@article {pmid41801306,
year = {2026},
author = {Xie, M and Weng, J and Li, C and Liu, Q and Feng, Y and Zhang, H and Chang, Q and Chung, KF and Adcock, IM and Li, F and Fan, X},
title = {Mechanisms of Anti-Oxidants, N-Acetylcysteine and Elamipretide (SS-31), on Ozone-Induced Airway Hyperresponsiveness and Mucus Hypersecretion.},
journal = {Lung},
volume = {204},
number = {1},
pages = {},
pmid = {41801306},
issn = {1432-1750},
support = {81870031//National Natural Science Foundation of China/ ; U1803126//National Natural Science Foundation of China/ ; YG2019ZDA24//Shanghai Jiao Tong University/ ; 202304295107020044//Anhui Provincial Institute of Translational Medicine/ ; },
mesh = {Animals ; Ozone ; *Acetylcysteine/pharmacology ; Mice, Inbred C57BL ; *Antioxidants/pharmacology ; *Mucus/metabolism ; Oxidative Stress/drug effects ; NLR Family, Pyrin Domain-Containing 3 Protein ; *Oligopeptides/pharmacology ; Reactive Oxygen Species/metabolism ; Mice ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Disease Models, Animal ; Male ; Cell Line ; Carrier Proteins/metabolism ; *Bronchial Hyperreactivity/chemically induced/metabolism/prevention & control/physiopathology ; Phosphatidylinositol 3-Kinases/metabolism ; *Lung/drug effects/metabolism/physiopathology ; Humans ; Mitochondria/metabolism/drug effects ; Caspase 1/metabolism ; Bronchoalveolar Lavage Fluid/cytology ; Inflammation Mediators/metabolism ; },
abstract = {BACKGROUND: Ozone (O3) exposure induces acute airway injury characterized by airway hyperresponsiveness (AHR) and airway mucus hypersecretion (AMH). Oxidative stress and mitochondria-derived reactive oxygen species (mtROS) are key contributors. We investigated and compared the protective mechanisms of N-acetylcysteine (NAC) and the mitochondria-targeted antioxidant Elamipretide (SS-31) in O3-induced airway inflammation, AHR and AMH.

METHODS: Wild-type C57BL/6J mice received intraperitoneal NAC or SS-31 1 h before a single O₃ exposure. AHR, bronchoalveolar lavage (BAL) inflammatory cells, mucus production and mucin expression, inflammatory mediators, oxidative stress indices, and PI3K/AKT and NLRP3/caspase-1/GSDMD pathway activation were assessed in vivo. BEAS-2B cells were pretreated with NAC, SS-31, or the PI3K/AKT inhibitor LY294002 before O₃ exposure, and pathway activation was evaluate d in vitro.

RESULTS: NAC and SS-31 comparably attenuated O₃-induced AHR, reduced BAL inflammatory cell influx, and decreased AMH and MUC5B expression. Both treatments improved redox balance by reducing ROS/mtROS, lowering malondialdehyde (MDA), increasing superoxide dismutase (SOD) activity, and improving GSH/GSSG. NAC and SS-31 also suppressed O₃-induced inflammatory gene expression and inhibited activation of PI3K/AKT and NLRP3/caspase-1/GSDMD signaling in mouse lungs and BEAS-2B cells. PI3K inhibition recapitulated these protective effects in vitro, supporting a mechanistic role for PI3K/AKT signaling during acute O₃ exposure.

CONCLUSIONS: NAC and SS-31 protect against acute O₃-induced AHR and AMH by alleviating oxidative stress and suppressing PI3K/AKT-driven inflammatory and pyroptotic pathways. Targeting oxidative stress, including mitochondrial ROS, may represent a viable strategy to mitigate airway damage caused by acute O₃ exposure.},
}

Animals
Ozone
*Acetylcysteine/pharmacology
Mice, Inbred C57BL
*Antioxidants/pharmacology
*Mucus/metabolism
Oxidative Stress/drug effects
NLR Family, Pyrin Domain-Containing 3 Protein
*Oligopeptides/pharmacology
Reactive Oxygen Species/metabolism
Mice
Proto-Oncogene Proteins c-akt/metabolism
Signal Transduction/drug effects
Disease Models, Animal
Male
Cell Line
Carrier Proteins/metabolism
*Bronchial Hyperreactivity/chemically induced/metabolism/prevention & control/physiopathology
Phosphatidylinositol 3-Kinases/metabolism
*Lung/drug effects/metabolism/physiopathology
Humans
Mitochondria/metabolism/drug effects
Caspase 1/metabolism
Bronchoalveolar Lavage Fluid/cytology
Inflammation Mediators/metabolism

@article {pmid40398422,
year = {2025},
author = {Sonar, SA and Bhat, R and Thompson, HL and Coplen, CP and Uhrlaub, JL and Jergovic, M and Nikolich, JŽ},
title = {Age-Related Oxidative Stress and Mitochondrial Dysfunction in Lymph Node Stromal Cells Limit the Peripheral T Cell Homeostatic Maintenance and Function.},
journal = {Aging cell},
volume = {24},
number = {8},
pages = {e70100},
pmid = {40398422},
issn = {1474-9726},
support = {P01 AG052359/AG/NIA NIH HHS/United States ; P30 CA023074/CA/NCI NIH HHS/United States ; //Bowman Professorship in Medical Sciences/ ; },
mesh = {*Oxidative Stress ; Animals ; *Mitochondria/metabolism/drug effects/pathology ; *Stromal Cells/metabolism ; *Lymph Nodes/metabolism/cytology/pathology/immunology ; Mice ; Reactive Oxygen Species/metabolism ; *Homeostasis ; *Aging ; *T-Lymphocytes/metabolism/immunology ; Mice, Inbred C57BL ; },
abstract = {Lymph nodes (LN) are the key organs in charge of long-term maintenance of naïve lymphocytes and their initial, primary activation upon infection. Accumulating evidence indicates that LN stromal cells undergo degenerative changes with aging that critically impair LN function, including the generation of protective primary immune responses. The nature of these defects remains incompletely understood. We here demonstrate that age-related LN stromal changes manifest themselves in mitochondrial dysfunction and oxidative stress. Ex vivo, all three major stromal cell subsets, fibroblastic reticular cells (FRC), lymphatic endothelial cells (LEC), and blood endothelial cells (BEC) exhibit elevated mitochondrial reactive oxygen species (ROS) stress, reduced mitochondrial potential, and elevated mitochondrial mass with aging. Old FRC also exhibited elevated cytoplasmic ROS production. This was accompanied by the reduced ability of old LN stromal cells to support Tn survival in vitro, a defect alleviated by pretreating old LN stroma with the general antioxidant N-acetyl cysteine (NAC) as well as by mitochondrial ROS-reducing (mitoquinone) and mitophagy-inducing (urolithin A) compounds. Mitochondrial dysfunction and, in particular, reduced mitochondrial potential in old FRC were also seen upon vaccination or infection in vivo. Consistent with these results, in vivo antioxidant treatment of old mice with NAC restored to adult levels the numbers of antigen-specific CD8[+] effector T cells and their production of granzyme B in response to antigenic challenge.},
}

*Oxidative Stress
Animals
*Mitochondria/metabolism/drug effects/pathology
*Stromal Cells/metabolism
*Lymph Nodes/metabolism/cytology/pathology/immunology
Mice
Reactive Oxygen Species/metabolism
*Homeostasis
*Aging
*T-Lymphocytes/metabolism/immunology
Mice, Inbred C57BL

@article {pmid41663723,
year = {2026},
author = {Zhang, XD and Atalla, N and Rodriguez, E and Teng, C and Bai, X and Teng, JMC},
title = {Development of a controlled ex vivo human skin platform for quantitative evaluation of age-related functional biomarkers following application of topical treatments.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41663723},
issn = {2045-2322},
mesh = {Humans ; *Biomarkers/metabolism ; *Skin Aging/drug effects/radiation effects ; *Zinc Oxide/pharmacology/administration & dosage ; *Skin/drug effects/metabolism/radiation effects/pathology ; Adult ; Middle Aged ; Female ; Male ; Aged ; Cellular Senescence/drug effects ; Ultraviolet Rays/adverse effects ; Administration, Topical ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Tumor Suppressor Protein p53/metabolism ; Acetylcysteine/pharmacology/administration & dosage ; Interleukin-1beta/metabolism ; },
abstract = {Targeting cellular senescence presents a promising approach to slow visible skin aging and promote tissue repair. However, most preclinical models fail to capture the full architecture of human skin or accommodate diverse skin types, limiting their translational relevance. To address this gap, we developed a controlled ex vivo human skin explant platform using freshly acquired tissues from donors of varying ages and Fitzpatrick skin types. This model applies standardized UVA and UVB doses to induce reproducible photodamage, enabling the assessment of both preventative and reparative effects of topical treatments. The results showed that ND-ZnO and NAC reduced levels of p16^INK4a and p53, which are key biomarkers measuring cellular senescence; ND-ZnO and exosomes lowered IL-1β expression, which is a biomarker measuring inflammation. Histological analysis confirmed these findings, with ND-ZnO-treated skins preserved epidermal structure, reduced inflammatory features, and maintained dermal collagen organization. We then conducted a four-week single-patient case study using the same ND-ZnO formulation. Visible improvements in redness, pigmentation, and texture were observed, aligned with the molecular and histological changes seen ex vivo. These findings suggested that the ex vivo platform has the potential to be used as a more inclusive, human-relavent model for evaluating and quantifying the anti-aging efficacies of topical treatments across diverse skin types and age groups.},
}

Humans
*Biomarkers/metabolism
*Skin Aging/drug effects/radiation effects
*Zinc Oxide/pharmacology/administration & dosage
*Skin/drug effects/metabolism/radiation effects/pathology
Adult
Middle Aged
Female
Male
Aged
Cellular Senescence/drug effects
Ultraviolet Rays/adverse effects
Administration, Topical
Cyclin-Dependent Kinase Inhibitor p16/metabolism
Tumor Suppressor Protein p53/metabolism
Acetylcysteine/pharmacology/administration & dosage
Interleukin-1beta/metabolism

@article {pmid41661511,
year = {2026},
author = {Appell, MB and Kanan, Y and Malmberg, K and Appidi, T and Khan, M and Campochiaro, PA and Ensign, LM},
title = {A gel-forming antioxidant eye drop for photoreceptor protection in retinitis pigmentosa.},
journal = {Drug delivery and translational research},
volume = {16},
number = {4},
pages = {1052-1063},
pmid = {41661511},
issn = {2190-3948},
support = {R01EY031041/EY/NEI NIH HHS/United States ; P30EY001765/EY/NEI NIH HHS/United States ; T32EY007143/EY/NEI NIH HHS/United States ; R01EY031041/EY/NEI NIH HHS/United States ; P30EY001765/EY/NEI NIH HHS/United States ; T32EY007143/EY/NEI NIH HHS/United States ; },
mesh = {Animals ; *Retinitis Pigmentosa/drug therapy/pathology ; *Antioxidants/administration & dosage/chemistry ; Ophthalmic Solutions/administration & dosage ; *Acetylcysteine/administration & dosage/analogs & derivatives/chemistry ; Mice ; Gels ; Disease Models, Animal ; Rats ; Male ; *Photoreceptor Cells, Vertebrate/drug effects ; Mice, Inbred C57BL ; },
abstract = {Retinitis pigmentosa (RP) is a chronic genetic condition that leads to progressive loss of photoreceptor cells and vision. While gene therapy is available for a small subset of patients with specific mutations, developing a therapeutic that broadly targets the cellular stresses that lead to cell death could address a major unmet need. One such option would be utilizing antioxidant therapies to neutralize reaction oxygen species (ROS) in the retina that underlie RP progression. Here, we describe an approach for delivering the antioxidants N-acetyl cysteine (NAC) or N-acetyl cysteine ethyl ester (NACET) with a gel-forming eye drop previously demonstrated to provide therapeutic drug delivery in the posterior segment in animals. We demonstrated therapeutic protection of photoreceptor structure and function in a chemically-induced rat model of RP (48% increase in photopic b-wave amplitude), as well as some limited protection in an aggressive genetic mouse model (rd10) of retinal degeneration (~ 31% increase in photopic b-wave amplitude) with once daily application. However, antioxidants have inherent stability issues when stored in solution, so we investigated the use of additional excipients to improve stability and retain potency. While a promising approach, future work to address product stability and efficacy in larger eyes is needed for further development.},
}

Animals
*Retinitis Pigmentosa/drug therapy/pathology
*Antioxidants/administration & dosage/chemistry
Ophthalmic Solutions/administration & dosage
*Acetylcysteine/administration & dosage/analogs & derivatives/chemistry
Mice
Gels
Disease Models, Animal
Rats
Male
*Photoreceptor Cells, Vertebrate/drug effects
Mice, Inbred C57BL

@article {pmid41790529,
year = {2026},
author = {Ommi, NB and Mattocks, DAL and Horowitz, MC and Nichenametla, SN},
title = {D, L-Buthionine-(S, R)-sulfoximine recapitulates the anti-obesity effects of sulfur amino acid restriction without the associated deleterious effects on bone in male mice.},
journal = {Aging},
volume = {18},
number = {1},
pages = {82-99},
doi = {10.18632/aging.206358},
pmid = {41790529},
issn = {1945-4589},
abstract = {Sulfur amino acid restriction (SAAR), a diet low in methionine and lacking cysteine, reduces obesity but also lowers bone mineral density (BMD) and increases marrow adipose tissue. Because the SAAR diet lacks cysteine, it exerts cysteine restriction (CysR), in addition to methionine restriction (MetR). We previously reported that the anti-obesity effect of the SAAR diet was exclusively due to CysR. Follow-up studies revealed that CysR decreases obesity by lowering glutathione (GSH), and that D, L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH biosynthesis, recapitulates the SAAR-induced lean phenotype on a methionine-replete diet. Here, we investigated whether the detrimental effects of the SAAR diet on bone are mediated solely by CysR and whether BSO, similar to the SAAR diet, exerts deleterious effects. Male obese C57BL6/NTac mice were fed high-fat diets with 0.86% methionine (control diet, CD), 0.12% methionine (SAAR diet), SAAR diet supplemented with a GSH precursor, N-acetylcysteine (NAC) in water, and CD supplemented with BSO in water. Femurs and tibiae of SAAR mice had lower trabecular and cortical BMD, fewer osteoblasts, reduced biomechanical strength, and more marrow adipocytes than in CD mice. NAC reversed all these effects, suggesting that CysR mediates the detrimental effects of the SAAR diet on bone. Despite its anti-obesity effects, BSO did not exert any detrimental effects on bones. Future studies should investigate mechanisms, age-at-onset, tissue-specific, and gender-specific effects of BSO on bone health. Long-term studies to establish the therapeutic efficacy and off-target effects of BSO are critical for developing it as an anti-obesity drug in humans.},
}

@article {pmid41780686,
year = {2026},
author = {Sun, W and Xie, L and Jiang, X and Zhu, Q and Feng, H and Cun, D and Wu, L and Yang, M},
title = {A functional lyoprotectant platform enables storage-stable, mucus-penetrating siRNA delivery to the lung.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114749},
doi = {10.1016/j.jconrel.2026.114749},
pmid = {41780686},
issn = {1873-4995},
abstract = {Respiratory diseases remain a major global health concern, where pathological mucus accumulation and chronic inflammation severely compromise lung function. RNA therapeutics have emerged as a transformative modality to address underlying molecular pathologies beyond the capabilities of small-molecule drugs. However, effective delivery of RNA therapeutics to the lungs remains hindered by significant challenges. The instability of lipid nanoparticles (LNPs) in liquid formulations compromises their storage and cold-chain transport, while the pathological mucus hypersecretion characteristic of chronic airway diseases impedes nanoparticle penetration and delivery efficacy. Herein, we propose a functional lyoprotectant strategy that bridges formulation stability and biological functionality within a single design. Specifically, N-acetylcysteine (NAC), a clinically used mucolytic, was incorporated into a sucrose-based lyoprotectant matrix as a functional additive, enabling lyophilization while introducing mucus-modulating capability. The lyophilized LNPs preserved physicochemical integrity, maintained siRNA encapsulation, and achieved efficient mucus penetration and gene silencing in vitro and in vivo. In murine models of mucus-hypersecretory lung disease, a single-dose administration achieved enhanced therapeutic outcomes through a sequential and dual-action complementary mechanism, including extracellular NAC-mediated mucolysis and intracellular RNAi-mediated inflammation suppression. This work pioneers the concept of a functional lyoprotectant, offering a generalizable platform for storage-stable and biologically active inhaled RNA therapeutics.},
}

@article {pmid41780678,
year = {2026},
author = {Cai, YY and Yang, LJ and Pan, MM and Nurtay, N and Yu, YP and Xie, M and Jiang, M and Wang, Y and Yu, X and Xu, L},
title = {PtCu-bimetallic modified MOF nanozyme composites for alleviating acute liver injury via reactive oxygen species elimination and inflammation regulation.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114774},
doi = {10.1016/j.jconrel.2026.114774},
pmid = {41780678},
issn = {1873-4995},
abstract = {Excessive reactive oxygen species (ROS) accumulation and dysregulated inflammation drive acetaminophen (APAP)-induced acute liver injury (ALI), yet the therapeutic effect of the commonly used clinical drug N-acetylcysteine (NAC) still has certain limitations at present. Here, we engineered a multifunctional nanozyme nanocomposite, MPCNH, by in situ deposition of bimetallic PtCu nanoparticles onto UiO-66 metal-organic frameworks (MOFs), loading NAC, and coating with hyaluronic acid (HA) to enhance biocompatibility. MPCNH exhibited cascade superoxide dismutase (SOD)-like and catalase (CAT)-like catalytic activities, enabling rapid ROS clearance and mitochondrial protection in APAP-challenged hepatocytes. Meanwhile, the delivery of the therapeutic drug NAC was achieved. In vivo, MPCNH lowered serum transaminases, activated the Keap1-Nrf2 antioxidant pathway, shifted macrophages polarization toward an anti-inflammatory M2 phenotype and restored metabolic balance. By integrating catalytic and pharmacological functions, MPCNH offers a synergistic strategy to simultaneously eliminate oxidative stress and regulate inflammation, providing a promising therapeutic platform for oxidative stress-driven liver injury.},
}

@article {pmid41780618,
year = {2026},
author = {Ge, Y and Luo, N and Zhang, M and Shi, J and Xu, X and Wang, Y},
title = {Advances on botanicals targeting programmed cell death in acetaminophen-induced liver injury.},
journal = {Journal of ethnopharmacology},
volume = {363},
number = {},
pages = {121466},
doi = {10.1016/j.jep.2026.121466},
pmid = {41780618},
issn = {1872-7573},
abstract = {Acetaminophen (APAP), a widely used analgesic and antipyretic drug, poses a significant clinical challenge worldwide due to its potential to induce hepatotoxicity following overdose. At present, limited therapeutic options exist for APAP overdose. Moreover, N-acetylcysteine (NAC), the first-line clinical agent in routine use, suffers from a narrow therapeutic window and numerous adverse effects, which limits its clinical utility. Plants constitute a rich reservoir of phytochemicals that engage in multiple pharmacological processes, positioning them as a cornerstone in pharmaceutical innovation. The therapeutic use of herbs for liver conditions is historically recognized in classical works such as the "Treatise on Febrile Diseases," "Compendium of Materia Medica," and "Thousand Golden Prescriptions."

AIM OF THE REVIEW: Chinese herbal medicines and their extracts have garnered significant attention for the prevention and treatment of acetaminophen (APAP)-induced liver injury (AILI), largely due to their therapeutic efficacy and favorable safety profile. The programmed cell death (PCD) induced by APAP, and the impact and potential mechanism on the pathogenesis of AILI are discussed in this review. Furthermore, various botanicals that can be used to prevent AILI, as well as the structure-activity relationships and potential mechanisms, are discussed.

METHODS: Articles published over the past decade were retrieved from databases including Web of Science, PubMed, and CNKI, using the keywords APAP, AILI, natural products, and traditional Chinese medicine. Studies that failed to clearly characterize the components of plant extracts were excluded. Subsequently, a preliminary classification was performed based on the chemical structures of the included natural products, with priority given to relatively novel agents supported by robust research data or notable research advances. Following a systematic review and synthesis of key study details, including experimental design, phenotypic alterations, and mechanism elucidation, the decision was made to conduct further in-depth analysis focusing on the type of PCD. Ultimately, more than 160 papers were selected and discussed in this review.

RESULTS: A systematic review of the literature identified plant extracts with anti-AILI properties, which can be categorized into nine distinct classes based on their bioactive structures. By comparing the experimental research evidence from 44 natural compounds, not only were several more promising compounds such as sinomenine, dihydromyricetin, tannic acid and pterostilbene obtained, but it also helped to clarify the protective mechanisms of these extracts. Studies have found that numerous derivatives of natural products are capable of concurrently modulating multiple signaling pathways, such as Nrf2-HO1, NF-κB, and RIPK/MLKL, to alleviate PCD caused by APAP, thereby offering potential strategies for the prevention or treatment of AILI.

CONCLUSION: This review systematically elucidates the mechanisms by which structurally diverse phytochemicals alleviate APAP-induced hepatotoxicity, with a specific focus on their modulatory roles in programmed cell death pathways implicated in AILI. These findings provide valuable insights for the development of novel hepatoprotective therapeutics.},
}

@article {pmid41779942,
year = {2026},
author = {Lucas, D and Munoz, C and Muller, CR and Gu, X and Wolfe, SR and Cuddington, CT and Palmer, AF and Cabrales, P},
title = {Acellular Hemoglobin Impairs Cardiomyocyte Excitation-Contraction Coupling.},
journal = {ASAIO journal (American Society for Artificial Internal Organs : 1992)},
volume = {},
number = {},
pages = {},
doi = {10.1097/MAT.0000000000002668},
pmid = {41779942},
issn = {1538-943X},
abstract = {Heart failure is a significant complication of chronic intravascular hemolysis, a condition characterized by red blood cells (RBCs) breakdown, leading to the release of acellular hemoglobin (Hb) and its oxidized form, methemoglobin (MetHb), into the bloodstream. Acellular Hb promotes nitric oxide (NO) scavenging, oxidative stress, inflammation, iron overload, and functional tissue impairment. This study investigates the direct impact of Hb and MetHb on cardiomyocyte function by assessing calcium transients, fractional shortening, and reactive oxygen species (ROS) formation. The study also evaluated the effects of polymerized Hb, NO scavenging, and antioxidant therapy using N-acetylcysteine (NAC) on cardiomyocyte contractility. Our results show that acellular Hb and MetHb impair cardiomyocyte function by prolonging calcium transient half-life, reducing contractility, and increasing ROS production. Polymerization of Hb and antioxidant supplementation offered partial protection but did not fully mitigate these effects. Inhibiting NO synthase did not increase Hb toxicity, indicating that NO scavenging is not the sole toxicity pathway. These findings demonstrate that Hb-induced cardiomyocyte dysfunction involves a multifactorial mechanism, including NO scavenging, oxidative stress, and disrupted calcium dynamics. Although Hb polymerization and antioxidants offer limited protection, novel multi-target strategies are essential to address Hb toxicity in hemolytic disorders and the use of Hb-based oxygen carriers.},
}

@article {pmid41771427,
year = {2026},
author = {Lu, Y and Cheng, S and Zhang, Y and Li, Y and Liu, L},
title = {Novel 1,2,3-triazole-based compound triggers apoptosis through DNA damage response involving ATM/ATR signaling in liver cancer cells.},
journal = {Biochemical pharmacology},
volume = {248},
number = {},
pages = {117856},
doi = {10.1016/j.bcp.2026.117856},
pmid = {41771427},
issn = {1873-2968},
abstract = {1,2,3-Triazole-substituted cabotegravir analogues, i.e., KJ-9, have been developed as lead structures to explore their potential as antitumor agents. The new analogue exhibited significant anti-proliferative activity against various human cancer cell lines, with particularly strong effects on the HepG2 and HCCLM3 liver cancer lines, as it induced a marked loss of colony-forming ability and triggered apoptosis upon KJ-9 exposure. Furthermore, treatment with KJ-9 increased the Bax-to-Bcl-2 protein ratio and activated cleaved caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP). Meanwhile, KJ-9 treatment induced a blockage in the cell cycle (G2/M), increased DNA damage levels, and induced the accumulation of histone variant H2AX (γ-H2AX) protein. Furthermore, there was strong induction of p-ATM and p-ATR proteins, along with their downstream effectors p-CHK1 and p-CHK2. Additionally, KJ-9 treatment increased phosphorylation levels of the tumor suppressor protein p53 and inhibited components of the PI3K/AKT pathway. Although it did not significantly affect AKT phosphorylation, the ATM/ATR inhibitor CGK733 significantly reversed KJ-9-induced upregulation of p-ATM, p-ATR, p-p53, γ-H2AX, and activated caspase-3. Moreover, reactive oxygen species (ROS) were generated in greater quantities by KJ-9 treatment. After KJ-9 treatment, ROS were suppressed by the addition of the antioxidant N-Acetylcysteine (NAC), leading to increased levels of p-AKT and reduced levels of p-ATM, p-ATR, p-p53, cleaved caspase-3, and γ-H2AX. These findings suggest that KJ-9 promotes oxidative stress, which further inhibits AKT activation while activating the ATM/ATR pathway, leading to p53 accumulation, sustained DNA damage responses, G2/M-phase cell cycle arrest, and apoptosis in both HepG2 cells and HCCLM3 cells.},
}

@article {pmid41761803,
year = {2026},
author = {Nasir, W and Ul Hassan, S and Aslam, B and Majeed, W},
title = {Unfolding protection: Terminalia arjuna targets UPR pathways to counteract ER stress in hepatotoxicity.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {4},
pages = {1073-1082},
doi = {10.36721/PJPS.2026.39.4.REG.14749.1},
pmid = {41761803},
issn = {1011-601X},
mesh = {Animals ; *Terminalia/chemistry ; *Endoplasmic Reticulum Stress/drug effects ; Rats, Wistar ; *Plant Extracts/pharmacology/isolation & purification ; Acetaminophen/toxicity ; *Chemical and Drug Induced Liver Injury/metabolism/prevention & control/pathology ; Oxidative Stress/drug effects ; Rats ; Male ; *Liver/drug effects/pathology/metabolism ; *Unfolded Protein Response/drug effects ; Apoptosis/drug effects ; Signal Transduction/drug effects ; Plant Bark/chemistry ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; },
abstract = {BACKGROUND: Drug-induced liver injury (DILI) from acetaminophen (APAP) overdose involves ER stress, oxidative damage, apoptosis, and inflammation.

OBJECTIVE: This study assesses Terminalia arjuna bark extract (TAE) against APAP-induced toxicity in rats, comparing its efficacy with N-acetylcysteine (NAC) through key signaling and inflammatory markers.

METHODS: Twenty-four Wistar rats were equally divided into four groups: Control Negative (CN, no treatment), Control Positive (CP, acetaminophen 350 mg/kg), N-acetylcysteine (NAC, 150 mg/kg), and Terminalia arjuna bark extract (TAE, ethanolic, 80 mg/kg). Over 14 days, liver injury was induced in the CP group via acetaminophen, while the NAC and TAE groups received their respective treatments. Animals were decapitated on day 15, and biological samples were collected for analysis. Biochemical assessments included liver function markers (ALT, AST) and oxidative stress parameters (SOD, TAC, TBARS, TOS). Gene expression studies were performed for oxidative stress regulators (Keap1, Nrf2) and ER stress signaling molecules (ERK, JNK, PPAR-α, AKT). Histopathological examination evaluated liver architecture and cellular integrity.

RESULTS: Acetaminophen induced significant hepatotoxicity, as reflected by elevated liver enzymes, increased oxidative stress, altered gene expression, and disrupted liver histology. APAP toxicity resulted in elevated oxidative stress, apoptosis, inflammation, and ER stress, leading to significant hepatic damage (p < 0.0001 vs CN). NAC and TAE treatments mitigated these effects, with TAE demonstrating superior improvement in oxidative stress markers (p < 0.0001 vs CP). Gene expression analysis revealed a protective shift in the Keap1-Nrf2 pathways in the treated groups. Histopathology confirmed reduced necrosis and preserved hepatic architecture in the NAC and TAE groups.

