration in the stomach post-meal is comparable to the present study, a substantial amount of BDA may form in the stomach following consumption of fried foods and meat. The risk assessment of ADE warrants a thorough re-evaluation, based on the toxicity mechanism of BDA.},
}

@article {pmid40199136,
year = {2025},
author = {Chuang, YT and Liu, W and Chien, TM and Cheng, YB and Jeng, JH and Chen, CY and Tang, JY and Chang, HW},
title = {Antiproliferative and apoptotic effects of (1R*,12R*)-dolabella-4(16),7,10-triene-3,13-dione (CI-A) in oral cancer cells are mediated by oxidative stress and ERK activation.},
journal = {International immunopharmacology},
volume = {155},
number = {},
pages = {114615},
doi = {10.1016/j.intimp.2025.114615},
pmid = {40199136},
issn = {1878-1705},
abstract = {The anticancer effects and mechanisms of the main component (CI-A) of methanol extracts of Clavularia inflat have not been reported. This study explores the anti-oral cancer effect and mechanism of (1R*,12R*)-dolabella-4(16),7,10-triene-3,13-dione (CI-A) and compared with normal cells. CI-A shows oxidative-stress-dependent preferential antiproliferation of oral cancer cells without normal cell toxicity. CI-A triggers cell cycle dysregulation, apoptosis/caspase activation, cellular/mitochondrial ROS induction, glutathione depletion, and oxidative DNA damage in oral cancer but not normal cells. After testing with three MAPK (p38, JNK, and ERK) inhibitors, only the ERK inhibitor (PD98059) protects against CI-A-induced antiproliferation in oral cancer cells. CI-A upregulates phosphorylated ERK in oral cancer cells compared to normal cells. Notably, a ROS inhibitor, N-acetylcysteine (NAC), attenuates all CI-A-modulated changes. Moreover, the CI-A-triggered annexin V-detected apoptosis and caspase 3/8/9 activations of oral cancer cells were downregulated by PD98059. In conclusion, CI-A induces the oxidative-stress- and ERK-dependent antiproliferative and apoptotic mechanism in oral cancer cells and shows the benefit of non-cytotoxicity to normal cells.},
}

@article {pmid40199010,
year = {2025},
author = {Ashraf, R and Khalid, Z and Qin, QP and Iqbal, MA and Taskin-Tok, T and Bayil, İ and Quah, CK and Daud, NAM and Alqahtany, FZ and Amin, MA and El-Bahy, SM},
title = {Synthesis of N-heterocyclic carbene‑selenium complexes modulating apoptosis and autophagy in cancer cells: Probing the interactions with biomolecules and enzymes.},
journal = {Bioorganic chemistry},
volume = {160},
number = {},
pages = {108435},
doi = {10.1016/j.bioorg.2025.108435},
pmid = {40199010},
issn = {1090-2120},
abstract = {Growing cancer resistance is a global threat that calls for development of newer chemotherapeutic analogues especially targeted based therapy to enhance efficacy and selectivity. In this contribution, herein, we report synthesis of selenium incorporated N-heterocyclic carbene (NHC) compounds to explore their potential cytotoxicity against HeLa cells. Test compounds were assured for suitability as drug candidates through physiochemical properties that showed lipophilicity logP 0.85-1.45 for C1-C3 and found stable in biological media (DMEM), whereas, least reactive with N-acetyl cysteine (NAC) and L-glutathione. All the studied compounds showed good cytotoxicity against various cancer strains while compound C1 [3,3-(hexane-1,6-diyl)bis(1-phenethyl-1H-imidazole-2(3H)-selenone)] and C2 [3,3-(hexane-1,6-diyl)bis(1-decyl-1H-imidazole-2(3H)-selenone)] showed promising results with IC50 values of 14.65 ± 0.66 and 8.05 ± 0.35 μg/mL respectively as compared to positive control 21.5 ± 0.05 μg/mL against HeLa cell lines. These compounds showed six-fold higher apoptosis than control with higher accumulation of Ca[+] ions intracellularly that alters the expression level of autophagy proteins and increased capase-9 activity. Cell cycle analysis indicated an arrest of cycle in G1 phase of HeLa cells when treated with C1 & C2. Test compounds showed prominent affinity for binding with DNA and inhibiting thioredoxin reductase enzymes in time dependent manners. These findings indicate that Selenium NHC compounds are promising drug candidates to induce cytotoxicity via apoptosis, autophagy and mitochondrial membrane disruptions to manage tumor growth.},
}

@article {pmid40188524,
year = {2025},
author = {Yang, W and Wang, F and Liu, J and Wang, X and Zhang, H and Gao, D and Wang, A and Jin, Y and Chen, H},
title = {β-Hydroxybutyrate aggravates LPS-induced inflammatory response in bovine endometrial epithelial cells by activating the oxidative stress/NF-κB signaling pathway.},
journal = {International immunopharmacology},
volume = {154},
number = {},
pages = {114609},
doi = {10.1016/j.intimp.2025.114609},
pmid = {40188524},
issn = {1878-1705},
abstract = {Ketosis, a metabolic disorder characterized by elevated levels of ketone bodies in the blood or urine, is known to impair the health and productivity of dairy cows, leading to substantial economic losses in the dairy industry. When ketosis occurs in dairy cows, the levels of β-hydroxybutyrate (BHBA), an abundant form of ketone bodies, in the blood increase significantly. Elevated BHBA levels have been shown to negatively impact reproductive performance and increase the incidence of periparturient diseases in dairy cows, including mastitis and endometritis. However, the role of BHBA in the development of endometritis in dairy cows and its underlying mechanisms remain largely unclear. The present study was designed to investigate the specific role of BHBA in the development of endometritis using an inflammatory response model of the bovine endometrial epithelial cell line (BENDs). Escherichia coli lipopolysaccharide (LPS) treatment (1 μg/mL) significantly increased the expression levels of interleukin (IL)-6 and IL-1β, as well as the phosphorylation of p65 and IκB in BENDs. In addition, co-treatment with BHBA (2.4 mM) and LPS (1 μg/mL) significantly increased the expression levels of proinflammatory cytokines (IL-6, IL-1β, and IL-8), as well as the phosphorylation of p65 and IκB, compared to the LPS-only treatment group. Immunofluorescence staining showed that the addition of LPS altered the nuclear localization of p65, and co-treatment with BHBA and LPS further promoted the translocation of p65 to the nucleus. Additionally, the addition of BHBA significantly increased the levels of oxidation indicators (MDA), whereas the levels of antioxidative indicators, including heme oxygenase-1 (HO-1) and catalase (CAT), were markedly decreased in BENDs. As a representative antioxidant, N-acetylcysteine (NAC) treatment significantly reduced the phosphorylation of p65 and IκB in the BHBA and LPS co-treatment group. SC75741, an NF-κB signaling pathway inhibitor, significantly decreased the expression levels of proinflammatory cytokines (IL-6, IL-1β, IL-8, and CCL5) in the BHBA and LPS co-treatment group. In summary, the current study demonstrates that BHBA aggravates LPS-induced inflammatory response in BENDs through the activation of oxidative stress/NF-κB signaling pathway, unravelling the mechanism by which BHBA exacerbates the inflammatory response in the BENDs of dairy cattle. This study elucidates the role of ketosis and its key metabolite BHBA in the pathogenesis of endometritis in dairy cows, providing valuable insights for understanding this pathological process.},
}

@article {pmid40187375,
year = {2025},
author = {Bruschi, M and Masini, S and Biancucci, F and Piersanti, G and Canonico, B and Menotta, M and Magnani, M and Fraternale, A},
title = {Redox modulation via a synthetic thiol compound reshapes energy metabolism in endothelial cells and ameliorates angiogenic expression in a co-culture study with activated macrophages.},
journal = {Biochimica et biophysica acta. General subjects},
volume = {1869},
number = {6},
pages = {130803},
doi = {10.1016/j.bbagen.2025.130803},
pmid = {40187375},
issn = {1872-8006},
abstract = {The vascular endothelium is the first interface exposed to circulating compounds and oxidative as well as pro-inflammatory stimuli. Nowadays, cysteine pro-drugs are emerging as new and potential therapies in cardiovascular and inflammatory diseases due to their cytoprotective effects. In this study, the effects of redox modulation by a synthetic thiol compound, i.e., I-152, a precursor of N-acetylcysteine (NAC) and cysteamine (MEA), were evaluated after 6 h and 24 h treatment on human umbilical cord endothelial cell (HUVECs) energy metabolism. Following I-152 treatment, higher cysteine and glutathione (GSH) content were detected via HPLC, in concomitance with I-152 derivatives, i.e., NAC and MEA. Untargeted metabolomics confirmed GSH upregulation and NAC presence in addition to I-152 itself and other metabolites, such as dithiol compound (NACMEAA) and triacetylated I-152. Mass spectrometry revealed that I-152 boosted ATP production, specifically through the mitochondrial OXPHOS, as determined via Seahorse assay without inducing oxidative stress. Additionally, I-152 treatment of HUVECs before co-culture with LPS-stimulated macrophages provided GSH and cysteine sustainment and attenuated the transcription of adhesion molecules as well as iNOS expression. Identifying the impact of redox regulation in physiological conditions and the possible metabolic targets could aid the application of novel thiol-based therapeutics.},
}

@article {pmid40186271,
year = {2025},
author = {Zhang, J and Liu, T and Wu, H and Wei, J and Qu, Q},
title = {Target oxidative stress-induced disulfidptosis: novel therapeutic avenues in Parkinson's disease.},
journal = {Molecular brain},
volume = {18},
number = {1},
pages = {29},
pmid = {40186271},
issn = {1756-6606},
support = {2021ZD0201808//Scientific and technological innovation 2030/ ; },
mesh = {*Oxidative Stress/genetics/drug effects ; *Parkinson Disease/genetics/pathology/drug therapy/therapy ; Animals ; Molecular Docking Simulation ; Humans ; Gene Expression Profiling ; Gene Regulatory Networks ; Mice ; *Molecular Targeted Therapy ; Gene Expression Regulation ; Reproducibility of Results ; Transcriptome/genetics ; Disulfidptosis ; },
abstract = {BACKGROUND: Parkinson's disease (PD), a globally prevalent neurodegenerative disorder, has been implicated with oxidative stress (OS) as a central pathomechanism. Excessive reactive oxygen species (ROS) trigger neuronal damage and may induce disulfidptosis-a novel cell death modality not yet characterized in PD pathogenesis.

METHOD: Integrated bioinformatics analyses were conducted using GEO datasets to identify PD-associated differentially expressed genes (DEGs). These datasets were subjected to: immune infiltration analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), intersection analysis of oxidative stress-related genes (ORGs) and disulfidptosis-related genes (DRGs) for functional enrichment annotation. Following hub gene identification, diagnostic performance was validated using independent cohorts. LASSO regression was applied for feature selection, with subsequent experimental validation in MPTP-induced PD mouse models. Single-cell transcriptomic profiling and molecular docking studies were performed to map target gene expression and assess drug-target interactions.

RESULT: A total of 1615 PD DEGs and 200 WGCNA DEGs were obtained, and the intersection with ORGs and DRGs resulted in 202 DEORGs, 11 DEDRGs, and 5 DED-ORGs (NDUFS2, LRPPRC, NDUFS1, GLUD1, and MYH6). These genes are mainly associated with oxidative stress, the respiratory electron transport chain, the ATP metabolic process, oxidative phosphorylation, mitochondrial respiration, and the TCA cycle. 10 hub genes have good diagnostic value, including in the validation dataset (AUC ≥ 0.507). LASSO analysis of hub genes yielded a total of 6 target genes, ACO2, CYCS, HSPA9, SNCA, SDHA, and VDAC1. In the MPTP-induced PD mice model, the expression of ACO2, HSPA9, and SDHA was decreased while the expression of CYCS, SNCA, and VDAC1 was increased, and the expression of the 5 DED-ORGs was decreased. Additionally, it was discovered that N-Acetylcysteine (NAC) could inhibit the occurrence of disulfidptosis in the MPTP-induced PD model. Subsequently, the distribution of target genes with AUC > 0.7 in different cell types of the brain was analyzed. Finally, molecular docking was performed between the anti-PD drugs entering clinical phase IV and the target genes. LRPPRC has low binding energy and strong affinity with duloxetine and donepezil, with binding energies of -7.6 kcal/mol and - 8.7 kcal/mol, respectively.

CONCLUSION: This study elucidates the pathogenic role of OS-induced disulfidptosis in PD progression. By identifying novel diagnostic biomarkers (e.g., DED-ORGs) and therapeutic targets (e.g., LRPPRC), our findings provide a mechanistic framework for PD management and lay the groundwork for future therapeutic development.},
}

*Oxidative Stress/genetics/drug effects
*Parkinson Disease/genetics/pathology/drug therapy/therapy
Animals
Molecular Docking Simulation
Humans
Gene Expression Profiling
Gene Regulatory Networks
Mice
*Molecular Targeted Therapy
Gene Expression Regulation
Reproducibility of Results
Transcriptome/genetics
Disulfidptosis

@article {pmid40183046,
year = {2025},
author = {Song, J and Qiao, J and Chen, M and Li, J and Wang, J and Yu, D and Zheng, H and Shi, L},
title = {Chaetoglobosin A induces apoptosis in T-24 human bladder cancer cells through oxidative stress and MAPK/PI3K-AKT-mTOR pathway.},
journal = {PeerJ},
volume = {13},
number = {},
pages = {e19085},
pmid = {40183046},
issn = {2167-8359},
mesh = {Humans ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; *Urinary Bladder Neoplasms/drug therapy/metabolism/pathology ; TOR Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Cell Line, Tumor ; Phosphatidylinositol 3-Kinases/metabolism ; *Indole Alkaloids/pharmacology ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Cell Proliferation/drug effects ; Cell Movement/drug effects ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; *Antineoplastic Agents/pharmacology ; },
abstract = {Chaetoglobosin A (ChA) is an antitumor compound produced by Chaetomium globosum. However, the mechanism of its antitumor effect has been rarely reported. In this study, we evaluated the anti-proliferative effect of ChA on T-24 human bladder cancer cells and explored its mechanism of action. ChA was found to have a good inhibitory effect on T-24 cells by MTT assay with an IC50 value of 48.14 ± 10.25 μΜ. Moreover, it was found to have a migration inhibitory ability and a sustained proliferation inhibitory effect on tumor cells by cell aggregation assay and cell migration assay. The cells morphological changes were determined by Hoechst33342 assay. While Annexin V-FITC/PI double-staining assay also demonstrated that the number of apoptotic cells increased with the increase of drug concentration. Flow cytometry results showed that ChA treatment increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) in T-24 cells and inhibited cell mitosis, resulting in an increase in the number of sub-G1 phase cells. Further western blot experiments demonstrated that MAPK and PI3K-AKT-mTOR pathways were activated after drug treatment in addition to endogenous and exogenous apoptotic pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) upregulated the expression level of Bcl-2 protein, decreased p38 phosphorylation, increased ERK phosphorylation and restored the levels of PI3K and p-mTOR after ChA treatment. These suggest that ChA induces apoptosis by regulating oxidative stress, MAPK, and PI3K-AKT-mTOR signaling pathways in T-24 cells.},
}

Humans
*Apoptosis/drug effects
*Oxidative Stress/drug effects
*Urinary Bladder Neoplasms/drug therapy/metabolism/pathology
TOR Serine-Threonine Kinases/metabolism
Proto-Oncogene Proteins c-akt/metabolism
Cell Line, Tumor
Phosphatidylinositol 3-Kinases/metabolism
*Indole Alkaloids/pharmacology
Signal Transduction/drug effects
Reactive Oxygen Species/metabolism
Cell Proliferation/drug effects
Cell Movement/drug effects
MAP Kinase Signaling System/drug effects
Membrane Potential, Mitochondrial/drug effects
*Antineoplastic Agents/pharmacology

@article {pmid40180519,
year = {2025},
author = {Oscullo, G and Méndez, R and Olveira, C and Girón, R and García-Clemente, M and Máiz, L and Sibila, O and Golpe, R and Rodríguez-Hermosa, J and Barreiro, E and Prados, C and Rodríguez-López, JL and de la Rosa-Carrillo, D and Martinez-García, MÁ},
title = {Effect of N-Acetylcysteine on Bronchiectasis in a Real-life Study. Data From the Spanish RIBRON Registry.},
journal = {Archivos de bronconeumologia},
volume = {61},
number = {4},
pages = {196-202},
doi = {10.1016/j.arbres.2025.02.015},
pmid = {40180519},
issn = {1579-2129},
mesh = {Humans ; *Bronchiectasis/drug therapy ; *Acetylcysteine/therapeutic use ; Male ; Female ; Middle Aged ; Aged ; Registries ; Spain ; *Expectorants/therapeutic use ; Longitudinal Studies ; Pseudomonas Infections/drug therapy/prevention & control ; Hospitalization/statistics & numerical data ; Sputum/metabolism ; Treatment Outcome ; Adult ; Pseudomonas aeruginosa/isolation & purification ; },
abstract = {INTRODUCTION: There is scarce information about the most used mucolytic drug in bronchiectasis N-acetylcysteine (N-AC). Our objective was to analyze the effect of N-AC with respect to some outcomes in bronchiectasis.

METHODS: Ambispective, longitudinal, observational, multi-center (43 centers) study of a cohort of 2461 adult patients diagnosed with bronchiectasis. Those patients treated in a stable situation with at least 600mg/d of N-AC (368; 15%) for at least 6 months were compared with patients not receiving this treatment. The variables analyzed and compared were those available two years before and after treatment. ANCOVA analysis was used to analyze the effect of N-AC as the inter-group difference of the basal intra-group difference for each variable, adjusted for relevant covariables.

RESULTS: The N-AC group showed a full adjusted improvement of 27% in exacerbations, 17% in hospitalizations, and 31% in total exacerbation rates compared with the no-N-AC group. Moreover, a decrease in the volume of sputum production of 59.7% was observed as well as a decrease of 12% of patients with bronchial infection by Pseudomonas aeruginosa (PA). The use of 1200mg/d (n=116) resulted in only a mild, albeit significative improvement in the exacerbation rate compared with the use of 600mg/d (-11% in absolute number). Both doses were well tolerated.

CONCLUSION: N-AC (in most cases at a dose of 600mg/d) is safe and effective and sufficient to reduce both the number of exacerbations and hospitalizations and the purulence and volume of sputum, as well as the isolation rate of PA in patients with bronchiectasis.},
}

Humans
*Bronchiectasis/drug therapy
*Acetylcysteine/therapeutic use
Male
Female
Middle Aged
Aged
Registries
Spain
*Expectorants/therapeutic use
Longitudinal Studies
Pseudomonas Infections/drug therapy/prevention & control
Hospitalization/statistics & numerical data
Sputum/metabolism
Treatment Outcome
Adult
Pseudomonas aeruginosa/isolation & purification

@article {pmid40177701,
year = {2025},
author = {Kamboj, SS and Sharma, SP and Mohamed, WMY and Sandhir, R},
title = {N-acetyl-L-cysteine mitigates diabetes-induced impairments in sciatic nerve.},
journal = {IBRO neuroscience reports},
volume = {18},
number = {},
pages = {512-519},
pmid = {40177701},
issn = {2667-2421},
abstract = {Diabetic neuropathy is a consequence of long-term hyperglycemia. The emergence of neuronal condition is a result of hyperglycemia-induced oxidative stress. In the present study, streptozotocin-induced diabetes exhibited notable decrease in the levels of phospholipids, glycolipids, gangliosides, and triglycerides in the sciatic nerve. The alterations in lipids resulted in increase in cholesterol to phospholipid ratio in sciatic nerve of diabetic animals. This ratio is crucial and determines the rheological properties of membranes and resulted in substantial reduction in the activity of membrane-bound enzymes; Ca[2 +] ATPase and acetylcholinesterase. Histological examination of the cross-section of the sciatic nerve in diabetic mice revealed axonal atrophy and disarrayed myelin sheath. The potential therapeutic impact of N-acetyl Cysteine (NAC), a powerful antioxidant, on a rat model of diabetic neuropathy was evaluated. NAC was administered to rats in drinking water for a period of 8 weeks. The results indicate that administration of NAC restored lipid composition; ratio of cholesterol to phospholipids, the activity of membrane linked enzymes, and improved the structural defects in sciatic nerve. NAC plays protective role against diabetes-induced alterations in lipid composition in sciatic nerve membranes leading to improvement in structure and function of membranes. Overall, the findings suggest NAC as a potential therapeutic strategy in preventing diabetic neuropathy and other diabetic complications.},
}

@article {pmid40170426,
year = {2025},
author = {Tang, H and Li, L},
title = {Effects of detergent component sodium dodecyl sulfate on growth hormone secretion in GH3 cells: Implications for pediatric exposure and accidental ingestion.},
journal = {Human & experimental toxicology},
volume = {44},
number = {},
pages = {9603271251332255},
doi = {10.1177/09603271251332255},
pmid = {40170426},
issn = {1477-0903},
mesh = {*Sodium Dodecyl Sulfate/toxicity ; *Oxidative Stress/drug effects ; *Cell Survival/drug effects ; Growth Hormone/metabolism ; NF-E2-Related Factor 2/metabolism/genetics ; Animals ; Detergents/toxicity ; Reactive Oxygen Species/metabolism ; Humans ; Rats ; Cell Line ; Human Growth Hormone ; },
abstract = {IntroductionSodium dodecyl sulfate (SDS), a widely used surfactant in detergents, has raised concerns due to its potential health risks, particularly in children. This study evaluates the impact of SDS exposure on GH secretion in GH3 cells, focusing on oxidative stress as a key mechanism.MethodsGH3 cells were treated with varying concentrations of SDS (0.001-10 mM) for 24 or 48 h. Cell viability was assessed using the MTT assay, while GH secretion was quantified via ELISA. Oxidative stress levels were evaluated through ROS fluorescence assays, and gene expression of Nrf2, IL-6, TNF-α, and caspase-3 was analyzed using qPCR. Additionally, the antioxidant N-acetylcysteine (NAC) was used to determine its protective effects against SDS-induced oxidative stress.ResultsSDS exposure led to a dose-dependent decrease in GH secretion and cell viability, with oxidative stress identified as a primary driver. Nrf2 exhibited a biphasic response, showing transient upregulation at low doses but suppression at higher concentrations, exacerbating oxidative damage. NAC treatment reduced ROS levels and partially restored GH secretion, confirming the role of oxidative stress in SDS-induced toxicity.DiscussionThese findings suggest that SDS exposure may disrupt endocrine function, warranting further risk assessment of its safety in consumer products. Given SDS's prevalence in household products, future research should focus on the long-term effects of SDS exposure to children and potential therapeutic interventions to mitigate oxidative damage.},
}

*Sodium Dodecyl Sulfate/toxicity
*Oxidative Stress/drug effects
*Cell Survival/drug effects
Growth Hormone/metabolism
NF-E2-Related Factor 2/metabolism/genetics
Animals
Detergents/toxicity
Reactive Oxygen Species/metabolism
Humans
Rats
Cell Line
Human Growth Hormone

@article {pmid40169142,
year = {2025},
author = {Kawaguchi, M and Yoshino, K and Ida, T and Moriyama, H and Ieda, N and Ohta, Y and Kasamatsu, S and Ihara, H and Nakagawa, H},
title = {Serendipitous Discovery of Photolytic Thiosulfoxide Formation: Application for Visible-Light-Inducible Manipulation of Supersulfide Level in Biological Systems.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c00196},
pmid = {40169142},
issn = {1520-5126},
abstract = {Tools to enable spatiotemporally controlled upregulation of supersulfides, which are highly reactive, unstable sulfur species, are needed to study the pathophysiological roles of post-translational protein modification with catenated sulfur atoms. Here, we set out to design N,N-diethylaminocoumarin (DEAC)-based visible-light-responsive N-acetylcysteine persulfide donors (NAC-SS-DEAC), and serendipitously found that upon visible light irradiation, they donate a sulfane sulfur (S[0]) atom to nucleophiles, including thiols and cyanate. Light-assisted tautomerization of the disulfide moiety of NAC-SS-DEAC to transiently afford unstable thiosulfoxide plays a key role in the S[0] donation. We show that this reaction can be utilized to achieve visible-light-inducible manipulation of supersulfide levels in living cells.},
}

@article {pmid40166462,
year = {2025},
author = {Zhang, Z and Yan, Z and Yuan, T and Zhao, X and Wang, M and Liu, G and Gan, L and Qin, W},
title = {PD-1 inhibition disrupts collagen homeostasis and aggravates cardiac dysfunction through endothelial-fibroblast crosstalk and EndMT.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1549487},
pmid = {40166462},
issn = {1663-9812},
abstract = {INTRODUCTION: Cardiac immune-related adverse events (irAEs) from PD-1-targeting immune check-point inhibitors (ICIs) are an increasing concern due to their high mortality rate. Collagen plays a crucial role in maintaining cardiac structure, elasticity, and signal transduction; however, the effects and mechanisms of PD-1 inhibitor on cardiac collagen remodeling remain poorly understood.

