title: Black currant anthocyanins abrogate oxidative stress through Nrf2- mediated antioxidant mechanisms in a rat model of hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC), considered to be one of the most lethal cancers with almost > 1 million deaths reported annually worldwide, remains a devastating disease with no known effective cure. Hence, chemopreventive strategies come into play, offering an effective and safe mode of treatment, ideal to ward off potential cancer risks and mortality. A major predisposing condition, pertinent to the development and progression of HCC is oxidative stress. We previously reported a striking chemopreventive effect of anthocyanin-rich black currant skin extract (BCSE) against diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats. The current study aims to elucidate the underlying antioxidant mechanisms of black currant anthocyanins implicated in the previously observed chemopreventive effects against experimental hepatocarcinogenesis. Dietary BCSE (100 and 500 mg/kg) administered four weeks before and 18 weeks after DENA challenge decreased abnormal lipid peroxidation, protein oxidation, and expression of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in a dose-responsive fashion. Mechanistic studies revealed that BCSE upregulated the gene expression of a number of hepatic antioxidant and carcinogen detoxifying enzymes, such as NAD(P)H:quinone oxidoreductase, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase isoenzymes, in DENA-initiated animals. Protein and mRNA expressions of nuclear factor E2-related factor 2 (Nrf2) were substantially elevated with BCSE treatment, providing a direct evidence of a coordinated activation of the Nrf2-regulated antioxidant pathway, which led to the upregulation of a variety of housekeeping genes. The results of our study provide substantial evidence that black currant bioactive anthocyanins exert chemopreventive actions against DENA-inflicted hepatocarcinogenesis by attenuating oxidative stress through activation of Nrf2 signaling pathway.
authors.affiliation: Cancer Therapeutics and Chemoprevention Group, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Roslin J
authors.initials: RJ
authors.lastname: Thoppil
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhatia
authors.forename: Kendra F
authors.initials: KF
authors.lastname: Barnes
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Haznagy-Radnai
authors.forename: Judit
authors.initials: J
authors.lastname: Hohmann
authors.forename: Altaf S
authors.initials: AS
authors.lastname: Darvesh
authors.forename: Anupam
authors.initials: A
authors.lastname: Bishayee
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D000872:Anthocyanins / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D004032:Diet; D004052:Diethylnitrosamine / Q000633:toxicity; D005982:Glutathione Transferase; D007124:Immunoenzyme Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D008517:Phytotherapy; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D031965:Ribes / Q000737:chemistry*; D015398:Signal Transduction; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D000872:Anthocyanins; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; C002744:3-nitrotyrosine; D004052:Diethylnitrosamine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D005982:Glutathione Transferase