CONCLUSION: T. arjuna exhibits potent hepatoprotective effects, comparable to NAC, through modulation of oxidative stress, apoptosis, and ER stress pathways. Further studies are needed to explore its clinical applicability in acute liver injury management.},
}

Animals
*Terminalia/chemistry
*Endoplasmic Reticulum Stress/drug effects
Rats, Wistar
*Plant Extracts/pharmacology/isolation & purification
Acetaminophen/toxicity
*Chemical and Drug Induced Liver Injury/metabolism/prevention & control/pathology
Oxidative Stress/drug effects
Rats
Male
*Liver/drug effects/pathology/metabolism
*Unfolded Protein Response/drug effects
Apoptosis/drug effects
Signal Transduction/drug effects
Plant Bark/chemistry
Acetylcysteine/pharmacology
Antioxidants/pharmacology

@article {pmid41754714,
year = {2026},
author = {Xie, Y and Ruan, B and Yin, Y and Fan, L and Tang, H and Dai, H and You, S and Yao, S and Wang, G and Xu, Y},
title = {A Biomimetic NAC-Loaded PCL/Modified Chitosan/dECM Fibrous Scaffold for Accelerating Diabetic Wound Healing and Minimizing Scarring.},
journal = {Polymers},
volume = {18},
number = {4},
pages = {},
pmid = {41754714},
issn = {2073-4360},
support = {ZDYF2025GXJS148//2025 Provincial Key R&D Sanya Yazhou Bay Science and Technology City Joint Innovation Project/ ; ZDYF2024GXJS016//2024 Key R & D projects in Hainan Province/ ; ZR202306010004//Natural Science Foundation of Shandong Province/ ; BZLX2023004//Research projects of the University Institute in the construction period of Shangyu District, Shaoxing City/ ; N/A//The 2024 Chu Tian Talent Plan Science and Technology Innovation Team Project/ ; },
abstract = {The development of innovative wound dressings capable of accelerating diabetic wound healing while simultaneously reducing scar formation is a significant clinical challenge. In this study, we designed and fabricated a multifunctional nanofibrous scaffold PCL/Az-CS/dECM/NAC by incorporating decellularized extracellular matrix (dECM) and N-acetylcysteine (NAC) into a composite backbone of polycaprolactone (PCL) and azidobenzoic acid-modified chitosan (AZCS). The scaffold exhibited ideal hydrophilicity and swelling capacity, and demonstrated excellent biocompatibility. In vitro studies demonstrated that the scaffold effectively scavenged reactive oxygen species (ROS) and promoted the polarization of macrophages from the M1 phenotype to the M2 phenotype; in vivo studies confirmed that the PCL/AZ-CS/dECM/NAC scaffold significantly accelerated wound closure, promoted mature angiogenesis, and facilitated orderly collagen deposition. The PCL/AZ-CS/dECM/NAC scaffold mitigated scar formation by increasing the proportion of regenerative type III collagen, optimizing the collagen I/III ratio. Our findings suggest that the PCL/AZ-CS/dECM/NAC scaffold is a highly promising candidate for a multifunctional dressing designed to treat recalcitrant diabetic wounds and prevent excessive scarring.},
}

@article {pmid41754089,
year = {2026},
author = {Dawi, J and Affa, S and Au, S and Misakyan, Y and Gonzalez, E and Chorbajian, A and Hammi, M and Dave, P and Qumsieh, K and Venketaraman, V},
title = {Efficacy and Safety of Glutathione Supplementation in Patients with HIV Infection and HIV-Tuberculosis Co-Infection.},
journal = {Nutrients},
volume = {18},
number = {4},
pages = {},
pmid = {41754089},
issn = {2072-6643},
abstract = {Glutathione (GSH), the most abundant intracellular non-protein thiol, is a central regulator F redox homeostasis, immune function, and mitochondrial integrity. In human immunodeficiency virus (HIV) infection, persistent oxidative stress and impaired precursor availability result in sustained glutathione deficiency, contributing to immune dysfunction, inflammation, and disease progression despite effective antiretroviral therapy. This redox imbalance is further exacerbated in HIV-tuberculosis co-infection, where compounded inflammatory and metabolic stress increases susceptibility to opportunistic infections and treatment-related complications. This review examines the efficacy and safety of glutathione supplementation and precursor-based strategies in HIV infection and HIV-tuberculosis co-infection. Evidence from mechanistic studies, clinical trials, and translational research suggests that glutathione repletion, achieved through direct supplementation or precursor approaches such as N-acetylcysteine, Glycine and N-acetylcysteine (GlyNAC), and cysteine-rich dietary interventions, can restore intracellular thiol balance, improve immune cell function, enhance mitochondrial performance, and reduce systemic oxidative stress. These interventions have shown consistent safety and tolerability across diverse populations, including individuals receiving complex antiretroviral and antitubercular regimens, with gastrointestinal discomfort being the most commonly reported adverse effect and serious toxicities remaining rare. Despite encouraging findings, translation into routine clinical practice remains limited by methodological heterogeneity, short study durations, and lack of standardized biomarkers and long-term outcome data. Future research should prioritize rigorously designed trials incorporating mechanistic endpoints, standardized redox measurements, and clinically meaningful outcomes. Collectively, the available evidence supports glutathione-centered strategies as promising adjuncts to existing HIV and tuberculosis treatment paradigms, warranting further investigation to define their role in improving immune resilience and long-term clinical outcomes.},
}

@article {pmid41753798,
year = {2026},
author = {Wang, F and Wang, W and Gu, H},
title = {Intrinsic Acidity of N-Acetylcysteine Mediates Enhanced Inhibition of Klebsiella pneumoniae and Its Biofilms by Polymyxin B.},
journal = {Microorganisms},
volume = {14},
number = {2},
pages = {},
pmid = {41753798},
issn = {2076-2607},
abstract = {This study investigated the combined antibacterial and anti-biofilm activity of polymyxin B (PB) with intrinsically acidic N-acetylcysteine (NAC) against Klebsiella pneumoniae. The minimum inhibitory concentrations (MICs) of PB, acidic NAC, and neutralized NAC against 34 K. pneumoniae strains were determined using the broth microdilution. Drug interactions were assessed by checkerboard assays and the fractional inhibitory concentration index (FICI), while biofilm inhibition was quantified using crystal violet staining. Polymyxin B resistance was identified in the reference multidrug-resistant strain K. pneumoniae ATCC BAA-1705. The PB-NAC combination showed an additive effect (FICI 0.53-0.63) against PB-resistant and PB-intermediately susceptible strains, whereas indifferent interactions were observed in PB-susceptible strains. Furthermore, sub-inhibitory concentrations of the combination produced significantly stronger biofilm inhibition than either agent alone. Neutralization of NAC markedly reduced its antibacterial and anti-biofilm activities, with substantial inhibition observed only at concentrations ≥ 32 mg/mL. These findings demonstrate that the combination of PB and acidic NAC exerts additive antibacterial effects, particularly against resistant K. pneumoniae strains, and enhances biofilm inhibition. Notably, the intrinsic acidity of NAC is essential for its antimicrobial and anti-biofilm activity.},
}

@article {pmid41752465,
year = {2026},
author = {Hu, C and Xu, P and Hu, J and Fang, B and Meng, J and Tang, Y},
title = {A Novel Pyrazole Pyrimidine Derivative MBP346 Induces Cell Death via ROS-Mediated Mitochondrial Damage in Human Head and Neck Squamous Cell Carcinoma.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {4},
pages = {},
pmid = {41752465},
issn = {1420-3049},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Pyrazoles/pharmacology/chemistry ; *Pyrimidines/pharmacology/chemistry ; Cell Line, Tumor ; *Mitochondria/drug effects/metabolism/pathology ; Cell Proliferation/drug effects ; *Squamous Cell Carcinoma of Head and Neck/metabolism/drug therapy/pathology ; *Head and Neck Neoplasms/metabolism/drug therapy/pathology ; Apoptosis/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Cell Survival/drug effects ; *Antineoplastic Agents/pharmacology/chemistry ; Cell Death/drug effects ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; },
abstract = {Background: Head and neck squamous cell carcinoma (HNSCC) represents almost 95% of head and neck cancer cases and ranks as the sixth most prevalent malignant tumor globally. Several treatment strategies, such as surgery, radiation, and chemotherapy, are implemented to boost the outcomes for patients with HNSCC. However, the overall survival rate for patients with HNSCC has remained poor. MBP346 is a novel pyrazole pyrimidine compound that is cytotoxic to HNSCC cells. Therefore, this study aims to investigate its effect on HNSCC and to explore its possible molecular mechanism. Methods: Cell viability of HNSCC (Cal33 and Scc15) cells and normal NOK cells treated with MBP346 was determined by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Colony formation assay and Edu assay were used to detect cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was used for detecting cell cycle-related and cell apoptotic-related proteins. Immunofluorescence assay was performed to analyze the effect of MBP346 on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Results: MBP346 significantly inhibited the proliferation of Cal33 and Scc15 cells, with half inhibitory concentrations of 1.56 ± 0.13 μmol·L[-1] and 4.41 ± 0.28 μmol·L[-1], respectively. The cell cycle-related proteins CyclinD1, CyclinA2, and CDK2 were downregulated, and P21 was upregulated in Cal33 and Scc15 cells treated with MBP346, which blocked the cell cycle in the S phase. MBP346 induced cell apoptosis in Cal33 and Scc15 cells by inducing ROS production. In addition, the elevated ROS decreased MMP to accelerate apoptosis. N-acetylcysteine (NAC), an ROS inhibitor, suppressed MBP346-induced cell apoptosis. Conclusions: MBP346 may serve as a therapeutic agent in HNSCC by inducing cell death. It achieves this by halting cell proliferation through cell cycle arrest and enhancing apoptosis due to increased ROS, which results in mitochondrial dysfunction.},
}

Humans
*Reactive Oxygen Species/metabolism
*Pyrazoles/pharmacology/chemistry
*Pyrimidines/pharmacology/chemistry
Cell Line, Tumor
*Mitochondria/drug effects/metabolism/pathology
Cell Proliferation/drug effects
*Squamous Cell Carcinoma of Head and Neck/metabolism/drug therapy/pathology
*Head and Neck Neoplasms/metabolism/drug therapy/pathology
Apoptosis/drug effects
Membrane Potential, Mitochondrial/drug effects
Cell Survival/drug effects
*Antineoplastic Agents/pharmacology/chemistry
Cell Death/drug effects
Cell Cycle/drug effects
Cell Cycle Checkpoints/drug effects

@article {pmid41750648,
year = {2026},
author = {Han, JS and Park, K and Kim, YL and Lim, JH and Park, SY and Park, SN},
title = {Evaluation of Intratympanic Alpha-Lipoic Acid and Diltiazem as Alternatives to Dexamethasone in Noise-Induced Hearing Loss in a Murine Model.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
pmid = {41750648},
issn = {2076-3921},
support = {RS-2022-NR075243 and RS-2024-00340841//National Research Foundation of Korea/ ; },
abstract = {This study evaluates the protective effects of alpha-lipoic acid (ALA), diltiazem (DIL), and N-acetylcysteine (NAC) as potential adjunctive agents to enhance intratympanic dexamethasone (IT-DEX) therapy in noise-induced hearing loss. A two-phase experiment using C57BL/6J mice was conducted. In phase 1, candidate drugs were screened by perilymph concentration analysis using ultra-high-performance liquid chromatography, auditory brainstem response (ABR) threshold, and organ of Corti (OC) morphology. Western blot analysis evaluated inflammatory markers. Phase 2 investigated the synergistic effects of co-administration of the most promising candidates with DEX. All drugs successfully penetrated the inner ear via IT injection. In the noise-induced hearing loss model, ALA and DIL individually demonstrated significant improvements in ABR thresholds and OC morphology compared to DEX alone, while NAC showed no therapeutic benefit. Western blot analysis revealed that ALA and DIL suppressed inflammatory markers through distinct antioxidant-mediated mechanisms, contrasting with DEX's anti-inflammatory pathway. However, combination therapy with DEX + ALA or DEX + DIL increased middle ear inflammation and failed to produce synergistic therapeutic effects. While ALA and DIL showed individual therapeutic promise through complementary mechanisms, combination with DEX did not enhance efficacy, suggesting that simple drug combinations may not translate to improved IT therapy outcomes.},
}

@article {pmid41750596,
year = {2026},
author = {Sun, M and Feng, Z and Wang, Z and Wu, R and Du, K and Zhu, J and Liu, K and Zhang, L and Zhang, M and Qiu, Z},
title = {BACH1-CHAC1-Glutathione Axis Aggravates Myocardial Ischemia-Reperfusion Injury by Enhancing Ferroptosis and Oxidative Stress.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
pmid = {41750596},
issn = {2076-3921},
support = {82370282//National Natural Science Foundation of China/ ; },
abstract = {Myocardial ischemia-reperfusion injury (MIRI) is a pathological process in which reperfusion-induced oxidative stress and metabolic derangement further aggravate myocardial damage and blunt the benefit of reperfusion. Ferroptosis is increasingly implicated in MIRI, with the glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis constituting a key antioxidant barrier. Although GSH depletion is recognized as a critical event, its upstream regulation in MIRI remains unclear. Against this background, we investigate the BACH1-CHAC1-GSH pathway as a putative upstream regulatory axis of ferroptosis in MIRI and a potential molecular target. Here, using an oxygen-glucose deprivation/reoxygenation (OGD/R) model in AC16 and the reversibility conferred by the ferrostatin-1, RNA sequencing identified the GSH-degrading enzyme CHAC1 as a modulator that is induced by stress and promotes ferroptosis. Experiments showed that CHAC1 overexpression aggravated OGD/R-induced injury, depleted GSH, suppressed GPX4 and enhanced lipid peroxidation, whereas CHAC1 knockdown was partially protective. N-acetylcysteine (NAC) replenished GSH, restored GPX4 activity and partially rescued CHAC1-driven injury. In a mouse myocardial I/R model, cardiotropic adeno-associated virus-mediated CHAC1 overexpression worsened cardiac dysfunction, enlarged infarct and fibrosis areas, and increased myocardial iron deposition. Dual-luciferase assays revealed that the transcription factor BACH1 activates the CHAC1 promoter, and BACH1 silencing attenuated ferroptosis by suppressing CHAC1 and restoring the GSH-GPX4 axis. Collectively, our data identify the BACH1-CHAC1-GSH axis as an upstream amplifier of ferroptosis in MIRI through glutathione depletion and impairment of GPX4-dependent antioxidant defense. These findings refine the mechanistic link between reperfusion-phase redox imbalance and ferroptosis and highlight BACH1/CHAC1 inhibition or augmentation of GSH precursors as potential cardioprotective strategies in ischemic heart disease.},
}

@article {pmid41749341,
year = {2026},
author = {Mudzengi, D and Mashatole, S and Xiang, Q and Adrion, C and Glover, N and Ngwanto, T and Mdluli, J and Boniface, S and Rassool, M and Matome, B and Paramo, L and Svensson, E and Fasanmi, A and Angelo, S and Moyo, M and Marx, C and Khosa, C and Mokaba, L and Mofokeng, N and Lalashowi, J and Nacy, C and Charalambous, S and Fumane, E and Maphossa, V and Beattie, T and Brumskine, W and Venter, C and Mapamba, D and Heinrich, N and Rajaram, S and Kooverjee, S and Botha, L and Nell, M and Easton, A and Foraida, S and Warren, RM and Sabi, I and Ntinginya, N and Wallis, RS and , },
title = {panTB-HM: a multi-arm clinical trial of a pan-TB regimen targeting both host and microbe.},
journal = {Trials},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13063-026-09568-9},
pmid = {41749341},
issn = {1745-6215},
support = {RIA2019AMR-2647//EDCTP/ ; },
abstract = {BACKGROUND: Newer oxazolidinones will be required to advance regimens in pan-TB indications. The addition of host-directed agents may help promote the recovery of lung function during TB treatment and prevent post-TB lung disease.

METHODS: The panTB-HM trial assesses the capacity of three novel regimens containing the oxazolidinone sutezolid and the antioxidant N-acetylcysteine (NAC) to meet the target criteria proposed by WHO for pan-TB indications (including use without rifamycin susceptibility testing and of 4 months or less duration) in a phase 2C trial.

DISCUSSION: This trial is ground-breaking in its objectives and design for a 4-month pan-TB indication (in a non-inferiority comparison to standard treatment) and its evaluation of lung function recovery (in a superiority comparison).

TRIAL REGISTRATION: ClinicalTrials.gov NCT05686356. Registered on 13 Jan 2023.},
}

@article {pmid41740408,
year = {2026},
author = {Wang, HZ and Xiong, YM and Song, SL and Zhao, QC and Chen, XY and Gao, JR and Li, YY and Qin, ZF},
title = {Low doses of chlorothalonil cause testicular impairment in mammals through the antimicrobial-like mechanism.},
journal = {Journal of hazardous materials},
volume = {506},
number = {},
pages = {141563},
doi = {10.1016/j.jhazmat.2026.141563},
pmid = {41740408},
issn = {1873-3336},
abstract = {Chlorothalonil is a widely used fungicide that exerts activity through interacting with glutathione (GSH) and thiol-containing proteins or other nucleophilic molecules due to its electrophilicity. However, it remains little known whether chlorothalonil exerts similar actions in mammals and causes male reproductive damage. Here, we detected reduced cell viability and glycolytic impairment coupled with the redox imbalance including ROS accumulation in GC-1 cells (testicular germ cell line) treated with chlorothalonil; however, the nucleophilic antioxidant N-acetylcysteine (NAC) rescued chlorothalonil-caused cell damage. In animal experiments, exposure to chlorothalonil (30, 300, and 3000 μg/kg/d) from gestational day 10 to postnatal day (PND) 10 caused slight effects on testicular development in suckling male mice. However, extended exposure to postnatal week (PNW) 15 resulted in testicular impairment in male offspring, including germ cell apoptosis, reduced sperm count, and increased sperm tail malformation, along with reduced GSH content and altered expression of redox-related genes, and certain significant alterations even occurred in the low-dose group. Furthermore, we also observed reduced motility and redox disturbance in mouse sperm in vitro, and NAC exerted significant rescue effects. Moreover, surface plasmon resonance (SPR) analysis revealed the binding of chlorothalonil to β-actin, a sensitive target of electrophilic substances. Taken together, all data indicate that low dose of chlorothalonil caused testicular impairment in mice possibly through interacting with nucleophilic molecules. This study challenges the acceptable daily intake (20 or 30 μg/kg/d) of chlorothalonil established previously, and calls for great attention on male reproductive hazards of more electrophilic pollutants.},
}

@article {pmid41737465,
year = {2026},
author = {Jiang, M and Lu, W and Zhuang, J and Song, J and Zhao, Y and Zhou, C and Zhou, Y and Shu, W and Zhu, Z and Jiang, L and Wu, P and Wu, A and Sheng, S and Zhu, S and Wang, Z},
title = {A bioinspired anisotropic anti-inflammatory scaffold enhances spinal nerve regeneration and neural circuit reconstruction via FGF13/Ca[2+]/CaMK2A/CREB pathway.},
journal = {Materials today. Bio},
volume = {37},
number = {},
pages = {102929},
pmid = {41737465},
issn = {2590-0064},
abstract = {Spinal cord injury (SCI) induces severe neurological impairment, exacerbated by secondary inflammation and disrupted neural circuitry. Inspired by the spinal cord's electromechanical microenvironment, we developed a biomimetic conductive nerve scaffold via directional freeze-casting of gelatin methacryloyl (GelMA) hydrogel incorporated with N-acetylcysteine-modified silver nanowires (NAC-AgNWs). The scaffold exhibits axially aligned microchannels, tunable mechanical strength, and conductivity akin to native spinal tissue. In a rat model of complete spinal cord transection (2 mm), the scaffold exhibited dual therapeutic effects: (1) early-stage anti-inflammatory modulation (mediated by the synergistic interplay between AgNWs and NAC), and (2) sustained neural reconstruction, evidenced by robust axonal bridging across the lesion, synapse reformation, and significant functional recovery. Integrated transcriptomic analyses revealed the FGF13/Ca[2+]/CaMK2A/CREB axis as the activated pathway driving neurite outgrowth and neural circuit reconstruction. This biomaterial design establishes a novel therapeutic paradigm for SCI repair, integrating structural guidance, immunomodulation, and activation of pro-regenerative signaling.},
}

@article {pmid41722831,
year = {2026},
author = {Perera, KDC and Vasta, AK and Menon, JU},
title = {Mucopenetrative Lipid-Polymer nanoparticles show Potent Anti-Inflammatory activity in a human Lung-on-Chip model.},
journal = {International journal of pharmaceutics},
volume = {693},
number = {},
pages = {126688},
doi = {10.1016/j.ijpharm.2026.126688},
pmid = {41722831},
issn = {1873-3476},
abstract = {Airway mucus presents a significant barrier to inhaled drug delivery, particularly for nanoparticle-based interventions, with this barrier exacerbated in chronic respiratory diseases (CRDs) due to hyperviscous secretions and persistent inflammation. In this study, a dual-functional lipid-polymer hybrid nanoparticle was developed to combine rapid mucolysis with sustained anti-inflammatory activity, and its performance was evaluated using both conventional in vitro assays and a physiologically relevant lung-on-a-chip model. Dipalmitoylphosphatidylcholine (DPPC)-coated PLGA nanoparticles (hydrodynamic diameter 378.1 ± 23.0 nm; 58-61 wt% lipid; ζ ≈ +3 mV) encapsulated N-acetylcysteine (NAC) within the lipid shell for rapid release and all-trans retinoic acid (ATRA) within the core for sustained delivery. NAC exhibited a burst release of 44.2-52.5% within 6 h and significantly reduced the viscosity of cystic fibrosis-mimetic mucus, enabling a 26.5-fold higher penetration across a ∼ 0.6 mm mucus plug compared to NAC-free controls. The formulation was well tolerated by pulmonary epithelial and fibroblast cells and demonstrated high cellular uptake driven by the DPPC coating. To assess efficacy under physiologically relevant airway conditions, a human lung-on-a-chip model incorporating air-liquid interface, flow, and cyclic stretch was employed. In this model, repeated dosing of NAC + ATRA nanoparticles resulted in a 2.6-fold reduction in IL-6 and a 2.3-fold reduction in IL-8 levels compared to diseased controls at 72 h, outperforming NAC-free nanoparticles at early timepoints and maintaining suppression over 9 days. These findings demonstrate the therapeutic promise of dual-functional mucopenetrative nanoparticles and establish the utility of lung disease-on-chip platforms for evaluating inhaled nanotherapeutics under physiologically relevant conditions.},
}

@article {pmid41720502,
year = {2026},
author = {Afşar, E and Öz, M and Eranıl, I},
title = {Hepato-Cardiac Axis in Epirubicin Toxicity: Role of Kynurenine Pathway and N-Acetylcysteine Antioxidant Intervention.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70118},
pmid = {41720502},
issn = {1099-1263},
abstract = {Epirubicin (EPI) is a widely used chemotherapeutic agent; however, its clinical utility is limited by severe side effects, particularly the production of reactive oxygen species (ROS). Among these, cardiotoxicity is one of the most critical issues, and it is worsened by impaired hepatic clearance resulting from liver dysfunction. This study aimed to investigate molecular changes induced by EPI in the liver within the kynurenine pathway (KP), their possible contribution to cardiotoxicity, and the protective effects of N-acetylcysteine (NAC). Rats received intraperitoneal injections of 50 or 300 mg/kg NAC, followed 1 h later by 9.6 mg/kg EPI. Tryptophan (Trp), kynurenine (Kyn), kynurenic acid (KYNA), quinolinic acid (QA), kynureninase, and kynurenine 3-monooxygenase (KMO) levels in the liver and cleaved caspase-3 levels in the liver and heart tissue were measured using ELISA. Hepatic and cardiac total antioxidant status (TAS) and total oxidant status (TOS) were determined using a colorimetric method. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), creatine kinase-MB isoenzyme (CK-MB), high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (T-chol), and triglyceride (TG) were analyzed with a clinical biochemistry analyzer. Cardiac morphology was examined using hematoxylin-eosin staining. EPI administration was associated with increases in plasma CK-MB, the AST/ALT ratio, LDL, T-chol, and TG, with these increases partially attenuated by NAC treatment. Hepatic levels of Trp, QA, and KMO were positively correlated with plasma CK-MB and the AST/ALT ratio. Additionally, EPI appeared to increase oxidative stress in heart tissue and induce morphological changes. At the same time, NAC treatment was associated with partial improvement in these parameters, suggesting that alterations in the hepatic KP may be linked to possible cardiac involvement. Our findings suggest that EPI-induced alterations in hepatic KP may impair hepatic clearance, and NAC administration may provide partial protection, warranting further investigation of a possible hepato-cardiac interaction.},
}

@article {pmid41713986,
year = {2026},
author = {Li, S and Xia, L and Wang, S and Ju, R and Han, Z and Lv, X and Han, B and Chi, J},
title = {N-acetylcysteine-functionalized biodegradable polysaccharide hydrogel patches for the repair of acute liver injury.},
journal = {Carbohydrate polymers},
volume = {379},
number = {},
pages = {124983},
doi = {10.1016/j.carbpol.2026.124983},
pmid = {41713986},
issn = {1879-1344},
mesh = {Animals ; *Hydrogels/chemistry/pharmacology ; *Acetylcysteine/chemistry/pharmacology ; Mice ; Humans ; Acetaminophen ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology/metabolism ; Male ; Human Umbilical Vein Endothelial Cells/drug effects ; Liver/drug effects/pathology ; Cell Proliferation/drug effects ; Hepatocytes/drug effects ; Chondroitin Sulfates/chemistry ; Apoptosis/drug effects ; Mice, Inbred C57BL ; Biocompatible Materials/chemistry/pharmacology ; *Polysaccharides/chemistry ; },
abstract = {Acute liver injury (ALI) caused by acetaminophen (APAP) has a high incidence rate worldwide, and severe cases may cause liver failure or even death. N-acetylcysteine (NAC), as an effective treatment drug approved for clinical application in ALI, has limitations such as a short half-life and the requirement for high-dose injections. Consequently, it is imperative to optimize new administration method of NAC and promote alternative therapeutic strategies for ALI. Herein, hydrogel patches ONC composed of oxidized chondroitin sulfate (OCS) and NAC-grafted CMCS were developed, and their reparative effects on APAP-induced ALI were investigated. ONC hydrogels exhibited excellent biocompatibility and appropriate biodegradability, and favorable hemostatic effects in the liver. In vitro experiments demonstrated that ONC could promote the proliferation and migration of hepatocytes, as well as the angiogenesis of HUVECs. By establishing an APAP-induced ALI model in mice, liver enzymes after ONC hydrogel patches treatment recovered to near-normal levels. Moreover, histological examination, RT-qPCR, and transcriptome sequencing results demonstrated that ONC patches could reduce the expression of inflammatory factors and apoptosis in the liver, while simultaneously activating antioxidant-related signaling pathways, thereby promoting the regeneration and functional repair of damaged tissues. Therefore, ONC hydrogel patches may be a promising alternative strategy for treating ALI.},
}

Animals
*Hydrogels/chemistry/pharmacology
*Acetylcysteine/chemistry/pharmacology
Mice
Humans
Acetaminophen
*Chemical and Drug Induced Liver Injury/drug therapy/pathology/metabolism
Male
Human Umbilical Vein Endothelial Cells/drug effects
Liver/drug effects/pathology
Cell Proliferation/drug effects
Hepatocytes/drug effects
Chondroitin Sulfates/chemistry
Apoptosis/drug effects
Mice, Inbred C57BL
Biocompatible Materials/chemistry/pharmacology
*Polysaccharides/chemistry

@article {pmid41708253,
year = {2026},
author = {Wang, P and Zhong, Y and Liu, J and Gao, L and Long, T and Li, Z},
title = {Dietary titanium dioxide particles (E171) promote colitis-associated colorectal cancer development in mice through macrophage-derived S100A8/S100A9secretion mediated by NLRP3/Caspase 1/GSDMD pathway.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {2},
pages = {215-226},
doi = {10.1016/S1875-5364(26)61092-8},
pmid = {41708253},
issn = {1875-5364},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Calgranulin A/metabolism/genetics ; Mice ; *Titanium/adverse effects/administration & dosage ; *Calgranulin B/metabolism/genetics ; *Macrophages/metabolism/drug effects ; *Caspase 1/metabolism/genetics ; Mice, Inbred C57BL ; RAW 264.7 Cells ; Male ; *Colitis-Associated Neoplasms/chemically induced/genetics/metabolism ; Humans ; Signal Transduction/drug effects ; *Colorectal Neoplasms/genetics/etiology/chemically induced/metabolism ; },
abstract = {Colitis-associated colorectal cancer (CAC) is a major contributor to cancer-related mortality worldwide. Titanium dioxide (TiO2, E171), a widely used food additive, has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development. In this study, CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo, while lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro. We found that dietary E171 intake accelerated CAC development, exacerbated inflammatory responses and oxidative stress, and upregulated CAC-associated genes, including S100a8, S100a9, Lcn2, S100a11, Cxcl2, and interleukin-1α (Il-1α). E171 also increased the expression of S100A8, S100A9, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and gasdermin-D N-terminal (GSDMD-N) in macrophages within colon tumors. In inflammatory macrophages, E171 exposure enhanced cell viability, increased reactive oxygen species (ROS) levels, and elevated the expression and secretion of S100A8 and S100A9, consistent with in vivo histological observations. Furthermore, E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors, including N-acetylcysteine (NAC, ROS inhibitor), MCC950 (NLRP3 inhibitor), Z-YVAD-FMK (caspase 1 inhibitor), disulfiram (GSDMD inhibitor), and transfection of NLRP3 small interfering ribonucleic acid (siRNA). These results indicate that dietary E171 promotes CAC development by activating macrophages, with S100A8 and S100A9 serving as key mediators, and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
*Calgranulin A/metabolism/genetics
Mice
*Titanium/adverse effects/administration & dosage
*Calgranulin B/metabolism/genetics
*Macrophages/metabolism/drug effects
*Caspase 1/metabolism/genetics
Mice, Inbred C57BL
RAW 264.7 Cells
Male
*Colitis-Associated Neoplasms/chemically induced/genetics/metabolism
Humans
Signal Transduction/drug effects
*Colorectal Neoplasms/genetics/etiology/chemically induced/metabolism

@article {pmid41704764,
year = {2026},
author = {Huang, X and Meng, Y and Song, J and Zhu, Y and Li, J and Xi, Y and Peng, X and Xiong, Y},
title = {KNSTRN knockdown impairs autophagy flux to inhibit bladder cancer progression.},
journal = {iScience},
volume = {29},
number = {2},
pages = {114734},
pmid = {41704764},
issn = {2589-0042},
abstract = {Bladder cancer (BLCA) is a common malignant tumor of the urinary system. Kinetochore-localized astrin-binding protein (KNSTRN) has been implicated in the initiation and progression of multiple cancers. Furthermore, abnormal autophagy levels have been shown to significantly impact tumor development. However, the mechanism by which KNSTRN regulates autophagy in BLCA remains unclear. This study reveals that KNSTRN knockdown inhibits autophagy flux in BLCA. The mechanism involves ROS-dependent disruption of lysosomal function upon KNSTRN knockdown, thereby impeding autophagosome-lysosome fusion. Clioquinol restores lysosomal activity by regulating lysosomal pH, subsequently reestablishing autophagy flux. The ROS scavenger N-acetylcysteine (NAC) reverses lysosomal dysfunction and reactivates the autophagic flux. Furthermore, the autophagy activator rapamycin (Rapa) effectively counteracts KNSTRN knockdown-induced cell death in both in vitro and in vivo experiments. Collectively, we demonstrate that KNSTRN knockdown induces intracellular ROS accumulation and lysosomal dysfunction, thereby disrupting autophagic flux and inhibiting BLCA progression.},
}

@article {pmid41701447,
year = {2026},
author = {Sabry, S and Ammar, MK and Taeima, M and Nassar, N and ElFiky, A and Saleh, A},
title = {Preventing Contrast-Induced Acute Kidney Injury in Egyptian Patients Undergoing Coronary Angiography: A Randomized Controlled Trial.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {41701447},
issn = {1179-1918},
abstract = {BACKGROUND AND OBJECTIVES: Contrast-induced acute kidney injury (CI-AKI) observed after coronary angiography (CAG) requires preventive strategies guided by clinical judgment. Evidence is still lacking regarding the prevention of CI-AKI in patients undergoing coronary angiography. This study aimed to compare the effect of a high dose of N-acetylcysteine (NAC) plus preprocedural hydration, a high dose of atorvastatin (HDS) plus preprocedural hydration, or preprocedural hydration alone on the prevention of CI-AKI in patients undergoing elective coronary angiography.

METHODS: A prospective multi-armed randomized comparative study was conducted on elective patients undergoing CAG. Patients were randomly assigned to either control group [n = 40], who received hydration with 0.9% saline started just before contrast media injection and continued for 12 h at a rate 1.0 mL/kg/min after angiography; NAC group [n = 40], who received oral NAC 1200 mg daily started 5 days before angiography and good hydration; or HDS group [n = 40], receiving one oral dose of atorvastatin 80 mg 24 h before angiography and good hydration. CI-AKI was defined as an increase in serum creatinine of > 25% of baseline or an absolute increase of 0.5 mg/dL above baseline after 48 h. Incidence of CI-AKI and incidence of complications were assessed for all groups.