METHODS: C57BL/6 mice were injected with anti-mouse PD-1 antibody to create a PD-1 inhibitor-treated model. Cardiac function was measured by echocardiography, and collagen distribution was analyzed with Masson's trichrome staining and Sirius Red staining. Single-nucleus RNA sequencing was performed to examine the effects of PD-1 inhibition on gene expression in cardiac fibroblasts (CFs) and endothelial cells (ECs). EC-CF crosstalk was assessed using co-culture experiments and ELISA. ChIP assay was performed to analyze the regulation of TCF12 on TGF-β1 promoter. Western blot, qRT-PCR, and immunofluorescence staining were used to detect the expression of TCF12, TGF-β1, and endothelial-to-mesenchymal transition (EndMT) markers. Reactive oxygen species (ROS) levels were evaluated by DHE staining, MDA content, and SOD activity assays.

RESULTS: We report a newly discovered cardiotoxic effect of PD-1 inhibitor, which causes aberrant collagen distribution in the heart, marked by a decrease in interstitial collagen and an increase in perivascular collagen deposition. Mechanistically, PD-1 inhibitor does not directly affect CFs but instead impact them through EC-CF crosstalk. PD-1 inhibitor reduces TGF-β1 secretion in ECs by downregulating TCF12, which we identify as a transcriptional promoter of TGF-β1. This subsequently decreases CF activity, leading to reduced interstitial collagen deposition. Additionally, PD-1 inhibitor induces EndMT, increasing perivascular collagen deposition. The endothelial dysfunction induced by PD-1 inhibitor results from ROS accumulation in ECs. Inhibiting ROS with N-acetylcysteine (NAC) preserves normal collagen distribution and cardiac function in PD-1 inhibitor-treated mice by reversing TCF12 downregulation and EndMT in ECs.

CONCLUSION: Our results suggest that PD-1 inhibitor causes ROS accumulation in cardiac ECs, leading to imbalanced collagen distribution (decrease in interstitial collagen and increase in perivascular collagen) in the heart by modulating TCF12/TGF-β1-mediated EC-CF crosstalk and EndMT. NAC supplementation could be an effective clinical strategy to mitigate PD-1 inhibitor-induced imbalanced collagen distribution and cardiac dysfunction.},
}

@article {pmid40163767,
year = {2025},
author = {Kruse, LD and Holte, C and Zapotoczny, B and Struck, EC and Schürstedt, J and Hübner, W and Huser, T and Szafranska, K},
title = {Hydrogen peroxide damage to rat liver sinusoidal endothelial cells is prevented by n-acetyl-cysteine but not GSH.},
journal = {Hepatology communications},
volume = {9},
number = {2},
pages = {},
pmid = {40163767},
issn = {2471-254X},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Hydrogen Peroxide/toxicity/pharmacology ; Rats ; *Glutathione/metabolism ; *Endothelial Cells/drug effects/metabolism ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Liver/drug effects/metabolism ; Male ; Cell Survival/drug effects ; Cells, Cultured ; Rats, Sprague-Dawley ; },
abstract = {BACKGROUND: Reactive oxygen species (ROS) are prevalent in the liver during intoxication, infection, inflammation, and aging. Changes in liver sinusoidal endothelial cells (LSEC) are associated with various liver diseases.

METHODS: Isolated rat LSEC were studied under oxidative stress induced by H2O2 at different concentrations (0.5-1000 µM) and exposure times (10-120 min). LSEC functions were tested in a dose-dependent and time-dependent manner.

RESULTS: (1) Cell viability, reducing potential, and scavenging function decreased as H2O2 concentration and exposure time increased; (2) intracellular ROS levels rose with higher H2O2 concentrations; (3) fenestrations exhibited a dynamic response, initially closing but partially reopening at H2O2 concentrations above 100 µM after about 1 hour; (4) scavenging function was affected after just 10 minutes of exposure, with the impact being irreversible and primarily affecting degradation rather than receptor-mediated uptake; (5) the tubulin network was disrupted in high H2O2 concentration while the actin cytoskeleton appears to remain largely intact. Finally, we found that reducing agents and thiol donors such as n-acetyl cysteine and glutathione (GSH) could protect cells from ROS-induced damage but could not reverse existing damage as pretreatment with n-acetyl cysteine, but not GSH, reduced the negative effects of ROS exposure.

CONCLUSIONS: The results suggest that LSEC does not store an excess amount of GSH but rather can readily produce it in the occurrence of oxidative stress conditions. Moreover, the observed thresholds in dose-dependent and time-dependent changes, as well as the treatments with n-acetyl cysteine/GSH, confirm the existence of a ROS-depleting system in LSEC.},
}

Animals
*Acetylcysteine/pharmacology
*Hydrogen Peroxide/toxicity/pharmacology
Rats
*Glutathione/metabolism
*Endothelial Cells/drug effects/metabolism
*Oxidative Stress/drug effects
*Reactive Oxygen Species/metabolism
*Liver/drug effects/metabolism
Male
Cell Survival/drug effects
Cells, Cultured
Rats, Sprague-Dawley

@article {pmid40163489,
year = {2025},
author = {Bao, Q and Wang, Z and Yang, T and Su, X and Chen, Y and Liu, L and Deng, Q and Liu, Q and Shao, C and Zhu, W},
title = {Curcumin induces mitochondrial dysfunction-associated oxidative DNA damage in ovarian cancer cells.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0319846},
pmid = {40163489},
issn = {1932-6203},
mesh = {*Curcumin/pharmacology ; Female ; Humans ; *Ovarian Neoplasms/drug therapy/pathology/metabolism/genetics ; *DNA Damage/drug effects ; Animals ; *Mitochondria/drug effects/metabolism ; Cell Line, Tumor ; *Oxidative Stress/drug effects ; Mice ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; Mice, Nude ; Xenograft Model Antitumor Assays ; Antineoplastic Agents/pharmacology ; },
abstract = {Resistance to chemotherapeutic agents is a critical challenge for the clinical management of ovarian cancer. While curcumin has been reported to possess anti-cancer properties, how it exerts its anti-neoplastic effect on ovarian cancer cells remains to be explored. We here characterized the fate of human ovarian cancer cell lines HO8910 and OVCAR3 treated with curcumin. Cell proliferation, cell death, mitochondrial function, oxidative damage and tumor formation in nude mice were examined. Significant inhibition of proliferation and induction of apoptosis were observed in ovarian cells treated with curcumin. The cancer cells exhibit cell cycle arrest at G2/M phase, mitochondrial accumulation, mitochondrial oxidative stress and high level of DNA damage after curcumin treatment. This effect of curcumin is independent of the BRCA mutation status. Curcumin-induced proliferation inhibition and apoptosis were effectively attenuated by the application of antioxidant N-acetylcysteine (NAC), suggesting that curcumin exerts its anti-cancer effect by inflicting oxidative stress. Curcumin applied at 200 mg/kg intraperitoneal infusion daily also inhibited the growth, oxidative damage, and mitochondrial accumulation of tumor xenografts in vivo. Together, the results indicate that curcumin can exert its anti-tumor effect via inducing mitochondrial dysfunction-associated oxidative DNA damage and can be potentially used in combination with other DNA repair-interfering therapeutics, such as PARP inhibitor, in the treatment of ovarian cancer.},
}

*Curcumin/pharmacology
Female
Humans
*Ovarian Neoplasms/drug therapy/pathology/metabolism/genetics
*DNA Damage/drug effects
Animals
*Mitochondria/drug effects/metabolism
Cell Line, Tumor
*Oxidative Stress/drug effects
Mice
*Apoptosis/drug effects
*Cell Proliferation/drug effects
Mice, Nude
Xenograft Model Antitumor Assays
Antineoplastic Agents/pharmacology

@article {pmid40163249,
year = {2025},
author = {Snorradottir, AO and Gutierrez-Uzquiza, A and Bragado, P and March, ME and Kao, C and Arkink, EB and Jonsdottir, S and Sigurdardottir, A and Isaksson, HJ and Mariasdóttir, HL and Bjorgvinsdottir, OY and Kowal, NM and Heimisdottir, HL and Sverrisdottir, A and Palsdottir, A and Bjornsson, HT and Hakonarson, H},
title = {N-Acetylcysteine for Hereditary Cystatin C Amyloid Angiopathy: A Nonrandomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
pmid = {40163249},
issn = {2168-6157},
abstract = {IMPORTANCE: Hereditary cystatin C amyloid angiopathy (HCCAA) is a lethal, dominantly inherited disease primarily affecting Icelandic young adults that leads to severe cerebral amyloid angiopathy, with no effective therapy.

OBJECTIVE: To investigate safety, tolerance, and therapeutic potential of N-acetylcysteine (NAC) in lowering disease-associated biomarkers in sequence variation carriers.

This phase 2a open-label clinical trial was conducted from March 2019 to December 2021 at a single study center at Landspitali University Hospital in Reykjavik, Iceland, and included 17 confirmed carriers of the L68Q-CST3 sequence variation.

INTERVENTION: High-dose NAC treatment was administered at 2400 mg daily for 9 months. Participants underwent regular monitoring for hemorrhages and disease progression, including blood and skin biopsy samples obtained every 3 months for biomarker testing.

MAIN OUTCOMES AND MEASURES: The primary outcomes were drug tolerability and safety, cognitive status, and reduction in disease-associated biomarkers in skin biopsies. Secondary outcomes included changes in blood and plasma biomarker levels.

RESULTS: Of 17 carriers treated, 6 were male and 11 were female, and mean (SD) participant age was 40.0 (4.2) years. Analysis of the primary outcomes showed that NAC was safe and well tolerated. Five cerebral bleeds occurred during the treatment period without permanent neurological sequela; no death occurred. There was significant reduction in median (IQR) disease-specific biomarker levels in skin after treatment, including collagen IV (baseline: 3.69% [2.48%-5.16%]; after treatment: 2.60% [1.99%-2.97%]; P < .001), fibronectin (baseline: 3.17% [2.09%-5.05%]; after treatment: 2.37% [1.87%-3.42%]; P = .01), vimentin (baseline: 1.60% [1.24%-2.37%]; after treatment: 1.31% [0.97%-1.68%]; P < .001), and SMAD (baseline: 2.25% [0.55%-4.36%]; after treatment: 1.56% [0.20%-2.54%]; P < .001) via Wilcoxon matched-pairs signed rank test. Secondary outcomes included a significant increase in reduced glutathione levels and decreased high-molecular-weight cystatin C aggregate levels in plasma after NAC treatment.

CONCLUSIONS AND RELEVANCE: In this single-center nonrandomized clinical trial, NAC was safe and well tolerated and decreased disease-associated biomarker and amyloid deposition, suggesting NAC may offer a preventive strategy against HCCAA.

TRIAL REGISTRATION: ClinicalTrialsRegister.eu Identifier: 2017-004776-56.},
}

@article {pmid40159744,
year = {2025},
author = {Adamczuk, P and Jamka, K and Bojar, H and Szala-Rycaj, J and Szewczyk, A and Sawicki, KB and Raszewski, G},
title = {The effect of the antioxidant N-acetylcysteine on cholinesterase activity in the brain and blood during Pirimiphos methyl poisoning in the course of treatment with atropine alone, and with atropine and obidoxime.},
journal = {Annals of agricultural and environmental medicine : AAEM},
volume = {32},
number = {1},
pages = {116-121},
doi = {10.26444/aaem/199716},
pmid = {40159744},
issn = {1898-2263},
mesh = {Animals ; *Atropine/pharmacology/administration & dosage ; *Acetylcysteine/pharmacology ; Male ; Mice ; *Antioxidants/metabolism ; *Brain/drug effects/metabolism ; *Obidoxime Chloride/pharmacology ; Organothiophosphorus Compounds ; Organophosphate Poisoning/drug therapy ; Butyrylcholinesterase/metabolism ; Acetylcholinesterase/metabolism ; Antidotes/pharmacology/administration & dosage ; Cholinesterases/metabolism/blood ; Cholinesterase Inhibitors ; },
abstract = {INTRODUCTION AND OBJECTIVE: The antioxidant N-acetylcysteine (NAC) may help in the treatment of organophosphates poisoning, including Pirymiphos methyl (PM). However, there is no information on the effect of NAC on target cholinesterases during the core treatment with atropine and obidoxime after acute and chronic exposure to PM. The impact was investigated of NAC on the functional status of target cholinesterases in the brain and blood during treatment with atropine (ATR) and/or obidoxime (OBID) in PM-induced toxicity.

MATERIAL AND METHODS: All experiments were performed on Male Swiss mice. The animals were intoxicated with PM and treated with OBID and/or ATR with or without and NAC, in various combinations (with 2-3 drugs) used simultaneously after intoxication. Total acetylcholinesterase activity (AChE) in brain and blood and plasma butyrylcholinesterase activity (BChE) were monitored at 2 and 72 h after intoxication. Enzyme activity was determined using Ellman's colorimetric method.

RESULTS: The applied therapies with OBID, ATR and NAC in various configurations significantly reactivated PM-inhibited AChE in the brain and erythrocytes and the BChE in the plasma. The benefits of NAC administration in combination with ATR and/or OBID therapy have also been reported to restore AChE activity in the brain. NAC may reduce the dose of ATR in the treatment of PM poisoning.

CONCLUSIONS: Adjunctive treatment offered by NAC can reduce or prevent the deleterious effects against PM-induced toxicity. Therefore, NAC remains a strong candidate for adjunct treatment for OP-poisoning, including PM, although additional preclinical and clinical studies are needed.},
}

Animals
*Atropine/pharmacology/administration & dosage
*Acetylcysteine/pharmacology
Male
Mice
*Antioxidants/metabolism
*Brain/drug effects/metabolism
*Obidoxime Chloride/pharmacology
Organothiophosphorus Compounds
Organophosphate Poisoning/drug therapy
Butyrylcholinesterase/metabolism
Acetylcholinesterase/metabolism
Antidotes/pharmacology/administration & dosage
Cholinesterases/metabolism/blood
Cholinesterase Inhibitors

@article {pmid40159690,
year = {2025},
author = {Chen, H and Wang, J and Zhao, B and Yang, Y and Yang, C and Zhao, Z and Ding, X and Li, Y and Zhang, T and Yingpai, Z and Huo, S},
title = {N-Acetylcysteine relieving hydrogen peroxide-induced damage in granulosa cells of sheep.},
journal = {Cell adhesion & migration},
volume = {19},
number = {1},
pages = {2484182},
doi = {10.1080/19336918.2025.2484182},
pmid = {40159690},
issn = {1933-6926},
mesh = {Animals ; *Hydrogen Peroxide/pharmacology/metabolism ; Female ; *Granulosa Cells/metabolism/drug effects ; *Oxidative Stress/drug effects ; Sheep ; *Acetylcysteine/pharmacology ; *Signal Transduction/drug effects ; *Phosphatidylinositol 3-Kinases/metabolism ; NF-E2-Related Factor 2/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; },
abstract = {Sheep ovarian granulosa cells (GCs) play a unique role in the ovary. Damage to GCs can affect the normal development of oocytes. The oxidative stress model was constructed by H2O2to study the biological changes. Specifically, pathological characteristic was assessed by immunohistochemistry (IHC), while signaling pathway was studied using western blot, quantitative RT-PCR, and immunofluorescence. Theresults showed that the oxidative damage model was successfully constructed by 200 μmol/LH2O2 for 12 h. NAC can protect the proliferation of GCs under H2O2-induced oxidative stress and reduce apoptosis. It can also promote the secretion of E2 and P4 by GCs and reduce the inflammatory response of GCs. NAC can enhance the expression of NRF2, PI3K and Akt. These findings suggest that NAC alleviates H2O2-induced oxidative stress injury through NRF2/PI3K/AKT signaling pathways. Provide ideas for studying the poor quality of mammalian oocytes.},
}

Animals
*Hydrogen Peroxide/pharmacology/metabolism
Female
*Granulosa Cells/metabolism/drug effects
*Oxidative Stress/drug effects
Sheep
*Acetylcysteine/pharmacology
*Signal Transduction/drug effects
*Phosphatidylinositol 3-Kinases/metabolism
NF-E2-Related Factor 2/metabolism
Proto-Oncogene Proteins c-akt/metabolism
Apoptosis/drug effects
Cell Proliferation/drug effects

@article {pmid40156629,
year = {2025},
author = {Xu, Y and You, J and Yao, J and Hou, B and Wang, W and Hao, Z},
title = {Klotho alleviates oxidative stress and mitochondrial dysfunction through the Nrf2/HO-1 pathway, thereby reducing renal senescence induced by calcium oxalate crystals.},
journal = {Urolithiasis},
volume = {53},
number = {1},
pages = {61},
pmid = {40156629},
issn = {2194-7236},
support = {82070724//the National Natural Science Foundation of China/ ; },
mesh = {*Klotho Proteins ; *Oxidative Stress/drug effects ; Animals ; *Calcium Oxalate/metabolism/toxicity ; *NF-E2-Related Factor 2/metabolism ; Mice ; *Glucuronidase/metabolism/genetics ; *Heme Oxygenase-1/metabolism/genetics ; *Signal Transduction/drug effects ; *Kidney/drug effects/metabolism/pathology ; *Mitochondria/drug effects/metabolism ; Male ; Cellular Senescence/drug effects ; Humans ; Disease Models, Animal ; Mice, Inbred C57BL ; Cell Line ; Aging/drug effects ; Membrane Proteins ; },
abstract = {Klotho is an antiaging protein that is primarily secreted by the kidneys. This study aimed to explore the protective effects of Klotho against calcium oxalate (CaOx) crystal-induced renal aging and the underlying mechanisms involved. We established a mouse model of CaOx crystal deposition via the intraperitoneal injection of glyoxylate (Gly) and constructed an in vitro model by stimulating HK2 cells with calcium oxalate monohydrate (COM). Renal aging levels were assessed through β-galactosidase (SA-β-gal) staining and the detection of senescence-associated markers. By overexpressing Klotho both in vitro and in vivo, we examined oxidative stress, mitochondrial function, and renal aging levels. We then evaluated the role of Nrf2/HO-1 signalling pathway-mediated oxidative stress in CaOx crystal-induced renal aging by applying the oxidative stress scavenger N-acetylcysteine (NAC) and overexpressing or inhibiting Nrf2 in HK2 cells. We subsequently overexpressed Klotho while inhibiting Nrf2 to confirm that Klotho exerts its protective effects through the Nrf2/HO-1 pathway. Finally, we measured the methylation levels of the Klotho promoter and assessed the degree of renal aging induced by CaOx crystals after the inhibition of Klotho DNA methylation. We found that the overexpression of Klotho alleviated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, thereby reducing renal aging. NAC mitigated CaOx crystal-induced renal aging. The overexpression of Nrf2 alleviated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, thus reducing renal aging, whereas the knockdown of Nrf2 exacerbated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, leading to more severe renal aging. The combination of Klotho overexpression and Nrf2 knockdown reversed the protective effects of Klotho. CaOx crystals induced an increase in the DNA methylation levels of Klotho in the kidneys, and the inhibition of DNA methylation alleviated CaOx-induced renal aging. This study revealed that Klotho plays a crucial role in calcium oxalate crystal-induced kidney senescence by influencing kidney oxidative stress and mitochondrial function through the Nrf2/HO-1 pathway.},
}

*Klotho Proteins
*Oxidative Stress/drug effects
Animals
*Calcium Oxalate/metabolism/toxicity
*NF-E2-Related Factor 2/metabolism
Mice
*Glucuronidase/metabolism/genetics
*Heme Oxygenase-1/metabolism/genetics
*Signal Transduction/drug effects
*Kidney/drug effects/metabolism/pathology
*Mitochondria/drug effects/metabolism
Male
Cellular Senescence/drug effects
Humans
Disease Models, Animal
Mice, Inbred C57BL
Cell Line
Aging/drug effects
Membrane Proteins

@article {pmid40155786,
year = {2025},
author = {Nasiri, MJ and Khoshdel, N and Venketaraman, V},
title = {Glutathione and N-acetylcysteine in TB management.},
journal = {The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease},
volume = {29},
number = {4},
pages = {171-177},
doi = {10.5588/ijtld.24.0604},
pmid = {40155786},
issn = {1815-7920},
mesh = {*Acetylcysteine/therapeutic use ; Humans ; *Glutathione ; Antitubercular Agents/administration & dosage/pharmacology ; Tuberculosis/drug therapy ; Oxidative Stress/drug effects ; Tuberculosis, Pulmonary/drug therapy ; },
abstract = {TB remains a major global health challenge. Glutathione (GSH) and N-acetylcysteine (NAC) have been proposed as adjunctive therapies with potential clinical and immunomodulatory benefits. This systematic review aims to evaluate the efficacy, safety, and immunomodulatory effects of GSH and NAC as adjunctive therapies in TB management.PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched until October 15, 2024. We included studies assessing the efficacy of GSH and NAC in TB management, focusing on clinical outcomes such as lung function recovery, sputum conversion, hepatoprotection, and immune response modulation. The quality of the studies was assessed using the Cochrane Risk of Bias tool.Eight controlled trials were included. GSH and NAC significantly improved lung function accelerated sputum conversion, and provided hepatoprotective effects. GSH, particularly in its liposomal form, enhanced immune responses by modulating cytokine levels and reducing oxidative stress. Most adverse effects reported were mild and manageable, indicating a favourable safety profile for both agents.GSH and NAC show promise as adjunctive therapies in TB management, demonstrating improvements in lung function, sputum conversion, and hepatoprotection while also enhancing immune responses..},
}

*Acetylcysteine/therapeutic use
Humans
*Glutathione
Antitubercular Agents/administration & dosage/pharmacology
Tuberculosis/drug therapy
Oxidative Stress/drug effects
Tuberculosis, Pulmonary/drug therapy

@article {pmid40153160,
year = {2025},
author = {Borovskaya, TG and Vychuzhanina, AV and Schemerova, YA and Stremlina, LA and Goldberg, VE and Dygai, AM and Zhdanov, VV},
title = {Genoprotective Properties of para-Tyrosol against Doxorubicin-Induced DNA Damage in Sperm and Testicular Tissue Cells of Rats.},
journal = {Bulletin of experimental biology and medicine},
volume = {},
number = {},
pages = {},
pmid = {40153160},
issn = {1573-8221},
abstract = {The effect of para-tyrosol (PT), a hydroxyalkylphenol exhibiting antioxidant properties, on the level of DNA damage in testicular tissue cells and sperm of rats treated with doxorubicin was studied using the DNA comet assay. N-acetylcysteine (NAC) was used as a reference drug. It was found that both drugs reduced the number of DNA breaks in rat testicular tissue cells (by 46-48%). The antigenotoxic effect, judging by %DNA in tail, in relation to spermatozoa was detected only in PT. The number of DNA damage in male germ cells after treatment with PT was reduced by 52% from the control (administration of doxorubicin alone). The results suggest that it is advisable to use PT in order to reduce the genotoxicity of doxorubicin, in the therapy of Hodgkin lymphoma (HL) in treatment regimens containing this anthracycline antibiotic.},
}

