Aug 2026· Drug and chemical toxicology (New York, N.Y. 1978)· pp.
1-12
· 0 citations· 44 references
Medicine
Abstract
Acrylamide (Acr) is a widely encountered environmental and dietary toxicant known to induce oxidative stress and disrupt male reproductive function. Leydig cells, due to their high metabolic activity and mitochondrial dependence, are particularly vulnerable to redox imbalance. N-acetylcysteine (Nac), a thiol-containing antioxidant and glutathione precursor, has been extensively studied for its cytoprotective properties. However, its modulatory effects on Acr-induced toxicity in Leydig cells and its pharmacodynamic interaction profile remain incompletely characterized. In this study, TM3 Leydig cells were exposed to Acr in the presence or absence of Nac. Cell viability was assessed by MTT assay, and chemical interaction profiles were evaluated using ZIP, Bliss, and Chou-Talalay combination index analyses. Oxidative stress parameters, including intracellular reactive oxygen species (ROS), lipid peroxidation, antioxidant enzyme activities (SOD, CAT, GPx), and glutathione levels, were measured. Apoptotic responses were analyzed through double fluorescence staining, RT-qPCR of apoptosis-related genes (Bax, Bcl2, Casp3, Trp53), and Western blot analysis of CASP3 protein expression. Acr exposure significantly reduced cell viability, increased ROS and lipid peroxidation levels, suppressed antioxidant defenses, and activated the mitochondrial apoptotic pathway. Nac treatment markedly improved cell viability, restored antioxidant capacity, reduced oxidative stress markers, and suppressed p53/Bax/Casp3-mediated apoptotic signaling. Combination analyses revealed an antagonistic interaction profile, indicating that Nac biologically limits Acr-induced cytotoxicity. Collectively, these findings demonstrate that Nac exerts protective effects in Leydig cells by modulating redox homeostasis and mitochondrial apoptosis, suggesting its potential as a protective regulator against Acr-induced reproductive toxicity.
Rationale — The male reproductive system is an organ sensitive to toxins, and nicotine exposure is recognized as a detrimental factor for male sexual function. Taraxasterol, a bioactive compound with antioxidant and antiapoptotic properties, has potential protective effects against cytotoxicity. This study aimed to evaluate the protective effects of taraxasterol against nicotine toxicity in murine Leydig (TM3) and Sertoli (TM4) cell lines.
Methods — Prior to the experiment, TM3/4 cells were treated with taraxasterol extract as a protective agent for 24 h. Cytotoxicity was then induced by exposure to nicotine for 24 h. Finally, cell viability was assessed using the MTT assay, and oxidative stress biomarkers, including malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS), were quantified using commercial kits. The expression of steroidogenic and antioxidant enzyme genes was assessed using quantitative real-time PCR, while apoptosis was measured by assessing the DNA fragmentation rate. All experiments were performed in triplicate, and statistical data processing included analysis of variance (ANOVA) followed by a Tukey’s post-hoc test (p
Mohammad Hashempour, Fuzieh Hemmatabadi, I. Rashidi et al.· Russian Open Medical Journal· 0 citations
Acrylamide (ACR), a potential neurotoxin, is produced during industrial and food processing. The mechanisms of ACR neurotoxicity are still under debate, and effective strategies need to be investigated. We examined the neuroprotective potential of losartan (LOS), an antihypertensive drug, against ACR-induced neurotoxicity. PC12 cells were treated with concentrations of LOS (10, 20, and 50 μM) for 24 h and then exposed to ACR (5 mM) for a further 24 h. Antioxidant markers (SOD and CAT) and oxidative damage markers (ROS and TBARS) were measured. Real-time PCR was used to examine the mRNA expression of Bax and Bcl-2. Western blotting was used to evaluate the protein expression of Nrf2, Keap1, HO-1, as well as total and cleaved caspase-3. Exposure to ACR caused a significant increase in ROS and TBARS levels and reduced activities of SOD and CAT. Exposure to ACR affected the mRNA expression of key apoptotic regulators Bax and Bcl-2, resulting in a higher Bax/Bcl-2 expression. Furthermore, ACR elevated the protein expression of total and cleaved caspase-3 and Nrf2, while decreasing Keap1 levels. ACR-induced changes were reversed by LOS treatment. The findings demonstrated that LOS can protect PC12 cells from ACR-induced neurotoxicity by enhancing antioxidant defenses and modulating apoptotic signaling.
