Naunyn-Schmiedeberg's archives of pharmacology最新文献

{"title":"Mechanistic insights into the mitigating role of dapagliflozin against radiation-triggered myocardial apoptosis: gating to AMPK-regulated autophagic machinery.","authors":"Walaa A El-Sabbagh, Noha A Fadel, Eman F Sanad, Wesam El-Bakly, Riham S Said","doi":"10.1007/s00210-026-05919-0","DOIUrl":"https://doi.org/10.1007/s00210-026-05919-0","url":null,"abstract":"<p><p>Cardiovascular complications are a major, mortality-associated consequence of radiotherapy in breast and lung cancer patients. Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 inhibitor, has recently exhibited significant cardioprotective properties in cancer patients. The present study evaluated the cardioprotective efficacy and the underlying molecular mechanisms of DAPA in a rat model of radiation-induced cardiotoxicity. Male Sprague-Dawley rats were randomized into four groups: the first served as control; the second received DAPA (1 mg/kg, p.o. for 28 days); the third and fourth were exposed to 15 Gy acute thoracic γ-irradiation, with the fourth group receiving DAPA for 28 days post-irradiation. The deleterious effect of radiation on cardiac tissue was evidenced by marked histopathological alterations, increased heart index, elevated serum CK-MB levels, alongside ECG changes, including bradycardia and tall T waves, all of which were significantly alleviated by DAPA treatment. DAPA exhibited significant cardiac antioxidant properties, as reflected by reduced MDA and increased reduced glutathione levels. Mechanistically, DAPA mediated AMPK phosphorylation and enhanced autophagy-related responses following irradiation, as evidenced by increased expression of autophagy proteins (LC3, Beclin-1), upregulating the transcription of autophagy-related genes (ATG5, ATG7, ATG12), and decreased SQSTM1/p62 accumulation. This autophagic activation was accompanied by a blockage of intrinsic cardiomyocyte apoptosis triggered by radiation, as shown by decreased transcription of p53 and Bax while increased Bcl2, resulted in a reduced Bax/Bcl2 ratio and suppressed cleaved caspase-3 expression. In conclusion, DAPA confers cardio-protection against radiation injury by improving oxidative status and modulating the balance between apoptosis and adaptive autophagy, accompanied by increased AMPK phosphorylation.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effect of dapagliflozin against phenytoin-induced cerebellar dysfunction and histological alterations in rats: the role of SIRT1/Nrf2/HO-1 pathway.","authors":"Heba Fathy El-Domiaty, Asmaa Eldesouky, Heba Rady Salem","doi":"10.1007/s00210-026-05915-4","DOIUrl":"https://doi.org/10.1007/s00210-026-05915-4","url":null,"abstract":"<p><p>Cerebellar dysfunction is a common issue emerges with long-term phenytoin use. This investigation was designed to test the protective role of sodium-glucose transporter 2 inhibitor (SGLT2I), dapagliflozin (DAPA) against cerebellar disorder accompanying phenytoin therapy in rats. Twenty-four adult male Wister rats were randomized into the control, phenytoin, and phenytoin + DAPA groups. Cerebellar functions were evaluated for all rats; then, cerebellar malondialdehyde (MDA), total antioxidant capacity (TAC), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) were determined. Histopathological examination of rats' cerebelli and immunohistochemical analysis of cerebellar nuclear factor erythroid 2-related factor-2 (Nrf2) and silent information-regulated transcription factor 1 (SIRT1) were also conducted. Phenytoin-treated rats presented a marked cerebellar dysfunction in the form of increased ataxia score and disturbed footprints in relation to control rats. Besides, cerebellar MDA, TNF-α, and IL-6 were highly elevated, while cerebellar TAC and HO-1 were apparently reduced in phenytoin-treated rats. Histological features of cerebellar degeneration and atrophy were obviously detected as well as attenuated cerebellar expression of Nrf2 and SIRT1. Concomitant DAPA and phenytoin administration resulted in a clear amelioration in cerebellar functions and morphology with better redox and inflammatory conditions than phenytoin rats. It also enhanced the cerebellar expression of HO-1, Nrf2, and SIRT1. Eventually, inhibition of SGLT2 via DAPA could protect from the cerebellar damaging effect of phenytoin in rats. Such protective impression could be a result of combating cerebellar oxidative stress and inflammation and upregulation of cerebellar SIRT1/Nrf2/HO-1 axis pathway.