Zhen Han

Capital Medical University, Peping, Beijing, China

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Publications (3)26.19 Total impact

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    ABSTRACT: BACKGROUND/AIMS: Sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) axis is involved in multiple biological processes, including liver fibrosis. Angiogenesis is an important pathophysiological process which is closely associated with liver fibrosis; however, the functional role of SphK/S1P/S1PR in this process remains incompletely defined. METHODS: Bile duct ligation or carbon tetrachloride was used to induce liver fibrosis in mice. Human fibrotic samples were obtained from livers of patients undergoing liver transplantation. S1P levels in the liver were examined by HPLC. Expression of angiogenic markers, including angiopoietin 1, CD31, vascular cell adhesion molecule-1 and von Willebrand factor, was characterized in fibrotic liver and primary mouse hepatic stellate cells (HSCs) by immunofluorescence, real-time RT-PCR and Western blot. SphK inhibitor (SKI) or S1PR antagonists were administrated intraperitoneally in mice. RESULTS: S1P levels in the liver were closely correlated with mRNA expression of angiogenic markers. Ang1 is expressed in activated HSCs of fibrotic liver and in primary HSCs. In HSCs, by using specific antagonists or siRNAs, we demonstrated S1P stimulation induced Ang1 expression via S1PR1 and S1PR3. In vivo, S1P reduction by SKI inhibits angiogenesis in fibrotic mice. Furthermore, S1PR1/3 antagonist significantly blocked up-regulation of angiogenic markers in injury liver, and attenuated the extent of liver fibrosis, while S1PR2 antagonist has no effect on angiogenesis, supporting the key role of S1PR1 and S1PR3 in angiogenesis underlying liver fibrosis process. CONCLUSION: SphK1/S1P/S1PR1/3 axis plays a crucial role in angiogenic process required for fibrosis development, which may represent an effective therapeutic strategy for liver fibrosis.
    Journal of Hepatology 03/2013; 59(1). DOI:10.1016/j.jhep.2013.02.021 · 10.40 Impact Factor
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    ABSTRACT: 15-Deoxy-Δ(12,14) -Prostaglandin J(2) (15d-PGJ(2) ), a natural peroxisome proliferator-activated receptor gamma (PPAR-γ) ligand, has been implicated as a new antiinflammatory compound with possible clinical applications. Based on this concept, this study was designed to evaluate the effects of 15d-PGJ(2) on bone marrow-derived monocyte/macrophage (BMM) migration, phagocytosis, and cytokine expression after liver injury using mouse models induced by cholestasis or carbon tetrachloride. Mice were lethally irradiated and received bone marrow transplants from enhanced green fluorescent protein transgenic mice. Our results showed that recruitment of BMM was significantly increased during chronic liver injury, and that 15d-PGJ(2) administration reduced BMM, but not neutrophil, dendritic, or T cell migration toward the damaged liver, involving reactive oxygen species generation and independently of PPAR-γ. Moreover, 15d-PGJ(2) inhibited the phagocytic activity of BMM and down-regulated inflammatory cytokine expression in vivo and in vitro. Accordingly, hepatic inflammation and fibrosis were strikingly ameliorated after 15d-PGJ(2) administration. CONCLUSION: Our findings strongly suggest the antiinflammation and antifibrogenic potential of 15d-PGJ(2) in chronic liver diseases.
    Hepatology 07/2012; 56(1):350-60. DOI:10.1002/hep.25672 · 11.19 Impact Factor
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    ABSTRACT: Sphingosine kinase (SphK) is involved in numerous biological processes, including cell growth, proliferation, and differentiation. However, whether SphK participates in the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) to myofibroblasts has been unknown. In a carbon tetrachloride-treated mouse model, SphK1 was expressed in BMSCs in damaged liver. Furthermore, mRNA expression of both SphK1 and transforming growth factor β1 (TGF-β1) was significantly increased after liver injury, with a positive correlation between them. The SphK inhibitor SKI significantly blocked BMSC differentiation to myofibroblasts during liver injury (the proportion of BMSC-derived myofibroblasts decreased markedly, compared with no SKI treatment) and attenuated the extent of liver fibrosis. Using primary mouse BMSCs, we demonstrated that TGF-β1 induced BMSC differentiation to myofibroblasts, accompanied by the up-regulation of SphK1 and modulation of sphingosine 1-phosphate (S1P) receptor (S1PR) expression. Notably, pharmacological or siRNA-mediated inhibition of SphK1 abrogated the prodifferentiating effect of TGF-β1. Moreover, using either S1PR subtype-specific antagonists or specific siRNAs, we found that the prodifferentiating effect of TGF-β1 was mediated by S1PR(1) and S1PR(3). These data suggest that SphK1 activation by TGF-β1 leads to differentiation of BMSCs to myofibroblasts mediated by S1PR(1) and S1PR(3) up-regulation, thus providing new information on the mechanisms by which TGF-β1 gives rise to fibrosis and opening new perspectives for pharmacological treatment of liver fibrosis.
    American Journal Of Pathology 05/2012; 181(1):85-97. DOI:10.1016/j.ajpath.2012.03.014 · 4.60 Impact Factor