Shahrzad Molavinia, Saeedeh Shariati, Shokooh Mohtadi et al.· International Journal of Env...· 0 citations
Bisphenol A (BPA) is a widespread environmental contaminant that causes hepatotoxicity through oxidative stress and apoptosis. In the present study, the dose-dependent protective effect of irisin against BPA-induced hepatotoxicity in AML12 hepatocytes was evaluated. AML12 hepatocytes were treated with BPA (100 µM) with or without irisin (50 and 100 nM). Cell viability was measured by MTT test and cytotoxicity was measured by lactate dehydrogenase (LDH) release. The oxidative status of the cells was characterized by evaluating malondialdehyde (MDA) levels, total oxidant status (TOS), total antioxidant status (TAS), and superoxide dismutase (SOD) activity. In addition, the oxidative stress index (OSI) and caspase-3 activity were assessed to provide insight into cellular redox balance and apoptotic responses. BPA significantly reduced cell viability and antioxidant capacity, and increased LDH release, lipid peroxidation and apoptotic activity. However, irisin significantly ameliorated these changes in a dose-dependent manner. More specifically, irisin significantly decreased MDA, TOS, OSI, and caspase-3 activity and increased SOD activity and TAS levels, and cell viability. The higher dose of irisin (100 nM) was more effective than the lower dose. This study found that irisin alleviated BPA-induced hepatotoxicity by mitigating oxidative stress and caspase-3-mediated apoptosis, implying that irisin may represent a potential therapeutic candidate for the treatment of toxin-induced liver injury.
Gözde Karabulut· Eskişehir Teknik Üniversites...· 0 citations
Mancozeb (MZB), a widely used fungicide, induces oxidative stress-mediated cytotoxicity through excessive reactive oxygen species (ROS) generation. Present study evaluated the cytoprotective potential of zerumbone (Zer), a bioactive sesquiterpenoid, against MZB-induced toxicity in Vero cells. Dose-response and time-course assays determined the EC50 of MZB and a non-cytotoxic dose of Zer. Pre-treatment with Zer (10 μM, 18 h) significantly improved cell viability (66 ± 7%) following MZB exposure (22 μM, 6 h) and markedly reduced intracellular ROS levels. Zer attenuated MZB-induced DNA damage, lowering genotoxicity from 44 ± 6% to 23 ± 12% (p < 0.05), and significantly reduced apoptotic and necrotic cell death. Expression of apoptosis (Bax, Bcl-2, caspase-3, -8, -9), antioxidant (Nrf2, Keap1, catalase, HO-1, NQO1, SOD, GPx, PHD2) and inflammation-related (p53, Akt) markers was analysed and validated by western blotting to characterize molecular responses to Zer pre-treatment. Dysregulated expression of apoptosis and antioxidant markers, including caspase-3, catalase and GPx, was restored by Zer. Additionally, Zer normalized MZB-elevated Nrf2 levels while inducing its regulatory partners Keap1, NQO1 and HO-1. Overall, zerumbone confers substantial protection against MZB-induced oxidative injury by restoring redox balance, reducing genotoxic stress and preventing cell death, highlighting its therapeutic potential against fungicide-induced toxicity.