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pseudoephedrine intoxication: sex-specific differences in clinical symptoms.","authors":"Funda Gezgin, Roland Seifert","doi":"10.1007/s00210-026-05941-2","DOIUrl":"https://doi.org/10.1007/s00210-026-05941-2","url":null,"abstract":"<p><p>Pseudoephedrine (PSE) is an indirectly acting sympathomimetic agent used worldwide to treat cold and flu symptoms, as well as allergic rhinitis. In Germany, PSE is available exclusively as a combination product with other active ingredients such as acetylsalicylic acid, paracetamol, ibuprofen, and first- and second-generation H1 receptor antagonists. Despite the widespread availability and frequent use of PSE, the active ingredient has repeatedly been linked to serious adverse drug reactions (ADRs). Most recently, in 2024, a red-hand letter was circulated after a link was established between PSE use and the occurrence of cerebral hypoperfusion. Furthermore, the drug is not always used in accordance with guidelines for treating specific symptoms but is also misused due to its indirect sympathomimetic effect. This study includes an analysis of published PSE intoxication cases from the literature. To this end, a systematic literature search was conducted in PubMed, from which 118 patient cases were extracted from a total of 81 case reports. The individual cases were then analyzed with regard to various aspects. The United States was the leading country in terms of case reports, followed by the United Kingdom. The analyzed patient cases show differences in terms sex and symptoms. Cardiovascular events occurred predominantly in men, while gastroenterological and dermatological symptoms occurred predominantly in women. To reduce the risk of PSE poisoning, increased educational efforts by physicians and pharmacists are necessary. Furthermore, checking for contraindications could reduce the risk. Education about PSE could also be provided through reputable online platforms. This study highlights the clinical relevance of PSE poisoning and the wide range of symptoms.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clemizole, a TRPC5 channel blocker rescues amyloid-β toxicity and cognitive impairment by modulating mitochondrial dysfunction and memory-related proteins.","authors":"Nishit Joshi, Bhupesh Vaidya, Priya Saha, Maneesh Kashyap, Shyam Sunder Sharma","doi":"10.1007/s00210-026-05945-y","DOIUrl":"https://doi.org/10.1007/s00210-026-05945-y","url":null,"abstract":"<p><p>Amyloid β (Aβ)-induced neuronal dysfunction is a key pathological feature of Alzheimer's disease (AD), characterized by oxidative stress, mitochondrial impairment, and calcium dyshomeostasis. Transient receptor potential canonical 5 (TRPC5), a calcium-permeable cation channel, has been implicated in neurodegeneration, but its role in AD remains unclear. This study investigated TRPC5 involvement in Aβ-induced neurotoxicity and evaluated the neuroprotective potential of Clemizole, a TRPC5 blocker, in preclinical AD models. In SH-SY5Y cells, Aβ-induced neurotoxicity was assessed by measuring cell viability, intracellular and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, and calcium influx. In rats, an intracerebroventricular (ICV) Aβ_25-35 (10 μg) induced cognitive impairment model was used. Behavioral tests assessed cognitive function. Hippocampal TRPC5 expression and memory as well as calcium associated protein expressions (p-CaMKII, PSD-95, BDNF, calcineurin A) were analyzed, and acetylcholinesterase (AChE) activity was measured following 3 weeks of Clemizole (10 and 30 mg/kg) treatment. Aβ exposure reduced neuronal survival, increased ROS, disrupted mitochondrial membrane potential, and elevated calcium influx in vitro. Clemizole mitigated oxidative stress, restored mitochondrial function, and restored calcium homeostasis. In vivo, Aβ induced cognitive deficits and upregulated hippocampal TRPC5 expression in rats. Clemizole reduced TRPC5 levels, improved cognitive performance, enhanced p-CaMKII, PSD-95, and BDNF expression, decreased calcineurin A, and reduced AChE activity. TRPC5 contributes to Aβ-induced neurotoxicity and cognitive impairment, and Clemizole-mediated TRPC5 inhibition confers neuroprotection by restoring calcium balance and attenuating the decrease in memory-associated protein expression. These findings support TRPC5 as a potential therapeutic target in AD; however, further studies using a transgenic AD model are warranted before clinical translation.