RESULTS: The study included 120 patients. The incidence of CI-AKI was [32.5%] in the control group, [20%] in the NAC group, and [12.5%] in the HDS group. The incidence of CI-AKI was significantly lower in the high-dose statin group compared with the control group (risk ratio = 1.658; 95% CI 1.050-2.433). In-hospital clinical outcomes showed no statistical significance among the three groups.

CONCLUSIONS: Both NAC and high-dose statins may reduce CI-AKI incidence in patients undergoing CAG, with statins showing more promising results. These findings support prophylactic strategies for CI-AKI prevention in high-risk patients undergoing CAG. In-hospital outcomes were comparable.

CLINICAL TRIAL REGISTRATION: Clinical-Trials.gov (ID; NCT06139952, Date; December 2023).},
}

@article {pmid41700562,
year = {2026},
author = {Gregory, E and Wilkinson, EP and Leyngold, I},
title = {N-acetylcysteine and Vitamin C oral antioxidant therapy for teprotumumab-related hearing dysfunction: case series and review of literature.},
journal = {Orbit (Amsterdam, Netherlands)},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/01676830.2025.2608253},
pmid = {41700562},
issn = {1744-5108},
abstract = {We report three cases of successful treatment of teprotumumab-related hearing dysfunction with N-acetylcysteine (NAC) and ascorbic acid (Vitamin C). To investigate NACs effectiveness in the treatment of other types of auditory symptoms through a review of available literature. Three patients with thyroid eye disease (TED) developed symptoms of ear fullness and hearing loss during infusions of teprotumumab. Audiogram revealed above-normal pure tone average hearing threshold frequencies. They were treated with once-daily oral administration of 600 mg N-acetyl cysteine and 500 mg ascorbic acid (Vitamin C). All patients experienced nearly complete resolution of their ear symptoms prior to completing their teprotumumab therapy. They continued to remain symptom-free throughout the remaining teprotumumab infusions and onwards. This study showcases that antioxidant therapy with N-acetylcysteine and Vitamin C appears to be a promising, safe, and inexpensive potential treatment option for teprotumumab-related hearing dysfunction in our patient group.},
}

@article {pmid41686281,
year = {2026},
author = {Moon, UY and Kim, YE and Nguyen, HD and Choi, HJ},
title = {CREB2 Functions as a Central Mediator of Oxidative Neuronal Death Triggered by Microglial Glutamate Release Under Neuroinflammatory Conditions.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01695-w},
pmid = {41686281},
issn = {1573-6830},
support = {2710086662/RS-2025-02213662//Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare/ ; RS-2023-00246655 and RS-2024-00356135//National Research Foundation of Korea/ ; },
abstract = {Glutamate-induced oxidative cytotoxicity is a major driver of neuronal loss in neurodegenerative diseases, yet the upstream transcriptional regulators linking oxidative stress to neuronal death remain unclear despite the known involvement of the p53-GADD45α pathway. CREB2 (ATF4) is a stress-responsive transcription factor, but its role in microglia-mediated oxidative neurotoxicity has not been fully defined. Here, we investigated CREB2 function in oxidative glutamate toxicity using HT22 hippocampal neurons, primary mouse hippocampal cells, and a kainic acid (KA)-injected rat model. Oxidative stress was induced by glutamate, intracellular ROS levels were quantified with DCFDA, and the antioxidant N-acetylcysteine (NAC) was used to confirm oxidative dependency. Microglia-derived glutamate was assessed by stimulating BV2 cells with lipopolysaccharide (LPS) and applying glutamate-containing conditioned medium (LPS-CM) to HT22 cells. Exogenous glutamate robustly increased CREB2 expression in HT22 and primary neurons, accompanied by ROS accumulation and cell death, whereas NAC suppressed these effects. Inhibition of p53 by siRNA or pifithrin-α (PFT-α) attenuated glutamate-induced CREB2 upregulation, and CREB2 knockdown blocked GADD45α induction and protected neurons. In Vivo, KA injection caused robust CREB2 upregulation in the damaged CA3 region. Importantly, conditioned medium from LPS-activated BV2 microglia increased CREB2 expression and ROS levels in HT22 cells in an NAC-sensitive manner, supporting a glutamate-associated oxidative mechanism rather than receptor-mediated excitotoxicity. Collectively, these results suggest that CREB2 functions between upstream p53 signaling and downstream GADD45α activation as a redox-sensitive mediator of oxidative neuronal death, and may represent a potential therapeutic target in neurodegenerative diseases associated with oxidative stress and neuroinflammation.},
}

@article {pmid41683511,
year = {2026},
author = {Hikisz, P and Adamus-Grabicka, AA and Budzisz, E},
title = {Multifaceted Anticancer Activity of Flavanone/Chromanone Intermediates for Five-Membered Heterocyclic Derivatives: Targeting Oxidative Stress, Apoptosis, and MAPK Signaling in Colorectal Cancer.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {3},
pages = {},
pmid = {41683511},
issn = {1420-3049},
support = {503/3-066-02/503-31-001//Medical University of Lodz/ ; 2024/08/X/NZ7/01232//National Science Center/ ; 2023/07/X/NZ3/01404//National Science Center/ ; },
mesh = {Humans ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; *Flavanones/pharmacology/chemistry ; *Colorectal Neoplasms/metabolism/drug therapy/pathology ; *Antineoplastic Agents/pharmacology/chemistry ; Cell Line, Tumor ; *MAP Kinase Signaling System/drug effects ; Reactive Oxygen Species/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; *Heterocyclic Compounds/pharmacology/chemistry ; },
abstract = {This study explores the multifaceted anticancer mechanisms of flavanone analogues and spiropyrazoline condensed with flavanone ring against colorectal cancer (CRC) cell lines. Five-membered heteroaromatic scaffolds, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. Building upon previous findings, we investigated three lead derivatives (1, 3, and 5) with potent antiproliferative activity (IC50 < 35 μM). The compounds induced pronounced oxidative stress, evidenced by increased lipid peroxidation and reduced membrane fluidity, primarily within the hydrophobic layers of cell membranes. Preincubation with the antioxidant N-acetylcysteine (NAC) significantly attenuated these effects, confirming the pivotal role of reactive oxygen species (ROS) in their cytotoxicity. Mechanistic studies revealed that the derivatives triggered intrinsic apoptosis, characterized by the cleavage of PARP and the activation of caspase-9 and caspase-3. Furthermore, the compounds modulated key signaling pathways involved in cell survival and proliferation. Specifically, they inhibited the pro-oncogenic ERK1/2 MAPK pathway while inducing cell line-dependent alterations in p38 and JNK activity. Concurrently, all derivatives reduced the level of the transcription factor Nrf2, a master regulator of antioxidant defense and a mediator of chemoresistance in CRC. Collectively, these findings indicate that flavanone/chromanone derivatives exert their anticancer activity through a synergistic mechanism involving ROS generation, disruption of redox homeostasis, inhibition of Nrf2 signaling, and modulation of MAPK-dependent apoptotic pathways. These results highlight the therapeutic potential of flavanone-based compounds and their spiropyrazoline analogues as multifunctional anticancer agents targeting oxidative stress and survival signaling in colorectal cancer.},
}

Humans
*Apoptosis/drug effects
*Oxidative Stress/drug effects
*Flavanones/pharmacology/chemistry
*Colorectal Neoplasms/metabolism/drug therapy/pathology
*Antineoplastic Agents/pharmacology/chemistry
Cell Line, Tumor
*MAP Kinase Signaling System/drug effects
Reactive Oxygen Species/metabolism
Cell Proliferation/drug effects
Cell Survival/drug effects
*Heterocyclic Compounds/pharmacology/chemistry

@article {pmid41681844,
year = {2026},
author = {Rodriguez, V and Villani, A and Sénica, M and Panebianco, C and Pazienza, V and Preto, A},
title = {Harnessing Postbiotics to Boost Chemotherapy: N-Acetylcysteine and Tetrahydro β-Carboline Carboxylic Acid as Potentiators in Pancreatic and Colorectal Cancer.},
journal = {Cancers},
volume = {18},
number = {3},
pages = {},
pmid = {41681844},
issn = {2072-6694},
support = {ID. 23006 project//Associazione Italiana Ricerca sul Cancro (AIRC) under IG 2019/ ; UIDB/04050/2020//Fundação para a Ciência e Tecnologia/ ; UID/04050//Centro de Biologia Molecular e Ambiental/ ; },
abstract = {BACKGROUND: Pancreatic cancer (PC) and colorectal cancer (CRC) are among the most lethal malignancies, with growing evidence pointing to the gut microbiota's role in their progression. This study aimed to explore the anticancer potential of two microbiota-derived postbiotics, N-acetylcysteine (NAC) and tetrahydro β-carboline carboxylic acid (THC), in targeting some hallmark traits of PC and CRC, both as standalone agents and in combination with standard chemotherapeutics (gemcitabine for PC and 5-fluorouracil (5-FU) for CRC).

METHODS: Cell viability assays and IC50 determination was assessed using either the Muse™ Count & Viability Kit or the Sulforhodamine B assay; cell death was determined by Annexin V/Propidium Iodide and cell cycle assessed by Propidium Iodide was analyzed by flow cytometry.

RESULTS: Here, we found that NAC selectively reduced the viability of PC cells BxPC-3 without triggering apoptosis, while effectively inducing apoptosis in PC cells Panc-1 and in CRC cell lines. THC exhibited stronger anticancer activity, inhibiting proliferation and promoting apoptosis in all tested PC and CRC cells, even at lower concentrations. Combination treatments yielded promising enhancement effects. NAC enhanced the cytotoxicity of gemcitabine in Panc-1 cells through increased apoptosis. NAC, when combined with 5-FU, also increased apoptosis of CRC cells. THC further potentiated gemcitabine's impact on Panc-1 cells by increasing apoptosis and by inducing cell cycle changes in BxPC-3. In the CRC model, THC co-treatment with 5-FU reduced cell viability and increased apoptosis in all cells.

CONCLUSIONS: These findings provide preliminary in vitro evidence supporting the potential of integrating microbiota-derived postbiotics with conventional chemotherapy both in PC and CRC.},
}

@article {pmid41678124,
year = {2026},
author = {Batsaikhan, T and Lee, HS and Yang, H and Ferdushi, R and Key, J and Seo, YJ},
title = {Therapeutic Effects of N-Acetylcysteine-Primed, Iron Oxide Nanoparticle-Enhanced Mesenchymal Stem Cell Exosomes in Ototoxicity Hearing Loss.},
journal = {Tissue engineering and regenerative medicine},
volume = {},
number = {},
pages = {},
pmid = {41678124},
issn = {2212-5469},
abstract = {BACKGROUND: Sensorineural hearing loss caused by ototoxic agents remains irreversible due to the limited regenerative capacity of cochlear hair cells. Exosome-based therapies derived from mesenchymal stem cells (MSCs) offer a promising, cell-free alternative to protect auditory structures by modulating oxidative stress and inflammation. In this study, we evaluated the therapeutic potential of exosomes isolated from nanoparticle (NP) labeled, N-acetylcysteine primed tonsil-derived mesenchymal stem cells (T-MSCs), hereafter referred to as SPISOME-NAC, in kanamycin-induced ototoxicity models.

METHODS: T-MSCs were labeled with positively charged PLGA-PEI clustered SPIONs, with or without NAC pretreatment. Antioxidant enzyme activity (SOD, CAT, GSH), ROS levels, and PRDX1 expression were assessed in vitro. Exosomes were isolated and analyzed via nanoparticle tracking analysis. Their therapeutic efficacy was evaluated in both ex vivo cochlear explants and mouse model of kanamycin-induced ototoxicity. Hair cell survival was quantified via Myosin VIIa immunostaining, and auditory function was assessed using auditory brainstem responses (ABR). Pro-inflammatory cytokines (TNF-α, IL-1, IL-6) were measured via qRT-PCR.

RESULTS: NAC pretreatment significantly enhanced cell viability, increased GSH activity, and reduced intracellular ROS and PRDX1 levels in NP-labeled T-MSCs. Exosomes derived from NAC-pretreated cells (SPISOME-NAC) conferred superior protection to cochlear hair cells, particularly in the basal turn, and significantly improved hearing thresholds in vivo. Furthermore, SPISOME-NAC treatment downregulated inflammatory cytokines in cochlear tissue.

CONCLUSION: SPISOME-NAC exhibit enhanced antioxidant and anti-inflammatory properties, providing functional protection in an ototoxicity-induced hearing loss model. By preventing ROS-mediated mitochondrial damage and apoptosis in cochlear hair cells, NAC interrupts a key pathogenic mechanism in ototoxicity, preserving auditory structure and function. These findings support NAC-primed exosomes as a novel therapeutic strategy for sensorineural hearing loss.},
}

@article {pmid41677644,
year = {2026},
author = {Khamineh, Y and Panahi-Alanagh, S and Zolghadri, S and Mavaddatiyan, L and Ryszkiel, I and Stanek, A and Talkhabi, M},
title = {Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
pmid = {41677644},
issn = {2073-4409},
mesh = {Humans ; Female ; *Acetylcysteine/pharmacology ; *Ovarian Neoplasms/pathology/genetics/drug therapy ; *Ketoglutaric Acids/pharmacology ; Cell Line, Tumor ; *Computational Biology/methods ; Apoptosis/drug effects ; Cell Movement/drug effects ; Cell Survival/drug effects ; Cell Proliferation/drug effects ; Protein Interaction Maps/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; },
abstract = {Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; however, their combined effects in ovarian cancer are not well characterized. In this study, we applied an integrative approach combining network pharmacology analysis with in vitro experiments to investigate the effects of NAC and AKG on OVCAR3 ovarian cancer cells. Common molecular targets of NAC and AKG were identified by intersecting predicted compound targets with ovarian cancer-associated genes, followed by protein-protein interaction network construction and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Experimental validation assessed the effects of NAC and AKG, alone and in combination, on cell viability, apoptosis, migration, and clonogenic capacity. Network analysis identified 70 shared target genes enriched in pathways related to apoptosis, cellular stress responses, and cell migration. In vitro experiments demonstrated that combined treatment with NAC (10 mM) and AKG (100 µM) significantly reduced cell viability, increased apoptotic cell death, and markedly suppressed cell migration and colony formation compared with single-agent treatments. Overall, these findings indicate that the combination of NAC and AKG exerts enhanced inhibitory effects on ovarian cancer cell growth and motility in vitro.},
}

Humans
Female
*Acetylcysteine/pharmacology
*Ovarian Neoplasms/pathology/genetics/drug therapy
*Ketoglutaric Acids/pharmacology
Cell Line, Tumor
*Computational Biology/methods
Apoptosis/drug effects
Cell Movement/drug effects
Cell Survival/drug effects
Cell Proliferation/drug effects
Protein Interaction Maps/drug effects
Gene Expression Regulation, Neoplastic/drug effects

@article {pmid41677304,
year = {2026},
author = {Higazy, D and Vergauwe, F and Coenye, T and Ciofu, O},
title = {Evolutionary adaptations of Pseudomonas aeruginosa biofilms to ciprofloxacin and antioxidant co-treatment in synthetic sputum medium.},
journal = {Microbiology spectrum},
volume = {14},
number = {3},
pages = {e0314925},
pmid = {41677304},
issn = {2165-0497},
support = {//Egyptian Ministry of Higher Education/ ; BOF20/GOA/002//Ghent University Special Research Fund/ ; },
mesh = {*Ciprofloxacin/pharmacology ; *Biofilms/drug effects/growth & development ; *Pseudomonas aeruginosa/drug effects/genetics/physiology ; *Antioxidants/pharmacology ; *Sputum/microbiology ; *Anti-Bacterial Agents/pharmacology ; Microbial Sensitivity Tests ; Humans ; Cystic Fibrosis/microbiology ; Pseudomonas Infections/microbiology ; Drug Resistance, Bacterial/drug effects/genetics ; Bacterial Proteins/genetics ; Culture Media/chemistry ; Mutation ; Acetylcysteine/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {UNLABELLED: Antimicrobial resistance (AMR) is a growing public health concern, particularly in biofilm-related infections, where microbial aggregates display high levels of tolerance. Oxidative stress has been hypothesized to accelerate the development of resistance, whereas antioxidants (AOs) may mitigate this process. In this study, we investigated the impact of AOs on the evolution of ciprofloxacin (CIP) resistance in Pseudomonas aeruginosa PAO1 using synthetic cystic fibrosis sputum medium (SCFM2), which mimics the physiochemical conditions of cystic fibrosis (CF) respiratory infections. Experimental evolution was performed over six passages with CIP alone or in combination with edaravone (ED), N-acetyl-cysteine (NAC), or thiourea (THU). Population analysis profiles and minimum inhibitory concentration (MIC) assays demonstrated that CIP treatment produced high-level resistance (MIC 8-32 mg/L), whereas CIP + AO treatments markedly suppressed resistance development (MIC 0.75-2 mg/L). Whole-genome sequencing revealed distinct mutational patterns. CIP-treated isolates carried mutations in mexR and nalC (efflux pump regulators), and gyrA (fluoroquinolone target), consistent with elevated resistance, along with additional mutations in rocR and dnaX. In contrast, evolved isolates in the presence of CIP + AO harbored nfxB mutations associated with lower resistance, while CIP + ED uniquely produced a mutation in parS. These findings support the role of reactive oxygen species (ROS) in driving resistance evolution under CF-like conditions and suggest that antioxidants can suppress this process, providing a potential strategy for limiting antimicrobial resistance in biofilm-associated infections.

IMPORTANCE: Fighting antimicrobial resistance (AMR) is one of the greatest health challenges of our time. To find new ways to stop it, we need to better understand how resistance develops. Our study suggests that antioxidants may help slow down the process that allows bacteria to become resistant. We also show that resistance develops more quickly, and in a different way, when bacteria grow in conditions that resemble the human body rather than in standard laboratory media. In particular, the synthetic sputum medium promoted the formation of aggregated biofilms-sticky communities of cells that often occur in chronic and hard-to-treat infections.},
}

*Ciprofloxacin/pharmacology
*Biofilms/drug effects/growth & development
*Pseudomonas aeruginosa/drug effects/genetics/physiology
*Antioxidants/pharmacology
*Sputum/microbiology
*Anti-Bacterial Agents/pharmacology
Microbial Sensitivity Tests
Humans
Cystic Fibrosis/microbiology
Pseudomonas Infections/microbiology
Drug Resistance, Bacterial/drug effects/genetics
Bacterial Proteins/genetics
Culture Media/chemistry
Mutation
Acetylcysteine/pharmacology
Oxidative Stress/drug effects

@article {pmid41666086,
year = {2026},
author = {Babayigit, Z and Yiğider, AP and Yiğit, O and Algün Gedik, A and Dumur, S and Uzun, H},
title = {Effect of intratympanic N-acetylcystein (NAC) on vestibulotoxicity model formed with intratympanic gentamicin in Guinea pigs.},
journal = {Acta oto-laryngologica},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/00016489.2025.2600090},
pmid = {41666086},
issn = {1651-2251},
abstract = {BACKGROUND: N-acetylcysteine (NAC) can protect against this damage.

AIM: To evaluate the effect of intratympanic NAC on the vestibulotoxicity model formed with intratympanic gentamicine in guinea pigs.

DESIGN: Experimental Animal Study.

METHODS: Guinea pigs were randomly divided into three groups. Group1 (control), group2 was treated with intratympanic(IT) gentamicin and group3 was treated with IT gentamicin + NAC. A single dose of NAC was applied on the 1st,3rd, and5th days. Cervical-vestibular evoked myogenic potentials (c-VEMP) measurements and blood samples were taken from the guinea pigs on the day 0,10,30.

RESULTS: In group2 on day 10 c-VEMP latency was prolonged and on day 30 c-VEMP responses were lost in half of animals. A partial loss of c-VEMP values was observed in the group3. Serum total antioxidant capacity (TAC) and superoxide dismutase (SOD) activity in group3 (on the 7th and 30th day) were significantly higher than those in the group2. Tissue SOD and glutathione (GSH) were lower, while the malondialdehyde (MDA) and lipid hydroperoxide (LOOH) were the higher in group2.

CONCLUSION: Gentamicin induced loss in c-VEMP responses and NAC played an effective role in reducing this loss which were confirmed by oxidative capacity at tissue and serum level.},
}

@article {pmid41663453,
year = {2026},
author = {Heshmati, ZS and Amiri-Yekta, A and Khosravifar, M and Akbarian, F and Moini, A and Eftekhari-Yazdi, P and Hafezi, M and Afsharian, P},
title = {Administration of N-acetylcysteine influence the expression of apoptotic genes in the granulosa cells of infertile women diagnosed with endometriosis.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41663453},
issn = {2045-2322},
support = {401000042//Royan Institute for Reproductive Biomedicine, ACECR, Iran/ ; 2447/1400/D//Royan Lotus Charity Foundation, Iran/ ; },
mesh = {Humans ; Female ; *Acetylcysteine/administration & dosage/pharmacology ; *Endometriosis/complications/drug therapy/genetics ; *Granulosa Cells/metabolism/drug effects ; Adult ; *Apoptosis/drug effects/genetics ; *Infertility, Female/drug therapy/genetics/etiology ; Superoxide Dismutase/blood ; Antioxidants ; Caspase 3/genetics/metabolism ; Oxidative Stress/drug effects ; Gene Expression Regulation/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; },
abstract = {Endometriosis is a chronic, multifactorial disorder. Reactive oxygen species (ROS) and oxidative stress (OS) contribute to the development of endometriosis by affecting apoptosis-related genes in granulosa cells. N-acetylcysteine (NAC) is an antioxidant that reduces OS. This randomized controlled trial aimed to investigate the effects of NAC on serum levels of superoxide dismutase (SOD) and total antioxidant capacity (TAC), as well as the expression of apoptotic genes in granulosa cells. Infertile women with endometriosis were enrolled and administered either NAC (1200 mg/day; n = 11) or placebo (n = 14). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum SOD and TAC levels. The expression of Bcl-2, Bax, and Caspase-3 genes in granulosa cells was evaluated by Real-Time Polymerase Chain Reaction. NAC treatment increased serum SOD and TAC levels. Additionally, the expression of pro-apoptotic genes Bax and Caspase-3 in granulosa cells decreased compared to the placebo group, while the expression of the anti-apoptotic gene Bcl-2 increased. We conclude that administration of N-acetylcysteine (NAC) can reduce apoptosis in granulosa cells of women with infertility due to endometriosis.},
}

Humans
Female
*Acetylcysteine/administration & dosage/pharmacology
*Endometriosis/complications/drug therapy/genetics
*Granulosa Cells/metabolism/drug effects
Adult
*Apoptosis/drug effects/genetics
*Infertility, Female/drug therapy/genetics/etiology
Superoxide Dismutase/blood
Antioxidants
Caspase 3/genetics/metabolism
Oxidative Stress/drug effects
Gene Expression Regulation/drug effects
Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
bcl-2-Associated X Protein/genetics/metabolism

@article {pmid41659018,
year = {2025},
author = {Spurrier-Best, L and Butcher, D and Blackham-Hayward, E and Kertesz, Z and Chichger, H},
title = {Nicotine-free electronic vape fluid stimulates angiogenic processes in vitro through ARF6-mediated oxidative stress.},
journal = {Frontiers in toxicology},
volume = {7},
number = {},
pages = {1699112},
pmid = {41659018},
issn = {2673-3080},
abstract = {INTRODUCTION: The increase in e-cigarette use in the population has led to substantial interest in the health impacts associated with e-cigarette smoking. E-cigarette smoking represents a key external environmental cell stressor. Whilst there have been several studies to investigate the effect of nicotine-containing e-cigarette fluid, there is still a significant lack of understanding of how nicotine-free e-cigarette smoking can impact individuals. However, preliminary studies indicate that nicotine-free e-cigarette smoking can cause impaired endothelial function in humans.

MATERIALS AND METHODS: In the present study, we therefore used a common brand of nicotine-free e-cigarette and human umbilical vein endothelial cells to assess angiogenic processes in vitro.

RESULTS: We observed a significant upregulation in endothelial cell adhesion, migration and new tube formation with exposure to nicotine-free e-cigarette condensate (eVape) which was abrogated with exposure to the antioxidant, N-acetyl cysteine. Proteome analysis demonstrated that eVape exposure increased expression of the pro-angiogenic factors, angiogpoeitin-2, endoglin (CD105), PIGF and VEGF, as well as the ADP ribosylation factor, ARF6, and ARF6-GEF, ARNO. Chemical inhibition of ARNO reduced eVape-induced oxidative stress, angiogenic processes, and release of angiogpoeitin-2, endoglin (CD105) and VEGF.

DISCUSSION: These findings demonstrate that nicotine-free eVape causes aberrant upregulated angiogenesis in an in vitro model of the human endothelium through ARNO-dependent signalling. This study is the first to demonstrate the molecular mechanisms in response to the cellular stressor, nicotine-free eVape which underlie impaired vascular function.},
}

@article {pmid41657721,
year = {2026},
author = {Peerapen, P and Putpeerawit, P and Boonmark, W and Thongboonkerd, V},
title = {Systematic evaluation and comparison of the in vitro inhibitory activities of dietary supplements against calcium oxalate crystal formation, growth and aggregation: Implications for kidney stone prevention.},
journal = {Current research in food science},
volume = {12},
number = {},
pages = {101326},
pmid = {41657721},
issn = {2665-9271},
abstract = {Kidney stone disease (KSD), particularly calcium oxalate (CaOx) type, remains a global health problem. Many efforts have been made to prevent KSD, including the use of some dietary supplements. However, mechanisms underlying their anti-KSD properties have remained poorly understood, and their relative anti-KSD properties have previously been unknown. Herein, we systematically evaluated and compared the inhibitory effects of five well-known dietary supplements on CaOx crystals. Caffeine (CAF), epigallocatechin-3-gallate (EGCG), N-acetylcysteine (NAC), resveratrol (RES) and trigonelline (TRIG) (at 1, 10 and 100 μM, which are within their physiologic levels in the urine) were subjected to CaOx crystallization, growth and aggregation assays. Degrees of their CaOx crystal-inhibitory activities were then compared. CAF inhibited crystal formation, EGCG inhibited crystal formation and growth, NAC inhibited crystal aggregation, RES inhibited crystal growth, and TRIG inhibited crystal formation and growth. However, RES promoted crystal aggregation and thus served as a dual modulator (acting as an inhibitor and promoter at different steps of stone formation). Almost all of these inhibitory effects were concentration-dependent. Comparing the CaOx-inhibitory activities of these compounds revealed that EGCG was the most potent inhibitor against CaOx crystal formation (with the crystal abundance-inhibitory activity of 85.61 ± 5.12 %), whereas RES was the most potent inhibitor against CaOx crystal growth (with the crystal growth-inhibitory activity of 92.99 ± 1.67 %). NAC was the only inhibitor against CaOx crystal aggregation (with the crystal aggregation-inhibitory activity of 22.97 ± 0.75 %). These data indicate the direct inhibitory effects of various dietary supplements against CaOx crystal formation, growth and aggregation, supporting their roles in KSD prevention.},
}

@article {pmid41654163,
year = {2026},
author = {Thakur, M and Mutyala, D and Amoliga, AA and Kondati, R and Batra, S},
title = {ROS-Driven Rewiring of Hippo-Inflammation-Polycomb Axis by PFOA in 2D and 3D Lung Epithelial Models.},
journal = {Toxicology},
volume = {},
number = {},
pages = {154426},
doi = {10.1016/j.tox.2026.154426},
pmid = {41654163},
issn = {1879-3185},
abstract = {Perfluorooctanoic acid (PFOA), a persistent organic pollutant and prominent member of the per- and polyfluoroalkyl substances (PFAS) family, continues to raise global concern due to its bioaccumulation and potential for chronic human exposure. While hepatic and systemic toxicities of PFOA are well documented, its effects on lung epithelial integrity, particularly at environmentally relevant concentrations, remain incompletely understood. In this study, we investigated the cellular and molecular responses to PFOA in human alveolar lung epithelial cells (A549) cultured under both 2D submerged monolayer and 3D air-liquid interface (ALI) conditions, representing systemic and barrier-relevant exposure models. Cells were exposed to 10-1000nM PFOA for 24h to assess changes in pro-inflammatory mediators, including transcription factors-NF-κB and STAT3, pattern recognition receptors (TLR4 and RAGE), cytokine/chemokine production (IL-6, IL-8, CCL2, CCL5), and damage-associated molecular patterns (HSP70, HMGB1). PFOA also appeared to trigger translational stress responses, including stress granule and P-body formation, along with alterations in Hippo signaling via YAP/TAZ overactivation. PFOA-challenged cells exhibited activation of Polycomb Repressive Complexes and associated silencing histone marks (H3K27me3, H2AK119Ub), along with HDACs and SIRT family members, indicative of a redox-driven Polycomb-mediated gene silencing program. Oxidative stress was identified as the central driver of epigenetic and Hippo pathway disruptions, as observed in cells pre-exposed to 1 mM N-acetylcysteine (NAC). Despite these molecular alterations, epithelial cell migration capacity remains unaffected under acute exposure. Our results provide key mechanistic insights into PFOA-mediated disruption of redox homeostasis, immune signaling, and epigenetic plasticity in A549 cells, as well as identifying biomarkers for future biomonitoring efforts and studying regulatory frameworks.},
}

@article {pmid41654007,
year = {2026},
author = {Dutta, D and Behera, A and Roy, D and Sukla, S and Banerjee, S},
title = {Mechanistic exploration of methylglyoxal-induced hepatotoxicity involving oxidative stress, apoptosis, and gluconeogenic modulation.},
journal = {Chemico-biological interactions},
volume = {428},
number = {},
pages = {111954},
doi = {10.1016/j.cbi.2026.111954},
pmid = {41654007},
issn = {1872-7786},
mesh = {*Pyruvaldehyde/toxicity ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; Humans ; Animals ; *Gluconeogenesis/drug effects ; Hep G2 Cells ; Reactive Oxygen Species/metabolism ; Mice, Inbred BALB C ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Liver/drug effects/metabolism/pathology ; Male ; Sirtuin 1/metabolism ; Acetylcysteine/pharmacology ; Chemical and Drug Induced Liver Injury/pathology/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Cell Survival/drug effects ; },
abstract = {Methylglyoxal (MG) is a precursor of advanced glycation end-products produced during glycolysis. MG accumulation is linked to various pathophysiological conditions through the production of reactive oxygen species (ROS). This investigation uncovers the mechanism of MG-induced hepatotoxicity in vitro and in vivo. We assessed MG's dose- and time-dependent cytotoxicity (0.001-10 μM) in HepG2 cells using the cell viability assay. We examined the protective effects of N-acetylcysteine (NAC) against MG toxicity using MTT reagent, monitoring ROS generation, apoptosis (via flow cytometry), and mitochondrial membrane potential (with JC1 dye staining). For the in vivo study, BALB/c mice received MG (290 mg/kg and 400 mg/kg) at 6 h and 14 h intervals to induce hepatotoxicity. We conducted liver histopathology and protein expression analysis for apoptotic markers (Bax, Bcl-2, and caspase-3) and gluconeogenesis regulators (SIRT1, PGC1α, and glucose 6-phosphatase or G6Pase) in both cell lines and liver tissues. MG caused significant dose- and time-dependent toxicity in HepG2 cells by promoting cell death, increasing ROS and apoptosis, and altering the mitochondrial membrane potential at 5 μM. NAC (5 and 10 mM) protected against MG-induced toxicity. In mice, MG led to elevated spleen and liver weight, aspartate transferase (AST), alanine transaminase (ALT), glucose, malondialdehyde, and decreased superoxide dismutase levels. MG upregulated pro-apoptotic and gluconeogenic proteins in HepG2 cells, while NAC significantly reduced their levels. MG also increased the expression of proteins involved in apoptosis and gluconeogenesis. MG-induced caspase-dependent hepatotoxicity was mediated by the production of ROS and the activation of gluconeogenesis via SIRT1-dependent PGC1α activation.},
}

*Pyruvaldehyde/toxicity
*Apoptosis/drug effects
*Oxidative Stress/drug effects
Humans
Animals
*Gluconeogenesis/drug effects
Hep G2 Cells
Reactive Oxygen Species/metabolism
Mice, Inbred BALB C
Membrane Potential, Mitochondrial/drug effects
Mice
Liver/drug effects/metabolism/pathology
Male
Sirtuin 1/metabolism
Acetylcysteine/pharmacology
Chemical and Drug Induced Liver Injury/pathology/metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Cell Survival/drug effects

@article {pmid41653207,
year = {2026},
author = {Zhang, M and Guan, C and Sheng, G and Ding, Z and Zhao, Y and Zhao, G and Li, W and Hu, Z and Peng, Y and Zheng, J},
title = {Pyrazinamide-induced hepatotoxicity mediated by aldehyde oxidase and xanthine oxidase.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {41653207},
issn = {1432-0738},
support = {ZK[2023]319//Guizhou Provincial Science and Technology Department/ ; },
abstract = {Pyrazinamide (PZA) has been approved for the treatment of tuberculosis in clinical practice. However, its adverse effects, particularly hepatotoxicity, have raised concerns. The present study aimed at exploring the potential relationship between PZA-induced hepatotoxicity and its metabolites resulting from metabolic activation. Glutathione (GSH) conjugates with confirmed structures were detected in mouse cytosol incubations containing PZA or pyrazinoic acid (POA, a major metabolite of PZA) supplemented with glutathione (GSH). Such GSH metabolites were also observed in both liver homogenates from mice administered with PZA and mouse primary hepatocytes exposed to PZA. Aldehyde oxidase (AO) and xanthine oxidase (XOD) were identified as key enzymes in the metabolic activation of PZA and POA. Both vitamin C (VC) and N-acetylcysteine (NAC) were found to reduce the generation of GSH conjugates derived from PZA and POA in incubation systems. Additionally, VC alleviated the susceptibility of hepatocytes to PZA-induced cytotoxicity. Consecutive administration of PZA for 7 days resulted in a marked elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice, and PZA-derived hepatic protein adduction was detected. Allopurinol administration attenuated the elevated serum ALT and AST in company with a reduction in the formation of GSH conjugates. This work provides solid evidence for the correlation between the metabolic activation of PZA and PZA-induced hepatotoxicity, enhancing the understanding of the underlying mechanisms of PZA toxicity in terms of molecular chemical structure.},
}

@article {pmid41642676,
year = {2026},
author = {Anandakrishnan, A and O'Halloran, A and Diamond, T},
title = {Successful Heat Stroke-Induced Pediatric Acute Liver Failure Treatment With N-Acetylcysteine Case Report.},
journal = {Critical care explorations},
volume = {8},
number = {2},
pages = {e1371},
pmid = {41642676},
issn = {2639-8028},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Heat Stroke/complications ; Male ; Child ; *Liver Failure, Acute/drug therapy/etiology ; *Free Radical Scavengers/therapeutic use ; },
abstract = {BACKGROUND: Previously healthy children are at risk of developing exertional heat stroke when experiencing extreme heat. Pediatric clinicians in primary care, emergency department, and critical care settings should be versed in the management of complications of exertional heat stroke. Pediatric acute liver failure (PALF) in the setting of heat stroke is rarely reported in published literature.

