title: Pomegranate protects against arsenic-induced p53-dependent ROS-mediated inflammation and apoptosis in liver cells.
abstract: Molecular mechanisms involved in arsenic-induced toxicity are complex and elusive. Liver is one of the most favored organs for arsenic toxicity as methylation of arsenic occurs mostly in the liver. In this study, we have selected a range of environmentally relevant doses of arsenic to examine the basis of arsenic toxicity and the role of pomegranate fruit extract (PFE) in combating it. Male Swiss albino mice exposed to different doses of arsenic presented marked hepatic injury as evident from histological and electron microscopic studies. Increased activities of enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase corroborated extensive liver damage. It was further noted that arsenic exposure initiated reactive oxygen species (ROS)-dependent apoptosis in the hepatocytes involving loss of mitochondrial membrane potential. Arsenic significantly increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB), coupled with increase in phosphorylated Iκ-B, possibly as adaptive cellular survival strategies. Arsenic-induced oxidative DNA damage to liver cells culminated in p53 activation and increased expression of p53 targets like miR-34a and Bax. Pomegranate polyphenols are known to possess remarkable antioxidant properties and are capable of protecting normal cells from various stimuli-induced oxidative stress and toxicities. We explored the protective role of PFE in ameliorating arsenic-induced hepatic damage. PFE was shown to reduce ROS generation in hepatocytes, thereby reducing arsenic-induced Nrf2 activation. PFE also inhibited arsenic-induced NF-κB-inflammatory pathway. Data revealed that PFE reversed arsenic-induced hepatotoxicity and apoptosis by modulating the ROS/Nrf2/p53-miR-34a axis. For the first time, we have mapped the possible signaling pathways associated with arsenic-induced hepatotoxicity and its rescue by pomegranate polyphenols.
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Sreetama
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Sayan
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata 700009, India.
authors.forename: Payal
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata 700098, India.
authors.forename: Saurav
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata 700098, India.
authors.forename: Arghya
authors.initials: A
authors.lastname: Adhikary
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata 700009, India; Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata 700098, India. Electronic address: scphys@caluniv.ac.in.
authors.forename: Sreya
authors.initials: S
authors.lastname: Chattopadhyay
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D020261:Arsenic Poisoning / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018053:Arsenites / Q000008:administration & dosage; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D004249:DNA Damage; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D005638:Fruit / Q000737:chemistry; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D029561:Lythraceae / Q000737:chemistry*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008855:Microscopy, Electron, Scanning; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D017670:Sodium Compounds / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018053:Arsenites; D015415:Biomarkers; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; C017947:sodium arsenite
keywords: Apoptosis; Arsenic; Hepatotoxicity; Nrf2; Pomegranate; p53