@article {pmid40143181,
year = {2025},
author = {Alhaddad, A and Mosalam, EM and AboShabaan, HS and Sallam, AS and Mahfouz, MM and Elhosary, E and Mohammed, AA and Metwally, EM and Shaldam, MA and Ghoneim, ME},
title = {Mechanistic and Molecular Insights into Empagliflozin's Role in Ferroptosis and Inflammation Trajectories in Acetaminophen-Induced Hepatotoxicity.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {3},
pages = {},
pmid = {40143181},
issn = {1424-8247},
abstract = {Background: Acetaminophen (APAP)-induced acute liver injury (ALI) is increasingly becoming a public health issue with high rate of morbidity and mortality. Therefore, there is a critical demand for finding protective modalities by understanding the underlying proposed mechanisms including, but not limited to, ferroptosis and inflammation. Objectives: This study seeks to investigate the possible hepatoprotective effect of empagliflozin (EMPA) against APAP-induced ALI through modulation of ferroptosis and inflammatory cascades. Methods: Mice were allocated into the following five groups: vehicle control, APAP, EMPA 10, EMPA 20 (10 and 20 mg/kg/day, respectively, P.O.), and N-acetylcysteine (NAC, hepatoprotective agent against APAP-induced ALI). The hepatic injury was detected by determining liver enzymes and by histopathological examination. Inflammation, oxidative stress, apoptosis, and ferroptosis were also evaluated. Results: The APAP group showed an elevated level of hepatic enzymes with disrupted hepatic architecture. This toxicity was promoted by inflammation, oxidative stress, apoptosis, and ferroptosis, as indicated by elevated cytokines, lipid peroxidation, reduced antioxidants, increased caspase-3, decreased Bcl-2, and activation of the NF-κB/STAT3/hepcidin pathway. Pretreatment with EMPA remarkably reversed these features, which was reflected by restoration of the histoarchitecture of hepatic tissue, but the higher dose of EMPA was more efficient. Conclusions: APAP can induce ALI through initiation of inflammatory and oxidative conditions, which favor ferroptosis. EMPA hindered these unfavorable consequences; an outcome which indicates its anti-inflammatory, antioxidant, anti-apoptotic, and anti-ferroptotic effects. This modulatory action advocated EMPA as a potential hepatoprotective agent.},
}

@article {pmid40143066,
year = {2025},
author = {Liu, Y and Yao, L and Liu, Y and Yang, Y and Liang, A and He, H and Lei, Y and Cao, W and Chen, Z},
title = {Micheliolide Alleviates Hepatic Fibrosis by Inhibiting Autophagy in Hepatic Stellate Cells via the TrxR1/2-Mediated ROS/MEK/ERK Pathway.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {3},
pages = {},
pmid = {40143066},
issn = {1424-8247},
support = {82100131, 82004168//National Natural Science Foundation of China/ ; CSTB2023NSCQ-MSX0136//Natural Science Foundation Project of Chongqing/ ; KJQN202215101, KJZD-K202315101//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; W0066//CQMU Program for Youth Innovation in Future Medicine/ ; },
abstract = {Background: Hepatic fibrosis is a major global health issue without an optimal drug treatment, highlighting the urgent need to find effective therapies. This study aimed to clarify the role and mechanism of micheliolide in treating hepatic fibrosis. Methods: The efficacy of MCL was evaluated in a mouse model of CCl4-induced hepatic fibrosis. LX-2 cells were subjected to MCL treatment, and subsequent changes in fibrosis markers, autophagy, and the MEK/ERK pathway were analyzed using transcriptomics and Western blotting. The interaction between MCL and TrxR1 or TrxR2 were validated using cellular thermal shift assays (CETSA) and drug affinity responsive target stability (DARTS) assays. Results: Our findings indicated that MCL significantly alleviated CCl4-induced hepatic fibrosis, improved liver function, and downregulated the expression of fibrosis markers. Additionally, MCL significantly inhibited LX-2 cell activation by suppressing cell proliferation, extracellular matrix (ECM) production, and autophagy, while activating the MEK/ERK pathway. Moreover, MCL elevated intracellular and mitochondrial reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential, and altered mitochondrial morphology. The ROS scavenger N-acetylcysteine (NAC) attenuated MCL-induced MEK/ERK pathway activation and increased collagen type I alpha 1 (COL1A1) and fibronectin (FN) expression. Further analysis confirmed that MCL directly interacts with TrxR1 and TrxR2, leading to the inhibition of their enzymatic activities and the induction of ROS generation. Ultimately, MCL attenuated the fibrotic process and autophagic flux in LX-2 cells. Conclusions: The findings of our study confirmed that MCL has the potential to alleviate hepatic fibrosis, thereby introducing a novel candidate drug and therapeutic strategy for management of this condition.},
}

@article {pmid40141299,
year = {2025},
author = {Mokra, D and Porvaznik, I and Mokry, J},
title = {N-Acetylcysteine in the Treatment of Acute Lung Injury: Perspectives and Limitations.},
journal = {International journal of molecular sciences},
volume = {26},
number = {6},
pages = {},
pmid = {40141299},
issn = {1422-0067},
support = {APVV-15-0075//Slovak Research and Development Agency/ ; APVV-18-0084//Slovak Research and Development Agency/ ; APVV-22-0342//Slovak Research and Development Agency/ ; VEGA 1/0131/22//Ministry of Education, Science, Research and Sport of the Slovak Republic/ ; VEGA 1/0093/22//Ministry of Education, Science, Research and Sport of the Slovak Republic/ ; },
mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Acute Lung Injury/drug therapy ; Animals ; *Oxidative Stress/drug effects ; COVID-19 ; Antioxidants/therapeutic use/pharmacology ; COVID-19 Drug Treatment ; SARS-CoV-2/drug effects ; Respiratory Distress Syndrome/drug therapy ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; },
abstract = {N-acetylcysteine (NAC) can take part in the treatment of chronic respiratory diseases because of the potent mucolytic, antioxidant, and anti-inflammatory effects of NAC. However, less is known about its use in the treatment of acute lung injury. Nowadays, an increasing number of studies indicates that early administration of NAC may reduce markers of oxidative stress and alleviate inflammation in animal models of acute lung injury (ALI) and in patients suffering from distinct forms of acute respiratory distress syndrome (ARDS) or pulmonary infections including community-acquired pneumonia or Coronavirus Disease (COVID)-19. Besides low costs, easy accessibility, low toxicity, and rare side effects, NAC can also be combined with other drugs. This article provides a review of knowledge on the mechanisms of inflammation and oxidative stress in various forms of ALI/ARDS and critically discusses experience with the use of NAC in these disorders. For preparing the review, articles published in the English language from the PubMed database were used.},
}

*Acetylcysteine/therapeutic use/pharmacology
Humans
*Acute Lung Injury/drug therapy
Animals
*Oxidative Stress/drug effects
COVID-19
Antioxidants/therapeutic use/pharmacology
COVID-19 Drug Treatment
SARS-CoV-2/drug effects
Respiratory Distress Syndrome/drug therapy
Anti-Inflammatory Agents/therapeutic use/pharmacology

@article {pmid40139162,
year = {2025},
author = {Megan, L and Sanchez-Migallon Guzman, D and Knych, H and Beaufrère, H},
title = {Pharmacokinetics of single-dose oral acetaminophen with and without concurrent administration of silymarin or N-acetylcysteine in orange-winged Amazon parrots (Amazona amazonica).},
journal = {American journal of veterinary research},
volume = {},
number = {},
pages = {1-11},
doi = {10.2460/ajvr.24.12.0402},
pmid = {40139162},
issn = {1943-5681},
abstract = {OBJECTIVE: To determine the pharmacokinetics of acetaminophen (N-acetyl-para-aminophenol [APAP]) and its metabolites after oral administration of a single dose of APAP, with or without silymarin or N-acetylcysteine (NAC), to orange-winged Amazon parrots (Amazona amazonica).

METHODS: Eight parrots received, in 3 separate studies, 1 of the following oral treatments: (1) APAP (100 mg/kg) with silymarin (50 mg/kg, twice, q 12 h); (2) APAP (100 mg/kg) with NAC (400 mg/kg); or (3) APAP (100 mg/kg) alone. For each study, blood samples were collected over 24 hours after drug administration to evaluate plasma concentrations of APAP, APAP-glucuronide, and APAP-sulfate. Pharmacokinetic parameters were calculated. Plasma biochemistry panels were performed before and after each study. In a fourth study, a single oral dose of APAP (100 mg/kg) was administered to 8 additional parrots for adverse effects evaluation alone.

RESULTS: Pharmacokinetic parameters for APAP, APAP-glucuronide, and APAP-sulfate were established. The APAP maximum plasma concentration, time of maximal plasma concentration, and half-life across studies ranged from 2,016.9 to 2,917.2 ng/mL, 1.13 to 2.1 hours, and 1.3 to 1.45 hours, respectively. Acetaminophen had marked metabolism to APAP-glucuronide and negligible to APAP-sulfate. Concurrent administration of APAP with silymarin resulted in a mild but significant elevation in glutamate dehydrogenase.

CONCLUSIONS: Acetaminophen plasma concentrations were lower than in other avian species despite a relatively high dose. Acetaminophen has fast absorption, short half-life, and marked glucuronidation. Single oral dose administration of APAP, alone or with NAC, appears safe based on plasma biochemistries. Multidose and pharmacodynamic studies are needed.

CLINICAL RELEVANCE: This is the first pharmacokinetic study of APAP in psittacines, which has the potential to be an effective and safe component of multimodal analgesia in these species.},
}

@article {pmid40136229,
year = {2025},
author = {Sinigaglia, G and Fortunato, LM and Grillo, ML and Partata, WA},
title = {Potential of N-acetylcysteine in the management of low back pain: a scoping review of studies in humans and animal models.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {58},
number = {},
pages = {e14382},
doi = {10.1590/1414-431X2025e14382},
pmid = {40136229},
issn = {1414-431X},
mesh = {*Acetylcysteine/therapeutic use ; Humans ; *Low Back Pain/drug therapy ; Animals ; Disease Models, Animal ; },
abstract = {Low back pain (LBP) is a common type of pain that causes disability and impairs cognitive function. With over 80% of adults estimated to experience LBP during their lifetime, this type of pain not only has a significant impact on the individual, but also on public health systems and national economies. Unfortunately, there is no single standard of care for patients with LBP. N-acetylcysteine (NAC), which is used clinically to treat acetaminophen overdose, has recently been tested as a potential treatment for LBP. NAC is inexpensive and commercially available, and it has an established tolerance and safety profile. However, NAC's efficacy in LBP has not been established. This scoping review presents a summary of studies investigating the effects of NAC and the potential benefits in LBP treatment, and highlights its potential molecular mechanisms and side effects. A systematic literature search in Pubmed/MEDLINE, Embase, Scopus, Science Direct, Web of Science, Cinahl, and Lilacs databases was conducted. The PRISMA-ScR checklist was used to ensure integrity of the review. The scoping review protocol was registered in the Open Science Framework. No limit was set on study language and publication date. In total, 2357 articles were located, of which 16 were included. The studies show that NAC has potential for LBP treatment, but data are derived only from a few clinical trials and preclinical studies. Thus, there is much to learn and more clinical studies should be performed before NAC can be clinically recommended for the treatment of LBP.},
}

*Acetylcysteine/therapeutic use
Humans
*Low Back Pain/drug therapy
Animals
Disease Models, Animal

@article {pmid40136129,
year = {2024},
author = {Hardt, M and Mayr, A and Kutschera, E and Marciniak, J and Küchler, EC and Kirschneck, C and Deschner, J and Jäger, A and Beisel-Memmert, S},
title = {Rho Kinases and Reactive Oxygen Species in Autophagy Regulation by Pressure in Periodontal Ligament Cells.},
journal = {Brazilian dental journal},
volume = {35},
number = {},
pages = {e245944},
doi = {10.1590/0103-6440202405944},
pmid = {40136129},
issn = {1806-4760},
mesh = {*Periodontal Ligament/cytology ; *Autophagy/drug effects/physiology ; Humans ; *rho-Associated Kinases/metabolism ; *Reactive Oxygen Species/metabolism ; *Pyridines/pharmacology ; *Amides/pharmacology ; *Pressure ; Cells, Cultured ; Flow Cytometry ; Acetylcysteine/pharmacology ; },
abstract = {Autophagy is a self-digestion mechanism of cells, which is related to cell stress. It enables cell survival by maintaining cellular homeostasis or initiates cell death. This study aimed to investigate the intracellular signaling of pressure-induced autophagy regulation in human periodontal ligament (PDL) cells and to analyze the involvement of Rho kinases (ROCK) and reactive oxygen species (ROS) in particular. Human PDL cells were treated with the ROCK inhibitor Y-27632 and the ROS scavenger N-acetylcysteine (NAC) in combination with pressure magnitudes of 2, 6, and 8 g/cm2 over 16 hours. Cells treated with rapamycin served as a positive control and untreated cells as a control group. The Cyto-ID® Autophagy Detection Kit was used for flow cytometric analysis. Statistical analysis was performed using ANOVA and post-hoc tests. The results show that the pressure-induced autophagy was affected differently by the two inhibitors (p<0.05). The application of Y-27632 led to a significant reduction in autophagy in all pressure groups. The application of NAC led to reduced autophagy at pressures of 2 g/cm2 and 6 g/cm2. At 8 g/cm2, this effect was no longer present. In the control group, autophagy was significantly reduced by Y-27632 and significantly increased by NAC. Our data suggest that both Rho-kinase and reactive oxygen species could influence pressure-induced autophagy regulation in PDL cells.},
}

*Periodontal Ligament/cytology
*Autophagy/drug effects/physiology
Humans
*rho-Associated Kinases/metabolism
*Reactive Oxygen Species/metabolism
*Pyridines/pharmacology
*Amides/pharmacology
*Pressure
Cells, Cultured
Flow Cytometry
Acetylcysteine/pharmacology

@article {pmid40133146,
year = {2025},
author = {Xu, R and Zhang, G and Huang, H and Zhao, Y and Tan, WS and Cai, H},
title = {Polyvinyl alcohol, N-acetylcysteine, and methyl-β-cyclodextrin exhibit albumin functions in natural killer cell culture.},
journal = {Journal of bioscience and bioengineering},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jbiosc.2025.02.008},
pmid = {40133146},
issn = {1347-4421},
abstract = {Albumin is a crucial component of serum-free media, playing a significant role in ex vivo cell culture as a lipid carrier and antioxidant. However, purified albumin contains undefined substances, making it challenging to achieve clinical application standards for effector cell culture. This study used natural killer (NK)-92 cells as a model to investigate the effects of the albumin substitute replacing bovine serum albumin (BSA) on cell expansion and metabolism in an in-house-designed, chemically defined, serum-free medium. We selected polyvinyl alcohol (PVA), N-acetylcysteine (NAC), and methyl-β-cyclodextrin (M-β-CD) as an albumin substitute combination and optimized their concentrations by using response surface methodology. The optimized albumin substitute was named PVA-NAC-M-β-CD (PNM). After 8 days of culture, NK-92 cells cultured with the PNM exhibited phenotype and cytotoxic function comparable to cells cultured with different concentrations of BSA. The expansion fold was 89.22 ± 3.55, significantly higher than the 51.23 ± 6.57 observed in the 0.75 g/L BSA group (p < 0.05). Further verification of functions of PNM showed that intracellular fatty acid levels, cholesterol consumption rates, and the pSTAT5 level in the PNM group were significantly higher than those in the 0.75 g/L BSA group (p < 0.05). Reactive oxygen species levels remained controlled, and mitochondrial membrane potential was similar. These findings suggested that the PNM can effectively replace the functions of BSA as a fatty acid carrier, antioxidant, and, to some extent, a cholesterol carrier. This study provides insights for developing chemically defined media to prepare clinical-grade NK cells efficiently.},
}

@article {pmid40133121,
year = {2025},
author = {Lucas-Herald, AK and Hussain, S and McGinley, K and Alves-Lopes, R and Amjad, SB and Flett, M and Lee, B and Steven, M and O'Toole, S and Ahmed, SF},
title = {ROS scavengers and genital skin healing in boys with hypospadias.},
journal = {Journal of pediatric urology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpurol.2025.02.023},
pmid = {40133121},
issn = {1873-4898},
abstract = {INTRODUCTION: Hypospadias repair is associated with high complication rates. Vascular cells from boys with hypospadias have increased reactive oxygen species (ROS) compared to controls. It is not clear if ROS affects wound healing in hypospadias.

OBJECTIVES: The aim of this study is to identify if cell migration and proliferation in genital skin is altered in hypospadias, and whether this is altered by antioxidants.

STUDY DESIGN: Genital skin fibroblasts (GSFs) were grown from boys undergoing hypospadias repair or routine circumcision. Cells were imaged immediately after creating a wound scratch and 48 h later, in the presence/absence of ROS scavengers, N-acetylcysteine (NAC) or Tempol. Cell migration was determined using ImageJ software. Cell proliferation was measured using a Cell Count Kit-8 (Abcam, UK).

RESULTS: Twenty-four cases (median age (range) 1.8 (1.2, 6.3) years) and 28 controls (1.6 (1.2, 6.1) years) were recruited. Boys with hypospadias had impaired cell migration with reduced wound closure at 48 h (2.0 fold, p < 0.0001) and reduced cell proliferation (1.3 fold, p = 0.01). External Masculinisation Score was positively correlated with wound closure (r = 0.5, p < 0.0001) and cell proliferation (r = 0.3, p = 0.002). Exposure to NAC and Tempol improved wound closure (1.9 fold, p = 0.01, and 1.5 fold, p = 0.02 respectively) and cell proliferation (1.5 fold, p = 0.02 and 1.4 fold, p = 0.05 respectively).

DISCUSSION: There is an association between wound healing and virilisation of the external genitalia in boys. ROS scavengers increase cell migration and proliferation in GSFs from boys with hypospadias.

CONCLUSION: Translational studies are required to confirm whether ROS scavengers may represent a therapeutic option for improving surgical outcome in boys with hypospadias.},
}

@article {pmid40126496,
year = {2025},
author = {Syarif, S and Makkaraka, MAG and Zainal, ATF and Birowo, P and Atmoko, W},
title = {Unlocking the potential of antioxidant supplementation with n-acetylcysteine to improve seminal parameters and analysis of its safety: a systematic review and meta-analysis of randomized controlled trials.},
journal = {Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica},
volume = {},
number = {},
pages = {13750},
doi = {10.4081/aiua.2025.13750},
pmid = {40126496},
issn = {2282-4197},
abstract = {INTRODUCTION AND OBJECTIVES: N-acetyl-cysteine (NAC) is one of the oldest and most powerful antioxidants used to treat various diseases. It plays an important role in protecting cells against oxidative damage and has the potential to improve seminal parameters in male with infertility. This systematic review and meta-analysis aim to comprehensively evaluate the efficacy and safety profile of antioxidant supplementation with NAC in male with infertility or impaired semen parameters.

MATERIALS AND METHODS: This systematic review and meta-analysis adhered to Cochrane Handbook guidelines. A literature search across PubMed, ScienceDirect, Cochrane Library and Scopus on February 21, 2024 of studies evaluating NAC supplementation for male infertility or impaired semen parameters was conducted. Study quality was assessed using Revised Cochrane's risk of bias (RoB 2.0) and RevMan 5.4 was used for meta-analysis.

RESULTS: Search yielded 1.106 articles and 5 studies were included in this meta-analysis. Our study showed that patients who received NAC had statistically significant results in improving sperm volume [MD: 0.69 (0.26-1.12), P = 0.002], sperm concentration [MD: 4.43 1.50-7.36), P = 0.003], sperm total motility [MD: 9.69 (6.61-12.77), P < 0.00001], and normal sperm morphology [MD: 1.36 (0.70-2.03), P < 0.0001] compared to control. Additionally, patients given NAC had no reported side effects based on our included studies.

CONCLUSIONS: We found NAC supplementation significantly improves seminal parameters and has a favorable safety profile. These findings highlight the potential role of NAC as a safe supplementation for male with infertility or in male with impaired semen parameters.},
}

@article {pmid40125296,
year = {2025},
author = {El-Sarnagawy, GN and Abd Eldayem, YB and Sobeeh, FG},
title = {Pattern and impact of antidotal administration in an Egyptian tertiary poison control center: A three-year retrospective study (2021-2023).},
journal = {Toxicology reports},
volume = {14},
number = {},
pages = {101973},
pmid = {40125296},
issn = {2214-7500},
abstract = {Timely antidote administration is a critical step in acute poisoning management. Awareness of poisoning patterns and the essential antidotal requirement could improve patient care with better hospital resource allocation. This study investigates the pattern and impact of antidotal administration on patient outcomes in an Egyptian tertiary poison control center, providing insights to optimize the antidote stocking of essential antidotes. A three-year cross-sectional study was conducted at Tanta University Poison Control Center from January 2021 to December 2023. Demographic data, poisoning characteristics, causative agents, and administered antidotal data were retrieved. The initial Poisoning Severity Score (PSS), total hospitalization period, and patient outcomes were also recorded. The included 447 antidote-treated poisoned patients showed near equal gender distribution and median age of 25 years. Atropine, oximes, N-acetylcysteine (NAC), and naloxone were the top administered antidotes among patients (48.3 %, 25.7 %, 19.9 %, and 11.2 %, respectively). Mortality and complications were recorded in 5.15 % and 20.8 %, respectively. Administration of atropine, oximes, NAC, and L-carnitine significantly improved all outcomes (p < 0.05). Although HBO therapy significantly improved mortality, it substantially increased intensive care unit admissions (p < 0.001). Despite folic acid administration significantly improved mortality and complication incidences (p < 0.05), its therapeutic efficiency is still questionable. Availability constraints of the digibind and botulinum antitoxin could affect patient outcomes. Administration of atropine, oximes, NAC, naloxone, and sodium bicarbonate was significantly linked to prolonged hospitalization (p < 0.001). Accordingly, the emergency department in each institution should regularly update the antidotal stock based on a review of the list of essential and commonly used antidotes.},
}

@article {pmid40122550,
year = {2025},
author = {Humphries, C and Clarke, E and Eddleston, M and Gillings, M and Irvine, S and Keating, L and Miell, A and Milne, L and Muir, L and O'Brien, R and Oatey, K and Raman, R and Thanacoody, R and Tuck, S and Weir, CJ and Wood, DM and Dear, JW and , },
title = {HiSNAP trial-a multicentre, randomised, open-label, blinded end point, safety and efficacy trial of conventional (300 mg/kg) versus higher doses of acetylcysteine (450 mg/kg and 600 mg/kg) in patients with paracetamol overdose in the UK: study protocol.},
journal = {BMJ open},
volume = {15},
number = {3},
pages = {e097432},
doi = {10.1136/bmjopen-2024-097432},
pmid = {40122550},
issn = {2044-6055},
mesh = {Humans ; *Acetaminophen/poisoning/administration & dosage ; *Acetylcysteine/administration & dosage/therapeutic use ; *Drug Overdose/drug therapy ; Analgesics, Non-Narcotic/poisoning/administration & dosage ; United Kingdom ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Antidotes/administration & dosage/therapeutic use ; Chemical and Drug Induced Liver Injury/drug therapy ; Glutathione/metabolism ; Dose-Response Relationship, Drug ; Male ; Adult ; },
abstract = {INTRODUCTION: In overdose, a larger proportion of paracetamol (acetaminophen) is converted in the liver to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Glutathione (GSH) is the endogenous antioxidant that protects cells from NAPQI-induced injury. In overdose, GSH stores may become depleted, leaving NAPQI free to produce liver damage. N-Acetylcysteine (NAC) helps prevent paracetamol toxicity by replenishing liver GSH. This protective effect of NAC produces specific metabolites in the circulation. Currently, regardless of the paracetamol dose ingested, patients in the UK receive a dose of NAC based only on their weight. Basic pharmacology, mathematical modelling and observational studies suggest that this dose may be insufficient in some patients (particularly those taking a large overdose).

METHODS AND ANALYSIS: A multicentre trial, taking place across several hospitals in Scotland, UK, within Emergency Departments and Acute Medical Units. Recruitment commenced on 19 February 2024 and is anticipated to run for approximately 2 years. This is a three-group dose-finding trial, in which participants are assigned in a 1:1:1 ratio to either Standard NAC (300 mg/kg) or higher doses of 450 mg/kg (Group 1) and 600 mg/kg (Group 2). The primary outcome is the proportion of paracetamol metabolites in the circulation that are directly produced by GSH/NAC detoxification of NAPQI. A higher proportion of these metabolites will indicate that the additional NAC is reducing the amount of toxic paracetamol metabolites in the body. The study will first test the primary outcome on the HiSNAP Group 2 against Standard NAC; only if that is significant will HiSNAP Group 1 be tested against Standard NAC.

