Black currant anthocyanins abrogate oxidative stress through Nrf2- mediated antioxidant mechanisms in a rat model of hepatocellular carcinoma.
Male; Animals; Rats; Diet; Signal Transduction; NF-E2-Related Factor 2/genetics/*metabolism; *Phytotherapy; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Alkylating Agents/toxicity; Anthocyanins/*therapeutic use; Antioxidants/therapeutic use; Diethylnitrosamine/toxicity; Glutathione Transferase; Immunoenzyme Techniques; Lipid Peroxidation/drug effects; Nitric Oxide Synthase Type II/genetics/metabolism; Oxidative Stress/*drug effects; Ribes/*chemistry; Tyrosine/analogs & derivatives/metabolism; Carcinoma; Sprague-Dawley; Blotting; Western; RNA; Liver Neoplasms; Messenger/genetics; Experimental/chemically induced/metabolism/*prevention & control; Hepatocellular/chemically induced/metabolism/*prevention & control
Hepatocellular carcinoma (HCC), considered to be one of the most lethal cancers with almost \textgreater 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.
Thoppil Roslin J; Bhatia Deepak; Barnes Kendra F; Haznagy-Radnai Erzsebet; Hohmann Judit; Darvesh Altaf S; Bishayee Anupam
Current cancer drug targets
2012
2012-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/156800912803987968" target="_blank" rel="noreferrer noopener">10.2174/156800912803987968</a>
Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms.
*Phytotherapy; Alkylating Agents/toxicity; Animals; Antioxidants/*therapeutic use; Blotting; Carcinoma; Diethylnitrosamine/toxicity; Experimental/chemically induced/*drug therapy/metabolism; GA-Binding Protein Transcription Factor/*metabolism; gamma-Glutamyltransferase/metabolism; Hepatocellular/chemically induced/*drug therapy/metabolism; Immunoenzyme Techniques; Lipid Peroxidation/drug effects; Liver Neoplasms; Male; Oxidative Stress; Plant Extracts/*therapeutic use; Punicaceae/*chemistry; Rats; Sprague-Dawley; Western
Hepatocellular carcinoma (HCC), one of the most prevalent and lethal cancers, has shown an alarming rise in the USA. Without effective therapy for HCC, novel chemopreventive strategies may effectively circumvent the current morbidity and mortality. Oxidative stress predisposes to hepatocarcinogenesis and is the major driving force of HCC. Pomegranate, an ancient fruit, is gaining tremendous attention due to its powerful antioxidant properties. Here, we examined mechanism-based chemopreventive potential of a pomegranate emulsion (PE) against dietary carcinogen diethylnitrosamine (DENA)-induced rat hepatocarcinogenesis that mimics human HCC. PE treatment (1 or 10 g/kg), started 4 weeks prior to the DENA challenge and continued for 18 weeks thereafter, showed striking chemopreventive activity demonstrated by reduced incidence, number, multiplicity, size and volume of hepatic nodules, precursors of HCC. Both doses of PE significantly attenuated the number and area of gamma-glutamyl transpeptidase-positive hepatic foci compared with the DENA control. PE also attenuated DENA-induced hepatic lipid peroxidation and protein oxidation. Mechanistic studies revealed that PE elevated gene expression of an array of hepatic antioxidant and carcinogen detoxifying enzymes in DENA-exposed animals. PE elevated protein and messenger RNA expression of the hepatic nuclear factor
Bishayee Anupam; Bhatia Deepak; Thoppil Roslin J; Darvesh Altaf S; Nevo Eviatar; Lansky Ephraim P
Carcinogenesis
2011
2011-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1093/carcin/bgr045" target="_blank" rel="noreferrer noopener">10.1093/carcin/bgr045</a>