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiotoxicity of macrolide antibiotics: a pharmacovigilance study integrating FAERS and JADER databases.","authors":"Lu Zhou, Yan Zhou, Chun Liu, Yun Lu, Ya Zou, Hua Wei, Shibo Lin, Xirui Guo, Qinchuan Li, Fangqing Xie, Hongju Wang, Shihao Yan, Jia Chen","doi":"10.1007/s00210-026-05949-8","DOIUrl":"https://doi.org/10.1007/s00210-026-05949-8","url":null,"abstract":"<p><p>Macrolides are widely prescribed antibiotics with a well-established risk of QT prolongation, but their broader cardiotoxic profile has not been systematically compared across countries using large-scale real-world data. The aim of this study is to characterize the spectrum, drug-specific signal patterns, and clinical outcomes of macrolide-associated cardiac adverse events (cAEs) through a cross-national comparison using two independent national pharmacovigilance databases. We performed a comprehensive disproportionality analysis of macrolide-associated cardiac adverse events (cAEs) using the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER) from 2016 Q1 through 2025 Q4. We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) for signal detection. Time-to-onset (TTO) was characterized using cumulative incidence curves and non-parametric Wilcoxon rank-sum tests across individual macrolides, clinical outcomes, and event types. Among 42,605 macrolide-related reports in FAERS and 4613 in JADER, cAEs accounted for 1415 (3.32%) and 128 (2.77%) reports, respectively. Azithromycin predominated in FAERS (72.3%) and clarithromycin in JADER (66.4%). Erythromycin showed the highest FAERS ROR for long QT syndrome (81.82, 95% CI 45.09-148.46), followed by azithromycin (34.71, 95% CI 25.15-47.91) and clarithromycin (18.11, 95% CI 8.61-38.08); azithromycin and clarithromycin signals were independently confirmed in JADER (ROR 24.42 and 13.17, respectively). Azithromycin was uniquely associated with heart-failure-related signals (acute right ventricular failure ROR 52.48, 95% CI 19.37-142.19), whereas clarithromycin showed the strongest ischemic heart disease signals (myocardial ischemia ROR 6.55, 95% CI 2.94-14.60; JADER coronary artery spasm ROR 10.37, 95% CI 4.25-25.33). Overall mortality among cAE cases was 10.2% in FAERS and 10.4% in JADER, with QT/torsade de pointes (TdP)-related case-fatality rates of 12.5% for clarithromycin and 10.3% for azithromycin. Most cardiac events occurred within the first 2 weeks of therapy (median time to onset, 1 day). Macrolide-associated cardiotoxicity extends beyond QT prolongation/TdP to heart failure and ischemic heart disease, with drug-specific and cross-national differences in signal pattern. As disproportionality signals, these findings are hypothesis-generating rather than causal, but support targeted cardiac monitoring in high-risk patients, particularly during the first 2 weeks of macrolide therapy.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eugenol-based carbazole-triazole derivative 5m exhibits potent anti-plasmodial activity associated with predicted plasmepsin II binding and oxidative stress in chloroquine-resistant Plasmodium falciparum.","authors":"Saurabh Kumar, Jyoti, Shivangi Maurya, Yogesh Kumar, Sudeep Tandon, Feroz Khan, Mahendra P Darokar","doi":"10.1007/s00210-026-05946-x","DOIUrl":"https://doi.org/10.1007/s00210-026-05946-x","url":null,"abstract":"<p><p>Malaria continues to be a significant health concern due to the resistance of Plasmodium species to existing drugs, highlighting the urgent need for new antimalarials. In our previous study, the eugenol-based carbazole-triazole derivative 5m was identified as a promising anti-plasmodial lead against the chloroquine-sensitive NF-54 strain. However, its activity against CQ-resistant parasites and its underlying mechanism of action remained unexplored. Therefore, the present study investigated the anti-plasmodial activity of compound 5m against both CQ-sensitive (3D7) and CQ-resistant (K1) strains of Plasmodium falciparum and elucidated its mechanism of action. Compound 5m exhibited potent anti-plasmodial activity (IC₅₀ < 5 μM) against both parasite strains. Molecular docking and molecular dynamics simulations suggested that Plasmepsin II may be a potential molecular target for compound 5m. Compound 5m also demonstrated an additive interaction with chloroquine. Interestingly, Derivative 5m reduced metabolic activity and increased reactive oxygen species (ROS) in a dose-dependent manner. Additionally, treatment with 5m, both alone and in combination with CQ, elevated ROS levels measured by the DCFH-DA fluorescence assay in drug-resistant parasites. Further, 5m was found to affect DNA damage, and increased phosphatidylserine externalization was observed. Derivative 5m was non-cytotoxic to Vero cells and exhibited favourable ADMET properties. Collectively, our findings substantially expand the pharmacological evaluation of compound 5m by demonstrating its activity against drug-resistant P. falciparum and providing mechanistic evidence supporting anti-plasmodial action.