CASE SUMMARY: A 9-year-old male presented with heat stroke-induced PALF. He initially presented to an emergency department for altered mental status. During his clinical course, despite appropriate identification and initial treatment of exertional heat stroke, his symptoms progressed, including ongoing agitation, hepatic encephalopathy, coagulopathy, and severe transaminase elevation meeting clinical criteria for PALF.

CONCLUSIONS: He was treated with N-acetylcysteine (NAC) with resolution of his PALF without complications. In this article, we review the patient's clinical course, the rationale for treatment with NAC, and the management of heat stroke-induced PALF.},
}

Humans
*Acetylcysteine/therapeutic use
*Heat Stroke/complications
Male
Child
*Liver Failure, Acute/drug therapy/etiology
*Free Radical Scavengers/therapeutic use

@article {pmid41642111,
year = {2026},
author = {Dos Santos, IWR and Souza-Monteiro, D and Frazão, DR and da Silva, ZAL and de Moura, JDM and Cruz, JN and Collares, FM and de Souza-Rodrigues, RD and Cintra, LTÂ and Lima, RR},
title = {N-Acetylcysteine Reduces Alveolar Bone Loss and Mitigates Systemic Oxidative Damage in Rats With Apical Periodontitis.},
journal = {International endodontic journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/iej.70108},
pmid = {41642111},
issn = {1365-2591},
support = {307747/2025-5//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 408329/2022-0//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 404431/2024-0//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 400706/2024-5//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 409576/2025-5//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil), Ministry of Education/ ; 406436/2022-3//National Institute of Science and Technology in 3D Printing and Advanced Materials Applied to Human and Veterinary Health/ ; },
abstract = {AIM: This study aimed to evaluate the effects of N-acetylcysteine (NAC) supplementation in apical periodontitis (AP) induced in rats.

METHODOLOGY: Eighteen male Wistar rats were randomly assigned to three groups: control, AP, and AP plus NAC. NAC was administered by oral gavage (100 mg/kg/day), beginning 1 day after lesion induction and continued daily until the day preceding euthanasia. AP induction was performed by exposing the dental pulp of the lower first molars bilaterally, maintaining this condition for 28 days. After this period, the animals were euthanized, and the following biological materials were collected: blood (for systemic oxidative stress analysis) and hemimandibles for histopathological and histochemical, and micro-computed tomography analyses, aiming to measure bone quality parameters and periapical volume. Statistical analyses were performed using one-way ANOVA and Tukey's post hoc test. In addition, correlation analyses and multivariate analyses of variance (MANOVA) were performed on the biochemical parameters.

RESULTS: The study results showed that animals supplemented with NAC had greater preservation of bone quality parameters and a reduction in periapical volume progression when compared to the only apical periodontitis group. Additionally, in the analysis of systemic oxidative stress, supplemented animals showed higher antioxidant parameter levels and lower oxidant levels compared to non-supplemented animals, which also showed reduced preservation of bone collagen content.

CONCLUSIONS: The study findings suggest that NAC supplementation promoted greater preservation of bone quality, reduced periapical volume development, and modulation of endogenous antioxidant and oxidant aspects. This indicates that NAC can decrease local and systemic damage caused by AP, highlighting its potential as an adjunctive agent in processes involving systemic oxidative stress and the preservation of biological structures.},
}

@article {pmid41637640,
year = {2026},
author = {Pandey, AM and Zhou, R and Singh, D and Li, F and He, M and Le, A and Herdrich, J and Chen, Y and Shah, R and Adusei-Poku, S and Rohlwing, NJ and Koo, J and Ong, ZY and Oldfield, E},
title = {Antifungal Activity of Lipophilic Bisphosphonates.},
journal = {ACS infectious diseases},
volume = {12},
number = {2},
pages = {766-780},
doi = {10.1021/acsinfecdis.5c00838},
pmid = {41637640},
issn = {2373-8227},
mesh = {*Antifungal Agents/pharmacology/chemistry ; *Diphosphonates/pharmacology/chemistry ; Humans ; Microbial Sensitivity Tests ; *Candida glabrata/drug effects/growth & development ; Drug Resistance, Fungal ; Drug Synergism ; },
abstract = {We investigated the activity of a series of 75 lipophilic bisphosphonates against Candida glabrata. Thirty-six compounds had MIC < 1 μg/mL, 18 had MIC < 0.5 μg/mL, and 2 had MIC = 0.13 μg/mL, comparable to amphotericin B and caspofungin. The lipophilic bisphosphonates were ∼20-fold more potent against C. glabrata than the most potent hydrophilic bisphosphonate, zoledronate. The most active compounds were pyridinium bisphosphonates followed by imidazolium bisphosphonates, while aryl bisphosphonates were less active. Several compounds had selectivity index values against a human cell line in the 1000-3600 range, the most selective compounds being para-substituted pyridinium bisphosphonates. We also found similar activity against a caspofungin-resistant FKS2 (F659S) mutant. Some combinations of lipophilic bisphosphonates had synergistic activity with FICI values in the ∼0.3-0.5 range, and similar synergies were observed with fluconazole, implicating ergosterol biosynthesis inhibition leading to compromised membrane structure and function. Cell growth inhibition was rescued by ascorbic acid, glutathione, and N-acetyl cysteine, indicating a ROS-based killing mechanism. There was also synergy with other antifungals but very strong antagonism with verapamil (FICI ∼4), which blocks calcium channels. Unlike hydrophilic bisphosphonates, which target farnesyl diphosphate synthase, lipophilic bisphosphonates also target squalene synthase, suggesting that the combination of multitargeting bisphosphonates is one origin of the synergistic interactions observed. Given that one of the lipophilic bisphosphonates studied here (BPH-1237) has been shown to have activity against many other human fungal pathogens, combinations with the compounds described here may be of interest as antifungal leads.},
}

*Antifungal Agents/pharmacology/chemistry
*Diphosphonates/pharmacology/chemistry
Humans
Microbial Sensitivity Tests
*Candida glabrata/drug effects/growth & development
Drug Resistance, Fungal
Drug Synergism

@article {pmid41632564,
year = {2026},
author = {Zhang, J and Yan, M and Tang, Y and Liu, M and Yao, W and Zhang, Q and Chen, H},
title = {A First-Aid Nanomedicine Endowed with Microenvironment Self-Adaptive Regulation Ability to Facilitate Acute Liver Failure Prophylaxis and Therapy.},
journal = {ACS nano},
volume = {20},
number = {6},
pages = {4989-5006},
doi = {10.1021/acsnano.5c18314},
pmid = {41632564},
issn = {1936-086X},
mesh = {Animals ; *Liver Failure, Acute/prevention & control/drug therapy/metabolism/pathology ; *Nanomedicine ; Mice ; *Copper/chemistry/pharmacology/therapeutic use ; Macrophages/drug effects/metabolism ; Humans ; Oxidative Stress/drug effects ; *Sulfides/chemistry/pharmacology/therapeutic use ; *Nanoparticles/chemistry ; Male ; Mice, Inbred C57BL ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; },
abstract = {Acute liver failure (ALF) represents a life-threatening medical emergency with high mortality, yet limited treatment is available clinically. Here, we report albumin-biomineralized nonstoichiometric copper sulfide nanoparticles serving as first-aid nanomedicine to combat ALF, conceptualized as NanoAID. The NanoAID exhibits an electron-donor nanoantioxidant property to scavenge reactive oxygen species and concurrent anti-inflammatory capacity to reprogram pro-inflammatory M1 macrophages into anti-inflammatory M2-phenotype, thereby mitigating excessive oxidative and inflammatory stress in ALF lesions. More interestingly, we found Cu ions release under an in situ oxidative stress switch and the resulting H2S gas generation by NanoAID degradation, which further enhance the biosynthesis of intrahepatic antioxidant enzyme SOD1 and the repolarization of M1-to-M2 macrophages, respectively, thereby self-reinforcing ALF therapy. Such microenvironment self-adaptive regulation confers NanoAID with effective prophylactic efficacy and significant ALF survival advantages over the FDA-approved N-acetyl cysteine in multiple animal models, extending the first-aid window to 6 h post APAP intoxication. Transcriptomics results reveal the molecular mechanisms of NanoAID by promoting antioxidative and inhibiting inflammatory pathways, underscoring its great potential as a next-generation first-aid nanomedicine for ALF management.},
}

Animals
*Liver Failure, Acute/prevention & control/drug therapy/metabolism/pathology
*Nanomedicine
Mice
*Copper/chemistry/pharmacology/therapeutic use
Macrophages/drug effects/metabolism
Humans
Oxidative Stress/drug effects
*Sulfides/chemistry/pharmacology/therapeutic use
*Nanoparticles/chemistry
Male
Mice, Inbred C57BL
RAW 264.7 Cells
Reactive Oxygen Species/metabolism

@article {pmid41630014,
year = {2026},
author = {Ali̇hossei̇ni̇, H and Çolakoğlu, EÇ and Haydardedeoğlu, AE and Özen, D},
title = {N-acetylcysteine reduces serum creatinine, blood urea nitrogen, symmetric dimethylarginine and urine protein to creatinine ratio in cats with chronic kidney disease: a double-blind, placebo-controlled clinical trial.},
journal = {BMC veterinary research},
volume = {22},
number = {1},
pages = {},
pmid = {41630014},
issn = {1746-6148},
abstract = {BACKGROUND: Oxidative stress is considered a significant contributing factor of chronic kidney disease (CKD). To date, there is a paucity of clinical data in the literature regarding the effect of N-Acetylcysteine (NAC) in cats with naturally developing CKD. The aim of the study is to evaluate whether the addition of NAC in the treatment of cats with acute exacerbations of CKD could improve kidney function biomarkers over the use of intravenous fluid therapy alone.

METHODS: A total of 50 client-owned cats were included in the study. The inclusion criteria comprised cats previously diagnosed with azotemic CKD (IRIS stage 2-4) in addition to ultrasonographic evidence of bilaterally decreased renal mass, rough surface contours, and alteration of renal cortical echogenicity. All cats were examined using standard clinical procedures, including clinical examination, blood analyses, abdominal ultrasonography, dipstick urinalysis and urine culture. Computer-generated randomisation was utilised to assign the cats into the following groups: NAC (n:40): N-acetylcysteine (70 mg/kg, diluted in 50 ml 0.9% saline solution, administered intravenously over a period of seven days, and a placebo group (n:10) 50 ml 0.9% saline solution, IV for 7 days. Blood analyses and dipstick urinalysis were repeated on the eighth day of treatment. Between-group differences in baseline age and weight were assessed using the Student's t-test, while sex distribution was evaluated with the Fisher's exact test. Treatment effects across time were analysed using a two-way mixed-design ANOVA, with "Group" and "Time" entered as fixed factors and their interaction term included in the model.

RESULTS: SDMA and creatinine concentrations decreased significantly in both groups, but the concentrations of both were significantly lower in the NAC group after treatment (Day 8 values: SDMA NAC 16.5 ± 1.21 µg/dl versus placebo 27 ± 3.89 µg/dl; P = 0.04 and Creatinine NAC 4.01 ± 0.25 mg/dl versus placebo 6.44 ± 0.9 mg/dl; P < 0.001). UPC and BUN decreased significantly in the NAC group, but no change was observed in the placebo group.

CONCLUSION: The incorporation of NAC into treatment regimens demonstrates potential as a treatment strategy for cats with acute-on-chronic kidney disease.},
}

@article {pmid41624281,
year = {2025},
author = {Pas, D and Oltmanns, H and Meißner, J},
title = {In vitro characterization of antimicrobial efficacy and cytotoxicity of polyvinylpyrrolidone-iodine, N-acetylcysteine, methylglyoxal, and N-chlorotaurine as alternative antimicrobials in treating bovine clinical endometritis.},
journal = {Frontiers in veterinary science},
volume = {12},
number = {},
pages = {1699857},
pmid = {41624281},
issn = {2297-1769},
abstract = {Bovine clinical endometritis (CE) is a common indication for antibiotic use in dairy cows. The increase in bacterial resistance and the aspired decrease in antibiotic use under the One Health concept call for alternatives in treatment. Polyvinylpyrrolidone-iodine (PVP), N-acetylcysteine (NAC), methylglyoxal (MGO), and N-chlorotaurine (NCT) are known substances with antibacterial properties that could potentially serve as those alternatives. In a broth microdilution assay, their efficacy against the common cause of endometritis, Trueperella pyogenes, was investigated. By cytotoxicity testing on a primary bovine endometrial epithelial cell culture, potential adverse effects on cell proliferation, viability, and immune response (IL-6) were examined. While all four substances had an antibacterial effect on T. pyogenes, PVP, MGO, and NCT also showed cytotoxic effects. In contrast, NAC was tolerated well by the cells. In sum, the four tested substances can be considered potential alternatives to antibiotic treatments. Further research is, however, necessary to investigate their toxic effects in ex vivo or in vivo models and to identify effective dosages in animals.},
}

@article {pmid41620910,
year = {2026},
author = {Bai, X and Luo, Y and Huang, J and Liu, G},
title = {Effect of linezolid combined with N-acetylcysteine on lung function, blood gas and inflammation in patients with severe pneumonia.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {3},
pages = {803-808},
doi = {10.36721/PJPS.2026.39.3.REG.13264.1},
pmid = {41620910},
issn = {1011-601X},
mesh = {Humans ; *Linezolid/therapeutic use/adverse effects ; *Acetylcysteine/therapeutic use/adverse effects ; Male ; Female ; Middle Aged ; *Pneumonia/drug therapy/physiopathology/blood ; Blood Gas Analysis ; *Anti-Bacterial Agents/therapeutic use/adverse effects ; Aged ; Drug Therapy, Combination ; *Lung/drug effects/physiopathology ; Adult ; Treatment Outcome ; Respiratory Function Tests ; Inflammation/drug therapy ; C-Reactive Protein/metabolism ; },
abstract = {BACKGROUND: Severe pneumonia is a serious lung disease. The continuous and regular administration of antibiotics is currently used for severe pneumonia. However, the single antibiotic may enhance the drug resistance and the overall efficacy is not ideal.

OBJECTIVES: This study aimed to investigate the efficacy and safety of linezolid combined with N-acetylcysteine (NAC) on lung function, blood gas and inflammation in patients with severe pneumonia.

METHODS: Eighty-four severe pneumonia patients were divided into linezolid group and linezolid +NAC group, which received the treatment using linezolid and linezolid combined with NAC for ten days, respectively. The total treatment efficacy was assessed. Before and after treatment, the pulmonary function indexes, blood gas indexes inflammatory response indexes were determined.

RESULTS: Compared with linezolid group, in linezolid +NAC group the disappearance time of cough, sputum and lung rales were shortened, the total effective rate, peak expiratory flow, forced expiratory volume in one second/forced vital capacity, arterial oxygen partial pressure and blood oxygen saturation were increased, the arterial carbon dioxide partial pressure and serum tumor necrosis factor α, interleukin 6 and hypersensitive C-reactive protein levels were decreased (all P < 0.05).

CONCLUSION: In treating severe pneumonia, linezolid combined with NAC can significantly improve the lung function of patients, improve the blood gas indicators and reduce the inflammatory response, thus alleviating the clinical symptoms.},
}

Humans
*Linezolid/therapeutic use/adverse effects
*Acetylcysteine/therapeutic use/adverse effects
Male
Female
Middle Aged
*Pneumonia/drug therapy/physiopathology/blood
Blood Gas Analysis
*Anti-Bacterial Agents/therapeutic use/adverse effects
Aged
Drug Therapy, Combination
*Lung/drug effects/physiopathology
Adult
Treatment Outcome
Respiratory Function Tests
Inflammation/drug therapy
C-Reactive Protein/metabolism

@article {pmid41619526,
year = {2026},
author = {Monti, DA and Zabrecky, G and Kremens, D and Liang, TW and Wintering, NA and Vedaei, F and Navarreto, E and Gupta, M and Steinmetz, A and Bazzan, AJ and Mohammed, F and Newberg, AB},
title = {N-Acetylcysteine is associated with changes in functional connectivity in patients with Parkinson's disease.},
journal = {Parkinsonism & related disorders},
volume = {144},
number = {},
pages = {108216},
doi = {10.1016/j.parkreldis.2026.108216},
pmid = {41619526},
issn = {1873-5126},
abstract = {INTRODUCTION: This study assessed the changes in functional connectivity from resting functional magnetic resonance imaging (fMRI) in patients with Parkinson's disease (PD) given N-Acetylcysteine (NAC), the prodrug to L-cysteine and a precursor to the natural biological antioxidant glutathione (GSH). The aim of this study was to determine whether NAC is associated with changes in functional connectivity, particularly in the basal ganglia, and improvements in Parkinson's symptoms.

METHODS: Forty-four patients with PD were randomized to either weekly intravenous infusions of NAC (50 mg/kg) plus oral doses (500 mg twice per day) for six months plus standard of care, or standard of care only. Participants received pre and post brain imaging with resting Blood Oxygen Level Dependent (BOLD) MRI to measure functional connectivity between key brain regions involved with PD. These findings were compared to changes in PD symptoms as measured by the Unified Parkinson's Disease Rating Scale (UPDRS).

RESULTS: There were significant differences in the NAC group compared to the control group in functional connectivity measures after NAC. Specifically, there was significantly different functional connectivity between basal ganglia structures and the precuneus, precentral gyrus, postcentral gyrus, and particularly the Rolandic operculum. Changes in the precuneus also correlated with changes in UPDRS scores.

CONCLUSION: The results suggest that NAC may positively affect brain functional connectivity in PD patients, with corresponding positive clinical effects. Larger scale studies are warranted.},
}

@article {pmid41617440,
year = {2026},
author = {Choi, SH and Seo, J and Jeong, SM},
title = {Splicing Factor SF3B4 Suppresses Pancreatic Cancer Growth and Migration by Inhibiting Autophagy.},
journal = {Anticancer research},
volume = {46},
number = {2},
pages = {737-747},
doi = {10.21873/anticanres.17983},
pmid = {41617440},
issn = {1791-7530},
mesh = {Humans ; *Autophagy/drug effects ; *RNA Splicing Factors/metabolism/genetics ; Cell Movement/drug effects ; *Pancreatic Neoplasms/pathology/genetics/metabolism/drug therapy ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Fluorouracil/pharmacology ; *Carcinoma, Pancreatic Ductal/pathology/genetics/metabolism/drug therapy ; Apoptosis/drug effects ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; },
abstract = {BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, characterized by aggressive progression, profound chemoresistance and unique metabolic adaptations such as elevated autophagy. Although the splicing factor SF3B4 has been reported to function as an oncogene in other malignancies, its role in PDAC remains unclear. This study aimed to elucidate the functional and mechanistic significance of SF3B4 in PDAC.

MATERIALS AND METHODS: SF3B4 expression in PDAC was analyzed using patient datasets and experimental models. Functional assays including cell proliferation, colony formation, migration, and autophagy analyses were performed in PDAC cells. Reactive oxygen species (ROS) levels were evaluated. Sensitivity to 5-fluorouracil (5-FU) and apoptotic responses were also evaluated.

RESULTS: SF3B4 acts as a tumor suppressor in PDAC by inhibiting autophagy, a process that this cancer uniquely depends on for survival. SF3B4 overexpression inhibited proliferation, colony formation and migration of PDAC cells. Mechanistically, SF3B4 suppressed autophagic flux, resulting in increased ROS accumulation and subsequent inhibition of tumorigenic phenotypes. Treatment with the antioxidant N-acetylcysteine (NAC) rescued the tumor suppressive effects of SF3B4 overexpression. Moreover, SF3B4 overexpression sensitized PDAC cells to 5-FU, accompanied by enhanced apoptotic responses.

CONCLUSION: SF3B4 is a context-dependent splicing factor that functions as a tumor suppressor in PDAC by regulating autophagy and redox homeostasis. Targeting the SF3B4-autophagy-ROS axis may represent a promising strategy to suppress PDAC progression and overcome chemoresistance.},
}

Humans
*Autophagy/drug effects
*RNA Splicing Factors/metabolism/genetics
Cell Movement/drug effects
*Pancreatic Neoplasms/pathology/genetics/metabolism/drug therapy
Cell Proliferation/drug effects
Cell Line, Tumor
Reactive Oxygen Species/metabolism
Fluorouracil/pharmacology
*Carcinoma, Pancreatic Ductal/pathology/genetics/metabolism/drug therapy
Apoptosis/drug effects
Gene Expression Regulation, Neoplastic
Animals
Mice

@article {pmid41616897,
year = {2026},
author = {Shirpoor, A and Zarrini, Z and Naderi, R},
title = {N-acetyl-cysteine alleviates nandrolone decanoate-induced hippocampal cell apoptosis in rats via reversing protein expressions of S1P1, Akt and FOXO3a signaling pathway.},
journal = {Steroids},
volume = {228},
number = {},
pages = {109759},
doi = {10.1016/j.steroids.2026.109759},
pmid = {41616897},
issn = {1878-5867},
mesh = {Animals ; *Hippocampus/drug effects/cytology/metabolism ; *Apoptosis/drug effects ; Male ; *Forkhead Box Protein O3/metabolism ; Rats, Wistar ; *Signal Transduction/drug effects ; Rats ; *Proto-Oncogene Proteins c-akt/metabolism ; Nandrolone Decanoate ; *Acetylcysteine/pharmacology ; *Nandrolone/analogs & derivatives/pharmacology ; },
abstract = {Illicit use of nandrolone can result in apoptosis in the hippocampus tissue but the underlying mechanism is unknown. The present study evaluated the role of S1P1/Akt/FOXO3a pathway in hippocampus cell apoptosis following exposure to nandrolone decanoate either alone or in combination with N-acetyl-cysteine. Twenty-four male Wistar rats were randomly divided into three groups (n = 8): control, nandrolone (10 mg/kg; intramuscularly; three times per week), and nandrolone + N-acetyl-cysteine (150 mg/kg; intraperitoneally). After six weeks of treatment, the number of apoptotic cells was significantly increased in the nandrolone treated group compared with the control group. Compared to control group, nandrolone group showed significant upregulation of NOX2, iNOS, 8-OHdG, P-FOXO3a/FOXO3a and lactate dehydrogenase (LDH) protein expression in rat hippocampus cells. Conversely, the protein expressions of P-Akt/Akt and S1P1 were significantly downregulated in hippocampus tissue of rats treated with nandrolone compared with control rats. Co-administration of N-acetyl-cysteine with nandrolone significantly reduced the apoptotic index and reversed the expressions of S1P1, P-Akt/Akt and P-FOXO3a/FOXO3a in the hippocampus neurons compared with the nandrolone group. These findings suggest that S1P1/Akt/FOXO3a signaling pathway may at least in part play an important role in the progression of apoptosis induced by nandrolone exposure, providing new insights into the pathogenesis and potential treatment of nandrolone-induced hippocampal damage.},
}

Animals
*Hippocampus/drug effects/cytology/metabolism
*Apoptosis/drug effects
Male
*Forkhead Box Protein O3/metabolism
Rats, Wistar
*Signal Transduction/drug effects
Rats
*Proto-Oncogene Proteins c-akt/metabolism
Nandrolone Decanoate
*Acetylcysteine/pharmacology
*Nandrolone/analogs & derivatives/pharmacology

@article {pmid41613139,
year = {2025},
author = {Gao, W and Lin, Z and Bao, Y and Liu, M and Ma, G and Chen, X and Yu, S and Zeng, Y},
title = {A stage specific NETs-related signature in alcoholic steatohepatitis: from molecular subtyping to therapeutic vulnerabilities.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1711388},
pmid = {41613139},
issn = {1664-3224},
mesh = {Humans ; *Fatty Liver, Alcoholic/genetics/immunology/diagnosis/metabolism/drug therapy ; Animals ; Mice ; Matrix Metalloproteinase 7/genetics/metabolism ; *Neutrophils/immunology/metabolism ; Gene Expression Profiling ; Proto-Oncogene Proteins c-fos/genetics/metabolism ; Male ; Transcriptome ; Gene Regulatory Networks ; Molecular Docking Simulation ; },
abstract = {BACKGROUND: Alcohol-associated steatohepatitis (ASH) is a globally prevalent liver disease, with robust evidence implicating neutrophil extracellular traps (NETs) as a central pathological phenomenon driving inflammation and progression. However, the core genomic signatures that govern NETs and underlying molecular mechanisms within the ASH microenvironment remain poorly defined.

METHODS: Building on the prominent NETs formation phenomenon in ASH, we established a core pool of NETs-related hub genes through intersection of ASH-derived differentially expressed genes (DEGs), key WGCNA modules, and a curated NETs gene set. From this NET-focused pool, a consensus of three machine learning algorithms (LASSO, SVM, RF) distilled a final diagnostic signature, which was rigorously validated in training and external cohorts via ROC analysis and neural networks. Patient heterogeneity was then investigated using consensus clustering with this signature, followed by immune profiling and functional validation in human and mouse ASH models. Therapeutic potential was explored through drug database enrichment and molecular docking.

RESULTS: A NETs-focused three-gene signature (FOS, MMP7, CXCL6) achieved exceptional diagnostic accuracy for ASH (AUC = 1.00 in training; 0.983 in validation). It stratified ASH into a Metabolic-dominant (C1) subtype and a Pro-inflammatory (C2) subtype, the latter exhibiting higher MMP7/CXCL6, lower FOS, and enriched cytotoxic infiltration. In vivo, FOS rose in acute injury but declined in chronic models and human ASH, whereas MMP7/CXCL6 remained elevated, suggesting a temporal shift from acute FOS-dominant response to sustained MMP7/CXCL6-mediated inflammation. Finally, drug-gene interaction analysis identified several potential therapeutic modulators, including N-acetylcysteine (NAC), with predicted high binding affinities to FOS and MMP7.

