Zhang Js

Over-expressed microRNA-27a and 27b influence fat accumulation and cell proliferation during rat hepatic stellate cell activation

Hepatic stellate cells (HSCs) activation is an initial event in liver fibrosis. MicroRNAs (miRNAs) have been found to play essential roles in cell differentiation, proliferation, and fat metabolism. In this study, we showed that down‐regulation of two over‐expressed miRNAs, miR‐27a and 27b allowed culture‐activated rat HSCs to switch to a more quiescent HSC phenotype, with restored cytoplasmic lipid droplets and decreased cell proliferation. Mechanistically, retinoid X receptor α was confirmed to be the target of miR‐27a and 27b. These results indicated a new role and mechanism of miR‐27a and 27b in regulating fat metabolism and cell proliferation during HSCs activation.

Over-expression of C/EBP-{alpha} induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-{gamma}

Hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic fibrosis. In our previous studies, CCAAT enhancer binding protein-alpha (C/EBP-alpha) has been shown to be involved in the activation of HSCs and to have a repression effect on hepatic fibrosis in vivo. However, the mechanisms are largely unknown. In this study, we show that the infection of adenovirus vector expressing C/EBP-alpha gene (Ad-C/EBP-alpha) could induce HSCs apoptosis in a dose- and time-dependent manner by Annexin V/PI staining, caspase-3 activation assay, and flow cytometry. Also, over-expression of C/EBP-alpha resulted in the up-regulation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and P53, while P53 expression was regulated by PPAR-gamma. In addition, Fas, FasL, DR4, DR5, and TRAIL were studied. The results indicated that the death receptor pathway was mainly involved and regulated by PPAR-gamma and p53 in the process of apoptosis triggered by C/EBP-alpha in HSCs.

Hydrogen sulphide inhibits cardiomyocyte hypertrophy by up-regulating miR-133a.

Hydrogen sulphide (H(2)S) has been shown to play a crucial role in cardiovascular physiology and disease. However, there is no information about the possible role of H(2)S in cardiomyocyte hypertrophy (CH). Our results showed that pretreatment with NaHS, an H(2)S donor, significantly reduced [(3)H]-leucine incorporation, cell surface area, mRNA expression of brain natriuretic peptide (BNP), intracellular reactive oxygen species (ROS), miR-21 and increased atrial natriuretic peptide (ANP) and miR-133a expression in hypertrophic cardiomyocytes. Anti-miR133a inhibitor transfection partly reduced the anti-hypertrophic effect of NaHS. In conclusion, H(2)S is a direct inhibitor of CH; it acts by increasing miR-133a and inhibiting the increase in intracellular ROS.

In vivo transfection of C/EBP-α gene could ameliorate CCL4-induced hepatic fibrosis in mice

Aim:u2002 Hepatic stellate cells (HSCs) play a key role in liver fibrosis. CCAAT/enhancer‐binding proteins‐alpha (C/EBP‐α) can inhibit HSCs activation in vitro, as described in our previous study. However, little is known about the in vivo effect of C/EBP‐α gene in hepatic fibrosis.

Adrenomedullin regulates expressions of transforming growth factor‐β1 and β1‐induced matrix metalloproteinase‐2 in hepatic stellate cells

Adrenomedullin (AM), a peptide isolated from human pheochromocytoma, can be produced and secreted by various types of cells including hepatic stellate cells (HSCs), and its possible role in HSCs is not clear now. In the present study, the interactive regulation between transforming growth factor (TGF)‐β1 and AM and the effect of AM on TGF‐β1‐induced matrix metalloproteinase (MMP)‐2 expression in HSCs were investigated. TGF‐β1 and AM inhibited gene transcript level mutually (real‐time reverse transcription‐polymerase chain reaction). AM suppressed the protein expression level of TGF‐β1 (Western blot), but TGF‐β1 might have no effect on AM secretion level. MMP‐2 protein expression in HSCs was increased in response to TGF‐β1, and upregulation of MMP‐2 expression stimulated with TGF‐β1 was suppressed by AM in dose‐dependent manner (Western blot). AM decreased the phosphorylation level of extracellular signal‐regulated kinase (ERK) in HSCs treated with TGF‐β1, and TGF‐β1‐induced MMP‐2 expression was suppressed by adding Mitogen‐activated protein Kinase/ERK (MEK) inhibitor U0126 (Western blot). Our results suggest that AM may intervene the activation of HSCs by inhibiting TGF‐β1 production and TGF‐β1‐induced MMP‐2 expression; AM may suppress the upregulation of MMP‐2 expression induced by TGF‐β1 partially through ERK pathway.

Fenretinide stimulates the apoptosis of hepatic stellate cells and ameliorates hepatic fibrosis in mice

Aim:u2002 To investigate whether fenretinide, a clinically proved apoptosis‐inducing chemopreventive agent in tumor cells, can induce apoptosis in hepatic stellate cells (HSCs) and resolve hepatic fibrosis.