Neuromodulatory and oxidative stress evaluations in African catfish Clarias gariepinus exposed to antipsychotic drug chlorpromazine.

Chlorpromazine (CPZ) is among the most famous drugs used for the treatment of psychosis such as delusions, hallucinations, schizophrenia, paranoia, or disordered thought in humans. In the present study, the acetylcholinesterase (AChE) activity and oxidative stress parameters in the brain of Clarias gariepinus juveniles exposed to CPZ were investigated. Fish were exposed to 0.53, 1.56, and 2.11 mg/L corresponding to 5, 10, and 20% of the 96 h LC50 of CPZ on C. gariepinus, respectively. The fish brain was sampled on days 1, 7, 14, and after 7-days recovery. Our results indicate that AChE values were significantly higher in exposed groups compared to the control on days 7, 14, and 7-days recovery. The values of lipid peroxidation (LPO), glutathione reductase (GR), and glutathione peroxidase (GPx) increased compared to the control while catalase (CAT) and superoxide dismutase (SOD) significantly declined at higher CBZ concentrations. While LPO and CAT returned to the same range as the control values after the 7-day withdrawal from the drug, AChE, SOD, GR, and GPx did not. The use and disposal of CPZ should be strictly regulated to avoid possible ecotoxicological impacts on non-target organisms.

Nicotine-induced oxidative stress contributes to EMT and stemness during neoplastic transformation through epigenetic modifications in human kidney epithelial cells.

Nicotine is a component of cigarette smoke and mounting evidence suggests toxicity and carcinogenicity of tobacco smoke in kidney. Carcinogenicity of nicotine itself in kidney and the underlying molecular mechanisms are not well-understood. Hence, the objective of this study was to determine the carcinogenic effects of chronic nicotine exposure in Hk-2 human kidney epithelial cells. The effects of nicotine exposure on the expression of genes for cellular reprogramming, redox status, and growth signaling pathways were also evaluated to understand the molecular mechanisms. Results revealed that chronic exposure to nicotine induced growth and neoplastic transformation in HK-2 cells. Increased levels of intracellular reactive oxygen species (ROS), acquired stem cell-like sphere formation, and epithelial-mesenchymal-transition (EMT) changes were observed in nicotine exposed cells. Treatment with antioxidant N-acetyl cysteine (NAC) resulted in abrogation of EMT and stemness in HK-2 cells, indicating the role of nicotine-induced ROS in these morphological changes. The result also suggests that ROS controls the stemness through regulation of AKT pathway during early stages of carcinogenesis. Additionally, the expression of epigenetic regulatory genes was altered in nicotine-exposed cells and the changes were reversed by NAC. The epigenetic therapeutics 5-aza-2'-deoxycytidine and Trichostatin A also abrogated the stemness. This suggests the nicotine-induced oxidative stress caused epigenetic alterations contributing to stemness during neoplastic transformation. To our knowledge, this is the first report showing the ROS-mediated epigenetic modifications as the underlying mechanism for carcinogenicity of nicotine in human kidney epithelial cells. This study further suggests the potential of epigenetic therapeutics for pharmacological intervention in nicotine-induced kidney cancer.

MicroRNA-214-3p protects against myocardial ischemia-reperfusion injury by targeting demethylase lysine demethylase 3A.

Objective: Many studies have explored the roles of microRNAs (miRs) in myocardial ischemia/reperfusion injury (MI/RI), while the function of miR-214-3p in MI/RI remained obscure. This study aims to unravel the regulatory mechanism of miR-214-3p in MI/RI via targeting histone demethylase lysine demethylase 3A (KDM3A). Methods: MI/RI rat model was established by ligating the left anterior descending coronary artery. MiR-214-3p and KDM3A expression in myocardial tissues of MI/RI rats was examined. Then, the serum oxidative stress factors, inflammatory factors, pathological changes of myocardial tissues, cardiomyocyte apoptosis, and fibrosis of myocardial tissues were detected in MI/RI rats intervening with miR-214-3p or KDM3A expression. The targeting relation between miR-214-3p and KDM3A was validated. Results: MiR-214-3p was low-expressed while KDM3A was high-expressed in MI/RI rat model. Up-regulated miR-214-3p or down-regulated KDM3A protected against MI/RI via mitigating serum oxidative response, reducing the levels of inflammatory factors, alleviating the pathological changes of myocardial tissues, and decreasing cardiomyocyte apoptosis and fibrosis of myocardial tissue. KDM3A amplification reversed the therapeutic effects of elevated miR-214-3p on MI/RI. KDM3A was targeted by miR-214-3p. Conclusion: miR-214-3p hinders cardiomyocyte apoptosis and myocardial injury in MI/RI rats via regulating KDM3A. Thus, miR-214-3p may function as a potential candidate for MI/RI treatment.