ETHICS AND DISSEMINATION: The HiSNAP trial has been approved by the East Midlands (Derby) Research Ethics Committee (reference 23/EM/0129), NHS Lothian Research and Development Department, and the MHRA. Results will be disseminated by peer-reviewed publication, conferences and linked on isrctn.com.

TRIAL REGISTRATION NUMBER: ISRCTN17516192.},
}

Humans
*Acetaminophen/poisoning/administration & dosage
*Acetylcysteine/administration & dosage/therapeutic use
*Drug Overdose/drug therapy
Analgesics, Non-Narcotic/poisoning/administration & dosage
United Kingdom
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
Antidotes/administration & dosage/therapeutic use
Chemical and Drug Induced Liver Injury/drug therapy
Glutathione/metabolism
Dose-Response Relationship, Drug
Male
Adult

@article {pmid40122511,
year = {2025},
author = {Peerapen, P and Rattananinsruang, P and Putpeerawit, P and Boonmark, W and Thongboonkerd, V},
title = {The direct inhibitory effects of an antioxidant, N-acetylcysteine, against calcium oxalate crystal growth, aggregation and adhesion to MDCK renal cells.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {115403},
doi = {10.1016/j.fct.2025.115403},
pmid = {40122511},
issn = {1873-6351},
abstract = {N-acetylcysteine (NAC), a potent antioxidant, can reduce nephrolithiatic pathogenesis by diminishing oxidative assault during crystalluria. However, its direct effects on calcium oxalate (CaOx) crystals that affect stone development were unknown. Herein, we examined the direct effects of NAC (at 1, 10 or 100 μM) on CaOx crystal formation, growth, aggregation, adhesion to MDCK renal cells, and internalization into the cells. The findings demonstrated that NAC at all these concentrations did not significantly affect size, number and mass of the newly generated CaOx crystals and their internalization into renal cells. However, NAC dose-dependently inhibited CaOx self-aggregation. Additionally, NAC at all concentrations significantly decreased the enlargement (growth) of the already-formed CaOx crystals and their adhesion to renal cells. Its dose-dependent inhibitory effects on crystal growth and adhesion were demonstrated at lower concentrations (0.01 and 0.1 μM). Measurement of adsorption energy (Eadsorption) between NAC molecule and Ca[2+] ion revealed adsorption or affinity between NAC and Ca[2+]. Their affinity/binding was also confirmed by an ion-selective electrode (ISE)-based titration assay. These data have shown, for the first time, the direct inhibitory effects of NAC against CaOx crystal growth, aggregation and crystal adhesion to renal cells via Ca[2+] binding that may impact the prevention of nephrolithiasis.},
}

@article {pmid40119667,
year = {2025},
author = {Büyükdoğan, H and Ertürk, C and Eren, E and Öztürk, Ç and Yıldırım, B and Sarıtaş, TB and Demirkol, M},
title = {The impact of N-acetylcysteine on early periods of tendon healing: histopathologic, immunohistochemical, and biomechanical analysis in a rat model.},
journal = {Connective tissue research},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/03008207.2025.2479501},
pmid = {40119667},
issn = {1607-8438},
abstract = {PURPOSE: This study aimed to evaluate the early effects of N-acetylcysteine, which has antioxidant, inflame-modulatory, and cytoprotective properties, on tendon healing.

MATERIALS AND METHODS: Thirty-five male Wistar Hannover rats were divided into five groups: first-week treatment (Group 1T), first-week control (Group 1C), third-week treatment (Group 3T), third-week control (Group 3C), and native tendons (Group N). Bilateral Achilles tenotomy was performed on all rats except Group N. After tenotomy, 150 mg/kg N-acetylcysteine was administered daily intraperitoneally to treatment groups, while isotonic saline was given to the control groups. Tendons were evaluated histopathologically, immunohistochemically, and biomechanically after sacrifice in the first and third weeks.

RESULTS: No significant differences were observed in the first week (p > 0.05). Movin and Bonar scores (lower scores reflect improved histologic healing) were significantly lower in Group 3T than in Group 3C (p = 0.002). Collagen type-I/type-III ratios were higher in Group 3T compared to Group 3C (p = 0.001). Fmax (N) values were similar across Group 3T, Group 3C, and Group N (p = 0.772). However, cross-sectional areas (mm[2]) were significantly smaller in Group 3T than in Group 3C (p = 0.001), with the smallest areas observed in native tendons. Thus, tensile strength (MPa, load per unit area) and toughness (J/10[3] mm[3], energy absorbed per unit volume) were significantly higher in Group 3T than in Group 3C (p = 0.001).

CONCLUSION: N-acetylcysteine supplied some improved results on early markers of tendon healing. Although our findings support the potential of NAC as a therapeutic adjunct in tendon injuries, further studies are needed to evaluate the long-term effects and underlying mechanisms.},
}

@article {pmid40113020,
year = {2025},
author = {Xiong, Z and Ou, Y and Chen, R and Zhou, M and Wang, Z and Wu, G and Che, M and Li, K and Gong, H and Wang, Y and Ling, X and Wang, H and Wang, X and Song, Q and Qi, S and Feng, Z and Peng, J},
title = {Tanycyte proliferation and migration through the sonic hedgehog pathway restores hypothalamic function after ischemic injury.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.03.026},
pmid = {40113020},
issn = {1873-4596},
abstract = {Tanycytes, a distinct type of glial cell within the hypothalamus, will be investigated in this study to elucidate the intrinsic mechanisms by which they facilitate the restoration of hypothalamic function. We injected endothelin 1 (ET-1) into the third ventricle to establish an ischemic hypothalamic injury model. Nestin CreER[T2] and Rosa26R-CAG:tdTomato mice were crossbred, and viral tracing was used to label and track tanycytes. Functional changes in these cells were observed with calcium imaging. Alterations in tanycytes were assessed with single-cell and transcriptomic sequencing analyses. The involvement of specific pathways was confirmed via intraperitoneal injection of N-acetyl cysteine (NAC) and cycloheximide. Following ischemic injury to the hypothalamus in mice, acute weight loss and impaired activity of Agrp neurons were observed, both of which recovered within 7 days. The fate of tanycytes was traced in Nestin-CreER[T2]: Rosa26R-CAG:Tdtomato mice to confirm their proliferation and migration after hypothalamic injury. Calcium imaging indicated that these proliferating and migrating cells participated in signal transduction, thereby reconstructing the regulatory network of tanycytes. The analysis of single-cell data on postnatal days 8 and 45 identified CDK1 as a marker of proliferative tanycytes. The roles of ROS and the Shh pathway in the proliferation and migration of tanycytes were validated via the intraperitoneal injection of NAC and cycloheximide inhibitors. After inducing ischemic injury to the arcuate nucleus of the hypothalamus, Agrp neuronal activity declined, accompanied by ROS fluctuations within tanycytes. Activation of the Shh pathway prompts the transition of tanycytes from a quiescent state to a proliferative state, thereby leading to their migration to the arcuate nucleus. This process re-establishes the regulatory network of tanycytes and restores metabolic balance. This finding may provide an important target for promoting the recovery of hypothalamic function.},
}

@article {pmid40111652,
year = {2025},
author = {Bai, H and Chen, H and Du, S and Qiu, D and Li, S and Ma, T and Gao, R and Zhang, Z},
title = {N-Acetylcysteine Mitigates Ketamine Neurotoxicity in Young Rats by Modulating ROS-Mediated Pyroptosis and Ferroptosis.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40111652},
issn = {1559-1182},
support = {SYKJYB202302//Discipline Project of College of Veterinary Medicine/ ; NDYB2022-4//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; NDYB2022-7//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; 2023MS03035//Natural Science Foundation of Inner Mongolia Autonomous Region of china/ ; },
abstract = {Ketamine, an N-methyl-D-aspartate receptor antagonist with anesthetic and analgesic properties, is extensively utilized for the induction and maintenance of pediatric perioperative anesthesia. Increasing evidence suggests that prolonged exposure to ketamine may induce neurotoxicity in developing animals, adversely affecting their long-term cognitive function. N-acetylcysteine (NAC) is an organic sulfur compound in the Allium genus; however, the mechanisms through which it alleviates ketamine-induced neurotoxicity during developmental stages remain inadequately understood. Refine the investigation of the mechanisms by which Nac mitigates ketamine-induced neurotoxicity during development via ferroptosis and pyroptosis pathways. Postnatal day 7 in SD rats PC12 cells and HAPI cells were used in this study. The neuroprotective mechanism of Nac was elucidated through pathological, histological, and molecular biological methodologies to assess pyroptosis, ferroptosis, hippocampal tissue damage, and behavioral modifications in adulthood. The results suggest that prior administration of Nac reduced lipid peroxidation and mitochondrial injury, along with pyroptosis activated by the NLRP3/caspase-1 pathway, hippocampal damage, and cognitive deficits after exposure to ketamine. In summary, our findings from both in vivo and in vitro studies indicate that ROS plays a significant regulatory role in the neurotoxic effects of ketamine during development. Furthermore, Nac mitigates hippocampal damage and cognitive deficits associated with ketamine exposure by inhibiting ROS-mediated ferroptosis and pyroptosis.},
}

@article {pmid40108283,
year = {2025},
author = {Charoensappakit, A and Sae-Khow, K and Vutthikraivit, N and Maneesow, P and Sriprasart, T and Pachinburavan, M and Leelahavanichkul, A},
title = {Immune suppressive activities of low-density neutrophils in sepsis and potential use as a novel biomarker of sepsis-induced immune suppression.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {9458},
pmid = {40108283},
issn = {2045-2322},
support = {N41A640076, N34A660583//The National Research Council of Thailand (NRCT)/ ; RA-MF-18/65, RA-MF-15/66, and RA-MF-14/67//Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University/ ; B16F640175//The Program Management Unit for Human Resources, Institutional Development, Research, and Innovation/ ; },
mesh = {Humans ; *Sepsis/immunology ; *Neutrophils/immunology/metabolism ; *Biomarkers ; Male ; Middle Aged ; Female ; *B7-H1 Antigen/metabolism ; Aged ; T-Lymphocytes/immunology/metabolism ; Antigens, CD/metabolism ; Leukocytes, Mononuclear/metabolism/immunology ; Adult ; Phagocytosis ; Apoptosis ; },
abstract = {Data of low-density neutrophils (LDN), the neutrophils in the peripheral blood mononuclear cells (PBMC) fraction, in sepsis is still less. As such, LDN (CD66b-positive cells in PBMC) was highest in intensive care unit (ICU) patients with sepsis (n=24) compared with non-sepsis (n=10) and healthy control (n=20), with a negative correlation with lymphocyte count and could predict secondary infection and mortality with the area under the curve (AUC) at 0.79 and 0.84, respectively. Compared with sepsis normal-density neutrophils (NDN), sepsis-LDN demonstrated higher expression of CD66b, CD63, CD11b, and CD184, but lower expression of CD62L and CD182 and defects of effector functions, including phagocytosis and apoptosis. The t-distributed stochastic neighbor embedding (t-SNEs) demonstrated high program cell death ligand-1 (PD-L1) in sepsis-LDN. In sepsis samples, the T cell proliferation in PBMC (T cells with LDNs) was lower than that in the isolated T cells (T cells alone) and incubation of anti-PD-L1 neutralizing antibody, but not a reactive oxygen species (ROS) scavenger (N-acetyl cysteine), improved the T cell suppression. Additionally, 30 min lipopolysaccharide (LPS) activation altered healthy control NDN into LPS-LDN (reduced density) and LPS-NDN (maintain density) with similarly elevated CD66b, CD11B, and CD62L. However, LPS-LDN (in vitro LDN) showed lower expression of CD63, CD184, and PD-L1 compared with LDN from patients (sepsis-LDN), suggesting a partial LPS impact on LDN generation. From the microscopic-based method (Wright's staining in PBMC), sepsis-LDN demonstrated a mixed population of mature and immature cells with a good correlation with the flow-based analysis (Bland-Altman analysis and AUC). In conclusion, LDN in sepsis, partly generated by LPS activation, was associated with secondary infection and T cell suppression, mainly through the expression of PD-L1, which might be an immune suppression biomarker, especially with a less expensive microscopic-based method.},
}

Humans
*Sepsis/immunology
*Neutrophils/immunology/metabolism
*Biomarkers
Male
Middle Aged
Female
*B7-H1 Antigen/metabolism
Aged
T-Lymphocytes/immunology/metabolism
Antigens, CD/metabolism
Leukocytes, Mononuclear/metabolism/immunology
Adult
Phagocytosis
Apoptosis

@article {pmid40106157,
year = {2025},
author = {Zhang, F and Zhang, C and Sun, W and Xie, S and Wu, P and Zeng, G and Liu, X},
title = {Proteomic Profiling and Therapeutic Targeting of Oxidative Stress in Autoimmune Encephalitis.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {2},
pages = {38},
pmid = {40106157},
issn = {1559-1166},
support = {82360251//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Oxidative Stress ; Mice ; *Mice, Inbred C57BL ; Humans ; Female ; *Acetylcysteine/therapeutic use/pharmacology ; *Encephalitis/metabolism/drug therapy ; *Encephalomyelitis, Autoimmune, Experimental/metabolism/drug therapy/blood ; Biomarkers/blood ; Male ; Adult ; Hashimoto Disease/drug therapy/metabolism/blood ; Proteome/metabolism ; Antioxidants/therapeutic use/metabolism ; Middle Aged ; },
abstract = {Autoimmune encephalitis (AE) is an immune-mediated non-infectious disease, and novel and robust biomarkers are needed to improve the diagnosis and prognostic outcomes of AE. Oxidative stress is a ubiquitous cellular process causing damage to various biological molecules. The aim of our study was to understand the clinical implication and mechanism underlying oxidative stress in AE. Liquid chromatography-mass spectrometry analysis was conducted on the serum of eight patients with AE and seven healthy controls, and oxidative stress was characterized. Experimental autoimmune encephalitis (EAE) models were established in C57BL/6 and SJL mice for investigation of the therapeutic effect and mechanism of anti-oxidative stress N-acetylcysteine (NAC). We provided proteomic landscape in the serum of AE and identified antioxidant ALB, APOE, GPX3, and SOD3 as serum diagnostic markers of AE. The antioxidant markers were lowly expressed both in the serum of AE patients and central nervous system (CNS) of EAE mice. NAC administration improved clinical signs and motor function and alleviated nerve injury of EAE mice as well as lowered oxidative stress (decreased MDA content and ROS accumulation and elevated SOD activity and GSH content). ALB, APOE, GPX3, and SOD3 expressions were elevated by NAC in the CNS of EAE mice. Moreover, NAC reduced tissue-resident CD4[+] and CD8[+] T cells and GFAP-marked astrocytes and Iba-1-marked microglia in EAE mice, thus alleviating autoimmunity-mediated damage and neuroinflammation. Our findings facilitate the discovery of novel oxidative stress-related biomarkers for AE and reveal the promise of anti-oxidative stress for AE management.},
}

Animals
*Oxidative Stress
Mice
*Mice, Inbred C57BL
Humans
Female
*Acetylcysteine/therapeutic use/pharmacology
*Encephalitis/metabolism/drug therapy
*Encephalomyelitis, Autoimmune, Experimental/metabolism/drug therapy/blood
Biomarkers/blood
Male
Adult
Hashimoto Disease/drug therapy/metabolism/blood
Proteome/metabolism
Antioxidants/therapeutic use/metabolism
Middle Aged

@article {pmid40106010,
year = {2025},
author = {Yuksel, C and Uz, YH},
title = {Protective effects of N-acetylcysteine against titanium dioxide nanoparticles-induced kidney damage in rats.},
journal = {Journal of molecular histology},
volume = {56},
number = {2},
pages = {112},
pmid = {40106010},
issn = {1567-2387},
support = {Project number: TUBAP 2022/57//Scientific Research Projects Coordination Unit of Trakya University, Turkey/ ; Project number: TUBAP 2022/57//Scientific Research Projects Coordination Unit of Trakya University, Turkey/ ; },
mesh = {Animals ; *Titanium/adverse effects/toxicity ; *Acetylcysteine/pharmacology ; Rats ; *Kidney/drug effects/pathology/metabolism ; Male ; Apoptosis/drug effects ; Nanoparticles ; NF-kappa B/metabolism ; Protective Agents/pharmacology ; Kidney Diseases/chemically induced/prevention & control/pathology ; Metal Nanoparticles ; Caspase 3/metabolism ; Rats, Sprague-Dawley ; },
abstract = {The objective of this study was to evaluate the potential protective effect of N-acetylcysteine (NAC) against kidney damage induced by titanium dioxide nanoparticles (TiO2NP) through biochemical, histological, and immunohistochemical analyses. Forty rats were randomly divided into four groups of 10 animals each. Saline was administered intragastrically to control group for 14 days. In NAC group, 150 mg/kg NAC was injected intraperitoneally for 21 days. In TiO2NP group, TiO2NP at a dose of 50 mg/kg/day, dissolved in saline, was administered intragastrically for 14 days. TiO2NP + NAC group received 50 mg/kg/day TiO2NP for 14 days and 150 mg/kg NAC for 21 days, starting 7 days before TiO2NP administration. At the end of experiment, rats were anesthetized, serum samples were collected for biochemical analysis, and kidney tissue was removed for histological and immunohistochemical analyses. There was no significant change in body weight, kidney weight, or serum urea-creatinine levels between the groups. TiO2NP caused a significant increase in vacuolization and brush border loss scores in tubular cells, as well as scores for congestion and leukocyte infiltration. However, NAC supplementation significantly ameliorated these impairments. Additionally, TiO2NP significantly increased NF-kB, TNF-α, and caspase-3 immunoreactivities, as well as the number of PCNA-positive and TUNEL-positive cells. NAC treatment decreased all immunoreactivities and TUNEL-positive cells, but did not change the number of PCNA-positive cells after TiO2NP exposure. The results of the study showed that the toxic effects of TiO2NP on the kidneys, commonly encountered in daily life, can be mitigated by the anti-inflammatory and anti-apoptotic properties of NAC.},
}

Animals
*Titanium/adverse effects/toxicity
*Acetylcysteine/pharmacology
Rats
*Kidney/drug effects/pathology/metabolism
Male
Apoptosis/drug effects
Nanoparticles
NF-kappa B/metabolism
Protective Agents/pharmacology
Kidney Diseases/chemically induced/prevention & control/pathology
Metal Nanoparticles
Caspase 3/metabolism
Rats, Sprague-Dawley

@article {pmid40097764,
year = {2025},
author = {Li, X and Li, W and Xie, X and Fang, T and Yang, J and Shen, Y and Wang, Y and Wang, H and Tao, L and Zhang, H},
title = {ROS Regulate Rotenone-induced SH-SY5Y Dopamine Neuron Death Through Ferroptosis-mediated Autophagy and Apoptosis.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40097764},
issn = {1559-1182},
abstract = {Rotenone, a plant-derived natural insecticide, is widely used to induce Parkinson's disease (PD) models. However, the mechanisms of rotenone-induced cell death remain unclear. Here, we found that rotenone (0.01, 0.1, or 1 μmol/L) suppressed SH-SY5Y dopamine neuron viability and led to PD-like pathological changes, such as reduced tyrosine hydroxylase (TH) but increased α-synuclein. Rotenone increased the levels of intracellular reactive oxygen species (ROS) and mitochondrial ROS, as well as the levels of the antioxidants nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), ultimately resulting in oxidative stress. Moreover, rotenone significantly downregulated the expression of GPX4 and xCT but upregulated the expression of COX2 and NCOA4, which are markers of ferroptosis. Furthermore, rotenone decreased phosphorylated mTOR level but increased Beclin-1, ATG5, LC3 and p62 expression, suggesting that rotenone enhances autophagy and reduces autophagy flux. Additionally, rotenone reduced Bcl-2 levels and the mitochondrial membrane potential (MMP) while promoting BAX and Caspase-3 expression, thus initiating cell apoptosis. N-acetylcysteine (NAC), a ROS scavenger, and ferrostatin-1 (Fer-1) and deferoxamine (DFO), two ferroptosis inhibitors, significantly eliminated rotenone-induced autophagy and apoptosis. Moreover, ML385, a specific inhibitor of Nrf2, suppressed rotenone-induced ferroptosis. Our results demonstrated that ROS might mediate rotenone-induced PD-like pathological changes by regulating iron death, autophagy, and apoptosis. Inhibiting ferroptosis blocked the rotenone-induced increase in autophagy and apoptosis. Thus, the ability of ROS to regulate rotenone-induced death through autophagy and apoptosis is dependent on ferroptosis. The findings require validation in multiple neuronal cell lines and in vivo.},
}

@article {pmid40094443,
year = {2025},
author = {Smieško, L and Mažerik, J and Gondáš, E and Dohál, M and Jošková, M and Šutovská, M and Fraňová, S},
title = {N-Acetylcysteine and Its Therapeutic Potential in an Animal Model of Allergic Asthma.},
journal = {Journal of aerosol medicine and pulmonary drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1089/jamp.2024.0049},
pmid = {40094443},
issn = {1941-2703},
abstract = {Background: N-acetylcysteine (NAC) is a classical mucolytic agent that, in addition to its mucolytic activity, also exhibits antioxidant activity. This could be beneficial in treating chronic inflammatory airway diseases, including asthma. Background: We evaluated the ability of NAC to modulate airway defense mechanisms, airway reactivity, inflammation, and remodeling after 10 days of administration [20 and 60 mg/(kg·d)] in an experimental guinea pig model of allergic inflammation. Methods: The concentrations of inflammatory cytokines (interleukins: IL-4, IL-5, IL-10, IL-12, and IL-13), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were measured in bronchoalveolar lavage fluid using a multiplex detection method. The concentration of remodeling marker transforming growth factor beta-1 (TGF-β1) was measured in lung homogenates using enzyme-linked immunosorbent assay. In vivo, changes in specific airway resistance and number of cough efforts were determined. Tracheal smooth muscle reactivity was evaluated in vitro. Ciliary beat frequency (CBF) indicated mucociliary clearance. Results: A 10-day administration of NAC at a higher dosage led to a significant decrease in the regulatory cytokines IL-4, IL-5, and GM-CSF. NAC, in both dosing schedules, decreased the levels of TGF-β1. NAC at a higher dosage reduced the number of chemically induced cough reflexes and CBF. NAC did not affect airway hyperreactivity parameters. Conclusion: NAC is a multifactorial drug, and under our experimental conditions of allergic inflammation, it showed positive effects on the levels of regulatory cytokines and growth factors, which probably led to a reduction in the intensity of airway defense mechanisms.},
}

@article {pmid40094059,
year = {2025},
author = {Yadav, N and Mondal, D and Raja, R and Ma, EL and Singh, KP and Sharma, DK and Das, AK},
title = {N-acetylcysteine enhances bone marrow activity in treating pancytopenia induced by canine hemoprotozoan diseases.},
journal = {Veterinary research forum : an international quarterly journal},
volume = {16},
number = {1},
pages = {1-10},
pmid = {40094059},
issn = {2008-8140},
abstract = {Canine hemoprotozoan diseases viz. ehrlichiosis and babesiosis are mostly associated with critical anemia and thrombocytopenia with pancytopenic changes, leading to multi-organ failure. For faster recovery of patients with complicated hemoprotozoan diseases, whole blood transfusion or bone marrow stimulating agents to produce more red blood cells (RBCs) and platelets might be helpful. Unfortunately, canine specific transfusion procedures are expensive and even not available in many developing countries. Development of alternate therapeutic modality by bone marrow stimulation to augment the production of RBCs and platelets and thus, to treat the critical pancytopenic patients is and an urgent necessity. N-acetylcysteine (NAC), acts as a precursor of reduced glutathione and increases the production of bone marrow B cells. It also improves viability and self-renewal capacity of stem cells and thus, boosts hematopoietic differentiation by protecting induced pluripotent stem cells. This study envisaged to develop alternate therapeutic approach to combat pancytopenia secondary to canine hemoprotozoan diseases. Bone marrow mediated aplastic pancytopenia was induced experimentally by administration of cyclophosphamide in rats. Bone marrow stimulating property of NAC was compared with desmopressin, another bone marrow stimulator, which revealed better in terms of hematobiochemical and histopathological changes. Results of rat model study were extrapolated in clinical canine hemoprotozoan cases having pancytopenia. Dogs treated with hemoprotozoan disease specific therapy along with NAC rendered favorable changes by haltering the progression of critical anemia and thrombocytopenia. Study revealed that supplementation of NAC along with canine hemoprotozoan specific therapy is beneficial to alleviate pancytopenia.},
}

