Abstract
Background Graptopetalum paraguayense (GP) is a folk herbal medicine with hepatoprotective effects that is used in Taiwan. The aim of this study was to evaluate the hepatoprotective and antifibrotic effects of GP on experimental hepatic fibrosis in both dimethylnitrosamine (DMN)- and carbon tetrachloride (CCl4)-induced liver injury rats.MethodsHepatic fibrosis-induced rats were fed with the methanolic extract of GP (MGP) by oral administration every day. Immunohistochemistry, biochemical assays, and Western blot analysis were performed. The effects of MGP on the expression of fibrotic markers and cytokines in the primary cultured hepatic stellate cells (HSCs) and Kupffer cells, respectively, were evaluated.ResultsOral administration of MGP significantly alleviated DMN- or CCl4-induced liver inflammation and fibrosis. High levels of alanine transaminase, aspartate transaminase, bilirubin, prothrombin activity and mortality rates also decreased in rats treated with MGP. There were significantly decreased hydroxyproline levels in therapeutic rats compared with those of the liver-damaged rats. Collagen I and alpha smooth muscle actin (α-SMA) expression were all reduced by incubation with MGP in primary cultured rat HSCs. Furthermore, MGP induced apoptotic cell death in activated HSCs. MGP also suppressed lipopolysaccharide-stimulated rat Kupffer cell activation by decreasing nitric oxide, tumor necrosis factor-α and interleukin-6 production, and increasing interleukin-10 expression.ConclusionsThe results show that the administration of MGP attenuated toxin-induced hepatic damage and fibrosis in vivo and inhibited HSC and Kupffer cell activation in vitro, suggesting that MGP might be a promising complementary or alternative therapeutic agent for liver inflammation and fibrosis.
Highlights
Hepatic fibrosis, a precursor of cirrhosis, is characterized by an excessive generation of extracellular matrix constituents that impair normal function with progression of liver disease to cirrhosis [1]
Our findings indicate that the protective effects of methanolic extract of GP (MGP) against liver injury likely involve multiple mechanisms, including an antiinflammatory effect through decreased tumor necrosis factor alpha (TNF-a), IL-6 and nitric oxide (NO) production in LPS-stimulated conditions as well as an antifibrogenic effect that is mediated by inhibiting the activation of cell transformation and by the induction of apoptosis in hepatic stellate cells (HSCs)
Repeated administration of DMN or CCl4 to rats resulted in a reproducible animal model of liver fibrosis [21,22] and enabled us to examine the hepatoprotective effects of MGP on DMN- and CCl4-induced chronic liver injury in rats
Summary
A precursor of cirrhosis, is characterized by an excessive generation of extracellular matrix constituents ( collagens) that impair normal function with progression of liver disease to cirrhosis [1]. Numerous agents, including corticosteroids, penicillamine, methotrexate, silymarin and colchicines, have been used in the therapy of hepatic fibrosis, but there is no definitive treatment [3,4,5,6]. An effective therapy for treatment of patients with hepatic fibrosis is urgently needed. Over the past several decades, there has been a growing trend in Western countries to use herbal medicines to treat a wide range of diseases, including obesity, insomnia, eczema, arthritis, immunodeficiency syndrome, inflammatory diseases, and chronic liver diseases [7]. Graptopetalum paraguayense (GP) is a folk herbal medicine with hepatoprotective effects that is used in Taiwan. The aim of this study was to evaluate the hepatoprotective and antifibrotic effects of GP on experimental hepatic fibrosis in both dimethylnitrosamine (DMN)- and carbon tetrachloride (CCl4)-induced liver injury rats
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