S. T, R. Aswati Nair· Food and Chemical Toxicology· 0 citations
Doxorubicin (DOX) is a commonly prescribed chemotherapeutic agent whose clinical application is limited by its toxicity to rapidly dividing organs, particularly the testes.This study explored the protective potential of ferulic acid-loaded niosomes (FA-NIO) against DOX-induced testicular dysfunction in rats and elucidated the underlying molecular mechanisms. Forty male rats were allocated into four groups: Group 1 was given saline, Group 2 was given DOX, Group 3 was given DOX + free FA, and Group 4 was given DOX + FA-NIO. Serum reproductive hormone levels, testicular oxidative stress indices, and the expression of genes and proteins relevant to NLRP3 inflammasome signaling, apoptosis (Bax and Bcl-2), and steroidogenesis (StAR, CYP11A1, and 3β-HSD) were assessed, along with histopathological changes in the testicular tissue. DOX administration significantly increased MDA (malondialdehyde) while suppressing antioxidant defences, accompanied by hormonal imbalance, severe histopathological damage, upregulation of Bax, NLRP3, and IL-1β, downregulation of Bcl-2, and inhibition of steroidogenic gene expression. On the other hand, these changes were partially mitigated in the DOX + free FA group. Notably, FA-NIO treatment reduced histopathological damage, normalised reproductive hormone levels, markedly increased steroidogenesis-related gene expression, suppressed apoptotic and inflammasome-related gene expression, and greatly restored antioxidant capacity. Compared with DOX + free FA, FA-NIO consistently demonstrated greater protective efficacy. In summary, FA-NIO targets oxidative stress-mediated apoptosis, attenuates NLRP3 inflammasome-related signaling, and restores steroidogenic function, thereby successfully attenuating DOX-induced testicular toxicity. These results suggest that FA-NIO may represent a promising nanotherapeutic strategy for attenuating chemotherapy-induced reproductive toxicity in a rat model.
M. M. A. El-Emam, A. Atia, Mona A. Bakry et al.· Biological Research· 0 citations
Background: Cisplatin is a widely used chemotherapeutic agent whose clinical application is often limited by severe hepatorenal toxicity associated with oxidative stress and cellular injury. Nicotinamide riboside (NR), a natural precursor of nicotinamide adenine dinucleotide (NAD+), has emerged as a promising cytoprotective compound with antioxidant and metabolic regulatory properties. This study investigated the protective effects of NR against cisplatin-induced hepatorenal toxicity and explored its potential mechanisms of action. Methods: Thirty-six adult male Wistar rats were randomly assigned to four groups (n = 6): control, cisplatin (7 mg/kg, i.p.), nicotinamide riboside (50 mg/kg/day, orally), and cisplatin plus NR. Renal and hepatic function biomarkers, lipid profile parameters, oxidative stress markers, and antioxidant status were evaluated. Relative mRNA expression of Nrf2 and NQO1 was determined using RT-qPCR. Histopathological examinations of liver and kidney tissues were also performed. Results: Cisplatin administration induced marked hepatorenal injury, evidenced by significant elevations in serum KIM-1 (395.27 vs. 116.04 ng/mL), urea (71.16 vs. 21.33 mg/dL), creatinine (3.49 vs. 0.26 mg/dL), AST (325.83 vs. 95.16 U/L), and ALT (102.83 vs. 45.50 U/L), accompanied by dyslipidemia, oxidative stress, and severe histopathological alterations. NR treatment significantly attenuated these changes, reducing KIM-1, urea, creatinine, AST, and ALT by 55.5%, 47.8%, 48.1%, 55.4%, and 33.5%, respectively, compared with the cisplatin group. NR also improved antioxidant status by increasing GSH and SOD levels while reducing MDA and NO concentrations. Hepatic NAD+ levels and the NAD+/NADH ratio were significantly decreased by cisplatin and significantly restored by NR treatment. In addition, NR significantly upregulated the relative mRNA expression of Nrf2 and NQO1 and markedly preserved hepatic and renal histological architecture. Pharmacological inhibition of Nrf2 with ML385 significantly attenuated these protective effects of NR across biochemical, lipid, and oxidative stress parameters, confirming that they are, at least in part, Nrf2-dependent. Conclusions: Nicotinamide riboside exerts protective effects against cisplatin-induced hepatorenal toxicity that are mechanistically linked to activation of the Nrf2/NQO1 antioxidant pathway and restoration of hepatic NAD+ homeostasis. This finding supports the potential of NR as an adjunctive strategy for mitigating cisplatin-associated hepatorenal injury and warrants further preclinical and clinical investigation.
W. Albahadly, M. Rasool, H. Al-Saedi et al.· Cells· 0 citations