@article {pmid40092853,
year = {2024},
author = {Wahab, A and Ganiger, C and Pawar, R and Phaphe, S and Ronad, Y},
title = {Anti-microbial and micro-leakage properties of orthodontic cement.},
journal = {Bioinformation},
volume = {20},
number = {10},
pages = {1368-1373},
pmid = {40092853},
issn = {0973-2063},
abstract = {Glass Ionomer Cement (GIC) is used for cementing orthodontic bands because of its anti-cariogenic property, which is attributed to the release of fluoride. Therefore, it is of interest to assess the antimicrobial property and micro-leakage of GIC incorporated with different concentration of N-acetylcysteine (N-AC) and copper nanoparticle (Cu-NP). Our study composed of 5 groups i.e. group I is control with different concentration of N-AC and Cu-NP involving each group with 8 samples. We found that, group V showed the highest zone of inhibition; while the micro-leakage was seen highest for group I with a score of 2.2 ± 1.09 and the least score was recorded for Group III (0.8± 0.37). Thus, addition of 2% Cu-NP and 15% N-AC resulted in minimal micro-leakage. We conclude that increase in concentration of N-AC and CU-NP antimicrobial property efficiency also increases; on the other hand, increase in the concentration of N-AC and CU-NP did not decrease the micro-leakage.},
}

@article {pmid40084379,
year = {2025},
author = {Yang, CC and Chen, WM and Shia, BC and Wu, SY},
title = {Impact of long-term N-acetylcysteine use on cancer risk.},
journal = {American journal of cancer research},
volume = {15},
number = {2},
pages = {618-630},
pmid = {40084379},
issn = {2156-6976},
abstract = {Chronic obstructive pulmonary disease (COPD) patients face an increased risk of developing various malignancies due to shared risk factors and underlying systemic inflammation. N-acetylcysteine (NAC) has shown potential anticancer properties in preclinical studies, but clinical evidence in COPD patients is limited. We conducted a nationwide propensity score-matched cohort study using data from Taiwan's National Health Insurance Research Database to evaluate the anticancer effects of NAC in COPD patients. Patients diagnosed with COPD between 2008 and 2019 were included, and those with pre-existing cancer were excluded. NAC use was defined as consistent administration for most days with an average dose exceeding 28 cumulative defined daily doses (cDDDs) annually. Cox regression models were adjusted for various covariates was employed. PSM yielded 91,546 patients, evenly distributed between NAC and non-NAC groups. Multivariate Cox regression analysis revealed a lower cancer risk in patients with long-term NAC use compared to non-users (adjusted hazard ratio [aHR] 0.69, 95% confidence interval [CI] 0.66-0.72; P<0.001). Dose-dependent relationships were observed, with higher daily NAC intake associated with reduced cancer risk. Time-varying Cox regression analysis demonstrated significant reductions in the risk of specific cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer, among NAC users compared to non-users. Our study provides clinical evidence supporting the potential anticancer effects of NAC in COPD patients. These findings highlight the importance of exploring NAC as a chemopreventive agent in high-risk populations and inform clinical practice and future research endeavors.},
}

@article {pmid40083413,
year = {2025},
author = {Hu, QL and Zhong, H and Wang, XR and Han, L and Ma, SS and Li, L and Wang, Y},
title = {Mitochondrial phosphate carrier plays an important role in virulence of Candida albicans.},
journal = {Mycology},
volume = {16},
number = {1},
pages = {369-381},
pmid = {40083413},
issn = {2150-1203},
abstract = {Candida albicans is a common fungal pathogen that can cause life-threatening infections. MIR1 is considered to be a mitochondrial phosphate carrier of C. albicans, while its role in virulence has not been fully elucidated. In this study, we found that mir1Δ/Δ mutant exhibited severe virulence defect in both nematode and murine models. Further mechanism studies revealed that the mir1Δ/Δ mutant grew more slowly than the wild-type strain and showed severe filamentation defects on the hypha-inducing agar media, including YPD + serum, Lee, Spider + glucose, SLAD, SLD, and YPS. Furthermore, the loss of MIR1 resulted in unfermentable carbon utilisation defect, ATP decrease, and reactive oxygen species (ROS) accumulation in C. albicans. Antioxidant proanthocyanidins, vitamin E, and N-acetyl cysteine (NAC) could reduce intracellular ROS levels and partially rescue the filamentation defects of the mir1Δ/Δ mutant. Accordingly, hypha-specific genes, as well as CEK1 and RIM101 were down-regulated in the mir1Δ/Δ mutant, and this down-regulation could be partially rescued by the addition of the antioxidant NAC. Collectively, MIR1 plays an important role in C. albicans mitochondrial function, filamentation and virulence, and would be a promising antifungal target.},
}

@article {pmid40080083,
year = {2025},
author = {Basaran, R and Efendioglu, M and Akça, M and Ceman, D and Demirtaş, C and Sürmeneli, YE and Yildirim, M},
title = {Antihyperalgesic effects of gabapentin and levetiracetam in a model of post-traumatic epilepsy.},
journal = {Physiology international},
volume = {},
number = {},
pages = {},
doi = {10.1556/2060.2025.00524},
pmid = {40080083},
issn = {2498-602X},
abstract = {OBJECTIVE: This study aimed to investigate the role of levetiracetam (LEV) and gabapentin (GBP) on mechanical and thermal pain thresholds, as well as n-acetylcysteine (NAC) as an adjuvant, in the pentylenetetrazol (PTZ)-induced post-traumatic epilepsy (PTE) model after mild-traumatic brain injury (TBI) in male Sprague-Dawley rats.

METHODS: Animals were randomly divided into 7 groups (Control, PTE, PTE+LEV, PTE+GBP, PTE+NAC, PTE+LEV+NAC and PTE+GBP+NAC). Rats received 50 mg kg-1 LEV, 100 mg kg-1 GBP, and combinations of these antiepileptics with 100 mg kg-1 NAC for 14 days after TBI.

RESULTS: While the thermal pain threshold decreased significantly in the PTE group (P < 0.05), it increased in the PTE+LEV, PTE+GBP, and PTE+LEV+NAC groups (P < 0.05, P < 0.001 and P < 0.01, respectively). Interestingly, NAC alone did not affect the thermal pain threshold, but the combination of PTE+LEV+NAC increased the thermal pain threshold. Furthermore, PTE+GBP+NAC administration prevented the effect of GBP on the thermal pain threshold.

CONCLUSIONS: The presented study is the first to examine the effect of LEV and GBP in PTE. It was found that PTE decreased the thermal pain threshold, but LEV and GBP applied for 14 days prevented the decrease in PTE-related pain threshold and increased the thermal pain threshold. NAC, which was used as an adjuvant to support antiepileptic drugs, did not influence the thermal pain threshold alone; however, it increased the pain threshold more by potentiating the effect of LEV. Both LEV and GBP have an antihyperalgesic effect in the PTE model facilitated by PTZ, and NAC further reinforces the antihyperalgesic effect of LEV.},
}

@article {pmid40069676,
year = {2025},
author = {Heydari, B and Aflatonian, M and Bagherizadeh, M and Hoseinzade, F and Saghafi, F},
title = {Evaluating the efficacy of N-acetylcysteine in diminishing the duration and frequency of rotavirus-induced gastroenteritis: a preliminary randomized, placebo-controlled, double-blind clinical trial.},
journal = {BMC pediatrics},
volume = {25},
number = {1},
pages = {186},
pmid = {40069676},
issn = {1471-2431},
support = {85//Shahid Sadoughi University of Medical Sciences/ ; },
mesh = {Humans ; Double-Blind Method ; *Rotavirus Infections/drug therapy/complications ; *Gastroenteritis/drug therapy/virology/complications ; *Acetylcysteine/therapeutic use ; Female ; Male ; Infant ; Child, Preschool ; *Diarrhea/drug therapy/etiology ; Treatment Outcome ; Time Factors ; Rotavirus ; },
abstract = {BACKGROUND: Globally, gastroenteritis stands as a primary contributor to child mortality, annually taking the lives of 3 million children under the age of 5 years. Rotavirus, a major factor in viral diarrhea among children aged 6 months to 2 years, presents with severe symptoms such as watery diarrhea and vomiting. Although mortality rates have decreased due to supportive care and vaccines, promising alternatives like N-acetylcysteine (NAC) show potential benefits in laboratory studies, indicating a possible supplementary strategy for managing rotavirus infections by reducing the duration and antigen excretion in feces.

METHODS: During this double-blind clinical trial, 71 patients, confirmed to have gastroenteritis resulting from rotavirus using a rapid diagnostic strip, were randomly allocated to two groups. One group was prescribed NAC at a dosage of 60 mg/kg/day, while the other received a placebo. The patient's progress was monitored daily until their gastroenteritis improved, and details regarding the duration of diarrhea and the frequency of bowel movements were recorded for each participant.

RESULTS: The average duration of diarrhea in the NAC group and the placebo group was 2 and 3 days, respectively, with a level of p = 0.121. During the diarrhea period, the number of bowel movements in the NAC group was recorded at 28.1 ± 21.6 times, whereas in the placebo group, it was 35.3 ± 33.1 times, yielding a p-value of 0.409.

CONCLUSIONS: Even though the effects of NAC were observed in lowering the duration of the period and decreasing the frequency of bowel movements in gastroenteritis, these results did not reach statistical significance. Hence, the data from this study suggest that NAC may not effectively reduce the duration of diarrhea and the frequency of bowel movements linked to gastroenteritis caused by rotavirus.

TRIAL REGISTRATION: IRCT20181208041882N13, 14-10-2023 (https://irct.behdasht.gov.ir/trial/68259).},
}

Humans
Double-Blind Method
*Rotavirus Infections/drug therapy/complications
*Gastroenteritis/drug therapy/virology/complications
*Acetylcysteine/therapeutic use
Female
Male
Infant
Child, Preschool
*Diarrhea/drug therapy/etiology
Treatment Outcome
Time Factors
Rotavirus

@article {pmid40058751,
year = {2025},
author = {Zhao, Y and Lv, R and He, Y and Dong, N and Wang, X and Pu, J and Yu, Q},
title = {The miR-21-5p/DUSP8/MAPK signaling pathway mediates inflammation and apoptosis in vascular endothelial cells induced by intermittent hypoxia and contributes to the protective effects of N-acetylcysteine.},
journal = {European journal of pharmacology},
volume = {997},
number = {},
pages = {177462},
doi = {10.1016/j.ejphar.2025.177462},
pmid = {40058751},
issn = {1879-0712},
abstract = {Obstructive sleep apnoea hypopnea syndrome (OSAHS) is a sleep disorder associated with significant cardiovascular complications, characterized by intermittent hypoxia (IH). IH causes endothelial dysfunction, an early event in cardiovascular disease. We investigated the role of dual-specificity phosphatase 8 (DUSP8), a key negative regulator of the mitogen-activated protein kinase (MAPK) signalling pathway, in IH-induced endothelial cell damage, and the therapeutic effects of N-acetylcysteine (NAC) by establishing IH models in human umbilical vein endothelial cells and C57BL/6 mice. DUSP8 and MAPK signalling pathway-related proteins were analysed by western blotting, and DUSP8 mRNA and miR-21-5p expression was assessed by RT-qPCR. Inflammatory cytokines were detected by an enzyme-linked immunosorbent assay, apoptosis-related proteins were analysed by western blotting, and apoptosis was assessed using flow cytometry. IH stimulation induced inflammation and apoptosis in endothelial cells, downregulated DUSP8 expression, and upregulated the phosphorylation of key molecules involved in the MAPK signalling pathway. However, DUSP8 overexpression alleviated IH-induced inflammation and apoptosis in endothelial cells and reduced the phosphorylation of key molecules in the MAPK signalling pathway. Bioinformatic analysis and dual-luciferase reporter assays confirmed that DUSP8 is a direct target of miR-21-5p. DUSP8 overexpression effectively reversed the damage caused by miR-21-5p upregulation under IH conditions. Furthermore, in cell and animal models of IH, NAC demonstrated protective effects against inflammation, apoptosis, and oxidative stress through a mechanism linked to the miR-21-5p/DUSP8/MAPK signalling pathway. Overall, this study elucidated the protective role of DUSP8 against IH-induced endothelial injury and confirmed the potential of NAC as a therapeutic agent for OSAHS-related diseases.},
}

@article {pmid40057704,
year = {2025},
author = {Qiu, X and Yang, S and Zhang, Y and Wang, Q and Kong, L and Zhou, L},
title = {Effect of N-acetylcysteine on antimicrobials induced nephrotoxicity: a meta-analysis.},
journal = {BMC nephrology},
volume = {26},
number = {1},
pages = {128},
pmid = {40057704},
issn = {1471-2369},
mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Acute Kidney Injury/chemically induced/prevention & control ; *Anti-Infective Agents/therapeutic use ; Randomized Controlled Trials as Topic ; Creatine/blood ; Creatinine/blood ; Blood Urea Nitrogen ; },
abstract = {OBJECTIVE: N-acetylcysteine (NAC) has antioxidant effects in reducing acute kidney injury. This study systematically reviewed and assessed the efficacy of NAC in preventing antimicrobials induced nephrotoxicity.

METHODS: Pubmed, Embase, Web of Science, and the Cochrane Library were searched extensively for relevant studies that evaluating NAC on antimicrobials induced nephrotoxicity until June 1, 2024. Eligible records were screened according to the inclusion and exclusion criteria. The odds ratio (OR) was selected to evaluate the effect of NAC on nephrotoxicity. We pooled the extracted data using a random effects model.

RESULTS: Three randomized controlled trials were included in the analysis. The pooled results showed that NAC could reduce the incidence of antimicrobials induced nephrotoxicity (OR = 0.487, 95% CI = 0.258, 0.918, P = 0.03, I[2] = 0%). Serum creatine (Scr) on Day 2 was significantly decreased in the NAC group compared to the placebo group (SMD, - 0.298; 95%CI, - 0.585 to - 0.010; I[2] = 23%; P = 0.04). No difference was observed in blood urea nitrogen (BUN), and creatinine clearance (CrCl).

CONCLUSION: In this meta-analysis, NAC was associated with a benefit in the prevention of antimicrobials induced nephrotoxicity. However, large-scaled and well-designed RCTs are required in the future.},
}

*Acetylcysteine/therapeutic use/pharmacology
Humans
*Acute Kidney Injury/chemically induced/prevention & control
*Anti-Infective Agents/therapeutic use
Randomized Controlled Trials as Topic
Creatine/blood
Creatinine/blood
Blood Urea Nitrogen

@article {pmid40057223,
year = {2025},
author = {Maartens, M and Vlok, M and van de Vyver, M},
title = {Antioxidants improve the viability of diabetic bone marrow MSCs without rescuing their pro-regenerative secretome function.},
journal = {Molecular and cellular endocrinology},
volume = {601},
number = {},
pages = {112519},
doi = {10.1016/j.mce.2025.112519},
pmid = {40057223},
issn = {1872-8057},
abstract = {Bone marrow mesenchymal stem cell (BM-MSC) dysfunction and poor viability are prominent in diabetes and limit their therapeutic efficacy. A proteomic investigation was performed to assess disease associated alterations and the efficacy of antioxidants to rescue cellular function. BM-MSCs were isolated from obese diabetic mice (B6.Cg-Lep[ob]/J) cultured in the presence or absence of N-acetylcysteine (NAC) and ascorbic acid-2phosphate (AAP). Label free Liquid Chromatography and Mass Spectrometry (LC-MS) analysis detected 5079 proteins with 251 being differentially expressed between treatment groups. NAC/AAP improved cellular growth/viability post isolation by up-regulating proteins involved in redox status, ATP synthesis, Rho-GTPase signaling and modulated the immunophenotype of BM-MSCs. Despite a single application of the secretome not providing any advantage for wound bed regeneration in full thickness excisional diabetic wounds, the intracellular proteome illustrated the potential mechanisms of action by which NAC/AAP targeted the respiratory chain and modulated the immune phenotype of BM-MSCs. Given these observations, antioxidant supplementation might be more effective as prophylactic strategy to protect MSCs against functional decline instead of using it as a restorative agent and warrants further investigation.},
}

@article {pmid40056000,
year = {2025},
author = {Zanganeh, Z and Hezavehei, M and Halvaei, I and Sharafi, M},
title = {Beneficial Effects of N-Acetyl Cysteine in the Different Equilibration Times on Post-Thawed Rooster Sperm Quality.},
journal = {Reproduction in domestic animals = Zuchthygiene},
volume = {60},
number = {3},
pages = {e70035},
doi = {10.1111/rda.70035},
pmid = {40056000},
issn = {1439-0531},
support = {TMU8216//Tarbiat Modares University/ ; },
mesh = {Animals ; Male ; *Acetylcysteine/pharmacology ; *Semen Preservation/veterinary/methods ; *Cryopreservation/veterinary/methods ; *Chickens ; *Spermatozoa/drug effects/physiology ; *Sperm Motility/drug effects ; *Semen Analysis/veterinary ; Antioxidants/pharmacology ; Cryoprotective Agents/pharmacology ; Cell Membrane/drug effects ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {Cryopreservation is the best method for preserving rooster sperm, especially in declining indigenous breeds. Cryopreserved semen is significantly compromised due to equilibration time, cold shock and oxidative stress encountered during the freezing-thawing process. To improve the quality and fertility of thawed semen, it is essential to protect sperm cells from peroxidative damage. This study assessed the effects of N-acetyl cysteine (NAC), an antioxidant supplement, on the functional parameters of thawed rooster sperm after pre-freezing equilibration periods of 2 and 4 h. Samples were collected from 10 male Ross 308 broiler breeders and diluted with Beltsville extenders containing different concentrations of NAC (0, 0.1, 1 and 10 mM/mL) during equilibrium periods of 2 and 4 h before freezing. Our findings showed that NAC-0.1 and NAC-1 groups in 2 h increased significantly total and progressive motility (59.85 ± 3.73, 59.67 ± 3.73, 42.85 ± 2.64 and 42.80 ± 2.64, respectively), viability, and plasma membrane functionality (62.45 ± 3.51, 62.36 ± 3.51, 56.81 ± 3.51 and 56.82 ± 3.56, respectively) compared to the control groups. Furthermore, NAC-0.1-2 h and NAC-1-2 h demonstrated the lowest levels of apoptosis and intracellular reactive oxygen species (ROS), as well as the highest mitochondrial membrane potential in comparison to the control groups. These findings indicate that NAC-0.1 and NAC-1 are effective in maintaining the quality of thawed rooster sperm during a 2-h equilibration period.},
}

Animals
Male
*Acetylcysteine/pharmacology
*Semen Preservation/veterinary/methods
*Cryopreservation/veterinary/methods
*Chickens
*Spermatozoa/drug effects/physiology
*Sperm Motility/drug effects
*Semen Analysis/veterinary
Antioxidants/pharmacology
Cryoprotective Agents/pharmacology
Cell Membrane/drug effects
Membrane Potential, Mitochondrial/drug effects

@article {pmid40051733,
year = {2025},
author = {Asgharzadeh, N and Diziche, AN and Amini-Khoei, H and Yazdanpanahi, N and Korrani, MS},
title = {N-acetyl cysteine through modulation of HDAC2 and GCN5 in the hippocampus mitigates behavioral disorders in the first and second generations of socially isolated mice.},
journal = {IBRO neuroscience reports},
volume = {18},
number = {},
pages = {350-359},
pmid = {40051733},
issn = {2667-2421},
abstract = {OBJECTIVES: Social isolation stress (SIS) in early life can lead to behavioral disorders. N-acetylcysteine (NAC), an antioxidant, may aid treatment. This study explored NAC's impact on behavior in first and second-generation mice after SIS, focusing on HDAC2 and GCN5 expression in the hippocampus.

MATERIALS AND METHODS: In this study, 24 male and 24 female mice were bred for one generation. The pups were divided into six (3male, 3female) groups (n = 20): 1- Control receiving normal saline, 2- SIS with normal saline, 3- SIS with NAC (150 mg/kg) IP for four weeks. Eight mice from each group underwent behavioral, histopathological, and molecular tests, while others were mated (4 males + 4 females) to produce second generations. These pups were divided into 9 groups (n = 8) for behavioral tests, including elevated plus maze, open field, forced swimming, and histopathological and molecular assessments (HDAC2 and GCN5 expression) in the hippocampus.

RESULTS: The SIS group showed increased HDAC2 and GCN5 expression. Following SIS, there was a decrease in open arm entries and passes in the open field test, alongside increased immobility in the forced swimming test and reduced CA1 and CA3 hippocampal diameters. NAC mitigated the adverse molecular, behavioral, and histopathological impacts of SIS across both generations.

CONCLUSION: NAC reduces behavioral disorders after SIS (first and second generation) by reducing the expression of GCN5 and HDAC2 and increasing neuronal diameter in the hippocampus. Future research should investigate the long-term therapeutic effects of NAC for behavioral disorders after SIS.},
}

@article {pmid40050926,
year = {2025},
author = {Tseng, TH and Chang, CH and Chen, CL and Chiang, H and Wang, JH and Young, TH},
title = {Enhanced antibiotic release and biocompatibility with simultaneous addition of N-acetylcysteine and vancomycin to bone cement: a potential replacement for high-dose antibiotic-loaded bone cement.},
journal = {Journal of orthopaedic surgery and research},
volume = {20},
number = {1},
pages = {246},
pmid = {40050926},
issn = {1749-799X},
mesh = {*Vancomycin/administration & dosage ; *Bone Cements/chemistry ; *Acetylcysteine/administration & dosage/pharmacology ; *Anti-Bacterial Agents/administration & dosage ; *Polymethyl Methacrylate ; Biocompatible Materials ; Animals ; Materials Testing/methods ; Mice ; Dose-Response Relationship, Drug ; },
abstract = {BACKGROUND: Antibiotic-loaded bone cement (ALBC) is crucial for treating orthopedic infections, but its use is limited by suboptimal antibiotic release patterns and potential toxicity. This study explores the dual addition of N-acetylcysteine (NAC) and vancomycin to polymethylmethacrylate (PMMA) as a strategy to enhance the antibacterial efficacy and reduce toxicity.

METHODS: PMMA cement cylinders were loaded with varying combinations of NAC and vancomycin and tested for antibiotic release, cytotoxicity, and antibacterial activity over a 35-day period. Porosity of the cements was also evaluated as a measure of potential antibiotic release enhancement.

RESULTS: The addition of NAC improved vancomycin release, particularly after the initial burst release phase, and reduced cytotoxicity compared to high-dose vancomycin alone. The optimal combination was found to be 2 gm vancomycin with either 2 gm or 4 gm of NAC, which maintained effective antibacterial activity over 35 days without the toxicity seen with higher doses of vancomycin alone. Moreover, NAC alone did not demonstrate antibacterial properties, indicating its role primarily as a bioenhancer in this context.

CONCLUSION: Simultaneous inclusion of NAC and vancomycin in PMMA bone cement provides a more favorable release profile and biocompatibility than high-dose vancomycin alone, suggesting a potential strategy for enhancing the therapeutic efficacy of ALBC in treating prosthetic joint infections. This approach allows for lower doses of antibiotics, reducing potential cytotoxicity, systemic toxicity and enhancing the duration of antibacterial activity.