CONCLUSION: FOS, MMP7, and CXCL6 constitute a clinically actionable signature capturing the stage-specific dynamics of NETs-driven inflammation in ASH. Beyond its diagnostic and stratifying utility, this signature highlights potential therapeutic avenues for clinical intervention.},
}

Humans
*Fatty Liver, Alcoholic/genetics/immunology/diagnosis/metabolism/drug therapy
Animals
Mice
Matrix Metalloproteinase 7/genetics/metabolism
*Neutrophils/immunology/metabolism
Gene Expression Profiling
Proto-Oncogene Proteins c-fos/genetics/metabolism
Male
Transcriptome
Gene Regulatory Networks
Molecular Docking Simulation

@article {pmid41607252,
year = {2026},
author = {Huang, R and Wu, Y and Liu, X and Zou, L and Li, J and He, J and Yang, L and Yang, X},
title = {Sulfur-Fumigation Engineered Ceria Nanoparticles With Augmented Oxygen Vacancies for Enhanced Therapy of Drug-Induced Liver Injury.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e13609},
doi = {10.1002/smll.202513609},
pmid = {41607252},
issn = {1613-6829},
support = {CSTB2024NSCQ-MSX0554//Natural Science Foundation of Chongqing/ ; },
abstract = {The excessive generation of reactive oxygen species (ROS) and its synergistic interplay with inflammation and apoptosis play a critical role in the progression of drug-induced liver injury (DILI). Ceria nanoparticles are potential DILI therapy candidates due to their self-renewable ROS scavenging activity. However, the clinical translation of ceria nanoparticles for DILI therapy is challenged by enhanced ROS scavenging activity and prolonged hepatic retention. Herein, the sulfur-fumigation approach is used to modulate the ROS scavenging activity of ceria nanoparticles through the surface microstructure reconfiguration mechanism. The sulfur-fumigation induces nanoparticle contraction and crystalline fusion. Crucially, sulfur-fumigation decreases (111) plane exposure but increases (200) and (220) plane exposure. These changes cause the generation of abundant oxygen vacancies, which significantly enhances the ROS scavenging activity of ceria nanoparticles, even when the surface area is decreased. Together with an appropriate hydrodynamic diameter (135.9 nm) for liver targeting, the sulfur-fumigated ceria nanoparticles can easily accumulate in the liver and alleviate ROS, inflammation, and apoptosis in DILI mice. Compared to the clinical standard N-acetylcysteine (NAC), the sulfur-fumigated ceria nanoparticles show better therapeutic efficacy across most of the detected parameters. These findings suggest that sulfur-fumigation is a potent surface reconfiguration strategy to engineer highly active ceria nanoparticles for DILI therapy.},
}

@article {pmid41606955,
year = {2026},
author = {Wang, C and Zhang, H and Guan, C and Li, Y and Yang, S and Huang, L},
title = {Glutamine transporter SLC1A5 inhibits autophagy-mediated CD276 degradation to promote esophageal cancer progression.},
journal = {Cancer biology & therapy},
volume = {27},
number = {1},
pages = {2621606},
pmid = {41606955},
issn = {1555-8576},
mesh = {Humans ; Animals ; *Amino Acid Transport System ASC/metabolism/genetics/antagonists & inhibitors ; Mice ; *Esophageal Neoplasms/pathology/metabolism/genetics ; *Autophagy ; *Minor Histocompatibility Antigens/metabolism/genetics ; Cell Proliferation ; Disease Progression ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Female ; Xenograft Model Antitumor Assays ; Male ; Glutamine/metabolism ; Mice, SCID ; Mice, Inbred NOD ; Proteolysis ; },
abstract = {BACKGROUND: CD276/B7-H3 is an immune checkpoint molecule often overexpressed in cancers, representing a potential therapeutic target. The underlying mechanisms for CD276 upregulation remain unclear. This study investigates how glutamine metabolism affects CD276 protein stability and esophageal squamous cell carcinoma (ESCC) progression.

METHODS: CD276 and SLC1A5 expression were analyzed in 90 ESCC clinical tissues and TCGA/GEO datasets. CCK-8, colony formation, wound healing and transwell assays were performed in KYSE150 and KYSE450 cells. Autophagy was quantified by immunofluorescence and western blot. Mitochondrial reactive oxygen species (ROS) levels measured by flow cytometry. Rescue experiments used N-acetylcysteine (NAC) and chloroquine (CQ). Finally, antitumor effects of SLC1A5 inhibitor V9302 in the presence or absence of CD276 were evaluated in NOD/SCID mice (n = 5 per group) bearing KYSE150 xenografts.

RESULTS: CD276 and SLC1A5 upregulated in ESCC tissues (P < 0.05). CD276 overexpression enhanced ESCC cell proliferation and migration by 42.3% and 58.7%, respectively (P < 0.01). CQ but not MG-132 increased CD276 expression in ESCC cells. SLC1A5 stabilized CD276 protein without altering CD276 mRNA levels, by suppressing ROS-dependent autophagic degradation. NAC reversed ROS-induced CD276 degradation, while CQ abrogated CD276 downregulation upon glutamine metabolism inhibition. Inhibiting glutamine metabolism could reverse ESCC cell proliferation induced by CD276 overexpression. Moreover, combination of V9302 and CD276 knockout significantly reduced KYSE150 cell-derived xenograft tumor volume by 65.2% (95% CI 58.3-72.1%, P < 0.001) in NOD/SCID mice, without affecting mouse body weight (P > 0.05).

CONCLUSION: SLC1A5 enhances CD276 stability by suppressing ROS-autophagy signaling, promoting ESCC progression. Targeting glutamine metabolism to enhance CD276 degradation might be a novel therapeutic strategy for ESCC.},
}

Humans
Animals
*Amino Acid Transport System ASC/metabolism/genetics/antagonists & inhibitors
Mice
*Esophageal Neoplasms/pathology/metabolism/genetics
*Autophagy
*Minor Histocompatibility Antigens/metabolism/genetics
Cell Proliferation
Disease Progression
Reactive Oxygen Species/metabolism
Cell Line, Tumor
Female
Xenograft Model Antitumor Assays
Male
Glutamine/metabolism
Mice, SCID
Mice, Inbred NOD
Proteolysis

@article {pmid41603285,
year = {2026},
author = {Karimi-Dehkordi, M and Saghaei, F and Saberian, M and Nejad, HS and Sohrabi, F and Zabihi, N},
title = {Feselol Ameliorates Acetaminophen-Induced Hepatotoxicity Through Multi-Pathway Modulation of Oxidative Stress, Inflammation, and Apoptosis in Mice.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {2},
pages = {e70710},
doi = {10.1002/jbt.70710},
pmid = {41603285},
issn = {1099-0461},
mesh = {Animals ; *Acetaminophen/adverse effects/toxicity ; *Oxidative Stress/drug effects ; Mice ; *Apoptosis/drug effects ; *Chemical and Drug Induced Liver Injury/metabolism/pathology/drug therapy/prevention & control ; Male ; *Inflammation/drug therapy/metabolism/chemically induced/pathology ; Liver/metabolism/pathology/drug effects ; },
abstract = {BACKGROUND AND AIM: Acetaminophen (APAP) overdose is a major cause of drug-related acute liver failure around the world. The limited treatment options beyond N-acetylcysteine (NAC) show a clear need for new liver-protective agents. Feselol, a natural compound known for its strong antioxidant effects, has become a potential candidate. This research aimed to evaluate feselol's anti-inflammatory, anti-apoptotic, and protective qualities against APAP-induced acute liver damage in a mouse model.

MATERIAL AND METHOD: The experiment included 42 mice divided into 7 groups, with some being administered a toxic dose of APAP only and others being given APAP in combination with 25 or 50 mg/kg of feselol. Serum levels of AST (serum aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase), and GGT (gamma-glutamyl transferase) were examined. SOD (superoxide dismutase), CAT (catalase), GPx (glutathione peroxidase) activities and MDA (malondialdehyde) levels were measured by colorimetric method. The liver tissue was analyzed through H&E staining. The expression of IL-1β, TNF-α, Bax, Caspase 3, and Bcl-2 genes was also examined by Real-time PCR.

RESULTS: The results showed that treatment of feselol at different doses with APAP led to a decrease in MDA levels to 23.25 nmol/mg (p < 0.05). Also, the activities of SOD, CAT and GPx enzymes in the group treated with a dose of 50 mg/kg of feselol with APAP were 33.09, 109.86, and 109.80, respectively, which was significant compared to the APAP group (p < 0.05). The results showed that simultaneous treatment with feselol and APAP resulted in a decrease in IL-1β and TNF-α gene expression by 1.67 and 1.015 fold, respectively (p < 0.05). Also, the expression of Bax (3.22-fold) and Caspase 3 (1.26-fold) genes decreased in the feselol-treated group and the expression of Bcl-2 (0.59-fold) gene increased. In the group that received APAP and feselol, the liver tissue was close to that of the control group. Feselol (50 mg/kg) coadministered with APAP significantly reduced ALT, AST, ALP, and GGP enzyme activity compared to the APAP-treated group (p < 0.05).

CONCLUSION: This study is notable for the discovery of feselol's pharmacological effects as a preventive drug against oxidative stress-associated hepatic impairment.},
}

Animals
*Acetaminophen/adverse effects/toxicity
*Oxidative Stress/drug effects
Mice
*Apoptosis/drug effects
*Chemical and Drug Induced Liver Injury/metabolism/pathology/drug therapy/prevention & control
Male
*Inflammation/drug therapy/metabolism/chemically induced/pathology
Liver/metabolism/pathology/drug effects

@article {pmid41602262,
year = {2025},
author = {Zacharia, GS and Ravte, V and Jyala, A and Shehi, E},
title = {Complementary and Alternative Medicine-Induced Combined Hepatorenal Toxicity: A Case Report.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e100197},
pmid = {41602262},
issn = {2168-8184},
abstract = {Drug-induced liver injury (DILI) is a leading cause of liver disease globally, with complementary and alternative medicine (CAM) representing a significant contributor due to its widespread use and limited regulation. CAM encompasses diverse practices and products, with regional and ethnic diversity, many of which are used to treat liver disease. Even though a few natural remedies have been utilized for centuries, most lack scientific evidence for their safety and efficacy. This report describes a 42-year-old male who self-treated his fatty liver with CAM, culminating in severe concomitant hepatic and renal dysfunctions. Comprehensive evaluation excluded viral, autoimmune, metabolic liver diseases, and obstructive biliary diseases. The Roussel Uclaf Causality Assessment Method (RUCAM) score indicated a probable causal link between CAM and DILI of hepatocellular pattern. The constituents of the CAM, extracts of Carica papaya, Alstonia boonei, and Tetrapleura tetraptera, have been implicated in hepatotoxicity in animal models. Discontinuing the supplements and supportive care, including N-acetyl cysteine, led to symptomatic and biochemical improvement. This case highlights the importance of clinicians' awareness of CAM-related DILI, emphasizing the need for vigilance and patient education about the potential risks associated with herbal products.},
}

@article {pmid41602127,
year = {2025},
author = {Zeng, Q and Sun, Y and Lei, M and Liu, Z and Yan, X and Li, R and Zheng, J and Zha, J and Zhang, L and Guan, X and Yao, J},
title = {Nicotinic acid protects against hepatic ischemia-reperfusion injury via suppressing mitochondrial damage-induced ferroptosis.},
journal = {Liver research (Beijing, China)},
volume = {9},
number = {4},
pages = {324-337},
pmid = {41602127},
issn = {2542-5684},
abstract = {BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (HIRI) is a major contributor to liver dysfunction and failure, particularly in the context of liver transplantation. Its pathogenesis is primarily driven by ferroptosis, oxidative stress, and mitochondrial dysfunction. Given the interplay among these mechanisms through redox imbalance and disrupted energy metabolism, nicotinic acid (NA)-recognized for its antioxidative and metabolic regulatory properties-emerges as a promising therapeutic candidate. This study aims to investigate the protective effects of NA on HIRI and elucidate its underlying mechanisms.

METHODS: An HIRI model in mice and a hypoxia/reoxygenation (H/R) model in primary hepatocytes were established to evaluate the effects of NA treatment on oxidative stress. NA was administered prior to model induction. N-acetylcysteine (NAC) was used as a comparator. Comprehensive assessments of ferroptosis, oxidative stress, mitophagy, and mitochondrial biogenesis markers were conducted using Western blotting, immunohistochemistry, immunofluorescence, and biochemical assays.

RESULTS: NA pretreatment reduced serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase (LDH) levels, suppressed inflammation by decreasing neutrophil infiltration and macrophage activation, and mitigated oxidative stress by lowering reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It enhanced antioxidant defenses, inhibited ferroptosis, and improved mitochondrial health through increased mitophagy, mitochondrial biogenesis, and mitochondrial permeability transition pore (mPTP) stabilization, leading to enhanced ATP production and mitochondrial function in HIRI.

CONCLUSIONS: NA improves mitochondrial function by promoting mitophagy and mitochondrial biogenesis, which reduces ferroptosis and oxidative stress, thereby alleviating HIRI.},
}

@article {pmid41601049,
year = {2026},
author = {Firouzjaei, Y and Hajizadeh Moghaddam, A and Sohabatzadeh, F and Khanjani Jelodar, S and Farhadi, M},
title = {Neuroprotective effects of plasma-activated N-acetylcysteine against streptozotocin-induced behavioral deficits in rats: Attenuation of oxidative stress and cholinergic dysfunction.},
journal = {Ecotoxicology and environmental safety},
volume = {309},
number = {},
pages = {119619},
doi = {10.1016/j.ecoenv.2025.119619},
pmid = {41601049},
issn = {1090-2414},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Male ; *Oxidative Stress/drug effects ; Rats ; *Neuroprotective Agents/pharmacology ; Streptozocin/toxicity ; Behavior, Animal/drug effects ; *Cognitive Dysfunction/chemically induced/drug therapy ; Plasma Gases ; },
abstract = {N-Acetylcysteine (NAC), a thiol-containing antioxidant, has demonstrated neuroprotective potential in various neurological disorders. Recently, cold atmospheric plasma (CAP) technology has emerged as a promising approach for modifying the physicochemical properties of biomolecules. This study investigated the neuroprotective effects of plasma-activated N-acetylcysteine (PAN) in a rat model of intracerebroventricular streptozotocin (icv-STZ)-induced cognitive impairment, with particular emphasis on redox homeostasis and cholinergic function. The physicochemical properties of PAN were characterized using FTIR, LC-MS/MS, and DPPH assay. Male rats received a single icv-STZ injection (3 mg/kg) on day 0, followed by oral administration of NAC or PAN (50 mg/kg) every other day for three weeks. Cognitive performance and anxiety-like behaviors were assessed using the shuttle box, novel object recognition, and elevated plus maze tests. Subsequently, oxidative stress indices (TAC, GSH, SOD, CAT, MDA, NO), cholinergic markers (AChE activity, ACh levels), and the expression of AChE, α7 nAChR, Nrf2, Keap1 and BDNF genes were quantified in the hippocampus and cerebral cortex. FTIR and LC-MS/MS analyses revealed plasma-induced chemical modifications in NAC, resulting in the generation of novel compounds. The DPPH assay further demonstrated superior radical scavenging activity of PAN compared with NAC. Behaviorally, PAN administration significantly alleviated STZ-induced cognitive deficits and anxiety-like behaviors. Biochemically, PAN normalized TAC, GSH, MDA, NO, and ACh levels, increased CAT and SOD activities, and reduced AChE activity. At the transcriptional level, PAN upregulated α7 nAChR, Nrf2 and BDNF expression while downregulating AChE and Keap1. Collectively, these findings suggest that PAN mitigates behavioral impairments in the icv-STZ rat model of Alzheimer's disease, potentially through attenuation of oxidative stress and restoration of cholinergic neurotransmission.},
}

Animals
*Acetylcysteine/pharmacology
Male
*Oxidative Stress/drug effects
Rats
*Neuroprotective Agents/pharmacology
Streptozocin/toxicity
Behavior, Animal/drug effects
*Cognitive Dysfunction/chemically induced/drug therapy
Plasma Gases

@article {pmid41597285,
year = {2026},
author = {Chung, YY and Kim, B and Lee, J and Kwak, S and Jung, M and Kim, YS and Baek, SK},
title = {Establishing a Non-Surgical Mouse Model of Laryngopharyngeal Reflux Disease: Acid-Induced Epithelial Disruption and Protective Role of N-Acetylcysteine.},
journal = {Cells},
volume = {15},
number = {2},
pages = {},
pmid = {41597285},
issn = {2073-4409},
support = {2021R1F1A1056645 (RS-2021-NR063002)//National Research Foundation of Korea/ ; 2023R1A2C1004538 (RS-2023-NR076554)//National Research Foundation of Korea/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Female ; Disease Models, Animal ; Mice, Inbred C57BL ; *Laryngopharyngeal Reflux/pathology/drug therapy/metabolism ; Mice ; Cadherins/metabolism ; Matrix Metalloproteinase 7/metabolism ; *Acids ; Epithelial Cells/drug effects/pathology/metabolism ; *Protective Agents/pharmacology ; },
abstract = {Laryngopharyngeal reflux disease (LPRD) results from the retrograde flow of gastric contents into the upper aerodigestive tract, causing epithelial injury. Progress in its management has been limited by the lack of objective biomarkers and reproducible in vivo models. This study aimed to establish a chronic, non-surgical mouse model of LPRD and to investigate the protective effect of N-acetylcysteine (NAC). Female C57BL/6 mice were randomly assigned to three groups: control (standard drinking water), study (acidified water, pH 3.0, for 12 weeks), and treatment (acidified water for 12 weeks plus NAC supplementation during the final 4 weeks). Body weight, food intake, and water consumption were monitored weekly. Pharyngeal tissues were analyzed by immunohistochemistry and Western blotting. Chronic acid exposure resulted in loss of membrane-localized E-cadherin, cytoplasmic redistribution, and upregulation of matrix metalloproteinase-7 (MMP-7). These molecular alterations were accompanied by enhanced phosphorylation of ERK and c-Jun, consistent with activation of the ROS-ERK-c-Jun signaling pathway. NAC supplementation was associated with partial restoration of E-cadherin, reduced MMP-7 expression, and attenuation of ERK/c-Jun phosphorylation. No systemic toxicity or weight loss was observed, indicating good tolerability of the model. This non-surgical ingestion-based model faithfully recapitulates key epithelial features of LPRD and provides a feasible platform for mechanistic investigation and exploratory therapeutic studies. NAC may exert protective effects against acid-induced epithelial injury in this model.},
}

Animals
*Acetylcysteine/pharmacology/therapeutic use
Female
Disease Models, Animal
Mice, Inbred C57BL
*Laryngopharyngeal Reflux/pathology/drug therapy/metabolism
Mice
Cadherins/metabolism
Matrix Metalloproteinase 7/metabolism
*Acids
Epithelial Cells/drug effects/pathology/metabolism
*Protective Agents/pharmacology

@article {pmid41596085,
year = {2025},
author = {Chen, X and Gao, D and Wang, M and Wang, L and Hu, H and Wen, C and Tang, Y},
title = {Neutrophil Extracellular Traps in Systemic Lupus Erythematosus: Pathogenic Mechanisms, Crosstalk with Oxidative Stress, and Antioxidant Therapeutic Potential.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {1},
pages = {},
pmid = {41596085},
issn = {2076-3921},
support = {82305145//National Natural Science Foundation of China/ ; LQ23H270006//Zhejiang Provincial Natural Science Foundation of China/ ; },
abstract = {Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and the formation of immune complexes (ICs), which lead to widespread inflammation and tissue damage. Neutrophil extracellular traps (NETs), web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils, play a crucial role in innate immunity by defending against pathogens. However, excessive NET formation and ineffective clearance of these structures contribute to the development of SLE. This review explores the mechanisms behind NET formation in SLE, their relationship with oxidative stress, and the potential role of antioxidants in treatment. Research indicates that SLE patients exhibit two key abnormalities: excessive NET formation and impaired NET clearance. Excessive NET formation is driven by proinflammatory low-density granulocytes (LDGs) and immune complexes (ICs). Impaired NET clearance stems from reduced DNase1/DNase1L3 activity or anti-nuclease autoantibodies. These two abnormalities lead to elevated circulating NETs. These NETs act as autoantigen reservoirs, forming pathogenic NET-ICs that amplify autoimmune responses. Oxidative stress drives NET formation by activating NADPH oxidase. In contrast, various antioxidants, including enzymatic and non-enzymatic types, can inhibit NET formation via scavenging reactive oxygen species (ROS) and blocking NADPH oxidase activation. Preclinical studies show that antioxidants such as curcumin, resveratrol, and mitochondrial-targeted MitoQ reduce NET formation and ameliorate lupus nephritis; clinical trials confirm that curcumin and N-acetylcysteine (NAC) lower SLE disease activity and reduce proteinuria, supporting their role as safe adjuvant therapies. However, high-dose vitamin E may exacerbate autoimmunity, highlighting the need for dose optimization. Future research should aim to clarify the mechanisms underlying NET formation in SLE and to optimize new antioxidant therapies, including assessments of their long-term efficacy and safety.},
}

@article {pmid41595622,
year = {2025},
author = {Dinç, M and Bayrak, HÇ and Karasu, R and Aykaç, B and Soydemir, ÖC and Saricetin, A},
title = {Intra-Articular N-Acetylcysteine Reduces Synovitis Without Preventing Cartilage Degeneration in Experimental Osteoarthritis.},
journal = {Biomedicines},
volume = {14},
number = {1},
pages = {},
pmid = {41595622},
issn = {2227-9059},
abstract = {Background/Objectives: Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized by synovial inflammation, oxidative stress, and progressive cartilage degeneration. This study investigated whether intra-articular N-acetylcysteine (NAC) attenuates synovial inflammation and oxidative stress and whether these effects translate into structural cartilage protection. Methods: OA was induced in rats by anterior cruciate ligament transection (ACLT). NAC (5 mg/50 µL) was administered intra-articularly once weekly for three weeks post-ACLT. Inflammatory cytokines (IL-1β, IL-6, TNF-α), oxidative stress markers (iNOS, TAS, TOS, OSI), and cartilage degradation markers (MMP-13, COMP, CTX-II) were quantified in synovial fluid and cartilage homogenates using ELISA. Cartilage integrity was evaluated histologically using the modified Mankin scoring system. Results: Compared with controls, NAC significantly reduced synovial IL-1β, IL-6, TNF-α, MMP-13, and iNOS levels and improved the synovial redox profile by increasing TAS and reducing TOS and OSI (all p < 0.05). In contrast, NAC did not significantly alter cartilage homogenate levels of inflammatory cytokines, oxidative stress indices, or degradation markers (COMP, CTX-II, MMP-13). Histological analysis demonstrated persistent cartilage fissuring, hypocellularity, and proteoglycan loss in both groups (p > 0.05). Conclusions: Intra-articular NAC exerts potent anti-inflammatory and antioxidative effects within the synovial compartment but fails to prevent cartilage degeneration in the ACLT model. These findings indicate a compartment-specific therapeutic profile, suggesting that NAC may function as a symptom-modifying agent in synovitis-dominant OA rather than a structure-modifying therapy. Future studies should focus on optimized delivery systems or combination strategies targeting cartilage and subchondral bone to achieve disease modification.},
}

@article {pmid41593603,
year = {2026},
author = {Jiang, Y and Ma, P and Yang, Y and Shi, X and Liu, X and Sun, M},
title = {The Achilles' heel of hepatocellular carcinoma: ginsenoside compound K as a novel GPX4 degrader promotes ferroptosis in hepatocellular carcinoma.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {277},
pmid = {41593603},
issn = {1479-5876},
support = {20DZ2272200//Key Laboratory of Chronic Deficiency Liver Disease of the State Administration of Traditional Chinese Medicine of the People's Republic of China/ ; shslczdzk01201//Shanghai Key Specialty of Traditional Chinese Clinical Medicine/ ; zyyzdxk-2023060//National Administration of Traditional Chinese Medicine/ ; },
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) remains a major therapeutic challenge, highlighting the need for agents that engage non-apoptotic regulated cell death pathways. Ginsenoside compound K (CK), a bioactive metabolite derived from ginseng saponins, has demonstrated antitumor activity, however, its efficacy and underlying mechanisms in HCC are not well defined. Given the emerging role of ferroptosis in HCC, we investigated whether CK suppresses HCC by inducing this iron-dependent form of cell death.

METHODS: The antitumor effects of CK were evaluated in HepG2 and Hep3B cells and in a xenograft mouse model. Ferroptotic cell death was assessed by measuring reactive oxygen species (ROS), ferrous iron (Fe²⁺), malondialdehyde (MDA), and glutathione (GSH) levels, and by rescue experiments using ferroptosis inhibitors (N-acetylcysteine, NAC; Trolox) or GPX4 overexpression. Mechanistic studies were performed using RNA sequencing, ubiquitination assays, and genetic manipulation of OTUB2 expression.

RESULTS: CK inhibited HCC cell proliferation in a dose-dependent manner and robustly induced ferroptosis hallmarks, including ROS accumulation, enhanced lipid peroxidation, and GSH depletion. These cytotoxic effects were largely abrogated by ferroptosis inhibitors or GPX4 overexpression, confirming a ferroptosis-dependent mechanism. In vivo, CK significantly reduced tumor growth in xenograft models and recapitulated key ferroptosis features. Mechanistically, CK was identified as a functional inhibitor of the deubiquitinase OTUB2. Suppression of OTUB2 promoted ubiquitin-dependent degradation of GPX4, a central negative regulator of ferroptosis, thereby sensitizing HCC cells to ferroptosis.

CONCLUSIONS: Our findings identify CK as a novel OTUB2 inhibitor that induces ferroptosis in HCC by destabilizing GPX4. This work delineates a previously unrecognized OTUB2/GPX4 regulatory axis in ferroptosis and supports CK as a promising candidate for further translational development for HCC therapy.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07587-9.},
}

@article {pmid41593161,
year = {2026},
author = {Ozhan, O and Ekici, C and Ates, B and Yildiz, A and Balcioglu, S and Vardi, N and Parlakpinar, H},
title = {N-acetyl cysteine amide mitigates oxidative stress and apoptosis in a rat model of renal ischemia-reperfusion injury.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {6323},
pmid = {41593161},
issn = {2045-2322},
support = {2209a//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; },
abstract = {Renal ischemia–reperfusion (IR) injury is a major cause of acute kidney injury, in which oxidative stress (OS) and apoptosis play central roles. N-acetyl cysteine amide (NACA), a lipophilic derivative of N-acetylcysteine, exhibits improved cellular penetration and antioxidant activity. This study investigated the renoprotective effects of NACA in a rat model of renal IR injury. Twenty-eight female Wistar albino rats were randomized into four groups (n = 7): Control, IR, NACA + IR (100 mg/kg i.p., 30 min before ischemia), and IR + NACA (100 mg/kg i.p., immediately after ischemia). Following right nephrectomy, the left renal pedicle was clamped for 60 min and reperfused for 24 h. Serum renal function markers, kidney OS parameters, histopathological injury, and caspase-3 immunoreactivity were evaluated. Renal IR injury significantly increased serum blood urea nitrogen and creatinine levels and induced histopathological damage characterized by tubular dilatation, cast formation, and degeneration. Catalase (CAT) and superoxide dismutase (SOD) activities were significantly altered; malondialdehyde increased after IR and was reduced by NACA pretreatment, whereas myeloperoxidase and total glutathione did not differ significantly among groups. NACA pretreatment attenuated inflammatory cell infiltration, tubular dilatation, and caspase-3 immunoreactivity, while partially restoring CAT and SOD activity. Post-ischemic NACA administration was less effective, particularly in reducing apoptosis and inflammatory infiltration. NACA confers partial renoprotection against renal IR injury, with pretreatment providing superior efficacy. These findings highlight the importance of antioxidant timing and suggest NACA as a potential prophylactic strategy when renal ischemia is predictable.},
}

@article {pmid41593024,
year = {2026},
author = {Chen, Z and Zhang, X and Li, J and Feng, C and Xiong, Y and Yan, L},
title = {Facile Synthesis of Thioketal-Functionalized Poly(amino acid) Nanocarriers for ROS-Triggered Drug Release in Cancer Therapy.},
journal = {ACS macro letters},
volume = {15},
number = {2},
pages = {259-266},
doi = {10.1021/acsmacrolett.5c00731},
pmid = {41593024},
issn = {2161-1653},
mesh = {*Reactive Oxygen Species/metabolism ; Animals ; *Doxorubicin/chemistry/pharmacology/administration & dosage/therapeutic use ; *Drug Carriers/chemistry/chemical synthesis ; Mice ; Drug Liberation ; Humans ; *Amino Acids/chemistry ; *Nanoparticles/chemistry ; *Polymers/chemistry/chemical synthesis ; Cell Line, Tumor ; *Antineoplastic Agents/chemistry ; Micelles ; Female ; Mice, Inbred BALB C ; Antibiotics, Antineoplastic/chemistry ; },
abstract = {Polymer nanocarriers offer significant advantages in antitumor drug delivery; however, achieving a balance between minimizing nonspecific drug release in blood circulation and maximizing specific intracellular drug release remains a critical challenge. To address this, this study developed a cross-linked poly(amino acid) nanocarrier sensitive to intracellular reactive oxygen species (ROS). A novel thioketal-functionalized, ROS-sensitive bicyclic amino acid N-carboxyanhydride (NCA) monomer was designed and synthesized, and ROS-responsive poly(amino acid)s were prepared via ring-opening polymerization. Polymeric nanomicelles loaded with doxorubicin (DOX) were successfully fabricated using a microemulsion method, and their ROS-responsive properties were systematically evaluated. In vitro release experiments demonstrated that the nanocarrier exhibited H2O2 concentration-dependent, ROS-triggered drug release characteristics. The oxidative response behavior of the drug-loaded nanomicelles was further validated in cellular and animal models by introducing the ROS scavenger N-acetylcysteine (NAC). In a 4T1 tumor-bearing mouse model, these drug-loaded nanomicelles showed enhanced tumor retention and superior tumor suppression compared to free DOX. This study demonstrates that thioketal-functionalized poly(amino acid) nanocarriers hold promise in balancing blood circulation stability and intracellular specific drug release, providing a novel design strategy for developing efficient and safe poly(amino acid)-based anticancer nanomedicines.},
}

*Reactive Oxygen Species/metabolism
Animals
*Doxorubicin/chemistry/pharmacology/administration & dosage/therapeutic use
*Drug Carriers/chemistry/chemical synthesis
Mice
Drug Liberation
Humans
*Amino Acids/chemistry
*Nanoparticles/chemistry
*Polymers/chemistry/chemical synthesis
Cell Line, Tumor
*Antineoplastic Agents/chemistry
Micelles
Female
Mice, Inbred BALB C
Antibiotics, Antineoplastic/chemistry

@article {pmid41586115,
year = {2025},
author = {Jafarzadeh, E and Pashaei-Asl, R and Hakimi, P and Pashaiasl, M},
title = {The Effect of Letrozole and N-Acetylcysteine on the Expression Levels of Genes Involved in Glucose Metabolism in Patients with Polycystic Ovary Syndrome: A Clinical Trial Study.},
journal = {Journal of reproduction & infertility},
volume = {26},
number = {2},
pages = {81-89},
pmid = {41586115},
issn = {2228-5482},
abstract = {BACKGROUND: N-acetylcysteine (NAC) is a supplement commonly used in patients with polycystic ovary syndrome (PCOS). The expansion of oocyte-associated cumulus cells (CCs) and the quality of the oocyte are critical factors influencing fertilization rates and clinical pregnancy outcomes in assisted reproductive techniques (ARTs). Genes such as phosphofructokinase (PFKP) and pyruvate kinase isoform M2 (PKM2) are involved in glucose metabolism and are crucial in the regulation of oocyte competence and developmental potential. The purpose of the current study was to evaluate the effects of letrozole and NAC on the expression of PFKP and PKM2 in CCs of PCOS patients undergoing ART.