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexmedetomidine attenuates hypoxia/reoxygenation-induced cardiomyocyte injury in association with ADRA2A/ADRA2B and Notch1/Hes1 modulation.","authors":"Dinghao Xue, Xinlu Chang, Mingru Zhang, Guyan Wang","doi":"10.1007/s00210-026-05929-y","DOIUrl":"https://doi.org/10.1007/s00210-026-05929-y","url":null,"abstract":"<p><p>This study evaluated whether dexmedetomidine (Dex) attenuates hypoxia/reoxygenation (H/R)-induced injury in H9c2 cells and examined concurrent changes in adrenergic receptor candidates, Notch receptor 1 (Notch1), and hairy and enhancer of split-1 (Hes1) expression to develop a hypothesis-generating model of Dex-associated protection. H9c2 cells underwent 12 h of hypoxia followed by 4 h of reoxygenation. Cell viability, myocardial injury markers, oxidative stress, inflammatory cytokines, apoptosis, candidate-gene expression, and NOTCH1 and HES1 protein abundance were assessed. Notch1 overexpression was used to test the functional relevance of increased Notch1 abundance. Network pharmacology, qRT-PCR profiling of six intersection targets, and molecular docking were integrated to prioritize receptor candidates and generate testable hypotheses. Dex improved cell viability and reduced myocardial injury following H/R. Dex increased alpha-2A adrenergic receptor (Adra2a) and alpha-2B adrenergic receptor (Adra2b) mRNA expression and reduced Notch1/Hes1 expression. Notch1 overexpression weakened several Dex-associated protective effects. Network pharmacology and six-target qRT-PCR validation prioritized ADRA2A and ADRA2B as Dex-responsive receptor candidates. Molecular docking further predicted favorable Dex binding to ADRA2B and ADRA2A, with AutoDock Vina scores of - 8.8 and - 7.4 kcal/mol, respectively. Dex attenuated H/R-induced injury in H9c2 cells. This protective phenotype was accompanied by increased Adra2a and Adra2b mRNA expression and reduced Notch1/Hes1 expression, whereas Notch1 overexpression weakened several Dex-associated protective effects. These correlative findings propose a hypothesis-generating model, providing a focused rationale for future studies to investigate the specific receptor-level mechanisms underlying Dex-mediated cardioprotection.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacovigilance and network toxicology analysis of risdiplam-associated adverse events in pediatric patients with spinal muscular atrophy.","authors":"Ben Liu, Jingzi Zhong, Qingqing Zheng, Wei Zhou","doi":"10.1007/s00210-026-05907-4","DOIUrl":"https://doi.org/10.1007/s00210-026-05907-4","url":null,"abstract":"<p><p>Risdiplam, a survival motor neuron 2 (SMN2) splicing modifier for pediatric spinal muscular atrophy (SMA), requires a comprehensive real-world safety evaluation. This study analyzed 1059 pediatric adverse event reports from the FDA Adverse Event Reporting System (2020 Q1-2025 Q4) with risdiplam as the primary suspect drug. Female patients slightly predominated, with 50.9% aged 0-5 years. Disproportionality analyses identified 25 positive signals. Infections and infestations, general disorders, and gastrointestinal disorders were most frequent. Pneumonia, pyrexia, diarrhoea, respiratory tract infection, and nasopharyngitis were most commonly reported. Notably, nephrolithiasis emerged as a novel unlabeled signal in pediatric patients (reporting odds ratio = 11.32). Median time-to-onset was 119 days, with approximately one-third of events occurring within 30 days and another one-third after 1 year. The Weibull model revealed that the top 5 most frequently reported PTs and top 5 SOCs all exhibited an early-onset pattern. Network toxicology identified 75 overlapping targets, with CASP3, HDAC1, and PDGFRA as core targets implicated in calcium signaling, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt), and apoptosis pathways. Molecular docking confirmed stable binding (- 10.1 to - 8.6 kcal/mol). Risdiplam demonstrates a generally acceptable long-term safety profile in clinical practice, yet vigilant monitoring of respiratory, infectious, gastrointestinal, and renal adverse events remains essential to optimize the benefit-risk balance.