LEVEL OF EVIDENCE: Laboratory study.},
}

*Vancomycin/administration & dosage
*Bone Cements/chemistry
*Acetylcysteine/administration & dosage/pharmacology
*Anti-Bacterial Agents/administration & dosage
*Polymethyl Methacrylate
Biocompatible Materials
Animals
Materials Testing/methods
Mice
Dose-Response Relationship, Drug

@article {pmid40049439,
year = {2025},
author = {Liu, JM and Lee, KI and Su, CC and Fang, KM and Liu, SH and Fu, SC and Kuo, CY and Chang, KC and Ke, JA and Chen, YW and Yang, CY and Huang, CF},
title = {Chlorpyrifos-oxon results in autophagic flux dysfunction contributing to neuronal apoptosis via a ROS/AMPK/CHOP activation pathway.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111452},
doi = {10.1016/j.cbi.2025.111452},
pmid = {40049439},
issn = {1872-7786},
abstract = {Chlorpyrifos (CPF) is a widely used organophosphate (OP) pesticide in agriculture and sanitation, known to elicit neurotoxic effects. Chlorpyrifos-oxon (CPO), a metabolite of CPF, is the primary neurotoxic agent, yet its mechanisms are less understood. In this study, we investigated the effects and underlying mechanisms of CPO-induced neurotoxicity. CPO exposure significantly induced cytotoxicity in Neuro-2a cells, alongside the activation of apoptosis, as evidenced by an increase in the apoptotic cell population, caspase-3 activity, and cleavage of caspaspe-3, -7, and PARP proteins. Furthermore, defective autophagy was observed in CPO-treated Neuro-2a cells, indicated by increased expression of Beclin-1, Atg5, LC3-II, and p62 proteins. 3-MA, an autophagy inhibitor, suppressed CPO-activated LC3-II and apoptotic marker proteins expression, but not p62. In contrast, chloroquine and bafilomycin A1, autophagic flux inhibitors, potentiated the CPO-induced elevation of LC3-II, p62, and cleaved caspase-3 and -7 protein levels. CPO exposure also upregulated CHOP protein expression. Transfection with CHOP-specific siRNA markedly reduced CHOP protein expression, autophagic flux dysfunction, and apoptosis. Additionally, CPO exposure significantly increased AMPKα phosphorylation and reactive oxygen species (ROS) generation. Antioxidant N-acetylcysteine (NAC), but not the AMPK inhibitor Compound C, effectively attenuated the CPO-induced ROS generation in neuronal cells, which was accompanied by the prevention of AMPKα activation, downstream CHOP expression, autophagic flux dysfunction, and apoptosis. Collectively, these findings suggest that CPO-induced neurotoxicity arises from autophagic flux dysfunction, contributing to apoptosis via the ROS-activated AMPK pathway, which regulates CHOP expression, ultimately leading to neuronal cell death. Targeting the ROS/AMPK/CHOP axis may offer a promising intervention to against CPO-induced neurotoxicity.},
}

@article {pmid40048297,
year = {2025},
author = {Flaherty, BF and Olsen, CS and Coon, ER and Srivastava, R and Cook, LJ and Keenan, HT},
title = {Patterns of Use of β-2 Agonists, Steroids, and Mucoactive Medications to Treat Bronchiolitis in the PICU: U.S. Pediatric Health Information System 2009-2022 Database Study.},
journal = {Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies},
volume = {26},
number = {3},
pages = {e294-e303},
pmid = {40048297},
issn = {1529-7535},
support = {UM1 TR004409/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; Infant ; Retrospective Studies ; *Bronchiolitis/drug therapy ; *Intensive Care Units, Pediatric/statistics & numerical data ; Female ; Male ; United States/epidemiology ; *Length of Stay/statistics & numerical data ; *Adrenergic beta-2 Receptor Agonists/therapeutic use ; Expectorants/therapeutic use ; Infant, Newborn ; Databases, Factual ; Steroids/therapeutic use ; Child, Preschool ; Practice Patterns, Physicians'/statistics & numerical data ; Saline Solution, Hypertonic/therapeutic use/administration & dosage ; Acetylcysteine/therapeutic use ; Hospitalization/statistics & numerical data ; },
abstract = {OBJECTIVES: Describe β2-agonists, steroids, hypertonic saline (HTS), n-acetylcysteine (NAC), and dornase alfa (DA) use to treat bronchiolitis, factors associated with use, and associations between use and PICU length of stay (LOS).

DESIGN: Retrospective, multicenter cohort study.

SETTING: PICUs in the Pediatric Health Information System database.

PATIENTS: PICU admitted children 24 months young or younger with bronchiolitis.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: We analyzed 47,520 hospitalizations between July 1, 2018, and June 30, 2022. We calculated the rate of medication use overall and the median (range) rate for each hospital: β2-agonist (24,984/47,520 [52.6%]; median hospital, 51.7% [21.4-81.7%]), steroid (15,878/47,520 [33.4%]; median hospital, 33.4% [6.0-54.8%]), HTS (7,041/47,520 [14.8%]; median hospital, 10.5% [0-66.1%]), NAC (1,571/47,520 [3.3%]; median hospital, 0.8% [0-22.0%], and DA (840/47,520 [1.8%]; median hospital, 1.4% [0-13.6%]). Logistic regression using generalized estimating equations (GEEs) identified associations between concurrent asthma and β2-agonist (adjusted odds ratio [aOR], 8.68; 95% CI, 7.08-10.65; p < 0.001) and steroid (aOR, 10.10; 95% CI, 8.84-11.53; p < 0.001) use. Mechanical ventilation was associated with all medications: β2-agonists (aOR, 1.79; 95% CI, 1.57-2.04; p < 0.001), steroids (aOR, 2.33; 95% CI, 1.69-3.21; p < 0.001), HTS (aOR, 1.82; 95% CI, 1.47-2.25; p < 0.001), NAC (aOR, 3.29; 95% CI, 2.15-5.03; p < 0.001), and DA (aOR, 7.65; 95% CI, 4.30-13.61; p < 0.001). No medication was associated with decreased PICU LOS. To assess changes in medication use over time and associations with the 2014 American Academy of Pediatrics bronchiolitis guidelines, we expanded our analysis to 83,820 hospitalizations between July 1, 2009, and June 30, 2022. Logistic regression with GEEs found no change in β2-agonist use; steroid use increased after guideline publication (aOR, 1.05; 95% CI, 1.01-1.10; p = 0.02), HTS use changed from increasing prior to the guidelines (aOR, 1.32; 95% CI, 1.11-1.56; p = 0.001) to stable since guideline publication (aOR, 0.93; 95% CI, 0.81-1.07; p = 0.33).

CONCLUSIONS: β2-agonists, steroids, and HTS are commonly, but variably used for PICU bronchiolitis treatment. Medication use appears relatively stable over the last decade.},
}

Humans
Infant
Retrospective Studies
*Bronchiolitis/drug therapy
*Intensive Care Units, Pediatric/statistics & numerical data
Female
Male
United States/epidemiology
*Length of Stay/statistics & numerical data
*Adrenergic beta-2 Receptor Agonists/therapeutic use
Expectorants/therapeutic use
Infant, Newborn
Databases, Factual
Steroids/therapeutic use
Child, Preschool
Practice Patterns, Physicians'/statistics & numerical data
Saline Solution, Hypertonic/therapeutic use/administration & dosage
Acetylcysteine/therapeutic use
Hospitalization/statistics & numerical data

@article {pmid40043915,
year = {2025},
author = {Chen, Y and Yang, X and Li, J and Luo, H and Huang, Q and Yang, W and Lei, T and Lui, S and Gong, Q and Li, H and Wu, H and Gao, H},
title = {A nasally administrated reactive oxygen species-responsive carrier-free gene delivery nanosystem for Alzheimer's disease combination therapy.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {113604},
doi = {10.1016/j.jconrel.2025.113604},
pmid = {40043915},
issn = {1873-4995},
abstract = {Combination therapies targeting multiple pathways are needed in order to improve treatment outcomes in Alzheimer's disease (AD) due to its complex pathogenesis. Amyloid-β and microglia-mediated neuroinflammation significantly contribute to AD pathogenesis. Amyloid-β-related nucleic acid drugs have demonstrated considerable potential in AD treatment; however, their clinical translation is limited by complex synthesis processes and carrier toxicity. Herein, an intranasally administrated, reactive oxygen species (ROS)-responsive, carrier-free gene delivery nanosystem (FTBR-NAC) was constructed for re-polarizing microglia and decreasing amyloid-β expression. In this nanosystem, fingolimod was conjugated with biguanide via an ROS-responsive linker to form the carrier for β-secretase 1 siRNA (siBACE1) to form FTBR nanoparticles. The electropositivity of FTBR and mucolytic activity of N-acetylcysteine (NAC) together enhanced the brain entry of FTBR. Upon reaching the brain, FTBR responded to the elevated ROS at the pathological site, releasing siBACE1 and fingolimod. Administration of FTBR-NAC improved cognitive function in AD mice, demonstrating the high therapeutic efficacy of this relatively simple nanosystem.},
}

@article {pmid40038825,
year = {2025},
author = {Emara, SM and Fahmy, SF and AbdelSalam, MM and Wakeel, LME},
title = {Effect of high-dose N-acetyl cysteine on the clinical outcome of patients with diabetic peripheral neuropathy: a randomized controlled study.},
journal = {Diabetology & metabolic syndrome},
volume = {17},
number = {1},
pages = {79},
pmid = {40038825},
issn = {1758-5996},
abstract = {BACKGROUND: Diabetic peripheral neuropathy (DPN) is a vastly common and bothersome disorder with a clinically challenging course of treatment affecting patients with diabetes. This study aimed to evaluate the efficacy and safety of high dose oral N-acetyl cysteine (NAC) as adjuvant therapy on clinical outcome of DPN.

METHODS: A prospective, randomized, parallel, open label, controlled clinical trial. Ninety eligible DPN patients were randomly assigned to either control group receiving standard of care or NAC group receiving standard of care treatment and NAC at a dose of 2400 mg/day for 12 weeks. Glutathione peroxidase (GPx), nuclear factor erythoid-2 related factor (NRF-2) and tumor necrosis factor (TNF) were measured at baseline and after 12 weeks to assess anti-oxidant and anti-inflammatory properties. Michigan neuropathy screening instrument (MNSI), Toronto clinical neuropathy score (TCNS), Diabetic neuropathy score (DNS), Diabetes-39 quality of life questionnaire (DQOL) and pain score were assessed at baseline and after 12 weeks.

RESULTS: NAC group showed a significant increase (p < 0.05) in NRF-2 by 25.3% and GPx by 100% and a decline of 21.45% in TNF-alpha levels versus controls that reported a decline in NRF-2 and GPx and an increase in TNF-alpha. HgbA1C and AST levels significantly decreased in NAC versus controls (7.2 ± 1 vs 8 ± 1.1, p = 0.028 and 29.1 vs 55.4, p = 0.012) respectively. NAC administration resulted in a significant decline in MNSA, TCNS, DNS and pain scores versus controls that showed increase in all scores. The QOL total score and the anxiety and energy and mobility domain scores significantly decreased in the NAC group versus controls, p < 0.001.

CONCLUSION: High dose NAC administered for 12 weeks modulated inflammation by reducing TNF-alpha and increasing GPx and NRF2 versus controls. NAC improved clinical outcomes of DPN reflected by a decline in neuropathy and pain scores and an improvement in QOL.

NCT04766450.},
}

@article {pmid40037730,
year = {2025},
author = {Chen, S and Hou, Z and Xiao, M and Wu, P and Yang, Y and Han, S and Xia, J and Hu, J and Zhang, K and Yang, L},
title = {Quaternized chitosan-based photothermal antibacterial hydrogel with pro-vascularization and on-demand degradation properties for enhanced infected wound healing.},
journal = {Carbohydrate polymers},
volume = {355},
number = {},
pages = {123350},
doi = {10.1016/j.carbpol.2025.123350},
pmid = {40037730},
issn = {1879-1344},
mesh = {*Chitosan/chemistry/pharmacology ; *Wound Healing/drug effects ; *Anti-Bacterial Agents/pharmacology/chemistry ; Animals ; *Hydrogels/chemistry/pharmacology ; Humans ; *Staphylococcus aureus/drug effects ; *Human Umbilical Vein Endothelial Cells/drug effects ; Rats ; *Rats, Sprague-Dawley ; Microbial Sensitivity Tests ; Wound Infection/drug therapy/microbiology ; Staphylococcal Infections/drug therapy ; Male ; Copper/chemistry/pharmacology ; Photothermal Therapy/methods ; Neovascularization, Physiologic/drug effects ; },
abstract = {Compromised skin barrier fails to prevent pathogenic bacterial invasion, leading to wound infection and potentially severe tissue damage, for which conventional wound dressings provide inadequate therapeutic outcomes. Herein, we have developed a multifunctional injectable hydrogel (QCS-APA/P@D@C) based on quaternized chitosan (QCS) and aldehyde-modified aliphatic polycarbonate (APA), incorporating Prussian Blue (PB) @Polydopamine (PDA) @Cu (P@D@C) submicron particles (SPs). This novel hydrogel exhibits photothermal antibacterial properties, on-demand removal capability, and Cu[2+]-facilitated wound healing enhancement. The QCS-APA/P@D@C hydrogel, crosslinked via dynamic Schiff-base bonds, exhibits remarkable antibacterial efficacy (>99 %) against various bacteria, including multidrug-resistant (MDR) bacteria, through the synergistic effects of QCS, Cu[2+], and 808 nm near-infrared (NIR) photothermal effect. The hydrogel demonstrates rapid degradation (~12 min) upon exposure to N-acetylcysteine (NAC), facilitating on-demand removal and minimizing secondary trauma during dressing changes. Furthermore, the sustained release of Cu[2+] within 1-10 μM significantly enhances the migration and tube formation of human umbilical vein endothelial cells (HUVECs). In a Staphylococcus aureus (S. aureus)-infected wound model of Sprague-Dawley (SD) rats, the QCS-APA/P@D@C hydrogel demonstrated effectively modulating wound inflammation, promoting collagen deposition and angiogenesis, and accelerating wound closure. These findings demonstrate that the QCS-APA/P@D@C hydrogel can effectively promote the healing of bacterially infected wounds.},
}

*Chitosan/chemistry/pharmacology
*Wound Healing/drug effects
*Anti-Bacterial Agents/pharmacology/chemistry
Animals
*Hydrogels/chemistry/pharmacology
Humans
*Staphylococcus aureus/drug effects
*Human Umbilical Vein Endothelial Cells/drug effects
Rats
*Rats, Sprague-Dawley
Microbial Sensitivity Tests
Wound Infection/drug therapy/microbiology
Staphylococcal Infections/drug therapy
Male
Copper/chemistry/pharmacology
Photothermal Therapy/methods
Neovascularization, Physiologic/drug effects

@article {pmid40037093,
year = {2025},
author = {Pan, H and Zhai, G and Jing, Q and Fan, Y and Fang, C and Shi, F},
title = {Two-step metabolic activation to ortho-benzoquinone intermediate and its role in 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside-induced liver injury in mice.},
journal = {Drug metabolism and disposition: the biological fate of chemicals},
volume = {53},
number = {3},
pages = {100047},
doi = {10.1016/j.dmd.2025.100047},
pmid = {40037093},
issn = {1521-009X},
abstract = {2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is the most abundant constituent of Polygonum multiflorum and is exclusively found in this herb. This renowned herbal medicine has been documented to lead to liver damage in humans. The present study demonstrated that TSG underwent 2-step metabolic activation to generate a reactive metabolite, involving both intestinal and hepatic metabolisms. TSG was hydrolyzed to its aglycone 2,3,5,4'-tetrahydroxystilbene (TS) in the intestine, and then, the 2,3 catechol of 2,3,5,4'-tetrahydroxystilbene was metabolized to an ortho-benzoquinone intermediate in the liver. The reactive metabolite was characterized as the N-acetyl-cysteine conjugate both in vivo and in vitro. Its structure was verified by a combined isotope-labeling strategy using the [14]N/[15]N, H/D, and [79]Br/[81]Br isotope pattern-based mass shifts. Intestinal β-glucosidase and hepatic CYP3A4 and CYP2C9 contributed to the reactive metabolite formation. The reactive intermediate could covalently modify the hepatic proteins through cysteine in mice. Combined with the treatment with β-glucosidase, a single oral administration of 400 mg/kg TSG caused liver centrilobular necrosis and degeneration in mice. Selective CYP3A inhibitor ketoconazole protected TSG-induced liver injury, concurrently attenuating protein adduct formation modified by reactive metabolites. The results indicate that TSG does not exert hepatotoxic effects but that the reactive ortho-benzoquinone metabolite from the oxidation of the 2,3 catechol of aglycone is responsible for TSG-induced liver injury. The study also facilitates a better understanding of the principal hepatotoxic chemicals in Polygonum multiflorum. SIGNIFICANCE STATEMENT: 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) undergoes intestinal deglycosylation to generate its aglycone, and then, the 2,3 catechol of aglycone was metabolized to an ortho-benzoquinone intermediate in the liver. β-glucosidase potentiates TSG-induced liver injury and protein adduction by the reactive metabolite. The results indicate that the reactive metabolite of TSG exerts hepatotoxic effects rather than the parent compound.},
}

@article {pmid40028879,
year = {2025},
author = {Truwit, JD and Fleming, K and Nanchal, RS},
title = {Empowering Respiratory Therapists to Restrict Nebulized 3% Saline and N-Acetylcysteine During Mechanical Ventilation.},
journal = {Respiratory care},
volume = {},
number = {},
pages = {},
doi = {10.1089/respcare.12586},
pmid = {40028879},
issn = {1943-3654},
abstract = {Background: We previously implemented a policy that enabled respiratory therapists to reject orders for nebulized 3% hypertonic saline and/or N-acetylcysteine (HTS/NAC) that did not conform to the American Association for Respiratory Care (AARC) Clinical Practice Guideline. Outcomes of adhering to this more conservative approach are not well studied. We sought to determine if an approach conforming to guidelines is noninferior to a previously practiced more liberal approach. Methods: We performed a retrospective analysis of 2,272 subjects receiving mechanical ventilation ≥48 h within 5 adult ICUs between June 2020 and August 2023. The primary outcome was ventilator-free days at day 28 (VFD28). Secondary outcomes included ventilator days, ICU days, hospital stay, re-intubation rates, and mortality. Analysis was stratified by before and after policy implementation (see intervention) and by receiving HTS/NAC or not (ϕHTS/NAC). The latter was examined before and after propensity matching. The Δ for noninferiority was -0.5 days for VFD28 and +0.5 days for other continuous variables. As outcomes were not normally distributed, we analyzed them using Mann-Whitney U statistics. Results: Two thousand two hundred seventy-two subjects were evaluated. The mean age was 58.70 + 16.13 years and 929 (40.9%) subjects were women. HTS/NAC administration was reduced after policy implementation (40.2% before policy and 8.9% after policy; a reduction of 77.9%). The post-policy group and ϕHTS/NAC before and after propensity matching groups were all noninferior to the comparators. Subjects had significantly more VFD28 in the post-policy group, median (IQR), post 21 (0-25), pre: 20 (0-24), P = .02; and in the ϕHTS/NAC group, before matching ϕHTS/NAC: 21 (0-25), HTS/NAC: 18 (0-23), P < .001 and after propensity matching ϕHTS/NAC: 21 (0-25), HTS/NAC; 18 (0-23), P < .001. Conclusions: Restricting practice to conform to the AARC Clinical Practice Guideline was noninferior to more liberal use. The use of HTS/NAC in mechanically ventilated subjects does not appear efficacious and is both costly and time-consuming.},
}

@article {pmid40023441,
year = {2025},
author = {Yonatan, E and Shukha, ON and Golani, I and Abu-Ata, S and Awad-Igbaria, Y and Khatib, N and Ginsberg, Y and Palzur, E and Beloosesky, R and Shamir, A},
title = {Maternal N-acetylcysteine Supplementation in Lactation Ameliorates Metabolic and Cognitive Deficits in Adult Offspring Exposed to Maternal Obesity.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110390},
doi = {10.1016/j.neuropharm.2025.110390},
pmid = {40023441},
issn = {1873-7064},
abstract = {Maternal obesity in pregnancy and lactation is linked to metabolic disturbances and neurodevelopmental problems in offspring, increasing the risk of psychiatric disorders in adulthood. We proposed that maternal N-acetyl cysteine (NAC) supplementation during lactation, a critical period for neurodevelopment, potentially protects offspring from developing cognitive impairment in adulthood. Fifteen young female ICR mice were randomly allocated to different experimental groups: high-fat diet (HFD; 60.3% fat before mating, during pregnancy and lactation), HFD-NAC of 300 mg/Kg/day during lactation, CD (high-fat diet before mating, during pregnancy, and regular chow control diet of 8.2% fat during lactation), CD-NAC of 300 mg/Kg/day during lactation and control group consuming regular chow diet. The serum inflammatory markers of the offspring were evaluated post-weaning, while metabolic markers, microglial density, and cognitive performance were assessed in adulthood using the novel Object Recognition and Morris Water Maze tests. Our results demonstrate maternal obesity during gestation and lactation increased body weight, hepatic steatosis, and microglial cell density in the dentate gyrus (DG) and cortex. Furthermore, these offspring exhibited reduced spatial learning abilities in adulthood, regardless of sex. However, maternal NAC administration during lactation and maternal diet intervention significantly reduced brain microglial density and improved both male and female offspring metabolic profiles. More importantly, NAC supplementation during lactation, regardless of maternal diet, enhanced male offspring's learning ability in adulthood. Our findings indicate that administering NAC to obese mothers during the critical lactation period may offer protection against metabolic disturbances and cognitive deficits in adult offspring previously exposed to maternal obesity.},
}

@article {pmid40023202,
year = {2025},
author = {Pangrazzi, L and Cerilli, E and Balasco, L and Khurshid, C and Tobia, C and Dall'O', GM and Chelini, G and Perini, S and Filosi, M and Barbieri, A and Ravizza, T and Vezzani, A and Provenzano, G and Pastore, A and Weinberger, B and Rubert, J and Domenici, E and Bozzi, Y},
title = {The interplay between oxidative stress and inflammation supports autistic-related behaviors in Cntnap2 knockout mice.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bbi.2025.02.030},
pmid = {40023202},
issn = {1090-2139},
abstract = {Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental condition characterized by social communication deficits and repetitive/restricted behaviors. Several studies showed that oxidative stress and inflammation may contribute to ASD. Indeed, increased levels of oxygen radicals and pro-inflammatory molecules were described in the brain and peripheral blood of persons with ASD and mouse models. Despite this, a potential direct connection between oxidative stress and inflammation within specific brain areas and ASD-related behaviors has not been investigated in detail yet. Here, we used RT-qPCR, RNA sequencing, metabolomics, immunohistochemistry, and flow cytometry to show that pro-inflammatory molecules were increased in the cerebellum and periphery of mice lacking Cntnap2, a robust model of ASD. In parallel, oxidative stress was present in the cerebellum of mutant animals. Systemic treatment with N-acetyl-cysteine (NAC) rescued cerebellar oxidative stress, inflammation, as well as motor and social impairments in Cntnap2[-/-] mice, concomitant with enhanced function of microglia cells in NAC-treated mutants. Intriguingly, social deficits, cerebellar inflammation, and microglia dysfunction were induced by NAC in Cntnap2[+/+] animals. Our findings suggest that the interplay between oxidative stress and inflammation accompanied by genetic vulnerability may underlie ASD-related behaviors in Cntnap2 mutant mice.},
}

@article {pmid40022144,
year = {2025},
author = {Okon, IA and Beshel, JA and Owu, DU and Orie, NN and Jim, AE and Edet, LI},
title = {Moderate aerobic exercise improves haematological indices without altering cardio-metabolic enzyme activities in sedentary healthy young adults.},
journal = {BMC sports science, medicine & rehabilitation},
volume = {17},
number = {1},
pages = {32},
pmid = {40022144},
issn = {2052-1847},
abstract = {BACKGROUND: Regular aerobic exercise regulates cardiorespiratory functions by its effect on specific enzyme activities. This study investigated the immediate effects of moderate aerobic exercise on haematological parameters and cardio-metabolic enzymes activity in healthy young male and female adults.