METHODS: The study evaluated 20 PCOS women undergoing ART to assess the effect of letrozole and NAC on the expression levels of PKM2 and PFKP genes in cumulus cells. Women were randomly assigned using a simple randomization method into four groups: control, NAC, letrozole, and NAC plus letrozole, with five women in each group. Gene expression levels of PKM2 and PFKP were measured using real-time PCR.

RESULTS: The expression level of PKM2 was significantly higher in the letrozole plus NAC group compared to the control group (p<0.05). In NAC group, PFKP was significantly expressed compared to the control group (p<0.05). There were no significant differences among the other groups compared to the control group.

CONCLUSION: NAC can improve the quality of oocytes by increasing the expression level of genes involved in the glucose metabolism (PKM2, PFKP) of CCs, thereby potentially improving ART success rate in PCOS patients. Therefore, administering NAC along with letrozole can have a synergistic effect on increasing the expression level of genes associated with blastocyst quality in PCOS patients.},
}

@article {pmid41582130,
year = {2026},
author = {Li, C and Yuan, Y and Bao, Y and Ni, Y and Chen, N and Piao, J and Wang, L and Zhu, Z},
title = {Synergistic regulation of TGF-β1/Smad2/3 signaling and inflammatory pathways via SA/NAC-based nanoplatforms: a novel strategy to enhance anti-fibrotic therapeutic outcomes in idiopathic pulmonary fibrosis.},
journal = {Journal of nanobiotechnology},
volume = {24},
number = {1},
pages = {173},
pmid = {41582130},
issn = {1477-3155},
support = {LQ20H270014//National Natural Science Foundation of Zhejiang Province/ ; LY23H280010//Zhejiang Provincial Natural Science Foundation of China/ ; 2023JKZKTS23//Research Project of Zhejiang Chinese Medical University/ ; },
mesh = {Animals ; *Transforming Growth Factor beta1/metabolism ; *Idiopathic Pulmonary Fibrosis/drug therapy/metabolism ; Mice ; Signal Transduction/drug effects ; *Smad2 Protein/metabolism ; Smad3 Protein/metabolism ; *Acetylcysteine/pharmacology/chemistry ; Humans ; Mice, Inbred C57BL ; Inflammation/drug therapy/metabolism ; Macrophages/metabolism ; Male ; Disease Models, Animal ; Bleomycin ; Nanoparticles/chemistry ; Fibroblasts/drug effects ; RAW 264.7 Cells ; },
abstract = {Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by progressive fibrosis and poor prognosis, with no current therapies capable of reversing the fibrotic changes. The aberrant repair driven by fibroblast activation and an inflammatory microenvironment results in irreversible IPF. In this work, a macrophage-derived apoptotic body delivery system (SA + NAC@AB) co-loaded with sodium arsenite (SA) and N-acetylcysteine (NAC) was developed to exert synergistic antifibrotic activity against IPF via coordinated regulation of TGF-β1 signaling and inflammation. Apoptotic bodies derived from macrophages inherit inflammation-homing capability, enabling targeted delivery to fibrotic lesions. In vivo evaluation in a bleomycin-induced IPF mouse model demonstrated that SA + NAC@AB effectively targeted the lungs, significantly improved body weight and survival, and alleviated pulmonary fibrosis. Immunofluorescence and Western blot analyzes revealed that SA + NAC@AB reduced Smad2/3 phosphorylation and M2 macrophage polarization, indicating regulation of the TGF-β1/Smad2/3 pathway and inflammation as part of its mechanism of action. Furthermore, in vitro studies validated the enhanced efficacy of SA + NAC@AB, which significantly promoted fibroblast uptake, thereby potentiating its inhibitory effects on fibroblast viability, as well as TGF-β1-induced migration and differentiation. In conclusion, our study demonstrates that SA + NAC@AB represents an effective therapeutic strategy for IPF, offering a promising novel approach by modulating both the TGF-β1/Smad2/3 signaling pathway and the inflammatory response.},
}

Animals
*Transforming Growth Factor beta1/metabolism
*Idiopathic Pulmonary Fibrosis/drug therapy/metabolism
Mice
Signal Transduction/drug effects
*Smad2 Protein/metabolism
Smad3 Protein/metabolism
*Acetylcysteine/pharmacology/chemistry
Humans
Mice, Inbred C57BL
Inflammation/drug therapy/metabolism
Macrophages/metabolism
Male
Disease Models, Animal
Bleomycin
Nanoparticles/chemistry
Fibroblasts/drug effects
RAW 264.7 Cells

@article {pmid41579736,
year = {2026},
author = {Mah, E and Gallagher, D and Gao, F and Ramirez, J and Rabin, JS and Survilla, K and Vieira, D and Chen, JJ and Kang, Y and Andreazza, A and Herrmann, N and Kiss, A and Marzolini, S and Oh, P and Swardfager, W and Black, SE and Lanctôt, KL},
title = {Frontal white matter hyperintensity burden predicts cognitive response to N-acetylcysteine and exercise in vascular mild cognitive impairment.},
journal = {Neurobiology of aging},
volume = {161},
number = {},
pages = {39-46},
doi = {10.1016/j.neurobiolaging.2026.01.005},
pmid = {41579736},
issn = {1558-1497},
mesh = {Humans ; *Cognitive Dysfunction/therapy/pathology/psychology/diagnostic imaging/etiology ; *White Matter/pathology/diagnostic imaging ; Male ; Female ; Aged ; *Acetylcysteine/therapeutic use/administration & dosage ; *Cognition/drug effects ; Magnetic Resonance Imaging ; Executive Function ; *Exercise Therapy ; Treatment Outcome ; Middle Aged ; Aged, 80 and over ; *Frontal Lobe/pathology/diagnostic imaging ; },
abstract = {Vascular mild cognitive impairment (vaMCI) is a prodromal stage of dementia defined by cognitive deficits due to cerebrovascular disease. Increased white matter hyperintensity (WMH) volume has been associated with reduced executive function (EF). We explored whether lower baseline frontal and global WMH volume predicted an improvement in EF in vaMCI participants treated with N-acetylcysteine (NAC) and exercise as compared to placebo and exercise. Fifty-eight individuals with vaMCI received exercise therapy and were randomized to NAC or placebo. EF was assessed using the Trail Making Test Part B (TMT-B), Digit Symbol-Coding Test (DSCT), and a test of phonemic fluency, at baseline, 3 months, and 6 months. WMH volumes were measured from baseline magnetic resonance imaging scans. Linear mixed models were used. All participants improved on TMT-B (β = -0.185, SE = 0.046, p < 0.001) and phonemic fluency (β = 4.440, SE = 0.911, p < 0.001) over 6 months. A significant three-way interaction between baseline frontal WMH volume, treatment group, and timepoint predicted TMT-B performance at 3 months (β = 0.160, SE = 0.076, p = 0.039), but not at 6 months. No significant interactions were found for DSCT or phonemic fluency. Global WMH did not predict treatment response. Participants demonstrated improvement in EF regardless of treatment group and WMH volume. Lower frontal WMH volume predicted a greater improvement in TMT-B performance at 3 months in those treated with NAC versus placebo. These findings underscore the importance of considering participant heterogeneity in trials for vaMCI.},
}

Humans
*Cognitive Dysfunction/therapy/pathology/psychology/diagnostic imaging/etiology
*White Matter/pathology/diagnostic imaging
Male
Female
Aged
*Acetylcysteine/therapeutic use/administration & dosage
*Cognition/drug effects
Magnetic Resonance Imaging
Executive Function
*Exercise Therapy
Treatment Outcome
Middle Aged
Aged, 80 and over
*Frontal Lobe/pathology/diagnostic imaging

@article {pmid41579706,
year = {2026},
author = {Madhavan, A and Schiano-Visconte, M and Dutton, L and Cantalupo, M and Balasco, L and Mavillonio, A and Chelini, G and Bozzi, Y and Pangrazzi, L},
title = {Astaxanthin improves behavioural and immune dysfunction in the Shank3b mouse model of autism spectrum disorder.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {119051},
doi = {10.1016/j.biopha.2026.119051},
pmid = {41579706},
issn = {1950-6007},
mesh = {Animals ; *Autism Spectrum Disorder/drug therapy/immunology/psychology/genetics/metabolism ; *Nerve Tissue Proteins/genetics ; Disease Models, Animal ; Mice ; *Behavior, Animal/drug effects ; Mice, Knockout ; Cytokines/metabolism ; Male ; Oxidative Stress/drug effects ; Xanthophylls/pharmacology/therapeutic use ; *Antioxidants/pharmacology ; Mice, Inbred C57BL ; *Anti-Inflammatory Agents/pharmacology ; Social Interaction/drug effects ; Microfilament Proteins ; },
abstract = {Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviours. Numerous studies have associated ASD with immune dysregulation and inflammation, with neuroinflammatory processes reported in ASD individuals and mouse models. Altered immune cell profiles and cytokine levels have been observed in the peripheral blood (PB), supporting systemic immune dysfunction. Recently we showed that the administration of antioxidant molecule N-acetylcysteine (NAC) reduced oxidative stress and inflammation and counteracted behavioural deficits in two mouse models of ASD, providing a rationale for exploring other redox-active compounds. Here, we investigated the effects of astaxanthin (AST), potent antioxidant and anti-inflammatory molecule, in the Shank3b model (Shank3b[-/-] mice). AST treatment significantly improved core ASD-like behaviours, including social interaction deficits, motor incoordination, and repetitive grooming. In the cerebellum, AST reduced pro-inflammatory cytokines and counteracted microglial hyperactivation. In peripheral immune compartments, AST modulated cytokine expression. Pro-inflammatory markers were downregulated in Shank3b[-/-] mice in the bone marrow and spleen while they were elevated in Shank3b controls, suggesting immune rebalancing (i.e. adaptive modulation suppressing harmful inflammation while supporting protective immunity). As a limitation, oxidative stress assays were not performed here. Receiver operating characteristic (ROC) analysis suggests that TNF and IFNγ expression in peripheral immune cells may be promising biomarkers of treatment response. Notably, unlike NAC, AST did not induce pro-inflammatory effects in Shank3b[+/+] animals. These findings show that AST administration may counteract behavioural deficits and immune dysfunction in Shank3b[-/-] mice, therefore suggesting its potential as a safe immunomodulatory therapy for ASD.},
}

Animals
*Autism Spectrum Disorder/drug therapy/immunology/psychology/genetics/metabolism
*Nerve Tissue Proteins/genetics
Disease Models, Animal
Mice
*Behavior, Animal/drug effects
Mice, Knockout
Cytokines/metabolism
Male
Oxidative Stress/drug effects
Xanthophylls/pharmacology/therapeutic use
*Antioxidants/pharmacology
Mice, Inbred C57BL
*Anti-Inflammatory Agents/pharmacology
Social Interaction/drug effects
Microfilament Proteins

@article {pmid41577060,
year = {2026},
author = {Abdeltawab, M and Ebid, AH and Ahmed, O and Mobarez, MA and Ibrahim, M},
title = {N-acetylcysteine reduces incidence and duration of linezolid-associated thrombocytopenia in critically ill patients: A randomized controlled trial.},
journal = {Environmental toxicology and pharmacology},
volume = {122},
number = {},
pages = {104944},
doi = {10.1016/j.etap.2026.104944},
pmid = {41577060},
issn = {1872-7077},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration & dosage ; *Thrombocytopenia/chemically induced/prevention & control/epidemiology/drug therapy ; Male ; Critical Illness ; Middle Aged ; Female ; *Linezolid/adverse effects ; Aged ; Double-Blind Method ; Incidence ; Adult ; *Anti-Bacterial Agents/adverse effects ; Aged, 80 and over ; },
abstract = {Linezolid-associated thrombocytopenia (LAT) limits its use in critically ill patients. This double-blind, randomized, placebo-controlled trial evaluated intravenous N-acetylcysteine (IV NAC) for LAT prevention in 250 critically ill adults receiving linezolid for ≥ 48 h. Patients received IV NAC (600 mg every 12 h) or placebo. The primary endpoint was LAT incidence (platelet count <150 × 10 [3]/mm[3] or >50 % reduction from baseline). NAC significantly reduced LAT incidence (16.8 % vs. 41.6 %; p < 0.001), platelet transfusions (1.6 % vs. 11.2 %; p = 0.003), and linezolid discontinuations (6.4 % vs. 32.0 %; p < 0.001). NAC delayed LAT onset (adjusted hazard ratio 0.24; p < 0.001) and accelerated platelet recovery (adjusted hazard ratio 3.88; p = 0.011), with greatest benefit in moderate-severity cases. These findings suggest IV NAC may offer a preventive benefit against LAT in critically ill patients, though multicenter validation is needed to confirm generalizability across diverse clinical settings. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05944458. Registered on July 6, 2023.},
}

Humans
*Acetylcysteine/therapeutic use/administration & dosage
*Thrombocytopenia/chemically induced/prevention & control/epidemiology/drug therapy
Male
Critical Illness
Middle Aged
Female
*Linezolid/adverse effects
Aged
Double-Blind Method
Incidence
Adult
*Anti-Bacterial Agents/adverse effects
Aged, 80 and over

@article {pmid41575655,
year = {2026},
author = {Li, B and Liu, P and Yang, X and Li, M and Lei, L and Meng, Z and Song, Y and Lan, J and Ouyang, C and Ma, J and Liu, Q},
title = {NAC and DNase I synergistically reduce NETs to attenuate severe acute pancreatitis via suppressing the NETs/NF-κB/CXCL3 pathway.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {2},
pages = {58},
pmid = {41575655},
issn = {1573-675X},
mesh = {*Deoxyribonuclease I/pharmacology/therapeutic use ; *Extracellular Traps/drug effects/metabolism ; *NF-kappa B/metabolism/genetics ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Pancreatitis/drug therapy/metabolism/pathology ; Mice ; Signal Transduction/drug effects ; Male ; Humans ; Neutrophils/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Neutrophil extracellular traps (NETs) drive severe acute pancreatitis (SAP) progression by promoting pancreatic injury, duct obstruction, and systemic inflammation. Reactive oxygen species (ROS) are critical for NETs formation, while NETs degradation remains therapeutically challenging. This study investigates whether combined N-acetylcysteine (NAC) and deoxyribonuclease I (DNase I) therapy mitigates SAP and associated lung injury by suppressing NETs formation and degradation, respectively, and explores the underlying molecular mechanisms. NETs were elevated in SAP pancreatic tissue. In vitro, NAC reduced NETs formation by inhibiting oxidative stress, while DNase I degraded preformed NETs. Combined therapy surpassed monotherapy efficacy, synergistically attenuating NETs burden. In vivo, Early dual intervention degraded NETs, reduced neutrophil infiltration and apoptosis, and lowered inflammatory cytokines, thereby alleviating pancreatitis and lung injury. Mechanistically, dual therapy suppressed NF-κB activation in pancreatic tissue, decreasing CXCL3 release and subsequent CXCR2-positive neutrophil recruitment, ultimately ameliorating SAP. NAC and DNase I synergistically target NETs generation and clearance, offering a promising redox-based therapeutic strategy for SAP.},
}

*Deoxyribonuclease I/pharmacology/therapeutic use
*Extracellular Traps/drug effects/metabolism
*NF-kappa B/metabolism/genetics
Animals
*Acetylcysteine/pharmacology/therapeutic use
*Pancreatitis/drug therapy/metabolism/pathology
Mice
Signal Transduction/drug effects
Male
Humans
Neutrophils/drug effects/metabolism
Reactive Oxygen Species/metabolism
Mice, Inbred C57BL
Apoptosis/drug effects
Oxidative Stress/drug effects

@article {pmid41574386,
year = {2026},
author = {Yadav, N and Singh, R and Mondal, SK and Mandal, AK},
title = {Molecular insights of p-benzoquinone-induced red blood cell dysfunction: probable implications to cigarette smoke-associated pathologies.},
journal = {Free radical research},
volume = {60},
number = {1},
pages = {67-90},
doi = {10.1080/10715762.2026.2620638},
pmid = {41574386},
issn = {1029-2470},
mesh = {Humans ; *Erythrocytes/drug effects/metabolism/pathology ; *Benzoquinones/adverse effects/toxicity ; Oxidation-Reduction ; *Cigarette Smoking/adverse effects ; },
abstract = {Cigarette smoke (CS) is a complex mixture of numerous chemicals, including p-benzosemiquinone (pBSQ), which oxidizes to p-benzoquinone (pBQ) in the lungs of smokers and enters circulation. Despite its high reactivity, the direct impact of pBQ on human red blood cells (RBC) remains underexplored. Herein, we investigated the molecular insights into how pBQ compromises human RBC physiology and its role in mediating CS-associated pathologies by integrating redox biochemistry, membrane integrity, and omics-based approaches. Our findings reveal that pBQ disrupted redox homeostasis, evidenced by glutathione depletion, elevated reactive oxygen species, lipid peroxidation, and reduced antioxidant enzyme activity. pBQ also triggered methemoglobin formation, hemoglobin aggregation, and reduced oxygen-binding capacity. Biophysical analysis of RBCs revealed reduced membrane fluidity, alterations in membrane proteins and lipids, disrupted zeta potential, and sedimentation dynamics, suggesting altered deformability, an indication of impaired microvascular transit. Untargeted metabolomics and lipidomics profiling revealed metabolic reprogramming and remodeling of the membrane lipids. Depletion of polyunsaturated fatty acids alongside accumulation of saturated species in the membrane points toward membrane stiffening. Pathway analysis highlighted perturbations in fatty acid biosynthesis and redox homeostasis. Disease enrichment analysis linked these changes to hypertension and other pathologies that are previously linked to redox imbalance and CS exposure. Notably, NAC co-treatment mitigated these effects, preserving RBC integrity and redox homeostasis. These findings underscore that pBQ is a critical mediator of CS-induced RBC dysfunction and establish a mechanistic link to its contribution to smoking-associated complications.},
}

Humans
*Erythrocytes/drug effects/metabolism/pathology
*Benzoquinones/adverse effects/toxicity
Oxidation-Reduction
*Cigarette Smoking/adverse effects

@article {pmid41563857,
year = {2026},
author = {Race, NS and Uchida, K and Burcham, PC and Shi, R},
title = {Multimodal Toxicity of Acrolein and Associated Therapeutic Strategies in Central Nervous System Trauma and Disease.},
journal = {Annual review of biomedical engineering},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-bioeng-103023-035352},
pmid = {41563857},
issn = {1545-4274},
abstract = {Acrolein is a highly reactive α,β-unsaturated aldehyde produced endogenously through lipid peroxidation and enzymatic metabolism and exogenously via environmental exposures. Acrolein covalently adducts to DNA and proteins, leading to oxidative stress, mitochondrial dysfunction, and inflammation, including innate immune response activation via natural antibodies. Acrolein is difficult to measure in biological systems, but acrolein-bound covalent products can be measured reliably. Therapeutically, nucleophilic small molecules that scavenge acrolein such as hydralazine, phenelzine, dimercaprol, carnosine, and N-acetylcysteine (NAC) have shown neuroprotective effects in animal models of multiple sclerosis, Parkinson's disease, spinal cord injury, and traumatic brain injury. These effects include preserved membrane and mitochondrial integrity, reduced inflammation, reduced pain, and improved motor, sensory, and cognitive outcomes. Alternative strategies that enhance clearance or inhibit production of acrolein show promise but face limitations. Acrolein is a key pathophysiological mediator and a viable therapeutic target in central nervous system trauma and neurodegenerative diseases.},
}

@article {pmid41562319,
year = {2026},
author = {Hossen, F and Kouwaki, T and Fujiwara, Y and Tsutsuki, H and Zhang, T and Guo, C and Rahman, A and Komohara, Y and Oshiumi, H and Sawa, T},
title = {Therapeutic Efficacy of the Supersulfide Donor NAC-S2 in Influenza Virus Pneumonia via Suppression of Excessive Inflammatory Responses.},
journal = {Microbiology and immunology},
volume = {70},
number = {3},
pages = {148-159},
pmid = {41562319},
issn = {1348-0421},
support = {21H05267//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 21H05258//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 25H01029//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 25K02477//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 23K06362//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 23K07942//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 25K22315//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 23gm161001h001//Japan Agency for Medical Research and Development/ ; },
abstract = {Influenza pneumonia is characterized by excessive inflammatory responses that contribute to severe lung injury and mortality. Supersulfides, endogenously produced cysteine-derived persulfides and polysulfides, exert potent antioxidant, anti-ferroptotic, and anti-inflammatory activities; however, their therapeutic potential after disease onset remains unclear. Here, we investigated the efficacy of N-acetylcysteine tetrasulfide (NAC-S2), a highly water-soluble and cell-permeable supersulfide donor, in a mouse model of influenza A virus (IAV)-induced pneumonia. Subcutaneous administration of NAC-S2 rapidly elevated systemic levels of cysteine- and glutathione-derived supersulfides. In therapeutic treatment starting 2 days post-infection, when body weight loss and clinical signs had already developed, NAC-S2 significantly improved survival and mitigated body weight loss compared with vehicle and oxidized NAC controls. Metabolomic analysis revealed that influenza virus infection depleted lung glutathione persulfide (GSSH), while NAC-S2 effectively restored tissue GSSH levels. NAC-S2 treatment markedly reduced pulmonary interleukin (IL)-1β and IL-6 production without affecting viral load or Type-I interferon responses. Furthermore, NAC-S2 suppressed NLRP3 inflammasome activation and gasdermin D expression, leading to decreased infiltration of CD3[+] T cells and myeloperoxidase-positive neutrophils. Histopathological analyses confirmed that NAC-S2 ameliorated epithelial injury, interstitial edema, and hemorrhage in infected lungs. Collectively, our findings demonstrate that NAC-S2 exerts therapeutic benefit even after the onset of severe influenza pneumonia, primarily by replenishing supersulfides and alleviating excessive inflammatory responses. Supersulfide donors represent a promising class of adjunctive therapeutics for severe viral pneumonia.},
}

@article {pmid41559638,
year = {2026},
author = {Li, H and Shen, H and Duan, X and Guo, M and Liu, X},
title = {Efficacy and safety of anti-inflammatory drug-assisted treatment of symptoms in patients with schizophrenia: a meta-analysis.},
journal = {BMC psychiatry},
volume = {26},
number = {1},
pages = {161},
pmid = {41559638},
issn = {1471-244X},
support = {Grant No. 202101BA070001-119//the Special Basic Research Cooperative Research Programs of the Yunnan Provincial Undergraduate Universities' Association/ ; Grant No. 202305AS350001//the Program for Innovative Research Team of Yunnan Province/ ; Grant No. AT2024002//the Yunnan Province Insect Biomedicine Research and Development Key Laboratory Open Project/ ; },
abstract = {BACKGROUND: Although anti-inflammatory agents have been explored as adjunctive treatments for schizophrenia, findings remain inconsistent. While some meta-analyses suggest benefit, concerns persist regarding methodological heterogeneity, language bias, and the influence of publication bias on reported effect sizes (ES). This updated meta-analysis aims to re-evaluate the efficacy and safety of anti-inflammatory drugs in schizophrenia, with a critical focus on robustness after accounting for these biases.

METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating anti-inflammatory drugs as adjunctive therapy in schizophrenia. Databases (PubMed, Embase, Scopus, Web of Science) were searched from inception to December 31, 2024, with restriction to English-language publications. Standardized mean differences (Hedges’s g) were calculated using a random-effects model. Heterogeneity was assessed using I², and publication bias was evaluated via Egger’s test and trim-and-fill analysis. Sensitivity analyses were performed to assess robustness.

RESULTS: Seventy-four RCTs involving 5,484 participants were included. Initial analyses suggested significant benefits for aspirin (ES = 0.64), celecoxib (ES = 0.49), estrogens (ES = 0.59), fatty acids (ES = 0.25), minocycline (ES = 0.38), N-acetylcysteine (NAC; ES = 0.60), monoclonal antibodies (mAbs; ES = 0.49), and pregnenolone (ES = 0.20). However, substantial heterogeneity (I² > 50%) and significant publication bias were detected for several agents, including estrogens (p < 0.001) and minocycline (p = 0.01). Trim-and-fill analysis indicated that the observed effects for estrogens and minocycline were likely inflated, with adjusted ES falling below conventional thresholds for statistical significance in some cases. Sensitivity analyses excluding high-risk-of-bias studies further weakened the evidence for several compounds. No significant benefit was found for statins or varenicline.

CONCLUSION: While some anti-inflammatory agents initially appear beneficial as adjunctive treatments in schizophrenia, these findings are tempered by high heterogeneity, potential language bias (due to exclusive inclusion of English-language studies), and significant publication bias. After correction for these biases, the clinical significance of many reported effects diminishes. Current evidence does not robustly support routine clinical use of these agents outside of research settings. Future large-scale, long-term, and globally representative RCTs with rigorous reporting standards are needed to determine whether any anti-inflammatory strategy offers reproducible and clinically meaningful benefits.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12888-026-07774-y.},
}

@article {pmid41558638,
year = {2026},
author = {Moseanko, A and Ginwalla, C and Eidman, M and Dash, S and Lewis, J and Albertson, TE},
title = {Pediatric Intravenous Acetaminophen Overdoses: A Continuing Iatrogenic Problem.},
journal = {Hospital pediatrics},
volume = {16},
number = {2},
pages = {e114-e118},
doi = {10.1542/hpeds.2025-008624},
pmid = {41558638},
issn = {2154-1671},
mesh = {Humans ; *Acetaminophen/poisoning/administration & dosage ; *Drug Overdose/epidemiology/drug therapy ; Retrospective Studies ; Child, Preschool ; Male ; Female ; Child ; *Iatrogenic Disease/epidemiology ; Acetylcysteine/therapeutic use ; California/epidemiology ; Infant ; *Analgesics, Non-Narcotic/poisoning/administration & dosage ; Adolescent ; Administration, Intravenous ; *Medication Errors/statistics & numerical data ; Poison Control Centers/statistics & numerical data ; Antidotes/therapeutic use ; },
abstract = {OBJECTIVE: To determine if intravenous (IV) acetaminophen use in children remains a source of iatrogenic overdosing.

METHODS: A cluster of 3 index cases in early 2025 stimulated a 14-year (2011-2024) retrospective study of calls from health care facilities to the California Poison Control System (CPCS) involving IV acetaminophen dosing errors in children aged 16 years or younger. All calls during this period that involved pediatric IV acetaminophen were reviewed and data abstracted. Date of call, age of child, location in the hospital, laboratory results, acetaminophen levels, intended dose, dose given, use of N-acetylcysteine (NAC), and outcomes were recorded. Descriptive statistics were used.

RESULTS: The 3 index pediatric cases of IV acetaminophen overdose ranged from 3 to 10 times the desired dose. Two of the 3 patients were treated with NAC. The retrospective review of CPCS calls resulted in 42 additional cases in which intravenous dosing errors occurred with mean doses of 45.5 ± 36.7 mg/kg (range, 14.7-147.1 mg/kg) and mean age of 4.9 years ± 4.0 (1 day to 16 years). Two additional patients were treated with NAC. These adverse events happened in operative/perioperative areas (13 cases), 11 cases on the pediatric inpatient units, 5 in intensive care units, 12 in the emergency department, and 4 in unknown areas. No long-term adverse effects were seen in the 45 children.

