Abstract
BackgroundActivation of hepatic stellate cells (HSCs) plays an important role in the development of cirrhosis through the increased production of collagen. p53, the “guardian of the genome”, is a transcription factor that can bind to promoter regions of hundreds of genes where it either activates or suppresses gene expression. Thereby, p53 serves as a tumor suppressor by inducing cell cycle arrest, apoptosis, senescence and DNA repair. Artesunate is a derivative of Artemisinin, Scholars had found it had more extensive pharmacological effects past 10 years. However, little is known about the expression of p53 in the effects of Artesunate on induction of apoptosis and inhibition of proliferation in rat HSCs.Methodology/Principal FindingsIsolated and cultured rat primary HSCs in the flask for 10 days to make cells activated. HSCs were divided into two groups: experimental groups and control groups, experimental groups included with various concentrations of Artesunate (125, 150, 175, 200, 225 µmol/L) for 24, 48 and 72 hours. Analysis of MTT revealed that activated HSCs treated with various concentrations of Artesunate (150–225 µmol/L) were inhibited on dose and time-effect relationships; Concentration of hydroxyproline in supernatant was detected by digestive method; Analysis of flow cytometry demonstrated that Artesunate could arrest cell cycle in G1 and induce apoptosis; The nuclear morphological changes in apoptotic cells were evaluated with DNA staining by Hoechst 33258 dye; The expression of p53 were up-regulated showed by western blotting and RT-PCR.ConclusionArtesunate could inhibit HSCs proliferation in dose-dependent and time-dependent manners in vitro through increase the expression of p53.
Highlights
Liver fibrosis is a compensatory response to a variety of chronic liver injury, is the hub of the development of ‘‘chronic hepatitis liver fibrosis – cirrhosis’’
Hepatic stellate cells isolation, culture and identification Freshly isolated rat hepatic stellate cells (HSCs) were cultured on plastic in serumcontaining media
Hepatic stellate cells growth curve HSCs growth curve showed that the cultured HSCs were proliferated after 72 h, turning into the logarithmic growth phase on the 4th, 5th day and into the plateau phase on the 6th, 7th day (Figure 2)
Summary
Liver fibrosis is a compensatory response to a variety of chronic liver injury, is the hub of the development of ‘‘chronic hepatitis liver fibrosis – cirrhosis’’. In the process of hepatic fibrosis, activation and proliferation of hepatic stellate cells (HSCs) is the central link in the incidence [2]. Known as ‘‘Ito cells’’ or ‘‘fat-storing cells’’, localize between hepatocytes and sinusoids (space of Disse) in mammalian livers. In their healthy state, HSCs control retinoid homeostasis, sinusoidal blood flow, macromolecule transport, and potentially act as antigen-presenting cells in the liver [3,4]. Little is known about the expression of p53 in the effects of Artesunate on induction of apoptosis and inhibition of proliferation in rat HSCs
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