METHODS: Forty young healthy sedentary subjects, twenty males (25 ± 5.6 years; 65 ± 4.0 kg; 176.9 ± 2.5 cm) and twenty females (25 ± 4.5 years, 62 ± 2.9 kg, 175 ± 1.3 cm) volunteered for the study. The exercise regimen was of moderate intensity lasting for 20 min daily on a treadmill at incremental speed of 3 km/h to 13 km/h for 14 consecutive days. The weight and height of participants were measured. Blood sample was collected via antecubital vein for haematological and biochemical analysis. The haematological parameters namely red blood cell and indices, leukocyte and differential white blood cell count, platelet and platelet indices were assessed. Cardiac troponin-T, creatine kinase, lactate dehydrogenase and N-acetyl-cysteine activated creatine kinase activities were assessed before and after exercise.

RESULTS: The result showed a significant (p < 0.05) increase in RBC (males 7%, females 11%) haemoglobin (males 8%, females 8.3%), haematocrit (males 5%, females 14%) leukocyte (males 54%, females 40%) and monocyte count (males 68%, females 55%) after 14 days of exercise. The enzymatic activities of lactate dehydrogenase, N-acetyl-cysteine activated creatine kinase (CK-NAC), creatine kinase (CK-MB) and cardiac troponin-T showed no significant change after 14 days of exercise.

CONCLUSION: It is concluded that moderate aerobic exercise increased haematological parameters and maintained cardio-metabolic enzymes activities in young male and female adults.},
}

@article {pmid40020975,
year = {2025},
author = {Liu, ZH and Zhai, Y and Zhang, J and Huang, W and Li, W and Qin, W},
title = {Mitochondrial iron deficiency mediated inhibition of ecdysone synthesis underlies lead (Pb) induced developmental toxicity in Drosophila melanogaster.},
journal = {Toxicology and applied pharmacology},
volume = {497},
number = {},
pages = {117283},
doi = {10.1016/j.taap.2025.117283},
pmid = {40020975},
issn = {1096-0333},
abstract = {Lead (Pb) is a pervasive heavy metal possessing developmental toxicity, at least in part, by disrupting iron homeostasis. In this study, we aimed to elucidate the underlying mechanism of iron deficiency mediated developmental defects in Pb exposed Drosophila melanogaster, mainly focusing on iron-dependent synthesis of ecdysone signaling, which plays a key role in the development of insects. Herein, we found Pb exposure resulted in iron deficiency in mitochondria by inhibiting expression of mitoferrin (evidenced by qPCR assay), the mitochondrial iron importer. Further study demonstrated that biosynthesis of ecdysone, a hormone synthesized with the help of iron-containing cytochrome P450s in mitochondria, was inhibited following Pb exposure. Ecdysone supplementation, to some extent, rescued Pb induced developmental delay and reproductive defects in Drosophila melanogaster. Furthermore, we found that disruption of mitoferrin and ecdysone synthesis was restored by NAC (N-Acetylcysteine, a well-known ROS scavenger), suggesting that oxidative stress plays a key role in Pb mediated mitochondrial iron dys-homeostasis and developmental toxicity. This study therefore revealed that mitochondrial iron deficiency mediated inhibition of ecdysone synthesis is a key event associated with iron dys-homeostasis mediated developmental defects caused by Pb exposure. Meanwhile, our study indicated that mitochondria may act as an important target of Pb, thus providing potential protective strategies against Pb toxicity.},
}

@article {pmid40020837,
year = {2025},
author = {Yaseen, K and Ejaz, S and Imran, M},
title = {Surface engineering of biomedical catheters using N-acetyl cysteine functionalized carboxymethyl chitosan nanosystems to combat biofouling and device-associated infections.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {141516},
doi = {10.1016/j.ijbiomac.2025.141516},
pmid = {40020837},
issn = {1879-0003},
abstract = {Functionalized anti-biofouling nanosystems were developed to engineer the surface of silicone catheters for mitigating the incidence of device-associated infections (DAIs). These infections are typically a consequence of microbial biofilms and antimicrobial resistance (AMR) which lead to increased hospitalization costs and mortality rates. Covalent coupling of N-acetyl cysteine (NAC) with O-carboxymethyl chitosan (O-CMC) was optimized to develop NAC-functionalized CMC nanosystems (NAC-CMC-NS). The coupling was confirmed by nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy and 4, 6-trinitrobenzene sulfonic acid (TNBS) assay indicating 80 ± 2 % functionalization efficacy. Subsequently, meropenem-loaded NAC-CMC NS exhibited an average particle size of 273 ± 4.2 nm with 0.4 ± 0.03 polydispersity index (PDI), a zeta potential of -9.15 ± 0.5 mV and encapsulation efficiency (EE) of 67 ± 3.2 %. These functionalized NS employing the dual strategy of contact-killing and meropenem-release, exhibited exceptional antimicrobial activity leading to the 76 ± 1.5 % and 60 ± 1 % inhibition of E. coli and P. aeruginosa biofilms, respectively. After the successful grafting of functionalized NS onto silicone catheters, the resulting substrate remarkably reduced the bacterial colonization, offering a promising solution for reducing DAIs like ventilator-associated pneumonia (VAP) and catheter-associated urinary tract infections (CAUTI). Moreover, the excellent hemocompatibility and low cytotoxicity of these nanovesicles highlight their potential applications for clinical use.},
}

@article {pmid40017063,
year = {2025},
author = {Bikal, P and Bhardwaj, JK},
title = {N-Acetyl-L-Cysteine Mediated Attenuation of Cadmium Induced Oxidative Stress and Apoptosis in Ovarian Antral Follicles In Vitro.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.24505},
pmid = {40017063},
issn = {1522-7278},
support = {//CSIR (Council of Scientific and Industrial Research)/ ; },
abstract = {Female fertility has been demonstrated to be directly correlated with cadmium, a heavy metal contaminant that is widely present in the environment. N-acetyl cysteine (NAC), a powerful antioxidant, has been shown to have therapeutic effects for a number of ailments. NAC's potential to prevent ovarian toxicity caused by Cd is still unknown. Therefore, the objective of the current study was to evaluate the concentration- and time-dependent protective effect of NAC supplementation against Cd-induced granulosa cell toxicity in healthy caprine ovaries. The in vitro cultured ovaries/follicles were subjected to different cytotoxic (ethidium bromide and acridine orange [EB/AO] staining), histomorphological, and biochemical analyses during study. The results revealed that NAC treatment significantly attenuated the Cd-instigated cytotoxicity in granulosa cells, as evidenced by diminished apoptotic attributes in NAC co-supplemented groups compared to only Cd-exposed groups. Moreover, NAC markedly restored the decline in enzymatic activity of antioxidant enzymes (GST, SOD, and CAT), along with ferric reducing antioxidant power, further diminishing the formation of MDA in Cd exposed caprine ovary. The findings of this study indicated that Cd, being an ovarian toxicant, adversely affects the female reproductive system. However, simultaneous NAC administration significantly reduced the Cd-caused ovarian damage, indicating that NAC has therapeutic potential in controlling female gonadotoxicity due to gradually growing environmental Cd pollution.},
}

@article {pmid40013897,
year = {2025},
author = {Nakatsu, L and Lopez, JR and Garcia, CM and Cherian, M and Nash, J and Tofighi, D and Seifert, SA and Smolinske, S and Warrick, BJ},
title = {Comparison of two-bag and three-bag acetylcysteine regimens in the treatment of paracetamol poisoning: a systematic review and meta-analysis.},
journal = {Clinical toxicology (Philadelphia, Pa.)},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/15563650.2025.2456116},
pmid = {40013897},
issn = {1556-9519},
abstract = {INTRODUCTION: Worldwide, paracetamol poisoning is a common cause of acute liver failure and referral to transplant centers. Acetylcysteine has long been the mainstay of treatment, but recent literature suggests that a simplification of the "three-bag" method may decrease adverse effects. Our primary hypothesis is that a simplified dosing regimen (two-bag regimen) is non-inferior to the three-bag method in preventing liver injury. Our secondary hypothesis is that a simplified regimen will have lower rates of adverse effects.

METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched Medline/PubMed, Google, Google Scholar, Cochrane Library, Embase and Toxnet on May 23, 2022. The Medical Subject Headings terms were NAC, acetaminophen toxicity, acetyl-cysteine, N-acetylcysteine, paracetamol, APAP, 2-bag, and 3-bag. The Embase terms were acetylcysteine, NAC, 2-bag, two bag, 3-bag, three bag, simplified dosing, acetaminophen, Tylenol[®], paracetamol, APAP, drug overdose, poisoning, and overdose. Studies included both non-United States Food and Drug Administration-approved and United States Food and Drug Administration-approved acetylcysteine regimens. Case reports, review articles, and animal studies were excluded. Two authors independently reviewed each study using Rayyan QCRI to determine if the studies met search criteria while blinded to the selections of each other. The two authors discussed until reaching a consensus. We used a primary outcome of non-inferiority of hepatotoxicity. We used secondary outcomes of non-allergic anaphylactoid reactions and adverse events. We conducted a fixed-effect meta-analysis using R package meta. To visually summarize the meta-analysis results, we also produced forest plots. We used Cochran's Q test and I[2] statistical analysis to assess heterogeneity between the studies.

RESULTS: Our search resulted in 657 total citations, which were reduced to unique citations. Of the 643 studies, 46 met the criteria for full text review, and eight met the study criteria. Of the eight studies investigating a simplified acetylcysteine regimen, four studies utilized some form of a modified two-bag infusion regimen, varying in duration or dosing of infusions, and four studies shared the same "common" two-bag treatment, a regimen that delivers acetylcysteine 200 mg/kg over 4 h, followed by 100 mg/kg acetylcysteine over 16 h. The six studies comparing a two-bag dosing regimen to the three-bag technique were utilized for our random effect model meta-analysis. We found no significant heterogeneity amongst the six studies for either hepatotoxicity (Q(5) = 1.11; P = 0.95; I[2] = 0%; 95% CI: 0%-74.6%) or non-allergic anaphylactoid reactions and adverse events (Q(5) = 10.15; P = 0.07; I[2] = 50.7%; 95% CI: 0%-80.4%). Compared to the traditional three-bag dosing regimen, the two-bag method did not demonstrate a difference in relative risk for hepatotoxicity (OR: 0.88; 95% CI: 0.72-1.08; P = 0.23) but did demonstrate a significantly decreased likelihood of non-allergic anaphylactoid reactions and other adverse events (OR: 0.24; 95% CI: 0.17-0.35; P <0.0001).

DISCUSSION: The two-bag method is a safe and effective treatment for acute paracetamol poisoning. The two-bag regimen is correlated with a significant reduction in non-allergic anaphylactoid reactions, compared to the three-bag method, and is non-inferior with respect to hepatotoxicity. While we feel this information is practice changing for many, further research in the form of a randomized control trial would be beneficial to compare even more abbreviated methods such as a "single bag method."

CONCLUSION: Two-bag acetylcysteine dosing regimens appear to be non-inferior to the three-bag method with respect to hepatotoxicity, and result in fewer anaphylactoid, cutaneous, and gastrointestinal reactions.},
}

@article {pmid40011998,
year = {2025},
author = {Wu, CH and Chou, WC and Jou, IM and Tu, YK and Ma, CH and Tsai, KL},
title = {Cisplatin-induced oxidative stress, apoptosis, and pro-inflammatory responses in chondrocytes through modulating LOX-1.},
journal = {Journal of orthopaedic surgery and research},
volume = {20},
number = {1},
pages = {206},
pmid = {40011998},
issn = {1749-799X},
mesh = {*Cisplatin/pharmacology ; *Chondrocytes/drug effects/metabolism ; *Scavenger Receptors, Class E/metabolism ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; Animals ; Humans ; Antineoplastic Agents/pharmacology ; NF-kappa B/metabolism ; Cells, Cultured ; Inflammation/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Cisplatin is a potent and efficacious anticancer medication. In pediatric cancer, the height of the growth plate's proliferating layer is known to be reduced by cisplatin, but researchers have not yet determined the specific mechanism behind this phenomenon. Lectin-like oxidized low-density lipoprotein receptor-1 is known to be involved in the development of osteoarthritis and atherosclerosis. The equilibrium of cartilage is regulated by LOX-1, but the function of LOX-1 in cisplatin-induced chondrocyte impairment remains unknown. Positive regulation of LOX-1 leads to increased cellular oxidative stress and cell damage. Research has shown that blocking of LOX-1 can reduce the chondrocyte damage and oxidative stress in cells induced by oxidized LDL treatment. However, the role of LOX-1 in cisplatin-mediated chondrocyte damage is still unclear. This study found that cisplatin increased ROS concentration and p38, ERK phosphorylation. Cisplatin activated NF-κB in chondrocytes. In addition, LOX-1 small interfering RNA transfection mitigated cisplatin-induced apoptosis in TC28a2 cells. Phosphorylated extracellular signal-regulated kinase and p38 were dose-dependently increased by administration of cisplatin. Silencing LOX-1 or MAPK inhibition reduces cisplatin-caused apoptosis. The findings suggest that cisplatin-induced growth plate dysfunction operates through the LOX-1/p38/NF-κB signaling pathway.},
}

*Cisplatin/pharmacology
*Chondrocytes/drug effects/metabolism
*Scavenger Receptors, Class E/metabolism
*Apoptosis/drug effects
*Oxidative Stress/drug effects
Animals
Humans
Antineoplastic Agents/pharmacology
NF-kappa B/metabolism
Cells, Cultured
Inflammation/metabolism
Reactive Oxygen Species/metabolism

@article {pmid40009511,
year = {2025},
author = {Kandel, H and Cruz, AR and Thom, RP and McDougle, CJ},
title = {N-Acetylcysteine for Nonsuicidal Self-Injurious Behavior in 3 Adults With Williams Syndrome: A Case Series.},
journal = {Journal of clinical psychopharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1097/JCP.0000000000001976},
pmid = {40009511},
issn = {1533-712X},
abstract = {BACKGROUND: Williams syndrome (WS) is a genetic disorder that results from a microdeletion of 25 to 27 genes on chromosome 7q11.23. Individuals with WS often exhibit comorbid neuropsychiatric symptoms, especially anxiety. To our knowledge, nonsuicidal self-injurious behavior (NSSIB) has not been reported in WS. N-acetylcysteine (NAC) is a safe and readily available drug that may modulate glutamate activity in the brain. NAC is effective for treating various neuropsychiatric symptoms and disorders. There are limited reports in the literature where NAC has been used to treat NSSIB effectively, but none in WS.

METHODS: This report describes using NAC to treat NSSIB in 3 adults with WS.

FINDINGS: Nonsuicidal self-injurious behavior was successfully treated in 3 adults with WS using NAC in doses ranging from 2400 to 3600 mg a day, resulting in significant improvement in their daily functioning. Additionally, NAC was well tolerated.

CONCLUSIONS: NAC was effective for treating NSSIB in 3 adults with WS. By addressing these challenging behaviors, NAC offers a promising pharmacological intervention that can significantly improve the quality of life for patients with WS who engage in NSSIB. Further research and clinical trials are necessary.},
}

@article {pmid40007988,
year = {2024},
author = {Habib, M},
title = {Combination of atorvastatin plus N-acetylcysteine versus atorvastatin alone to prevent contrast-induced nephropathy.},
journal = {Archives of medical sciences. Atherosclerotic diseases},
volume = {9},
number = {},
pages = {e207-e211},
pmid = {40007988},
issn = {2451-0629},
abstract = {INTRODUCTION: Contrast-induced acute renal injury is the third leading cause of hospital-acquired acute kidney injury. Our trial aimed to compare high-dose statin versus statin plus N-acetylcysteine (NAC) to prevent contrast-induced nephropathy.

MATERIAL AND METHODS: Randomized control trial included patients who undergoing elective percutaneous coronary intervention (PCI) at Alshifa Hospital in Gaza, the first group (statin: 50 patients) received 80 mg of atorvastatin orally once daily for 3 days. The second group (statin + NAC: 50 patients) received 80 mg of atorvastatin orally once daily for 3 days, plus NAC 1200 mg orally twice daily every 12 h for 2 days. All patients underwent measurement of serum creatinine and urea level before PCI and 2-3 days after the procedure. The primary endpoint was to compare development of contrast-induced nephropathy between the two groups.

RESULTS: The total group comprised 100 patients: 71 male patients and 29 female patients. Mean age was 59 ±9.8 years. After intervention serum creatinine decreased from 1.02 ±0.27 mg/dl to1.01 ±0.29 mg/dl in the statin group, while it decreased from 1.08 ±0.36 mg/dl to 0.92 ±0.13 mg/dl in the statin + NAC group. The difference between the two groups was significant (p = 0.048). Also, the urea plasma level in the statin group decreased from 34.5 ±9.7 mmol/l to 30.6 ±8.7 mmol/l after PCI, while in the statin + NAC group it decreased from 36.4 ±9.9 mmol/l to 26.2 ±10.6 mmol/l; the difference between the two groups was significant (p = 0.017). Contrast-induced nephropathy was seen in 9 (18%) patients in the statin group and in 2 (4%) patients in the statin + NAC group (p = 0.025).

CONCLUSIONS: The combination of high-dose atorvastatin plus NAC compared to atorvastatin alone was associated with a significant reduction of contrast-induced nephropathy in patients undergoing PCI.},
}

@article {pmid40005451,
year = {2025},
author = {Abdelbagi, O and Taha, M and Al-Kushi, AG and Alobaidy, MA and Baokbah, TAS and Sembawa, HA and Azher, ZA and Obaid, R and Babateen, O and Bokhari, BT and Qusty, NF and Malak, HA},
title = {Ameliorative Effect of N-Acetylcysteine Against 5-Fluorouracil-Induced Cardiotoxicity via Targeting TLR4/NF-κB and Nrf2/HO-1 Pathways.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {2},
pages = {},
pmid = {40005451},
issn = {1648-9144},
mesh = {Animals ; *Fluorouracil/adverse effects/pharmacology ; *Acetylcysteine/pharmacology/therapeutic use ; Rats ; *NF-E2-Related Factor 2/metabolism ; *Cardiotoxicity/prevention & control/etiology/drug therapy ; *Toll-Like Receptor 4/metabolism ; *NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Male ; Antimetabolites, Antineoplastic/adverse effects/toxicity ; Signal Transduction/drug effects ; },
abstract = {Background and Objectives: 5-Fluorouracil (5-FU) is a widely prescribed and effective chemotherapeutic drug, but its cardiotoxic side effects pose a significant challenge to its use. Identifying a protective agent that does not affect its anticancer efficacy is essential. Our study aimed to investigate the cardioprotective effect of N-acetyl cysteine (NAC) against 5-FU-induced cardiac injury and to elucidate the underlying mechanisms. Materials and Methods: This study included four experimental groups, each with eight rats (n = 8): Group I (control group), Group II (NAC group), Group III (5-FU group), and Group IV (combined group 5-FU+NAC). Cardiac enzymes, oxidative stress, inflammatory, and apoptotic markers were investigated, and cardiac sections from the different groups were histologically examined. Results: Co-treatment of 5-FU with NAC resulted in significantly lower levels of cardiac enzymes (alanine transaminase (ALT) by 62.1%, aspartate transaminase (AST) by 73.6%, lactate dehydrogenase (LDH) by 55.8%, and creatine kinase (CK) by 57.3%) compared to the 5-FU group, along with marked improvements in heart tissue histology. Additionally, NAC enhanced the activity of cardiac antioxidant enzymes (superoxide dismutase (SOD) by 295.6%, catalase (CAT) by 181%, and glutathione peroxidase (GPx) by 320.9%) while decreasing malondialdehyde (MDA) by 51.1%, a marker of membranous lipid peroxidation. This might be due to significant upregulation of the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway at the gene and protein levels. The combined treatment significantly decreased the gene expression of the toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) pathway. Furthermore, it downregulated the protein levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α) by 29.9%, interleukin-1 beta (IL-1β) by 21.9%, and interleukin-6 (IL-6) by 49.3%. Moreover, it upregulated the antiapoptotic marker B-cell lymphoma 2 (Bcl-2) protein levels by 269% and decreased apoptotic indicators Bcl-2-associated protein x (Bax) by 57.9% and caspase-3 by 30.6% compared to the 5-FU group. Conclusions: This study confirmed that NAC prevented the cardiotoxic effect of 5-FU through its antioxidant, anti-inflammatory, and antiapoptotic properties, suggesting its potential application as an adjuvant therapy in chemotherapy to alleviate 5-FU-induced cardiotoxicity.},
}

Animals
*Fluorouracil/adverse effects/pharmacology
*Acetylcysteine/pharmacology/therapeutic use
Rats
*NF-E2-Related Factor 2/metabolism
*Cardiotoxicity/prevention & control/etiology/drug therapy
*Toll-Like Receptor 4/metabolism
*NF-kappa B/metabolism
Oxidative Stress/drug effects
Male
Antimetabolites, Antineoplastic/adverse effects/toxicity
Signal Transduction/drug effects

@article {pmid40002497,
year = {2025},
author = {Lomelí Martínez, SM and Pacheco Moisés, FP and Bitzer-Quintero, OK and Ramírez-Jirano, J and Delgado-Lara, DLC and Cortés Trujillo, I and Torres Jasso, JH and Salazar-Flores, J and Torres-Sánchez, ED},
title = {Effect of N-Acetyl Cysteine as an Adjuvant Treatment in Alzheimer's Disease.},
journal = {Brain sciences},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/brainsci15020164},
pmid = {40002497},
issn = {2076-3425},
abstract = {Oxidative stress levels are exacerbated in Alzheimer's disease (AD). This phenomenon feeds back into the overactivation of oxidase enzymes, mitochondrial dysfunction, and the formation of advanced glycation end-products (AGEs), with the stimulation of their receptors (RAGE). These factors stimulate Aβ peptide aggregation and tau hyperphosphorylation through multiple pathways, which are addressed in this paper. The aim of this study was to evaluate the regulatory effect of N-acetyl cysteine (NAC) on oxidant/antioxidant balance as an adjuvant treatment in patients with AD. The results obtained showed that NAC supplementation produced improved cognitive performance, decreased levels of oxidative stress markers, lowered activities of oxidase enzymes, increased antioxidant responses, and attenuated inflammatory and apoptotic markers. Moreover, NAC reversed mitochondrial dysfunction, lowered AGEs-RAGE formation, attenuated Aβ peptide oligomerization, and reduced phosphorylation of tau, thereby halting the formation of neurofibrillary tangles and the progression of AD.},
}

@article {pmid40002335,
year = {2025},
author = {Chien, HJ and Hu, HM and Tsai, SJ and Lin, CL and Yang, SF and Chen, JK and Liu, CJ and Hsieh, YH},
title = {Licochalcone A Induces Uterine Leiomyoma Cell Apoptosis via the ROS-Mediated JNK Activation of the GRP78/NRF2 Pathway In Vitro and In Vivo.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {2},
pages = {},
doi = {10.3390/antiox14020148},
pmid = {40002335},
issn = {2076-3921},
support = {CSMU-CCH-112-01//Chung Shan Medical University and Changhua Christian Hospital/ ; KMU-TC113A02//Kaohsiung Medical University Research Center Grant/ ; },
abstract = {Licochalcone A (LicoA) possesses anti-tumor properties. However, the potential therapeutic effect of LicoA on uterine leiomyomas (ULs) remains unknown. In this study, the effects of LicoA on the proliferation of ULs and its underlying mechanism were explored. LicoA treatment significantly decreased the viability of uterine smooth muscle cells (UtSMCs) and ELT3 cells in a dose-dependent manner. The induction of ELT3 cell apoptosis by LicoA was accompanied by the increased generation of reactive oxygen species (ROS), elevated endoplasmic reticulum (ER) stress (GRP78/IRE1α/ATF6/CHOP), and the increased expression of proapoptotic proteins (c-caspase-3, c-caspase-9, and c-PARP). The ability of Z-VAD-FMK (a caspase inhibitor) and n-acetylcysteine (NAC; a cell membrane permeable antioxidant) to reverse LicoA-induced ROS-mediated ER stress pathways also observed. Furthermore, GRP78 or JNK knockdown was involved in LicoA-induced ROS-mediated ER stress and apoptosis in ELT3 cells. In immunodeficient mice, LicoA significantly suppressed the growth of ELT3 tumor cells, without toxicity. This study is the first to show that LicoA exerts anti-leiomyoma effects via the modulation of ROS-mediated ER stress-induced apoptosis through the JNK/GRP78/NRF2 signaling pathway.},
}

