Inhibition of arsenic induced-rat liver injury by grape seed exact through suppression of NADPH oxidase and TGF-{beta}/Smad activation

Journal Article · Mon Aug 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

OSTI ID:21587797

Xinjuan, Pan; Yujie, Dai; Xing, Li; Nannan, Niu; Wenjie, Li; Fangli, Liu; Yang, Zhao

Chronic arsenic exposure induces oxidative damage to liver leading to liver fibrosis. We aimed to define the effect of grape seed extract (GSE), an antioxidant dietary supplement, on arsenic-induced liver injury. First, Male Sprague-Dawley rats were exposed to a low level of arsenic in drinking water (30 ppm) with or without GSE (100 mg/kg, every other day by oral gavage) for 12 months and the effect of GSE on arsenic-induced hepatotoxicity was examined. The results from this study revealed that GSE co-treatment significantly attenuated arsenic-induced low antioxidant defense, oxidative damage, proinflammatory cytokines and fibrogenic genes. Moreover, GSE reduced arsenic-stimulated Smad2/3 phosphorylation and protein levels of NADPH oxidase subunits (Nox2, Nox4 and p47phox). Next, we explored the molecular mechanisms underlying GSE inhibition of arsenic toxicity using cultured rat hepatic stellate cells (HSCs). From the in vitro study, we found that GSE dose-dependently reduced arsenic-stimulated ROS production and NADPH oxidase activities. Both NADPH oxidases flavoprotein inhibitor DPI and Nox4 siRNA blocked arsenic-induced ROS production, whereas Nox4 overexpression suppressed the inhibitory effects of GSE on arsenic-induced ROS production and NADPH oxidase activities, as well as expression of TGF-{beta}1, type I procollagen (Coll-I) and {alpha}-smooth muscle actin ({alpha}-SMA) mRNA. We also observed that GSE dose-dependently inhibited TGF-{beta}1-induced transactivation of the TGF-{beta}-induced smad response element p3TP-Lux, and that forced expression of Smad3 attenuated the inhibitory effects of GSE on TGF-{beta}1-induced mRNA expression of Coll-I and {alpha}-SMA. Collectively, GSE could be a potential dietary therapeutic agent for arsenic-induced liver injury through suppression of NADPH oxidase and TGF-{beta}/Smad activation. - Research Highlights: > GSE attenuated arsenic-induced low antioxidant defense, oxidative damage, proinflammatory cytokines and fibrogenic genes. > GSE reduced arsenic-mediated Smad2/3 phosphorylation and NADPH oxidase subunits (Nox2, Nox4 and p47phox). > Beneficial effects of GSE on As-induced liver injury was via inhibition of NADPH oxidase and TGF-{beta}/Smad activation.

• OSTI ID: 21587797
• Journal Information: Toxicology and Applied Pharmacology, Vol. 254, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.04.022; PII: S0041-008X(11)00177-3; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACTIN
ALBUMINS
ARSENIC
CATTLE
COLLAGEN
ENZYME IMMUNOASSAY
GLUTATHIONE
GRAPES
INHIBITION
INJURIES
LIVER
LYMPHOKINES
MESSENGER-RNA
NADP
OXIDASES
OXIDATION
PEROXIDASES
PLASMINOGEN
RATS
SUPEROXIDE DISMUTASE
ANIMALS
BIOASSAY
BLOOD COAGULATION FACTORS
BODY
CHEMICAL REACTIONS
COENZYMES
DIGESTIVE SYSTEM
DISEASES
DOMESTIC ANIMALS
DRUGS
ELEMENTS
ENZYMES
FIBRINOLYTIC AGENTS
FOOD
FRUITS
GLANDS
GROWTH FACTORS
HEMATOLOGIC AGENTS
IMMUNOASSAY
MAMMALS
MITOGENS
NUCLEIC ACIDS
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANS
OXIDOREDUCTASES
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RNA
RODENTS
RUMINANTS
SCLEROPROTEINS
SEMIMETALS
VERTEBRATES