CONCLUSION: Rare pediatric iatrogenic IV acetaminophen overdoses continue to be seen in acute care settings. Determining potential toxicity and the need for NAC remains challenging. Further efforts are needed to prevent this infrequent serious medication error.},
}

Humans
*Acetaminophen/poisoning/administration & dosage
*Drug Overdose/epidemiology/drug therapy
Retrospective Studies
Child, Preschool
Male
Female
Child
*Iatrogenic Disease/epidemiology
Acetylcysteine/therapeutic use
California/epidemiology
Infant
*Analgesics, Non-Narcotic/poisoning/administration & dosage
Adolescent
Administration, Intravenous
*Medication Errors/statistics & numerical data
Poison Control Centers/statistics & numerical data
Antidotes/therapeutic use

@article {pmid41558404,
year = {2026},
author = {Aral, H and Aral, T and Sunkur, M and Çolak, M and Bağcık, M},
title = {N-acetylcysteine-functionalised a multimodal HPLC stationary phase for broad-range separations.},
journal = {Talanta},
volume = {302},
number = {},
pages = {129397},
doi = {10.1016/j.talanta.2026.129397},
pmid = {41558404},
issn = {1873-3573},
abstract = {In this study, a new multimodal HPLC stationary phase derived from N-acetyl-l-cysteine was synthesized and comprehensively evaluated across a broad polarity spectrum. In chromatographic stationary phase design, two fundamental criteria are particularly important: a facile, low-cost synthesis and broad applicability across diverse analyte classes. The present stationary phase fulfils both requirements, as it is prepared from a commercially available starting material via a simple single-step immobilisation onto silica, providing a practical and economical synthetic route alongside wide analytical utility. The molecular architecture of the ligand, incorporating a pH-responsive carboxyl group, a hydrogen-bond-donating and -accepting amide moiety, a polarisation-sensitive sulfur atom, and hydrophobic methyl and methylene units, creates a versatile interaction environment capable of mediating hydrophobic, polar, dispersive, and weak cation-exchange processes. This multifunctional design enables the stationary phase to adapt its selectivity according to analyte structure and mobile-phase conditions, supporting both reversed-phase-like and HILIC-like retention behaviour within a single chromatographic platform. The chromatographic performance of the NAC-derived stationary phase was systematically evaluated using a wide range of chemically and biologically relevant analytes. Under HILIC conditions, the column successfully resolved 7 of the 9 highly polar nucleobases and nucleosides. In reversed-phase mode, compounds with high hydrophobicity-including 6 alkyl benzenes, 4 polycyclic aromatic hydrocarbons, 6 Sudan dyes, 8 anilines, and 7 benzoic acid derivatives-were efficiently separated. Under the same reversed-phase conditions, the stationary phase successfully resolved 10 analytes from a twelve-analyte plant growth regulator mixture and 9 sulphonamides. In addition, a 6 herbicide was also effectively separated, highlighting the multimodal selectivity of the stationary phase. Retention trends were interpreted using analyte logD and pKa values, clarifying the combined contributions of hydrophobic, polar, and weak ion-exchange interactions to overall selectivity. The N-acetyl-l-cysteine-based stationary phase provides a finely balanced interaction profile, enabling high separation performance for analytes spanning from extreme polarity to pronounced hydrophobicity and demonstrating broad analytical utility.},
}

@article {pmid41553565,
year = {2026},
author = {Altındağ, F and İgit, T},
title = {Berberine and N-Acetylcysteine ameliorate diabetes-induced hippocampal damage by inhibiting apoptosis and neuroinflammation, and improve synaptic plasticity in rats.},
journal = {Journal of molecular histology},
volume = {57},
number = {1},
pages = {54},
pmid = {41553565},
issn = {1567-2387},
support = {TDK-2021-9565//Van Yuzuncu Yil University Scientific Research Coordination Unit/ ; TDK-2021-9565//Van Yuzuncu Yil University Scientific Research Coordination Unit/ ; },
mesh = {Animals ; *Apoptosis/drug effects ; *Berberine/pharmacology/therapeutic use ; *Acetylcysteine/pharmacology/therapeutic use ; *Diabetes Mellitus, Experimental/complications/pathology/drug therapy ; Rats ; *Hippocampus/drug effects/pathology/metabolism ; Male ; *Neuronal Plasticity/drug effects ; *Neuroinflammatory Diseases/drug therapy/pathology/etiology ; },
abstract = {Diabetes Mellitus (DM) is a metabolic disease characterized by hyperglycemia resulting from impaired insulin secretion and resistance. Berberine (BBR) and N-acetylcysteine are anti-inflammatory and antiapoptotic compounds that have beneficial effects on diabetic complications. This study aimed to investigate the effects of BBR and NAC on the Hippocampus in an experimental diabetes model in rats. Rats were divided into 5 groups: control, diabetes (D), D + NAC, D + BBR, and D + BBR + NAC. STZ (45 mg/kg, i.p.) was administered to the other four groups except the control group. BBR and NAC (50 mg/kg/day) were given intragastrically (i.g.) to the treatment groups for 28 days. Decreased cell body size, pyknotic cells and necrotic neurons were observed in the D group. However, these pathological changes were largely improved in the D + BBR, D + NAC, and D + BBR + NAC. Stereologically, there was no significant difference between the groups in terms of hippocampus volume. The number of pyramidal neurons in CA1 was significantly decreased in the D group. But the number of CA1 pyramidal neurons was higher in both the alone and combined BBR and NAC treatment groups than in the D group. Expressions of Caspase-3, TNF-α, and IL-1β increased in the D group, while expressions of Bcl-2 and SYP decreased. But, BBR and NAC treatments decreased Caspase-3, TNF-α, and IL-1β expressions and increased Bcl-2 and SYP expressions. These results revealed that BBR and NAC can have an antidiabetic effect against the neuronal damage caused by diabetes in the hippocampus CA1 region, suppressing inflammation and apoptosis and preventing the decrease in the number of pyramidal neurons. Also, they reveal that they may modulate synaptic plasticity by increasing synaptophysin expression.},
}

Animals
*Apoptosis/drug effects
*Berberine/pharmacology/therapeutic use
*Acetylcysteine/pharmacology/therapeutic use
*Diabetes Mellitus, Experimental/complications/pathology/drug therapy
Rats
*Hippocampus/drug effects/pathology/metabolism
Male
*Neuronal Plasticity/drug effects
*Neuroinflammatory Diseases/drug therapy/pathology/etiology

@article {pmid41552353,
year = {2025},
author = {Wu, Y and Yao, J and Zhang, Y},
title = {Effects of acetylcysteine combined with bronchoalveolar lavage under fiberoptic bronchoscopy on blood oxygenation and inflammation in elderly severe pneumonia patients.},
journal = {American journal of translational research},
volume = {17},
number = {12},
pages = {9317-9326},
pmid = {41552353},
issn = {1943-8141},
abstract = {OBJECTIVE: To determine the effects of acetylcysteine (NAC) plus bronchoalveolar lavage (BAL) under fiberoptic bronchoscopy (FB) on blood oxygenation and inflammation in elderly severe pneumonia patients.

METHODS: The data of 180 elderly patients with severe pneumonia treated in the Affiliated Hospital 2 of Nantong University between January 2022 and January 2024 were analyzed retrospectively. Eighty-six patients were treated with BAL under FB (BAL group) and 94 patients were treated with NAC based on BAL under FB (BAL + NAC group). Outcomes included pre-/post-treatment blood gas, pulmonary function, inflammatory factors, correlation between inflammatory markers and blood gas parameters, clinical efficacy, symptom resolution time, and adverse reactions.

RESULTS: After treatment, both groups exhibited an increase in arterial partial pressure of oxygen (PaO2), arterial oxygen saturation (SaO2), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and decreased C-reactive protein (CRP) and interleukin-6 (IL-6), with more significant changes in the BAL + NAC group (all P < 0.05). Inflammatory markers (CRP/IL-6) were negatively correlated with oxygenation parameters (PaO2/SpO2, all P < 0.01). Additionally, the BAL + NAC group had earlier resolution time of chest pain, expectoration, cough, and lung rales, a higher overall response rate, and no significant difference in adverse reaction incidence versus the BAL group.

CONCLUSION: NAC combined with BAL under FB is effective for elderly patients with severe pneumonia. It can strongly improve the blood gas indexes and lung function, relieve inflammatory reactions, and quickly relieve clinical symptoms, without increasing adverse reactions. Thus it is worthy of clinical promotion.},
}

@article {pmid41550647,
year = {2025},
author = {Zheng, Z and Chen, Z and Zhang, C and Peng, S and Hu, J and Wang, C and Liu, L and Yang, MX and Chen, H},
title = {Enhancing ferroptosis and inhibiting ABCB1 make the novel aldose reductase inhibitor 5F-E a promising sensitizer in liver cancer.},
journal = {Pharmaceutical science advances},
volume = {3},
number = {},
pages = {100088},
pmid = {41550647},
issn = {2773-2169},
abstract = {Multidrug resistance (MDR) poses a critical barrier to chemotherapy efficacy. While the promising agents, aldose reductase inhibitors (ARIs), to overcome multidrug resistance (MDR) has been investigated over recent decades, their underlying mechanisms remain unclear and clinically viable candidates are still lacking. In our study, we identified a novel ARI, 5F-E, which exhibited a more potent sensitizing effect on doxorubicin (DOX) resistant HepG2 cells (HepG2/ADR) compared to epalrestat (EPA). Both 5F-E and EPA were observed to decrease intracellular GSH levels while elevating reactive oxygen species (ROS), Fe[2+] and lipid peroxidation; these effects could be reversed by N-acetyl cysteine (NAC), suggesting that enhanced ferroptosis may be involved in restoring DOX sensitivity. Furthermore, inhibition of AKR1B1 by either compound led to marked reductions in p-STAT3 and SLC7A11 expression, an outcome that was recapitulated by AKR1B1 gene knockdown. The results demonstrate that ARIs exert antitumor effects on HepG2/ADR cells by triggering ferroptosis, a process dependent on AKR1B1/STAT3/SLC7A11 signaling. And, 5F-E, but not EPA, was found to increase intracellular DOX accumulation by inhibiting ABCB1. Our integrated experimental approach reveals that 5F-E exhibits strong chemosensitizing effects against multidrug-resistant liver cancer, highlighting its therapeutic promise.},
}

@article {pmid41547222,
year = {2026},
author = {Su, H and Wu, F and Haque, K and Sha, SH},
title = {Furosemide prevents noise-induced hearing loss and enhances the preventive effect of N-acetylcysteine.},
journal = {Hearing research},
volume = {471},
number = {},
pages = {109537},
doi = {10.1016/j.heares.2026.109537},
pmid = {41547222},
issn = {1878-5891},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration & dosage ; *Hearing Loss, Noise-Induced/prevention & control/physiopathology/metabolism/pathology ; *Furosemide/pharmacology/administration & dosage ; Mice ; Disease Models, Animal ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Auditory Threshold/drug effects ; Reactive Oxygen Species/metabolism ; *Antioxidants/pharmacology ; Male ; Drug Synergism ; *Cochlea/drug effects/physiopathology/metabolism ; Hair Cells, Auditory, Outer/drug effects/metabolism/pathology ; *Hearing/drug effects ; },
abstract = {Disruption of reactive oxygen species (ROS) homeostasis is a key mechanism underlying noise-induced sensory hair cell damage. Antioxidant treatments such as N-acetylcysteine (NAC) have been shown to attenuate noise-induced hearing loss (NIHL), supporting the role of ROS accumulation. However, no FDA-approved pharmaceutical therapy currently exists for the prevention or treatment of NIHL, likely due to the complexity of the damaging mechanisms and the presence of the blood-labyrinth barrier (BLB), which limits drug permeability and prevents therapeutic compounds from reaching effective concentrations via systemic administration. Furosemide (FRS) has demonstrated potential to reduce NIHL and facilitate drug delivery into inner ear by transiently opening the BLB. In this study, we investigated the mechanisms by which FRS pretreatment prevents NIHL. A single dose of 200 mg/kg FRS administered immediately before noise exposure significantly reduced NIHL in FVB/NJ mice. One hour after FRS treatment, the endocochlear potential (EP) was temporarily reduced without altering cochlear sensitivity (ABR thresholds), outer hair cell function (DPOAE amplitudes), or synaptic transmission integrity between hair cells and auditory nerve fibers (suprathreshold ABR wave I amplitudes). Furthermore, this dose of FRS selectively increased stria vascularis permeability to small molecules but not to large protein-bound tracers. Combined treatment with FRS and NAC enhanced NAC's antioxidant effect and additively prevented noise-induced outer hair cell (OHC) loss and NIHL, with OHC loss almost entirely prevented. These findings provide important insight into future strategies for the prevention and treatment of NIHL.},
}

Animals
*Acetylcysteine/pharmacology/administration & dosage
*Hearing Loss, Noise-Induced/prevention & control/physiopathology/metabolism/pathology
*Furosemide/pharmacology/administration & dosage
Mice
Disease Models, Animal
Evoked Potentials, Auditory, Brain Stem/drug effects
Auditory Threshold/drug effects
Reactive Oxygen Species/metabolism
*Antioxidants/pharmacology
Male
Drug Synergism
*Cochlea/drug effects/physiopathology/metabolism
Hair Cells, Auditory, Outer/drug effects/metabolism/pathology
*Hearing/drug effects

@article {pmid41546819,
year = {2026},
author = {Elhence, A and Mishra, P and Rai, P},
title = {N‑acetylcysteine for post-ERCP pancreatitis prophylaxis: A systematic review and meta-analysis.},
journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology},
volume = {},
number = {},
pages = {},
pmid = {41546819},
issn = {0975-0711},
abstract = {BACKGROUND: Oxidative stress is an early step in the cascade of events triggering post-ERCP pancreatitis (PEP). N-acetylcysteine (NAC), a free radical scavenger, can be used to check this oxidative stress for PEP prophylaxis. METHODS: A systematic search of MEDLINE, EMBASE and Scopus was undertaken from inception to May 30, 2025. The relative risks (RR) of PEP and severe PEP were pooled using a random effects model with the inverse variance method. Funnel plot and Egger's test were used to evaluate publication bias. The quality of studies was assessed using the Cochrane risk of bias tool. Further sensitivity analysis was undertaken to evaluate oral route dosing and a leave-alone-one sensitivity analysis was done to confirm the robustness of the results (PROSPERO ID CRD420251062268).

RESULTS: The five studies meeting the inclusion criteria included 784 participants of which 388 received NAC and 396 received placebo. PEP occurred in 50 participants in the NAC group as compared to 68 participants in the placebo group with a pooled RR of 0.74 (95% confidence interval [CI] 0.48 to 1.15) with moderate heterogeneity, I[2] 35%. Severe PEP occurred in none of the participants administered NAC as compared to three participants administered placebo with a pooled RR of 0.27 (95% CI of 0.03 to 2.43), with I[2] of 0% and no publication bias confirmed by no funnel plot visual asymmetry or Egger's test (p = 0.220). Sensitivity analysis confirmed the robustness of the results.

CONCLUSION: The pooled results of the meta-analysis suggest that NAC prophylaxis does not prevent the occurrence of PEP or severe PEP as compared to placebo.},
}

@article {pmid41546041,
year = {2026},
author = {Wu, PH and Cheng, N and Lo, WC and Chang, CM and Cheng, PW and Liu, SH},
title = {Functional and biochemical protection by combined N-acetylcysteine and D-methionine in guinea pig noise-induced hearing loss.},
journal = {Head & face medicine},
volume = {22},
number = {1},
pages = {},
pmid = {41546041},
issn = {1746-160X},
abstract = {PURPOSE: This study examined whether combining antioxidants could enhance protection and permit lower dosing for treating noise-induced hearing loss (NIHL). The therapeutic effects of D-methionine (DMET) and N-acetylcysteine (NAC) were evaluated in a guinea pig model.

METHODS: Ninety-six guinea pigs were randomly assigned to eight groups: control, saline, three NAC-only groups (100, 150, 200 mg/kg), and three NAC + DMET groups (100, 200, 400 mg/kg). One hour after six hours of broadband noise exposure, treatments were administered intraperitoneally every 12 h for seven days. Auditory brainstem responses (ABR) were measured before exposure and on day 14. Cochlear tissues were analyzed for Na⁺/K⁺-ATPase and Ca²⁺-ATPase activities and lipid peroxidation (LPO) levels.

RESULTS: No significant body weight differences were observed between saline and treated groups. NAC alone and in combination with DMET improved ABR thresholds in a dose-dependent manner. The combined NAC (200 mg/kg) + DMET (400 mg/kg) group achieved complete ABR recovery. Noise-induced reductions in ATPase activities were dose-dependently reversed by both treatments. The highest-dose combination restored 87.3% of Na⁺/K⁺-ATPase and 94.7% of Ca²⁺-ATPase activity compared to controls. LPO levels declined with increasing NAC doses, with NAC 200 mg/kg alone showing the greatest reduction.

CONCLUSIONS: Combined NAC (200 mg/kg) and DMET (400 mg/kg) yielded the most substantial functional protection against NIHL. This combination was accompanied by lower LPO levels and higher Na⁺/K⁺-ATPase and Ca²⁺-ATPase activities in the cochlear lateral wall, indicating a potential role in maintaining cochlear homeostasis following acoustic injury.},
}

@article {pmid41541699,
year = {2026},
author = {Ahmad, F and Rendina, BP and Chen, C and Ren, H and Brantner, C and Dukic, T and Miles, D and Winkles, JA and Woodworth, GF and Bhetawal, S and Stone, E and Bar, EE},
title = {Systemic cyst(e)inase administration induces ferroptosis and synergizes with temozolomide in glioblastoma.},
journal = {iScience},
volume = {29},
number = {1},
pages = {114350},
pmid = {41541699},
issn = {2589-0042},
abstract = {Glioblastoma exhibits profound therapeutic resistance, driven by tumor heterogeneity and highly plastic glioma stem cells (GSCs). This study exploits GSC metabolic dependence on cysteine using systemic cyst(e)inase, a cysteine-degrading enzyme. In patient-derived GSCs and orthotopic xenograft models, cyst(e)inase potently inhibited GSC proliferation and extended animal survival by inducing ferroptosis. Mechanistically, cyst(e)inase triggered elevated reactive oxygen species (ROS), glutathione (GSH) depletion, and significant lipid peroxidation. Crucially, these effects were reversed by N-acetylcysteine (NAC), and lipid peroxidation was abrogated by the iron chelator deferoxamine (DFX), unequivocally confirming iron-dependent ferroptosis. Characteristic mitochondrial morphological changes further validated ferroptosis induction. Acyl-CoA synthetase long-chain family member-4 (ACSL4) was identified as essential for this process. Critically, cyst(e)inase synergized with temozolomide (TMZ), markedly enhancing its anti-tumor efficacy and prolonging survival, even in TMZ-resistant xenografts. These findings establish cysteine metabolism as a promising therapeutic target and position cyst(e)inase, especially with TMZ, as a potent strategy to overcome GBM resistance.},
}

@article {pmid41537173,
year = {2026},
author = {Wang, S and Zhang, F and Zhou, X and Yang, J and Li, Z and Li, S and Lu, Q and Sun, H and Liu, P},
title = {Chondrocyte-Targeted Nanoparticles Loaded with N-Acetylcysteine Protect Articular Cartilage and Attenuate Osteoarthritis by Inhibiting Ferroptosis via Glutathione Maintenance.},
journal = {Small science},
volume = {6},
number = {1},
pages = {e202500440},
pmid = {41537173},
issn = {2688-4046},
abstract = {Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation. Abnormal mechanical loading exacerbates intracellular ROS accumulation and glutathione (GSH) depletion. While N-acetylcysteine (NAC) has potent antioxidant properties, its therapeutic potential in OA is limited by rapid degradation and poor intraarticular retention. In this study, chondrocyte-targeted, chondroitin sulfate (CS)-modified PLGA nanoparticles (CS-NAC-NPs) is developed for sustained and localized delivery of NAC. These nanoparticles exhibit excellent physical and chemical properties, biocompatibility, and chondrocyte targeting capabilities. In vitro, CS-NAC-NPs attenuated mechanical stress-induced ROS accumulation, preserved mitochondrial integrity, restored GSH levels, and suppressed ferroptosis, as evidenced by increased GPX4 expression and improved chondrocyte viability. In a murine model of OA, intraarticular injection of CS-NAC-NPs significantly reduced cartilage degradation and osteophyte formation, improved histological scores, and maintained extracellular matrix homeostasis more effectively than free NAC or nontargeted NAC-NPs. Notably, the therapeutic effect is abolished in GPX4-deficient mice, confirming that CS-NAC-NPs act via GPX4-mediated ferroptosis inhibition. Furthermore, in vivo tracking demonstrated excellent joint retention and no off-target toxicity, underscoring their translational safety. This study introduces a novel nanotherapeutic platform that couples biomechanical targeting with redox-responsive delivery to modulate ferroptosis, offering a promising disease-modifying approach for OA treatment.},
}

@article {pmid41535111,
year = {2026},
author = {Afşar, E and Öz, M and Özkan, E and Eranıl, I},
title = {Maternal Immune Activation Disrupts Autophagy and Glucose Homeostasis: Experimental Evidence for the Protective Effects of N-Acetylcysteine on Maternal and Offspring Outcomes in a Rat Model.},
journal = {Journal of applied toxicology : JAT},
volume = {46},
number = {4},
pages = {1372-1388},
doi = {10.1002/jat.70063},
pmid = {41535111},
issn = {1099-1263},
support = {KÜN.2025-BAGP-005//Kapadokya University/ ; },
mesh = {Animals ; Female ; *Acetylcysteine/pharmacology ; *Autophagy/drug effects/immunology ; Pregnancy ; Rats, Wistar ; Homeostasis/drug effects ; Rats ; Male ; Lipopolysaccharides/toxicity ; *Glucose/metabolism ; *Prenatal Exposure Delayed Effects/immunology ; *Blood Glucose/drug effects ; Insulin Resistance ; },
abstract = {Maternal immune activation during pregnancy has been shown to disrupt maternal glucose regulation, predisposing the mother to postpartum diabetic conditions while also exerting long-lasting metabolic effects on the offspring. This study aimed to investigate the impact of lipopolysaccharide (LPS)-induced maternal immune activation on glucose homeostasis at different postpartum stages, the modulatory role of N-acetylcysteine (NAC), and the effects on the offspring, including sex-specific differences. Albino Wistar female and male rats were used; pregnant females received a single intraperitoneal injection of LPS (0.5 mg/kg) on gestational day 16, with a subset pretreated with NAC (300 mg/kg). Mothers were sacrificed at the end of gestation or on postpartum day 21 (PP21), and offspring were analyzed at PP21. Maternal glucose tolerance was assessed using OGTT, and HOMA-IR and HOMA-β indices were used to determine insulin resistance and β-cell function. Maternal and offspring tissues were analyzed for key markers of signaling, autophagy, proliferation, apoptosis, and inflammation. Phosphorylated protein kinase B (p-Akt), mammalian target of rapamycin (mTOR), Ki-67 (a proliferation marker), phosphorylated AMP-activated protein kinase (p-AMPK), Beclin-1, and microtubule-associated protein 1 light chain 3 beta (LC3B) were measured in tissue homogenates; pancreatic insulin and pro-insulin levels were determined; plasma cytokines, including interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), as well as cleaved caspase-3. All of them were quantified using enzyme-linked immunosorbent assay (ELISA) kits. Total antioxidant capacity (TAC) and total oxidant status (TOS) were measured in plasma using colorimetric assays. At PP0, LPS decreased muscle glucose uptake, increased hepatic gluconeogenesis and glucose output, and enhanced pancreatic insulin production, autophagy, apoptosis, and proliferation while maintaining plasma glucose levels, indicating an adaptive response. NAC improved muscle glucose uptake, suppressed hepatic gluconeogenesis, and normalized pancreatic changes. At PP21, LPS exposure led to increased hepatic gluconeogenesis, impaired pancreatic function, and higher plasma glucose levels. NAC reduced hepatic gluconeogenesis but did not restore glucose balance and worsened pancreatic dysfunction. In offspring of LPS-treated dams, IL-6, TNF-α, and IFN-γ levels decreased, whereas IL-10 increased only in females. Markers of pancreatic apoptosis, autophagy, and proliferation were reduced in both sexes. NAC exposure decreased IL-10 and increased IL-6, TNF-α, and IFN-γ in all offspring and selectively enhanced pancreatic markers in males. Maternal LPS exposure differentially affected glucose regulation through the muscle, liver, and pancreas across postpartum stages. NAC exerted beneficial effects mainly in the early postpartum period but was insufficient later. Furthermore, NAC induced sex-specific effects in the offspring, with a more substantial impact observed in males.},
}

Animals
Female
*Acetylcysteine/pharmacology
*Autophagy/drug effects/immunology
Pregnancy
Rats, Wistar
Homeostasis/drug effects
Rats
Male
Lipopolysaccharides/toxicity
*Glucose/metabolism
*Prenatal Exposure Delayed Effects/immunology
*Blood Glucose/drug effects
Insulin Resistance

@article {pmid41534829,
year = {2026},
author = {Yadav, A and Richartz, N and Bhagwat, S and Burman, MM and Munthe-Kaas, MC and Skålhegg, BS and Wik, JA and Naderi, S and Blomhoff, HK},
title = {Starvation of leukemic cells enhances DNA damage-induced apoptosis in vitro via ROS/p38 MAPK and prevents leukemia progression in fasting xenograft mice.},
journal = {The Journal of biological chemistry},
volume = {302},
number = {3},
pages = {111143},
pmid = {41534829},
issn = {1083-351X},
abstract = {Most children with acute lymphoblastic leukemia (ALL) achieve long-term survival due to intensive multimodal chemotherapy. However, the use of cytotoxic DNA-damaging agents is frequently associated with severe long-term side effects, prompting continued efforts to improve treatment strategies. This study explores the potential of starving the leukemic cells to enhance the efficacy of DNA-damaging therapy in ALL. Previous work demonstrated that cAMP signaling attenuates DNA damage-induced apoptosis in ALL cells, both in vitro and in a xenograft model. The current findings show that glucose and serum deprivation reverse the effect of cAMP, converting it from a survival factor to a promoter of DNA damage-induced apoptosis in ALL-derived cell lines and patient-derived leukemic cells in vitro. The starvation-induced sensitization was independent of p53 but was shown to require increased levels of reactive oxygen species (ROS). In turn, the elevated ROS levels enhanced the activation of the mitogen-activated protein kinase p38 (p38 MAPK). The resulting augmented cell death was inhibited both by the ROS scavenger N-acetyl cysteine and the p38 MAPK inhibitor SB 202190. The translational potential of increasing the efficacy of DNA damaging agents in starving ALL cells was supported by in vivo data showing that intermittent fasting, combined with subtherapeutic doses of irradiation, significantly inhibits the leukemia progression in a xenograft model of severe combined immunodeficiency mice.},
}

@article {pmid41534554,
year = {2026},
author = {Fu, W and Yan, Y and Shu, C and Xu, C and Chen, Y and Xia, Y and Chen, J and Chen, Y and Cui, R and Zou, P and Ni, D},
title = {6-Methoxydihydrosanguinarine synergizes with cisplatin to enhance lung cancer cell death via ROS-mediated autophagy, ER stress, and JNK activation.},
journal = {European journal of pharmacology},
volume = {1014},
number = {},
pages = {178544},
doi = {10.1016/j.ejphar.2026.178544},
pmid = {41534554},
issn = {1879-0712},
mesh = {Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Cisplatin/pharmacology ; *Lung Neoplasms/pathology/metabolism/drug therapy ; *Autophagy/drug effects ; Drug Synergism ; Cell Line, Tumor ; *Carcinoma, Non-Small-Cell Lung/pathology/drug therapy/metabolism ; *Isoquinolines/pharmacology ; *Benzophenanthridines/pharmacology ; MAP Kinase Signaling System/drug effects ; *Antineoplastic Agents/pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Animals ; },
abstract = {6-Methoxydihydrosanguinarine is a natural alkaloid derived from medicinal plants that exhibits significant antitumor activity, making it a promising candidate for cancer therapy. However, the exact molecular mechanisms underlying its effects require further investigation. In this study, we investigated the cytotoxicity and underlying mechanisms of 6-Methoxydihydrosanguinarine in human non-small cell lung cancer (NSCLC) cells. Our findings reveal that reactive oxygen species (ROS) accumulation is the key driver of its antitumor activity. Mechanistically, 6-Methoxydihydrosanguinarine activates the JNK signaling pathway and induces endoplasmic reticulum (ER) stress, both of which can be reversed by the ROS scavenger N-acetylcysteine (NAC). Interestingly, 6-Methoxydihydrosanguinarine also activates autophagy, and inhibition of autophagy reverses the JNK and ER stress pathway activation induced by 6-Methoxydihydrosanguinarine. Notably, 6-Methoxydihydrosanguinarine synergistically enhances cisplatin-induced NSCLC cell death, and this synergistic effect is abolished by NAC, highlighting the critical role of ROS accumulation in their combined efficacy. This study systematically elucidates the molecular mechanisms of 6-Methoxydihydrosanguinarine against NSCLC, revealing that, in addition to the JNK and autophagy pathways, ER stress also mediates its antitumor effects. Moreover, our data establish a rationale for exploring 6-Methoxydihydrosanguinarine in NSCLC therapy and highlight its combination with cisplatin as a potentially effective strategy.},
}

Humans
*Endoplasmic Reticulum Stress/drug effects
*Reactive Oxygen Species/metabolism
*Cisplatin/pharmacology
*Lung Neoplasms/pathology/metabolism/drug therapy
*Autophagy/drug effects
Drug Synergism
Cell Line, Tumor
*Carcinoma, Non-Small-Cell Lung/pathology/drug therapy/metabolism
*Isoquinolines/pharmacology
*Benzophenanthridines/pharmacology
MAP Kinase Signaling System/drug effects
*Antineoplastic Agents/pharmacology
JNK Mitogen-Activated Protein Kinases/metabolism
Animals

@article {pmid41534303,
year = {2026},
author = {Feng, J and Carreño, M and Jung, H and Dayalan Naidu, S and Arroyo-Diaz, N and Ang, AD and Kulkarni, B and Kisielewski, D and Suzuki, T and Yamamoto, M and Hayes, JD and Honda, T and Wilson, L and Leon-Ruiz, B and Eggler, AL and Vitturi, DA and Dinkova-Kostova, AT},
title = {The electrophilic metabolite of kynurenine, kynurenine-CKA, requires C151 in Keap1 to derepress Nrf2.},
journal = {Redox biology},
volume = {90},
number = {},
pages = {104009},
pmid = {41534303},
issn = {2213-2317},
mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics/chemistry ; Animals ; Humans ; Mice ; Receptors, Aryl Hydrocarbon/metabolism/genetics ; *Kynurenine/analogs & derivatives/metabolism/pharmacology ; NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism ; },
abstract = {The Kelch-like ECH-associated protein 1/Nuclear factor-erythroid 2 p45-related factor 2 (Keap1/Nrf2) system responds to a wide array of structurally diverse small molecules, of both exogenous and endogenous origin, by inducing a robust cytoprotective program that allows adaptation during oxidative, metabolic and inflammatory stress. Here, we report that exposure to the tryptophan metabolite kynurenine and its electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA) leads to an increase in the abundance of transcription factor Nrf2 and induction of Nrf2-target genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), in murine and human cells. Additionally, both kynurenine and Kyn-CKA activate the aryl hydrocarbon receptor (AhR). Using cellular thermal shift assays, we found that Kyn-CKA increases the thermal stability of Keap1-mCherry fusion protein, but not free mCherry, indicating target engagement of Keap1, the principal repressor of Nrf2. Critically, the ability of Kyn-CKA to increase the abundance of Nrf2 and expression of NQO1 in mouse embryonic fibroblasts (MEFs) expressing wild-type Keap1 was greatly diminished in C151S-Keap1 mutant MEFs. Furthermore, Kyn-CKA reacts with Keap1 C151 much faster in vitro than with the small molecule thiol N-acetyl cysteine, suggesting that Kyn-CKA is targeted to C151 by the surrounding active site. Experiments in wild-type, AhR-knockout, and Nrf2-knockout primary murine bone marrow-derived macrophages showed that Nrf2 is required for the acute anti-inflammatory activity of Kyn-CKA, whereas AhR is dispensable. Together, these findings demonstrate that Kyn-CKA requires C151 in Keap1 to derepress Nrf2 and reveal that Nrf2, but not AhR, is a main contributor to the anti-inflammatory activity of Kyn-CKA in macrophages.},
}

*NF-E2-Related Factor 2/metabolism/genetics
*Kelch-Like ECH-Associated Protein 1/metabolism/genetics/chemistry
Animals
Humans
Mice
Receptors, Aryl Hydrocarbon/metabolism/genetics
*Kynurenine/analogs & derivatives/metabolism/pharmacology
NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism

@article {pmid41533906,
year = {2026},
author = {Guo, Y and Luo, S and Li, W and Wang, X and Sun, W and Zha, W and Zhang, R and Liu, D and Wei, M and Zhang, H and Liu, Q and Liu, Z},
title = {Ferroptosis in Meibomian Gland Progenitor Cells Contributes to Pathogenesis of Meibomian Gland Dysfunction.},
journal = {Investigative ophthalmology & visual science},
volume = {67},
number = {1},
pages = {9},
pmid = {41533906},
issn = {1552-5783},
mesh = {*Ferroptosis/physiology ; Animals ; Mice ; *Meibomian Glands/pathology/metabolism ; Disease Models, Animal ; *Meibomian Gland Dysfunction/metabolism/pathology/etiology ; *Stem Cells/pathology/metabolism ; Mice, Inbred C57BL ; Humans ; Hydrogen Peroxide ; Male ; Epithelial Cells/metabolism/pathology ; Cells, Cultured ; },
abstract = {PURPOSE: Meibomian gland (MG) atrophy in Meibomian gland dysfunction (MGD) is critically linked to progenitor cell (PC) abnormalities. However, the mechanisms underlying PC abnormalities during MGD pathogenesis remain unclear. This study investigates the role of ferroptosis in MG PC abnormalities during MGD pathogenesis.

