Human & Experimental Toxicology

Zhang, Qiqi; Wang, Jiabin; Wang, Jinchun; Xu, Zhengyuan

doi: 10.1177/09603271261420420pmid: N/A

BackgroundAtonal bHLH transcription factor 8 (ATOH8) plays heterogenous roles in different types of cancer, but its function and molecular mechanism in esophageal squamous cell carcinoma (ESCC) remain to be clarified.MethodsATOH8 expression was analyzed using TCGA data and experimental assays. Its functional impact was assessed through in vitro assays (CCK-8, transwell) and in vivo mouse models (xenograft, lung metastasis). Molecular interactions between ATOH8, OCT4, and TFAP2A were characterized using co-immunoprecipitation (Co-IP), ubiquitination, luciferase, and chromatin immunoprecipitation (ChIP) assays.ResultsOur results revealed that ATOH8 was significantly downregulated in ESCC. ATOH8 overexpression effectively inhibited the viability, mobility, and epithelial-mesenchymal transition (EMT) and promoted apoptosis of ESCC cells in vitro. Similarly, in vivo experiments suggested that the growth of xenograft tumors and lung metastasis were substantially suppressed by overexpressing ATOH8. Mechanistically, ATOH8 was confirmed to negatively regulate the protein stability of OCT4 by promoting its ubiquitination. The inhibitory effect of ATOH8 on ESCC aggressiveness was partially abrogated when OCT4 was overexpressed. Moreover, we found that ATOH8 deficiency in ESCC was caused by TFAP2A-induced transcriptional suppression.ConclusionOur results demonstrated a critical role of the TFAP2A-ATOH8-OCT4 signaling axis in the aggressiveness of ESCC. Specifically, TFAP2A-mediated suppression of ATOH8 expression facilitated OCT4-induced EMT and tumor progression. These findings offer insights to identify ATOH8 as a novel biomarker for ESCC management.

doi: 10.1177/09603271261453113pmid: N/A

Kale, Oluwafemi Ezekiel; Gündüz, Miyase Gözde; Osonuga, Ifabunmi Oduyemi; Awodele, Olufunsho; Ekor, Martins

doi: 10.1177/09603271261446916pmid: N/A

IntroductionDoxorubicin (DOX) is an anthracycline anticancer agent whose clinical utility is constrained by dose-dependent cardiotoxicity. This exploratory experimental-focused study evaluated HM12, a 1,4-dihydropyridine calcium channel blocker (CCB) derivative, for protective effects against DOX-induced toxicity.MethodsEight groups of adult male Wistar rats received saline, DOX (20 mg/kg, i.p.), lower and upper HM12 doses (5 or 20 mg/kg, p.o.), nifedipine (NFD, 20 mg/kg, p.o.), or combinations of DOX with HM12 or NFD. Assessments included blood biochemistry, cardiac biomarkers, oxidative-antioxidant indices, renal and hepatic function tests, and organ histology. In silico docking was performed using the human topoisomerase IIβ (PDB ID: 3QX3).ResultsDOX induced marked cardiotoxicity, evidenced by elevated tumor necrosis factor-alpha, C - reactive protein, lactate dehydrogenase, interleukin-6 and malondialdehyde. Renal and hepatic toxicity were also observed. However, HM12 improved heart weight, selectively reduced cardiac biomarkers, and improved antioxidant defenses. The HM12 doses mitigated cardiac damage, but offered limited protection to renal and hepatic tissues. Notably, in silico HM12 exhibited greater binding affinity than NFD and engaged in distinct interaction patterns with 3QX3.DiscussionHM12 exhibits cardioprotective effects against DOX-induced toxicity through antioxidant enhancement and modulation of inflammatory markers, although its protection of renal and hepatic tissues is limited.

doi: 10.1177/09603271261452720pmid: N/A

Adeniyi, Temidayo Daniel; Moronkeji, Akinpelu; Adunmo, Godwin Olawoyin; Okunnuga, Adetokunbo Adedotun; Ajala, Olayinka Joshua; Oyeleke, Abiodun; Umeboro, Puritan Chinonso; Thomas, Oluwatimilehin Kemisola

doi: 10.1177/09603271261442765pmid: N/A

BackgroundThe rising consumption of herbal alcoholic beverages in Nigeria, driven by unverified health claims, poses growing public health risks and adds to the global disease burden.AimTo evaluate the effects of ascorbate and alpha-tocopherol supplementation on hepatorenal biochemical parameters, histopathology, and expression of oxidative stress-related genes (Nrf2 and CYP2E1) in rats exposed to a herbal-based alcoholic beverage.MethodsTwenty-eight adult male Wistar rats were randomly assigned into four groups (n=7 per group) using a computer-generated randomisation, with all outcome assessments performed under blinded conditions. Group I consisted of the unexposed control rats. Group II rats received a daily oral dose of alcohol at 0.2 mL/kg/bw. Groups III and IV were also administered alcohol daily at 0.2 mL/kg/bw but were additionally treated with ascorbate (500 mg/kg) and alpha-tocopherol (300 mg/kg), respectively, for 28 days. Hepatorenal biochemical parameters, hepatic and renal Nrf2 and CYP2E1 expression, and histopathological changes were subsequently evaluated.ResultsSupplementation with ascorbate (500 mg/kg) or α-tocopherol (300 mg/kg) was associated with significantly lower (p < 0.05) ALP, ALT, AST, creatinine, and urea levels compared with alcohol-exposed untreated rats. Vitamin supplementation was associated with the modulation of alcohol-induced overexpression of CYP2E1 and Nrf2, and partially restored the altered biochemical parameters. Histopathological examination further revealed mitigated alcohol-induced architectural disruptions in the liver and kidney, suggestive of the protective effects of antioxidant supplementation.ConclusionAscorbate and alpha-tocopherol supplementation were associated with attenuation of alcohol-induced hepatorenal biochemical alterations, partial normalisation of liver and kidney function parameters, and modulation of oxidative stress-related gene expression (CYP2E1, Nrf2), findings consistent with a potential adjunctive role of these vitamins in mitigating alcohol-related organ toxicity rather than indicating definitive therapeutic effects. Mechanistic conclusions are limited by the absence of direct oxidative stress marker measurements (lipid peroxidation, glutathione status, antioxidant enzyme activities), and interpretation is limited by the absence of pure ethanol and vitamin-only control groups and the lack of independent chemical verification of the test beverage.