title: Pomegranate phytoconstituents blunt the inflammatory cascade in a chemically induced rodent model of hepatocellular carcinogenesis.
abstract: Liver cancer, predominantly hepatocellular carcinoma (HCC), represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation. Due to dismal prognosis and limited therapeutic intervention, chemoprevention has emerged as a viable approach to reduce the morbidity and mortality of HCC. Pomegranate fruit is a rich source of phytochemicals endowed with potent antioxidant and anti-inflammatory properties. We previously reported that pomegranate phytochemicals inhibit diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats though nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant mechanisms. Since Nrf2 also acts as a key mediator of the nuclear factor-kappaB (NF-κB)-regulated inflammatory pathway, our present study investigated the anti-inflammatory mechanisms of a pomegranate emulsion (PE) during DENA-induced rat hepatocarcinogenesis. Rats were administered with PE (1 or 10 g/kg) 4 weeks before and 18 weeks following DENA initiation. There was a significant increase in hepatic expressions of inducible nitric oxide synthase, 3-nitrotyrosine, heat shock protein 70 and 90, cyclooxygenase-2 and NF-κB in DENA-exposed rat livers. PE dose-dependently suppressed all aforementioned elevated inflammatory markers. A conspicuous finding of this study involves lack of cardiotoxicity of PE as assessed by monitoring cardiac function using noninvasive echocardiography. Our results provide substantial evidence that suppression of the inflammatory cascade through modulation of NF-κB signaling pathway may represent a novel mechanism of liver tumor inhibitory effects of PE against experimental hepatocarcinogenesis. Data presented here coupled with those of our earlier study underline the importance of simultaneously targeting two interconnected molecular circuits, namely, Nrf2-mediated redox signaling and NF-κB-regulated inflammatory pathway, by pomegranate phytoconstituents to achieve chemoprevention of HCC.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, American University of Health Sciences, Signal Hill, CA 90755, USA. abishayee@auhs.edu
authors: Anupam
authors: A
authors: Bishayee
authors: Roslin J
authors: RJ
authors: Thoppil
authors: Altaf S
authors: AS
authors: Darvesh
authors: Vahagn
authors: V
authors: Ohanyan
authors: J Gary
authors: JG
authors: Meszaros
authors: Deepak
authors: D
authors: Bhatia
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D004452:Echocardiography; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006321:Heart / Q000502:physiology; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D029561:Lythraceae / Q000737:chemistry*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; D010936:Plant Extracts; C002744:3-nitrotyrosine; D004052:Diethylnitrosamine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2