METHODS: Three mouse MGD models were established: alkali burn-induced MGD (AK-MGD), blue light-induced MGD (BL-MGD), and age-related MGD (AR-MGD). All exhibited MG atrophy and Lrig1-positive PC abnormalities. Dihydroethidium (DHE) and immunofluorescent staining for Gpx4 and Ptgs2 in MGs were applied to observe the distribution of ferroptotic cells during MGD. Ferroptosis was evaluated in H2O2-treated human MG epithelial cells (HMGECs) by measuring intracellular Fe2+, iron metabolism gene expression, and levels of Gpx4, Slc7a11, and Ptgs2. Ferroptosis signatures were evaluated across models. Ferroptosis inhibitors including Ferrostatin-1 (Fer-1), deferoxamine (DFO), and N-acetylcysteine (NAC) targeting different ferroptosis pathways were applied therapeutically in these MGD models.

RESULTS: All MGD models demonstrated lipid peroxidation and ferroptosis in MG PCs. In HMGECs, we confirmed that H2O2 treatment induced ferroptosis, which was rescued by ferroptosis inhibitors. Acute and chronic MGD models exhibited distinct ferroptosis signatures. Therapeutic intervention with ferroptosis inhibitors ameliorated MGD manifestations to varying degrees in MGD models.

CONCLUSIONS: Ferroptosis in MG PCs contributes to the pathogenesis of MGD. MG PCs are preferentially susceptible to ferroptosis. Pharmacological inhibition of ferroptosis represents a promising therapeutic strategy for MGD.},
}

*Ferroptosis/physiology
Animals
Mice
*Meibomian Glands/pathology/metabolism
Disease Models, Animal
*Meibomian Gland Dysfunction/metabolism/pathology/etiology
*Stem Cells/pathology/metabolism
Mice, Inbred C57BL
Humans
Hydrogen Peroxide
Male
Epithelial Cells/metabolism/pathology
Cells, Cultured

@article {pmid41531336,
year = {2026},
author = {Azuma, R and Yamasaki, T and Sano, K and Mukai, T},
title = {Development of a radioiodinated boronic acid probe for the detection of hydrogen peroxide and peroxynitrite.},
journal = {Free radical research},
volume = {60},
number = {1},
pages = {28-38},
doi = {10.1080/10715762.2026.2617613},
pmid = {41531336},
issn = {1029-2470},
mesh = {*Peroxynitrous Acid/analysis ; *Hydrogen Peroxide/analysis ; Animals ; *Boronic Acids/chemistry ; Mice ; *Iodine Radioisotopes/chemistry ; Male ; Tissue Distribution ; },
abstract = {Hydrogen peroxide and peroxynitrite play important roles as signaling molecules to maintain the biological functions; however, excess levels of these oxidants are associated with various diseases. Despite their important roles in vivo, effective methods to measure these oxidants in the body with high sensitivity have not yet been established. Therefore, in this study, we aimed to design a radioiodinated boronic acid probe for the in vivo detection of hydrogen peroxide and peroxynitrite. The probe contained boronic acid, a well-known substructure that reacts with hydrogen peroxide and peroxynitrite, at positions 3 and 6 of the xanthene moiety and radioiodine at the phthalide moiety of fluorescein. I-125 labeling was successful, resulting in a radiochemical yield of 60% and radiochemical purity of >95%. In vitro selectivity studies demonstrated that the probe showed significant responses to both hydrogen peroxide and peroxynitrite while exhibiting minimal reactivity toward other reactive oxygen species including superoxide, nitric oxide, and peroxy radicals. In biodistribution studies using lipopolysaccharide (LPS)-treated mice generating reactive oxidants, the boronic acid probe was significantly accumulated in various organs damaged by LPS. However, this phenomenon was inhibited by administration of the antioxidant, N-acetylcysteine, to LPS-treated mice. These results highlight the potential of the developed radioiodinated boronic acid probe to detect hydrogen peroxide and peroxynitrite in living organisms, suggesting it as a candidate for the in vivo detection and functional evaluation of these oxidants in various diseases.},
}

*Peroxynitrous Acid/analysis
*Hydrogen Peroxide/analysis
Animals
*Boronic Acids/chemistry
Mice
*Iodine Radioisotopes/chemistry
Male
Tissue Distribution

@article {pmid41524784,
year = {2026},
author = {Penney, C and Piper, AK and Holliday, J and Tincknell, G and Joosse, SA and Pantel, K and Brungs, D and Ranson, M},
title = {Adaphostin-induced oxidative stress in oesophageal neuroendocrine carcinoma: a potential therapeutic strategy.},
journal = {Medical oncology (Northwood, London, England)},
volume = {43},
number = {2},
pages = {109},
pmid = {41524784},
issn = {1559-131X},
support = {RSP-316-FY2023//Tour de Cure/ ; RSP-316-FY2023//Tour de Cure/ ; RSP-316-FY2023//Tour de Cure/ ; },
mesh = {Humans ; *Esophageal Neoplasms/drug therapy/pathology/metabolism ; *Carcinoma, Neuroendocrine/drug therapy/pathology/metabolism ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Apoptosis/drug effects ; *Antineoplastic Agents/pharmacology ; Cell Survival/drug effects ; DNA Damage/drug effects ; },
abstract = {Advanced oesophageal neuroendocrine carcinoma (ENEC) is a highly aggressive and rare malignancy with poor prognosis. Due to the rarity of this cancer there are currently no standardised treatment regimens for ENEC, and models to study this disease are difficult to obtain. To address this, we screened our established circulating tumour cell line from a patient with metastatic ENEC, termed UWG01CTC, using the LOPAC[®][1280] drug repurposing library. The redox modulatory agent adaphostin was identified as a potent cytotoxin against UWG01CTC but not non-ENEC cell lines. Secondary adaphostin cell viability screens returned IC50 values of 0.201 ± 0.024 µM confirming the high sensitivity of this ENEC CTC line to the drug. Inclusion of the antioxidant N-acetyl cysteine significantly protected the UWG01CTCs against the cytotoxic effects of adaphostin (IC50 = 0.928 ± 0.425 µM), corroborating a mechanism mediated through the generation of reactive oxygen species (ROS). The expression of DNA damage marker phospho-γH2AX and apoptotic marker cleaved PARP1 were both elevated in cells treated with adaphostin, suggesting that the increased intracellular ROS levels induced by the drug causes downstream DNA damage and ultimately apoptosis. Thus, adaphostin shows promise as a potential new and selective treatment for ENEC.},
}

Humans
*Esophageal Neoplasms/drug therapy/pathology/metabolism
*Carcinoma, Neuroendocrine/drug therapy/pathology/metabolism
*Oxidative Stress/drug effects
Reactive Oxygen Species/metabolism
Cell Line, Tumor
Apoptosis/drug effects
*Antineoplastic Agents/pharmacology
Cell Survival/drug effects
DNA Damage/drug effects

@article {pmid41523401,
year = {2025},
author = {Rasheed, A and Hassan, SH and Mehmood Qadri, H and Ahmed, AB and Ahmed, M and Khan, H and Fatima, N and Azam, A and Dar, SA and Khawaja, AA},
title = {Neurological Manifestations of Aluminum Phosphide (Wheat-Pill/Rice-Pill) Poisoning: A Narrative Review.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e98910},
pmid = {41523401},
issn = {2168-8184},
abstract = {The clinical manifestations of Aluminium Phosphide (AlP) that stem from its misdirected human consumption range from nausea and vomiting to acute respiratory failure, cardiotoxicity and hepatotoxicity, causing sudden death. Currently, there is no standard regimen to deal with this menacing product. This review aimed to highlight the neurological manifestations and treatment options for dealing with wheat pill poisoning. After the literature search, a total of eight studies were included in this study. Study types included five case reports, a prospective case series, a retrospective review, and an autopsy with sample sizes ranging from a single patient to 471 patients. The major symptoms included were dizziness, headache, and weakness in both upper and lower extremities. Reported neurological findings included progressive decline in consciousness, anisocoria with non-reactive pupils, loss of consciousness, convulsions, variable coma grades, and motor deficits. The CT brain findings mentioned in one case report were significant for diffuse bilateral hypoattenuation in the cerebellar hemispheres, midbrain, thalamus, and globus pallidus nuclei. MRI brain revealed multiple cortical and subcortical diffusion restrictions in cerebral hemispheres, consistent with prior global hypoperfusion injury in one case report, while the other showed an acute ischemic infarct in the left posterior cerebral artery (PCA) territory involving left medial temporal, parieto-occipital lobes, left half of the splenium of the corpus callosum and left thalamus. There is some evidence that paraffin oil, co-enzyme Q10, hyperinsulinemia euglycemia, and N-acetylcysteine (NAC) decrease mortality in this poisoning. However, further large-scale randomised controlled trials are needed to definitively evaluate their mortality benefit.},
}

@article {pmid41523131,
year = {2025},
author = {Kim, J and Yi, S and Kang, S and Yae, C and Choi, JM and Kim, SB and Kim, HK},
title = {Liquiritigenin, a licorice-derived flavanone, reduces dry eye pathology via dual anti-inflammatory and antioxidant action.},
journal = {Taiwan journal of ophthalmology},
volume = {15},
number = {4},
pages = {598-610},
pmid = {41523131},
issn = {2211-5072},
abstract = {PURPOSE: Liquiritigenin (LIQ), an active flavanone derived from Glycyrrhiza uralensis, is known to possess potent antioxidant and anti-inflammatory properties. This study aimed to evaluate the antioxidative and anti-inflammatory effects of LIQ on experimental dry eye disease (DED) models.

MATERIALS AND METHODS: In vitro effects of LIQ were assessed using a hyperosmotic stress model with assays including quantitative polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, and immunofluorescent staining. The antioxidative effect was compared with n-acetyl cysteine (NAC) and the anti-inflammatory effect with dexamethasone (DEX). In vivo, DED was induced by desiccation stress in a controlled environmental chamber mouse model. Tear production rate, corneal staining scores, pro-inflammatory cytokine expression, conjunctival goblet cell density, infiltration of T-helper (Th) 17 cells, and reactive oxygen species (ROS) levels in the lacrimal gland were evaluated.

RESULTS: In vitro studies demonstrated that LIQ significantly reduced ROS levels, comparable to NAC, and exhibited anti-inflammatory effects similar to DEX. In the mouse model, LIQ treatment significantly increased tear production and reduced corneal staining scores compared to controls, decreased the expression of Interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-13, tumor necrosis factor α, Interferon γ, restored conjunctival goblet cell density, reduced Th17 cell infiltration, and lowered ROS levels in the lacrimal gland Microarray analysis revealed LIQ regulated cytokine expression and ROS levels through the modulation of the aldo-keto reductase (AKR) superfamily in hyperosmotic stress conditions.

CONCLUSION: LIQ shows potential as a therapeutic agent for DED through its dual anti-inflammatory and antioxidative actions, primarily through modulation of the AKR superfamily.},
}

@article {pmid41520042,
year = {2026},
author = {Liu, PK and Chi, YC and Chang, YC and Lin, YH and Chen, CY and Liu, C and Tyan, YC and Chang, KC},
title = {Quercetin attenuates high glucose-induced VEGFA expression in ARPE-19 cells by inhibiting ROS generation, p38 MAPK phosphorylation, and NF-κB activation.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {4987},
pmid = {41520042},
issn = {2045-2322},
support = {114-2314-B-037-115//NSTC/ ; 113-3R45//Kaohsiung Medical University Chung-Ho Memorial Hospital/ ; P30-EY008098/GF/NIH HHS/United States ; unrestricted research grant//Research to Prevent Blindness/ ; P30 EY008098/EY/NEI NIH HHS/United States ; },
abstract = {UNLABELLED: Hyperglycemia-driven oxidative stress and inflammatory signaling in retinal pigment epithelium (RPE) promote overexpression of vascular endothelial growth factor A (VEGFA), contributing to the pathogenesis of diabetic retinopathy (DR). Quercetin, a dietary flavonoid with antioxidant and anti-inflammatory properties, has not been fully evaluated for its ability to counteract high glucose–induced VEGFA upregulation in RPE. Here, ARPE-19 cells were exposed to high glucose (30 mM) with or without quercetin (5 or 20 µM) treatment. VEGFA expression was measured by qPCR and ELISA; intracellular reactive oxygen species (ROS) were assessed using a DCFH-DA probe; and pathway activation was examined by immunoblotting for p38 MAPK and ERK1/2 phosphorylation, IκBα stability, and NF-κB p65 nuclear translocation. N-acetylcysteine (NAC) served as an antioxidant control, and cell viability was monitored using the CCK-8 assay. Quercetin at non-cytotoxic concentrations significantly suppressed high glucose–induced VEGFA mRNA and protein expression, reduced ROS accumulation, and attenuated p38 MAPK phosphorylation without altering ERK1/2 activation. Quercetin also prevented IκBα degradation and diminished p65 nuclear translocation, indicating inhibition of NF-κB signaling. These findings support a model in which quercetin mitigates hyperglycemia-induced VEGFA upregulation in RPE cells at least in part by modulating a ROS–p38 MAPK–NF-κB axis, while not excluding contributions from other glucose- and ROS-sensitive pathways. Quercetin may therefore represent a readily accessible adjunctive strategy to address oxidative stress, inflammation, and VEGFA dysregulation in DR, warranting further in vivo validation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-35409-5.},
}

@article {pmid41519441,
year = {2026},
author = {Li, Z and Xue, Y and Li, K and Qian, M and Wang, F and Luo, JL and Gao, XJ},
title = {Dietary zinc deficiency regulates the ROS/TLR4/NF-κB pathway to induce pancreatic inflammation and cell death in mice.},
journal = {The Journal of nutritional biochemistry},
volume = {151},
number = {},
pages = {110262},
doi = {10.1016/j.jnutbio.2026.110262},
pmid = {41519441},
issn = {1873-4847},
mesh = {Animals ; *Zinc/deficiency ; *Reactive Oxygen Species/metabolism ; *NF-kappa B/metabolism ; *Toll-Like Receptor 4/metabolism ; Mice ; Signal Transduction ; Cell Death ; *Pancreas/metabolism/pathology ; *Pancreatitis/metabolism/etiology/pathology ; Oxidative Stress ; Male ; Inflammation/metabolism ; Diet ; },
abstract = {Zinc (Zn) deficiency disrupts redox homeostasis in the body. The pancreas is a vital digestive and endocrine organ of the body, and its normal functional operation cannot proceed without the involvement of Zn. In this study, we established in vivo mouse models, including the normal Zn group (CG, 34 mg Zn/kg), Zn-deficient group (LZn, 2 mg Zn/kg), and Zn-supplemented group (HZn, 100 mg Zn/kg), as well as an in vitro Zn-deficient model of Mouse INsulinoma 6 (MIN6) cells. We systematically investigated the effects of Zn deficiency on pancreatic oxidative stress, inflammation, and cell death. The results showed that Zn deficiency significantly decreased the activities of α-amylase and lipase in the pancreas, and led to pancreatic histological damage. Through flow cytometry and detection of antioxidant enzyme activities, it was found that Zn deficiency induces excessive accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA) in the pancreas, and inhibits antioxidant enzyme activities. Using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot, it was observed that Zn deficiency activates the TLR4/NF-κB pathway and significantly increases the expression of the NLRP3 inflammasome and inflammatory factors. Furthermore, Zn deficiency significantly upregulates the expression of apoptosis-related factors (Bax, Caspase-3, Caspase-7, Caspase-9) and necroptosis-related factors (RIPK1, RIPK3, MLKL). Treatment with the antioxidant N-acetylcysteine (NAC) reduces the level of ROS and inhibits the activation of the TLR4/NF-κB pathway, thereby alleviating Zn deficiency-induced inflammation and cell death. Taken together, Zn deficiency induces pancreatic inflammation and cell death by regulating the ROS/TLR4/NF-κB pathway.},
}

Animals
*Zinc/deficiency
*Reactive Oxygen Species/metabolism
*NF-kappa B/metabolism
*Toll-Like Receptor 4/metabolism
Mice
Signal Transduction
Cell Death
*Pancreas/metabolism/pathology
*Pancreatitis/metabolism/etiology/pathology
Oxidative Stress
Male
Inflammation/metabolism
Diet

@article {pmid41519036,
year = {2026},
author = {Yang, X and Zhou, J and Shangguan, D},
title = {Self-oxidation and proximity crosslinking of G-quadruplex in G-quadruplex /hemin peroxidase system.},
journal = {Talanta},
volume = {302},
number = {},
pages = {129344},
doi = {10.1016/j.talanta.2025.129344},
pmid = {41519036},
issn = {1873-3573},
mesh = {*G-Quadruplexes ; *Hemin/chemistry/metabolism ; Oxidation-Reduction ; *DNA, Catalytic/chemistry/metabolism ; Hydrogen Peroxide/chemistry/metabolism ; Biosensing Techniques ; *Peroxidase/chemistry/metabolism ; *Peroxidases/metabolism/chemistry ; },
abstract = {G-quadruplex (G4)/hemin peroxidase has emerged as a robust platform for signal amplification in biosensors. While offering distinct advantages over protein enzymes, its susceptibility to inactivation often results in low apparent catalytic activity, thereby limiting broader applications. To address this, we investigated the side reactions occurring during the catalytic process of G4/hemin DNAzyme in both N-acetyl-cysteine (NAC) and H2O2 systems. Notably, high-molecular-weight products were observed when the hemin/G4 ratio exceeded 10. Further analysis revealed that these products primarily resulted from the self-oxidation of G4 sequences or proximity cross-linking with hemin fractions, substrates, and coexisting DNA sequences. Our findings provide critical insights into the inactivation mechanism and offer guidance for enhancing the catalytic efficiency of G4-based biosensors.},
}

*G-Quadruplexes
*Hemin/chemistry/metabolism
Oxidation-Reduction
*DNA, Catalytic/chemistry/metabolism
Hydrogen Peroxide/chemistry/metabolism
Biosensing Techniques
*Peroxidase/chemistry/metabolism
*Peroxidases/metabolism/chemistry

@article {pmid41516400,
year = {2026},
author = {Zhang, J and Wang, D and Wang, H and Wu, Q and Liu, M and Li, Q and Gong, Z},
title = {Antioxidant N-Acetylcysteine Facilitates Breast Cancer Metas-Tasis via Immunosuppressive Reprogramming of Neutrophils.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
pmid = {41516400},
issn = {1422-0067},
support = {2023KYQD002//Institute of Health and Medicine, Hefei Comprehensive National Science Center/ ; 32400758//National Natural Science Foundation of China/ ; 32470974//National Natural Science Foundation of China/ ; 82472960//National Natural Science Foundation of China/ ; },
mesh = {*Acetylcysteine/pharmacology ; Animals ; *Neutrophils/immunology/drug effects ; Female ; Mice ; *Breast Neoplasms/pathology/immunology/drug therapy ; *Antioxidants/pharmacology ; Humans ; T-Lymphocytes/immunology/drug effects ; Cell Line, Tumor ; *Lung Neoplasms/secondary/immunology ; },
abstract = {N-acetylcysteine (NAC) is a widely used antioxidant. It has also attracted significant research interest with regard to its role in cancer progression, although the mechanisms involved remain controversial and poorly understood. Here, using murine models of breast cancer metastasis, we found that systemic NAC administration significantly enhanced pulmonary metastasis without altering primary tumor growth in immunocompetent mice, whereas this metastasis-promoting property of NAC was abrogated in T cell-deficient mice. This phenomenon was not due to the direct effects of NAC on T cells or tumor cells, since in vitro studies indicated that NAC exhibited no impact on the effector functions of T cells or the malignant behavior of breast cancer cells. Mechanistically, we demonstrated that NAC endows neutrophils with an immunosuppressive phenotype, which is characterized by the upregulation of immunosuppressive genes, and these NAC-educated neutrophils potently suppress the activation and effector functions of T cells. Collectively, our study reveals a previously unrecognized role played by NAC in regulating breast cancer lung metastasis by orchestrating the myeloid-dependent suppression of anti-tumor T cell immunity and suggests a need to consider immune-mediated mechanisms when evaluating the systemic impact of antioxidant agents in cancer patients.},
}

*Acetylcysteine/pharmacology
Animals
*Neutrophils/immunology/drug effects
Female
Mice
*Breast Neoplasms/pathology/immunology/drug therapy
*Antioxidants/pharmacology
Humans
T-Lymphocytes/immunology/drug effects
Cell Line, Tumor
*Lung Neoplasms/secondary/immunology

@article {pmid41516202,
year = {2025},
author = {Chrószcz-Porębska, M and Waśkiewicz, S and Gołofit, T and Gadomska-Gajadhur, A},
title = {Synthesis and Characterization of Bioactive Oligoitaconates with Amino Acid Functional Groups for Tissue Engineering.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
pmid = {41516202},
issn = {1422-0067},
support = {504/04496/1020/45.010045//Warsaw University of Technology/ ; },
mesh = {*Tissue Engineering/methods ; Cysteine/chemistry ; *Amino Acids/chemistry ; Spectroscopy, Fourier Transform Infrared ; Acetylcysteine/chemistry ; *Biocompatible Materials/chemistry/chemical synthesis ; },
abstract = {Improving the hydrophilicity and tissue adhesion of polymers remains a significant challenge in tissue engineering and is often addressed by introducing functional groups that enhance polymer-tissue interactions. In this field, L-cysteine (Cys) and N-acetyl-L-cysteine (NAC) are particularly interesting due to their functional carboxyl and amine groups, which are prone to hydrogen bonding. Following this trend, this study (i) investigated the feasibility of grafting Cys or NAC onto the linear oligoitaconates via thio-Michael addition and (ii) examined the influence of amino acid incorporation on the material's physicochemical properties. NMR-based calculations confirmed nearly 100% addition efficiency for Cys and a slightly lower, but still high, efficiency for NAC. FT-IR spectra confirmed thiol-based addition, as signal from the Cys/NAC S-H stretching vibrations was not observed in the adduct's spectra. The obtained adducts showed thermal stability up to 200 °C and glass transition temperatures below -20 °C. They were soluble in common organic solvents, except for Cys adducts with oligo(propylene itaconate) and oligo(hexylene itaconate), which were water-soluble only. Due to the low molecular weight (below 1000 g/mol) of oligoitaconates, their adducts cannot serve as standalone scaffold components. However, they showed potential for use as modifiers for high-molecular-weight polylactide or poly(ɛ-caprolactone)-based scaffolds.},
}

*Tissue Engineering/methods
Cysteine/chemistry
*Amino Acids/chemistry
Spectroscopy, Fourier Transform Infrared
Acetylcysteine/chemistry
*Biocompatible Materials/chemistry/chemical synthesis

@article {pmid41512939,
year = {2026},
author = {Lei, Y and Xu, R and Zhan, J and Liu, J},
title = {Activation of the Nrf2-Keap1 pathway is associated with NAC-mediated alleviation of nitrite-induced oxidative and endoplasmic reticulum stress and apoptosis in Marsupenaeus japonicus.},
journal = {Fish & shellfish immunology},
volume = {170},
number = {},
pages = {111114},
doi = {10.1016/j.fsi.2026.111114},
pmid = {41512939},
issn = {1095-9947},
mesh = {*Penaeidae/cytology/drug effects ; Animals ; *Nitrites/toxicity ; Oxidative Stress/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Apoptosis ; *Acetylcysteine/pharmacology ; Signal Transduction ; Gene Expression ; Hepatopancreas/drug effects ; Gills/drug effects ; },
abstract = {Nitrite accumulation poses a serious threat to aquatic animals in intensive aquaculture systems. Although the antioxidant role of the Nrf2-Keap1 pathway is well established, its regulatory mechanisms under nitrite stress in crustaceans remain poorly understood. This investigation focused on the protective impact of N-acetylcysteine (NAC) on Marsupenaeus japonicus exposed to nitrite toxicity. Shrimp were injected with NAC or PBS and then exposed to 100 mg/L of nitrite nitrogen for 72 h. The findings revealed that pretreatment with NAC markedly reduced tissue damage in both the hepatopancreas and gills, in comparison to the PBS control group. Additionally, the NAC-treated M. japonicus exhibited upregulated mRNA levels of Nrf2 and its associated antioxidant genes including NQO1, HO-1, CAT, GPx, GST, and SOD, while Keap1 expression was notably suppressed. Additionally, the NAC group downregulated endoplasmic reticulum stress (ERS)-related genes (PERK, eIF2α, ATF4, GRP78, CHOP, IRE1, XBP1, ATF6) and apoptosis-related genes (Caspase-3, Caspase-9, p53, Bax, Apaf-1), while upregulating Bcl-2. Additionally, the NAC group improved total antioxidant capacity (T-AOC) and SOD activity, reduced malondialdehyde (MDA) content and Caspase-3 activity, and decreased the apoptosis rate in the hepatopancreas. The results indicate that NAC alleviates oxidative stress, ERS, and apoptosis triggered by nitrite in M. japonicus. This protective effect is associated with the activation of the Nrf2-Keap1 signaling pathway, suggesting its potential as a therapeutic strategy for nitrite toxicity in crustacean aquaculture.},
}

*Penaeidae/cytology/drug effects
Animals
*Nitrites/toxicity
Oxidative Stress/drug effects
Endoplasmic Reticulum Stress/drug effects
Apoptosis
*Acetylcysteine/pharmacology
Signal Transduction
Gene Expression
Hepatopancreas/drug effects
Gills/drug effects

@article {pmid41510997,
year = {2026},
author = {Du, Z and Wu, J and Zhang, T and Ma, X and Li, Z and Xu, J and You, J and Chen, N and Wu, J},
title = {Lack of receptor for advanced glycation end products attenuates obesity-induced adipose tissue senescence in mice.},
journal = {Adipocyte},
volume = {15},
number = {1},
pages = {2611481},
pmid = {41510997},
issn = {2162-397X},
mesh = {Animals ; *Obesity/metabolism/genetics ; *Receptor for Advanced Glycation End Products/metabolism/genetics/deficiency ; Mice ; *Adipose Tissue/metabolism/pathology ; *Cellular Senescence ; Reactive Oxygen Species/metabolism ; Diet, High-Fat/adverse effects ; Mice, Knockout ; Male ; Sirtuin 1/metabolism ; Mice, Inbred C57BL ; Adipocytes/metabolism ; },
abstract = {The receptor for advanced glycation end products (RAGE) and its ligands are critical drivers of adipose tissue inflammation. While RAGE expression increases in ageing cells and pathological conditions, its specific role in high-fat diet (HFD)-induced adipose tissue senescence remains to be fully elucidated. In this study, we investigated the function of RAGE in the development of adipose tissue senescence associated with obesity. We observed that HFD-fed RAGE-deficient (RAGE[-/-]) mice exhibited significantly reduced body weight and adipocyte hypertrophy compared to wild-type (WT) controls. At the molecular level, RAGE[-/-] mice displayed lower mRNA expression of cell cycle regulators and markers of the senescence-associated secretory phenotype. This anti-senescent phenotype was accompanied by decreased reactive oxygen species (ROS) production and elevated expression of anti-oxidant genes. Mechanistically, the lack of RAGE resulted in the upregulation of silent information regulator type 1 (SIRT1) in adipose tissues. Notably, the inhibition of SIRT1 reversed these anti-senescent effects and attenuated anti-oxidant gene expression in RAGE-deficient mice. Furthermore, while antioxidant treatment with N-acetylcysteine (NAC) reduced p53 in WT mice, it failed to fully suppress p16 and p21, whereas NAC treatment in RAGE[-/-] mice significantly downregulated all senescence markers, suggesting a synergistic protective effect. In conclusion, our results demonstrated that RAGE deficiency improved anti-oxidant properties and prevents adipocyte senescence via the SIRT1 signalling pathway, highlighting a potential therapeutic target for obesity-associated tissue dysfunction.},
}

Animals
*Obesity/metabolism/genetics
*Receptor for Advanced Glycation End Products/metabolism/genetics/deficiency
Mice
*Adipose Tissue/metabolism/pathology
*Cellular Senescence
Reactive Oxygen Species/metabolism
Diet, High-Fat/adverse effects
Mice, Knockout
Male
Sirtuin 1/metabolism
Mice, Inbred C57BL
Adipocytes/metabolism

@article {pmid41509112,
year = {2025},
author = {Esparham, F and Rajabian, F and Ghasemzadeh Rahbardar, M and Razavi, BM and Khajavi Rad, A and Amoueian, S and Hosseinzadeh, H},
title = {Evaluating the effect of rutin on contrast-induced nephropathy in rats.},
journal = {Avicenna journal of phytomedicine},
volume = {15},
number = {6},
pages = {1726-1740},
pmid = {41509112},
issn = {2228-7930},
abstract = {OBJECTIVE: Contrast-induced nephropathy is a common cause of acute kidney injury, and oxidative stress plays an important role in its development. The flavonoid rutin is of interest for its potential antioxidant properties. This study aimed to assess the protective effects of rutin against contrast-induced renal toxicity in rats.

MATERIALS AND METHODS: Eight groups of male Wistar rats (n=6 in each group) were designed: (1) Sham, (2) Premedication-control (N(ω)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.)+indomethacin (10 mg/kg, i.p.)), (3) Contrast medium (L-NAME+indomethacin+diatrizoate (12.5 ml/kg, i.p)), (4-6) Rutin (25, 50, and 100 mg/kg, p.o., for 7 days)+L-NAME+indomethacin+ diatrizoate, (7) N-acetylcysteine (NAC, 125 mg/kg, i.p.), L-NAME+indomethacin+diatrizoate, and (8) Rutin-alone (100 mg/kg). All study groups except for the sham and rutin-alone were subjected to 48 hr of water deprivation. On day 8, blood and kidney samples were isolated to evaluate oxidative stress, biochemical and histopathological changes.

RESULTS: The levels of serum blood urea nitrogen (BUN), creatinine, and malondialdehyde (MDA) were raised by diatrizoate, while glutathione (GSH) levels in renal tissue were reduced. Rutin (25, 50, and 100 mg/kg) improved biochemical parameters and oxidative stress. Diatrizoate also resulted in interstitial edema, medullary congestion, proteinaceous casts, and severe tubular necrosis in kidney tissue. Rutin (100 mg/kg) reduced tubular necrosis and interstitial edema but had no significant effect on the formation of medullary congestion and proteinaceous casts in renal tissue.

CONCLUSION: Oxidative stress triggered by contrast-induced nephropathy is caused by a rise in MDA and a decline in GSH amounts. Rutin protects kidney tissue against contrast-induced damage through its antioxidant effect.},
}