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hesperidin attenuates gentamicin-induced nephrotoxicity: Association with SIRT3 and PAX2 expression, oxidative stress, and tubular injury.","authors":"Murat Celebi, Cagla Celebi, Hasan Susar, Ozhan Karatas","doi":"10.1007/s00210-026-05952-z","DOIUrl":"https://doi.org/10.1007/s00210-026-05952-z","url":null,"abstract":"<p><p>Gentamicin (GEN) is an effective aminoglycoside antibiotic whose clinical use is limited by nephrotoxicity driven largely by oxidative stress, inflammation, mitochondrial dysfunction, and tubular injury. Although hesperidin (HES) has antioxidant and anti-inflammatory properties, its effects on SIRT3 and PAX2 expression and early renal injury biomarkers remain unclear. Twenty-eight male Wistar albino rats were randomly assigned to four groups (Control, GEN, HES, and GEN + HES; n = 7). Gentamicin (100 mg/kg/day, intraperitoneally) and hesperidin (100 mg/kg/day, orally) were administered for seven days. Renal function was assessed by serum creatinine and blood urea nitrogen (BUN). Oxidative stress markers, inflammatory cytokines, tubular injury biomarkers (KIM-1 and NGAL), and renal SIRT3 and PAX2 mRNA expression were evaluated. Histopathological changes and immunoreactivity for Caspase-3 and 8-hydroxy-2'-deoxyguanosine were also examined. Gentamicin significantly impaired renal function, increased relative kidney weight, oxidative stress, inflammatory cytokines, KIM-1 and NGAL levels, decreased SIRT3 mRNA expression, increased PAX2 mRNA expression, and aggravated histopathological damage and Caspase-3 and 8-OHdG immunoreactivity (all p < 0.05). Hesperidin significantly improved these alterations by restoring antioxidant defenses, reducing inflammation and tubular injury, increasing SIRT3 mRNA expression, attenuating PAX2 upregulation, and improving histopathological and immunohistochemical findings, although most parameters remained different from controls. Hesperidin attenuated gentamicin-induced renal injury across functional, oxidative, inflammatory, tubular, and histopathological endpoints. These protective effects were accompanied by partial restoration of SIRT3 mRNA expression and attenuation of injury-associated PAX2 upregulation, supporting an association of these molecular responses with the protective phenotype without establishing causality. These findings support the renoprotective potential of hesperidin under the experimental conditions evaluated.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Syringic acid attenuates chlorpyrifos-induced redox imbalance, mitochondrial depolarization, and apoptosis-related transcriptional changes in HepG2 cells.","authors":"İbrahim Gecili, Adem Güner","doi":"10.1007/s00210-026-05943-0","DOIUrl":"https://doi.org/10.1007/s00210-026-05943-0","url":null,"abstract":"<p><p>Chlorpyrifos (CPF) is an organophosphate pesticide associated with hepatocellular toxicity, oxidative stress, and mitochondrial dysfunction. Syringic acid (SA) is a naturally occurring phenolic acid known for its antioxidant and cytoprotective properties. This study evaluated whether SA attenuates CPF-induced injury in HepG2 cells by assessing cytotoxicity, oxidative stress parameters, mitochondrial membrane potential, cell-cycle distribution, and mRNA expression of genes related to antioxidant defense, inflammation, and apoptosis. CPF exposure reduced MTT-derived metabolic activity and increased membrane damage, intracellular oxidant-associated DCF fluorescence, total oxidant status, and malondialdehyde, while decreasing total antioxidant capacity, superoxide dismutase, and glutathione peroxidase activities. CPF also increased mitochondrial depolarization and altered antioxidant-, inflammation-, and apoptosis-related mRNA expression. Co-treatment of SA with CPF attenuated oxidative stress, improved antioxidant-related biochemical parameters, reduced mitochondrial depolarization, and partially normalized these transcriptional changes. These findings indicate that SA attenuates CPF-induced cellular injury in association with improved redox status, preserved mitochondrial membrane potential, and changes in stress-related transcripts.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}