@article {pmid40002315,
year = {2025},
author = {Ückert, AK and Suciu, I and Land, A and Spreng, AS and Welte, H and Herzog, D and Basler, M and Leist, M},
title = {Chemical and Biological Mechanisms Relevant to the Rescue of MG-132-Treated Neurons by Cysteine.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {2},
pages = {},
doi = {10.3390/antiox14020128},
pmid = {40002315},
issn = {2076-3921},
support = {TRR353//Deutsche Forschungsgemeinschaft/ ; 161L0243B//Federal Ministry of Education and Research/ ; 016LW0146K//Federal Ministry of Education and Research/ ; 964537//European Union/ ; 964518//European Union/ ; 101057014//European Union/ ; GP/EFSA/ED/2022/01//European Food Safety Authority/ ; },
abstract = {Proteasome dysfunctions are observed in many human pathologies. To study their role and potential treatment strategies, models of proteasome inhibition are widely used in biomedical research. One frequently used tool is the proteasome inhibitor MG-132. It triggers the degeneration of human neurons, and several studies show protection from pathological events by glutathione or its precursors. It has therefore been concluded that glutathione protects cells from proteasome dysfunction. However, an alternative explanation is that MG-132, which is a peptide aldehyde, is chemically inactivated by thiols, and the apparent protection by glutathione from proteasome dysfunction is an artefact. To clarify this issue, we examined the chemical inactivation of MG-132 by thiols and the role of such reactions for neuroprotection. Using mass spectrometry and nuclear magnetic resonance spectroscopy, we found that MG-132 reacted with L-cysteine to form a stable end product and with glutathione to form an unstable intermediate. Using a cell-free proteasome inhibition assay, we found that high concentrations of L-cysteine can scavenge a substantial fraction of MG-132 and thus reduce proteasome inhibition. Glutathione (or N-acetyl-cysteine) did not alter proteasome inhibition (even at high concentrations). In a final step, we studied human neuronal cultures. We exposed them to MG-132, supplemented the culture medium with various thiols, and assessed intracellular L-cysteine concentrations. The transcriptome response pattern also indicated an inhibition of the proteasome by MG-132 in the presence of L-cysteine. We conclude that thiol concentrations that can be reached in cells do not inactivate MG-132 in pathological models. They rather act in a cytoprotective way as antioxidants.},
}

@article {pmid40001479,
year = {2025},
author = {Zhao, M and Han, M and Guo, S and Tang, Z},
title = {CXCL12 as a Potential Hub Gene for N-Acetylcysteine Treatment of T1DM Liver Disease.},
journal = {Biomolecules},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/biom15020176},
pmid = {40001479},
issn = {2218-273X},
support = {No. 31572585//National Natural Science Foundation of China/ ; },
mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; *Chemokine CXCL12/genetics/metabolism ; *Diabetes Mellitus, Type 1/drug therapy/genetics/metabolism ; Dogs ; *Liver Diseases/drug therapy/genetics/metabolism ; Humans ; Liver/metabolism/drug effects ; Male ; Disease Models, Animal ; },
abstract = {The etiology of type 1 diabetes mellitus (T1DM) is intricate, leading to its classification as an autoimmune metabolic disorder. T1DM often coexists with various visceral diseases. N-acetylcysteine (NAC) is widely acknowledged for its potent antioxidant properties. Studies have demonstrated that the combination of NAC and insulin can effectively alleviate iron-induced nephropathy in T1DM and mitigate oxidative stress injury in skeletal muscle associated with the condition. However, the potential impact of NAC alone on liver disease in individuals with T1DM remains uncertain. In this study, a beagle model was established to simulate T1DM, enabling investigation into the role of NAC in liver disease using RNA-seq biogenic analysis and subsequent validation through molecular biological methods. The findings revealed suppressed expression of CXCL12 chemokine in the livers of individuals with T1DM, while treatment with NAC induced specific activation of CXCL12 within the liver affected by T1DM. These results suggest that CXCL12 may serve as a regulatory factor involved in the therapeutic effects of NAC on liver disease associated with TIDM. This discovery holds significant implications for utilizing NAC as an adjunctive therapy for managing complicated liver diseases accompanying type 1 diabetes mellitus.},
}

*Acetylcysteine/pharmacology/therapeutic use
Animals
*Chemokine CXCL12/genetics/metabolism
*Diabetes Mellitus, Type 1/drug therapy/genetics/metabolism
Dogs
*Liver Diseases/drug therapy/genetics/metabolism
Humans
Liver/metabolism/drug effects
Male
Disease Models, Animal

@article {pmid40000992,
year = {2025},
author = {Kumar, S and Das, B and Maurya, G and Dey, S and Gupta, P and Sarma, JD},
title = {Limonoid-rich fraction from Azadirachta indica A. Juss. (neem) stem bark triggers ROS-independent ER stress and induces apoptosis in 2D cultured cervical cancer cells and 3D cervical tumor spheroids.},
journal = {BMC cancer},
volume = {25},
number = {1},
pages = {334},
pmid = {40000992},
issn = {1471-2407},
support = {BT/MEDII/NIBMG/SYMEC/2014/Vol.II//Department of Biotechnology, Ministry of Science and Technology, India/ ; },
mesh = {Humans ; *Azadirachta/chemistry ; *Reactive Oxygen Species/metabolism ; *Uterine Cervical Neoplasms/drug therapy/pathology/metabolism ; *Limonins/pharmacology/chemistry/isolation & purification ; *Apoptosis/drug effects ; Female ; *Plant Bark/chemistry ; *Plant Extracts/pharmacology/chemistry ; HeLa Cells ; *Endoplasmic Reticulum Stress/drug effects ; *Spheroids, Cellular/drug effects ; Antineoplastic Agents, Phytogenic/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; },
abstract = {BACKGROUND: The existing anticancer drugs in clinical practice show poor efficacy in cervical cancer patients and are associated with multiple side effects. Our previous study demonstrated the strong antineoplastic activity of crude extract prepared from the stem bark of Azadirachta indica (Neem) against cervical cancer. However, the active phytoconstituents of neem stem bark extract and its underlying anticancer mechanism are yet to be investigated. Thus, the present study aimed to identify the active fraction from crude neem stem bark extract to further dissect its anticancer mechanism and determine the active components.

METHODS: Dichloromethane (DCM) extract from neem stem bark was prepared and fractionated using thin-layer chromatography. The fractions obtained were screened against HeLa and ME-180 cervical cancer cell lines to identify the most active fraction, which was then selected for further studies. Clonogenic assay, cell cycle analysis, apoptosis assay, and reactive oxygen species (ROS) assay were performed to determine the cytotoxicity of the active fraction. Gene expression was analyzed using real-time PCR and western blot to determine the mechanism. Additionally, the HeLa cells-derived 3D spheroid model was used to determine the antitumor efficacy of the active fraction. Electrospray ionization-mass spectrometry, Fourier-transform infrared spectroscopy, and proton nuclear magnetic resonance were used to identify the phytoconstituents of the fraction.

RESULTS: Initial screening revealed fraction 2 (F2) as the most active fraction. Additionally, F2 showed the least cytotoxic effect on normal human fibroblast cells. Mechanistically, F2 induced cell cycle arrest and apoptosis in cervical cancer cells. F2 increased ROS levels, induced ER stress, and activated cell survival pathway. Treatment with N-acetyl cysteine revealed that F2 induced ROS-independent ER stress and apoptosis. 3D spheroid viability and growth delay experiments demonstrated the strong antitumor potential of F2. Finally, six compounds, including one flavonoid (nicotiflorin) and five limonoids, were identified in the F2 fraction.

CONCLUSION: This is the first study to identify the active fraction and its phytoconstituents from neem stem bark and demonstrate the anticancer mechanism against cervical cancer. Our study highlights the importance of investigating neem stem bark-derived limonoids and nicotiflorin as a potential source to develop new anticancer therapeutic agents.},
}

Humans
*Azadirachta/chemistry
*Reactive Oxygen Species/metabolism
*Uterine Cervical Neoplasms/drug therapy/pathology/metabolism
*Limonins/pharmacology/chemistry/isolation & purification
*Apoptosis/drug effects
Female
*Plant Bark/chemistry
*Plant Extracts/pharmacology/chemistry
HeLa Cells
*Endoplasmic Reticulum Stress/drug effects
*Spheroids, Cellular/drug effects
Antineoplastic Agents, Phytogenic/pharmacology
Cell Line, Tumor
Cell Proliferation/drug effects

@article {pmid39992072,
year = {2025},
author = {Eid, SY and Koshak, MF and Elzubier, ME and Refaat, B and Almaimani, RA and Althubiti, M and Nour Eldin, EEM and Alahmadi, NH and Fatani, SH and Aslam, A and Khidir, EBA and Abdellatif, AA and El-Readi, MZ},
title = {Protective Effects of Oral Pharmaceutical Solution of Fucoxanthin Against Paracetamol-Induced Liver Injury: Modulation of Drug-Metabolizing Enzymes, Oxidative Stress, and Apoptotic Pathways in Rats.},
journal = {Drug development and industrial pharmacy},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/03639045.2025.2469808},
pmid = {39992072},
issn = {1520-5762},
abstract = {BACKGROUND: Paracetamol (PAC) overdose causes acute liver injury through oxidative stress, inflammation, and apoptosis. While N-acetyl cysteine (NAC) is the standard treatment, fucoxanthin (FUC), a carotenoid from brown seaweed, has shown hepatoprotective effects in animal studies, but its role in PAC toxicity is unclear.

OBJECTIVE: Compared to NAC, this study assessed the hepatoprotective potential of oral FUC solution towards PAC-induced injury to the rat's liver.

METHOD: FUC was formulated as a pharmaceutical solution and characterized via UV-VIS spectroscopy. Six groups of male Wistar rats each contain five animal which are in total thirty rats: negative control (NC), positive control (PC, 2 g/kg PAC), NAC (1200 mg/kg), and three oral FUC doses (100, 200, and 500 mg/kg) for seven days, with PAC administered on day-8. Liver tissues were analyzed for oxidative stress, gene expression, and histology.

RESULTS: FUC solution was clear with absorbance at 433 nm. PAC caused 30% mortality (p < 0.01 vs. others). NAC reduced ALT (56%), AST (78%), ALP (28%), and increased TP by 25% (p < 0.001 vs. PC). FUC at 500 mg/kg (F500) was superior, reducing ALT (82%), AST (93%), ALP (40%), and increasing TP (35%) (p < 0.001 vs. NAC). PAC increased oxidative stress, CYP2E1/CYP3A2 expression, apoptosis markers, and suppressed Nrf2/AMPK/AKT1. F500 improved antioxidants, reduced oxidative stress, and apoptosis, enhanced the Nrf2/AMPK pathway, and downregulated CYP2E1/CYP3A2 (p < 0.01).

CONCLUSION: FUC, particularly at 500 mg/kg, offers significant hepatoprotection against PAC-induced liver injury by modulating drug metabolizing enzymes and enhancing antioxidant defences, warranting further research.},
}

@article {pmid39989173,
year = {2025},
author = {Jiang, ZB and He, QH and Kang, LP and Jiang, S and Liu, JN and Xu, C and Wang, WJ and Wang, XR and Wu, QB and Huang, DH},
title = {Rutecarpine Suppresses Non-Small Cell Lung Cancer Progression Through Activating the STING Pathway and Elevating CD8+ T Cells.},
journal = {Chemical biology & drug design},
volume = {105},
number = {2},
pages = {e70070},
doi = {10.1111/cbdd.70070},
pmid = {39989173},
issn = {1747-0285},
support = {//Beijing Science and Technology Innovation Medical Development Foundation: KC2021-JX-0186-4/ ; //Zhuhai Hospital of Integrated Traditional Chinese & Western Medicine (No.202303)/ ; //Guangdong Province-Provincial Chinese Medicine construction special fund named Traditional Chinese Medicine Inheritance Studio construction project Guangdong Chinese Medicine Office Letter [2023] 108/ ; //Guangdong Provincial Administration of Traditional Chinese Medicine (No. 20221361, No. 20251345, No. 20241285)/ ; //Zhuhai Science and Technology Innovation Bureau (No. 2420004000022, No. 2320004000290, No. 2420004000007)/ ; //China Postdoctoral Science Foundation (2022M713652 and 2022M721411)/ ; //Guangdong Basic and Applied Basic Research Foundation of China (2022A1515110790 and 2024A1515012478)/ ; //"Towards a New Horizon" Research Project of the Beijing Chao Enxiang Traditional Chinese Medicine Heritage and Development Foundation in 2023 (No. 2023CX03)/ ; },
mesh = {*Carcinoma, Non-Small-Cell Lung/drug therapy/pathology/metabolism ; Animals ; Humans ; *CD8-Positive T-Lymphocytes/drug effects/metabolism ; *Lung Neoplasms/drug therapy/pathology/metabolism ; Mice ; Cell Line, Tumor ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; Membrane Proteins/metabolism ; Signal Transduction/drug effects ; Antineoplastic Agents/pharmacology/chemistry ; Quinazolines/pharmacology/chemistry ; Cell Survival/drug effects ; },
abstract = {Globally, non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths. Rutecarpine (RUT), a quinazolinocarboline alkaloid that is naturally occurring and present in Chinese medicinal herbs, has been shown to have anticancer properties in several cancer cell lines. However, the specific antitumor mechanisms of RUT in NSCLC remain unclear. This study demonstrates that RUT induces apoptosis and significantly reduces the viability of NSCLC cell lines. This effect is achieved by stimulating intracellular ROS production, leading to mitochondrial dysfunction. The decreased cell viability observed with RUT treatment is attributed to the elimination of ROS and apoptosis through the suppression of ROS by N-acetylcysteine (NAC). Furthermore, RUT therapy elevated the production of CXCL10 and CCL5 in NSCLC cell lines and markedly activated the STING pathway in NSCLC cells. Mechanistically, RUT substantially decreased the levels of PD-L1 protein in NSCLC cells. Notably, in vivo experiments demonstrated that RUT significantly inhibits mouse NSCLC tumor growth in mice, exhibiting anti-tumor activity by elevating CD8[+] T cells. These findings strongly support RUT as a promising anti-cancer drug for NSCLC.},
}

*Carcinoma, Non-Small-Cell Lung/drug therapy/pathology/metabolism
Animals
Humans
*CD8-Positive T-Lymphocytes/drug effects/metabolism
*Lung Neoplasms/drug therapy/pathology/metabolism
Mice
Cell Line, Tumor
*Reactive Oxygen Species/metabolism
*Apoptosis/drug effects
Membrane Proteins/metabolism
Signal Transduction/drug effects
Antineoplastic Agents/pharmacology/chemistry
Quinazolines/pharmacology/chemistry
Cell Survival/drug effects

@article {pmid39988222,
year = {2025},
author = {Xu, H and Mao, X and Mo, D and Lv, M},
title = {6PPD impairs growth performance by inducing intestinal oxidative stress and ferroptosis in zebrafish.},
journal = {Comparative biochemistry and physiology. Toxicology & pharmacology : CBP},
volume = {},
number = {},
pages = {110161},
doi = {10.1016/j.cbpc.2025.110161},
pmid = {39988222},
issn = {1532-0456},
abstract = {N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), a tire-derived pollutant, has gained increasing attention due to its potential toxicity to aquatic organisms. Although previous studies have revealed that 6PPD impacts early developmental stages of larval fish, its effects on adult fish, particularly on key organs, remain unclear. In this study, we observed that adult zebrafish exposed to 6PPD exhibited reduced growth performance and increased fecal output. Histological examination with hematoxylin and eosin (H&E) staining revealed damage to the intestinal villi and a reduction in goblet cell numbers, indicating that 6PPD impairs growth performance by disrupting the digestive system. Comparative transcriptomic analysis revealed that 6PPD caused significant changes in the expression of 727 genes in the intestine, of which 280 genes were up-regulated and 447 genes were down-regulated. These genes were primarily associated with nutrient digestion and absorption, energy metabolism, immune response, and redox regulation. Mechanistically, 6PPD induced oxidative stress and triggered ferroptosis in the intestine, leading to structural damage of the intestinal villi. Treatment with the antioxidant N-acetylcysteine (NAC) alleviated 6PPD-induced oxidative stress and ferroptosis, thereby improving intestinal villi structure and promoting fish growth. This study provides insights into the mechanisms by which 6PPD impairs growth in adult zebrafish and highlights NAC as a potential therapeutic strategy to mitigate its toxicity.},
}

@article {pmid39985580,
year = {2025},
author = {Shariati, S and Mohtadi, S and Khodayar, MJ and Salehcheh, M and Azadnasab, R and Mansouri, E and Moosavi, M},
title = {Quinic acid alleviates liver toxicity induced by acetaminophen in mice via anti-oxidative and anti-inflammatory effects.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {39985580},
issn = {1432-1912},
support = {TRC-9924//Ahvaz Jundishapur University of Medical Sciences/ ; },
abstract = {Acetaminophen (N-acetyl-para-aminophenol: APAP)-induced hepatotoxicity is a common toxicity that is associated with oxidative stress and inflammation. Quinic acid (QA) is a naturally occurring metabolite that exhibits antioxidant and anti-inflammatory properties. In this research, the effect of QA on hepatotoxicity caused by APAP was investigated. The mice were divided into six groups: control, APAP (300 mg/kg, i.p.), QA (100 mg/kg, i.p.), N-acetylcysteine (NAC) (100 mg/kg, i.p.), and treatment groups, which pretreated with QA at two doses of 50 and 100 mg/kg. NAC and QA were injected for 7 days, and APAP was injected on the seventh day. On day 8, mice were euthanized, and serum factors, markers of oxidative stress, tumor necrosis factor-α (TNF-α), and expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and cytochrome P450 2E1 (CYP2E1) proteins were measured. The results showed that the APAP-treated group significantly increased the activity of serum enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase). APAP decreased hepatic total thiol content, as well as catalase, superoxide dismutase, and glutathione peroxidase activities, and increased thiobarbituric acid reactive substances and TNF-α levels. In addition, Nrf2 and CYP2E1 protein expression was upregulated in APAP-induced injury. Moreover, histopathological findings confirmed APAP hepatotoxicity. However, QA protected mice against the detrimental effects resulting from an imbalance in the oxidant/antioxidant system. QA ameliorated APAP-induced inflammation and histopathological changes and was able to upregulate the protein expression of Nrf2, while also reversing the increase in protein expression of CYP2E1 in APAP-intoxicated mice. These findings demonstrate the potential of QA in preventing APAP-induced hepatotoxicity, which is comparable to the effects of NAC.},
}

@article {pmid39983406,
year = {2025},
author = {Zhang, C and Peng, S and Zheng, Z and Chen, Z and Li, M and Huang, N and Liu, Z and Yang, MX and Chen, H},
title = {Novel bis-pocket binding aldose reductase inhibitors sensitize MCF-7/ADR cells to doxorubicin in a dual-role manner.},
journal = {Bioorganic chemistry},
volume = {157},
number = {},
pages = {108286},
doi = {10.1016/j.bioorg.2025.108286},
pmid = {39983406},
issn = {1090-2120},
abstract = {Multidrug resistance (MDR) represents a bottleneck in the treatment of breast cancer. Although the potential of aldose reductase inhibitors (ARIs) as sensitizers against MDR has been explored in recent decades, the intrinsic mechanism still needs to be elucidated, and promising agents in the clinic need to be developed. In this study, three novel ARIs (5a-c), characterized by bis-pocket binding, were designed and synthesized. Inhibitory activity is positively correlated with antioxidation and benefits from rigid spacers. Only 5a with less activities in inhibition and antioxidation was demonstrated as a stronger sensitizer against doxorubicin (DOX)-resistant MCF-7 cells (MCF-7/ADR) than epalrestat (EPA). Either 5a or EPA may decrease GSH abundance and increase ROS, Fe[2+], and lipid peroxidation levels. The restorative effects of both ARIs may be blocked by N-acetyl cysteine (NAC). These data suggest that both 5a and EPA may restore the sensitivity of MCF-7/ADR cells to DOX by increasing ferroptosis activity. Furthermore, the inhibition of AKR1B1 by 5a, as well as by EPA, dramatically decreased both p-STAT3 and SLC7A11 expression. Gene knockdown of AKR1B1 has the same effects as AKR1B1 inhibition. This evidence indicates that both ARIs can suppress MCF-7/ADR cell growth via the upregulation of ferroptosis activity via the AKR1B1/STAT3/SLC7A11 axis. Additionally, 5a was found to increase the accumulation of intramolecular DOX by inhibiting ABCB1, but EPA did not. These results support that 5a is a promising sensitizing agent against multidrug resistance in breast cancer.},
}

@article {pmid39981906,
year = {2025},
author = {Chen, J and Cheng, Y and Cui, H and Li, S and Duan, L and Jiao, Z},
title = {N‑acetyl‑L‑cysteine protects rat lungs and RLE‑6TN cells from cigarette smoke‑induced oxidative stress.},
journal = {Molecular medicine reports},
volume = {31},
number = {4},
pages = {},
doi = {10.3892/mmr.2025.13462},
pmid = {39981906},
issn = {1791-3004},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Acetylcysteine/pharmacology ; Rats ; *Lung/drug effects/metabolism/pathology ; Male ; Rats, Wistar ; Cell Line ; Apoptosis/drug effects ; Antioxidants/pharmacology ; Alveolar Epithelial Cells/metabolism/drug effects ; Smoke/adverse effects ; Malondialdehyde/metabolism ; Superoxide Dismutase/metabolism ; Cigarette Smoking/adverse effects ; },
abstract = {Cigarette smoke (CS) is a key contributor of chronic obstructive pulmonary disease (COPD); however, its role in the pathogenesis of COPD has not been fully elucidated. N‑acetyl‑L‑cysteine (NAC), as an antioxidant, has been used in the treatment of COPD; however, the mechanisms of action of NAC are not fully understood. Alveolar epithelial type 2 (ATII) cells serve an essential role in the maintenance of alveolar integrity. The aim of the present study was to identify the effect of CS on rat lungs and ATII cells. A subacute lung injury model of Wistar rats was established using CS exposure for 4 weeks. Interalveolar septa widening, infiltration of inflammatory cells, edema fluid in airspaces and abnormal enlargement of airspaces were observed through H&E staining. ELISA revealed that NAC could protect against CS‑induced increases in serum levels of malondialdehyde and decreases in serum levels of superoxide dismutase. Additionally, 8‑hydroxy‑deoxyguanosine was detected using immunohistochemical staining, and this was also expressed at increased levels in the lung tissue of the CS‑exposed group. In addition, the expression levels of Bcl‑2, BAX and caspase‑3 p12 in lung tissue were detected by western blotting or immunohistochemical staining. The expression levels of Bcl‑2 decreased and those of caspase3 p12 were increased in response to CS exposure when compared with those in the control group. These effects were prevented by treatment with NAC. In vitro, the effect of CS extract (CSE) on rat lung epithelial‑6‑T‑antigen negative (RLE‑6TN) cells was observed, flow cytometry was used to detect intracellular reactive oxygen species (ROS) levels and the occurrence of apoptosis, and the content of glutathione (GSH) was detected using a colorimetric assay. Additionally, the expression levels of heme oxygenase‑1 (HO‑1), p53 and Bcl‑2 were examined by western blotting, and HO‑1 mRNA expression was also examined using reverse transcription‑quantitative PCR. The results of the present study revealed that CSE induced apoptosis of RLE‑6TN cells, accompanied by increased levels of intracellular ROS and exhaustion of GSH. Significantly increased protein levels of HO‑1 and p53, as well as decreased protein levels of Bcl‑2 were also observed. These effects were prevented by administration of NAC. Overall, these findings suggested that CS could promote apoptosis in rat lung tissues and alveolar epithelial cells by inducing intracellular oxidative injury, and NAC may serve an antioxidant role by replenishing the intracellular GSH content.},
}

Animals
*Oxidative Stress/drug effects
*Acetylcysteine/pharmacology
Rats
*Lung/drug effects/metabolism/pathology
Male
Rats, Wistar
Cell Line
Apoptosis/drug effects
Antioxidants/pharmacology
Alveolar Epithelial Cells/metabolism/drug effects
Smoke/adverse effects
Malondialdehyde/metabolism
Superoxide Dismutase/metabolism
Cigarette Smoking/adverse effects