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Peng J.-H.,Shanghai University of Traditional Chinese Medicine | Peng J.-H.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine | Cui T.,Shanghai University of Traditional Chinese Medicine | Huang F.,Shanghai University of Traditional Chinese Medicine | And 8 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Puerarin, an isoflavone component extracted from Kudzu (Pueraria lobata), has been demonstrated to alleviate alcoholrelated disorders. Our study examined whether puerarin ameliorates chronic alcoholic liver injury through inhibition of endotoxin gut leakage, the subsequent Kupffer cell activation, and endotoxin receptors expression. Rats were provided with the Liber-DeCarli liquid diet for 8 weeks. Puerarin (90 mg/kg or 180 mg/kg daily) was orally administered from the beginning of the third week until the end of the experiment. Chronic alcohol intake caused increased serum alanine aminotransferase, aspartate aminotransferase, hepatic gamma-glutamyl transpeptidase, and triglyceride levels as well as fatty liver and neutrophil infiltration in hepatic lobules as determined by biochemical and histologic assays. A significant increase of liver tumor necrosis factor a was detected by enzyme-linked immunosorbent assay. These pathologic effects correlated with increased endotoxin level in portal vein and upregulated protein expression of hepatic CD68, lipopolysaccharide- binding protein, CD14, Toll-like receptor 2, and Toll-like receptor 4. Meanwhile, the intestinal microvilli were observed to be sparse, shortened, and irregularity in distribution under the transmission electron microscope in conjunction with the downregulated intestinal zonula occludens-1 protein expression. These hepatic pathologic changes were significantly inhibited in puerarintreated animals as were the endotoxin levels and hepatic CD68 and endotoxin receptors. Moreover, the pathologic changes in intestinal microvillus and the decreased intestinal zonula occludens-1 were also ameliorated with puerarin treatment. These results thus demonstrate that puerarin inhibition of endotoxin gut leakage, Kupffer cell activation, and endotoxin receptors expression is involved in the alleviation of chronic alcoholic liver injury in rats. © 2013 by The American Society for Pharmacology and Experimental Therapeutics. Source


Tao Y.-Y.,Shanghai University of Traditional Chinese Medicine | Wang Q.-L.,Shanghai University of Traditional Chinese Medicine | Wang Q.-L.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine | Shen L.,Shanghai University of Traditional Chinese Medicine | And 5 more authors.
Experimental Biology and Medicine | Year: 2013

Salvianolic acid B (Sal B) is a major water soluble component extracted from Radix Salviae miltiorrhizae, a traditional Chinese herb widely used for treating cardiovascular and hepatic diseases. Sal B has been reported to inhibit transforming growth factor (TGF)-β1-stimulated hepatic stellate cells (HSCs) activation and collagen type I expression. In this study, we further investigated the mechanisms of Sal B on liver fibrosis relating to TGF-β/Smads signalling pathway, especially to TGF-β1 receptors. Liver fibrosis model was induced by intraperitoneal injection of dimethylnitrosamine (DMN) for four weeks. Rats were randomly divided into three groups: normal, model, and Sal B groups. Rats in Sal B group were treated by oral administration of Sal B for four weeks from the first day of DMN exposure. Hydroxyproline (Hyp) content in liver tissue was assayed using Jamall's method and collagen deposition was visualized using Sirius red staining. HSCs were isolated from normal rats, and were cultured primarily in uncoated plastics. At day 4 after isolation, cells were stimulated with 2.5 ng/mL TGF-β1, and treated with 1 and 10 μmol/L Sal B and 10 μmol/L SB-431542 (TβR-I inhibitor) for 24 h, respectively. Cell proliferation was examined with 5-ethynyl-2'-deoxyuridine assay. The expressions of alpha smooth muscle actin (α-SMA) and Smad3 were assayed by immunofluorescent stain and Western blotting. The expression of TβR-I was analysed by Western blotting and real-time polymerase chain reaction. The activity of TβR-I kinase was measured by ADP-Glo kinase assay. The results showed that Sal B could inhibit collagen deposition and reduce Hyp content significantly, and decrease expressions of TGF-β1 and TβR-I in fibrotic liver in vivo. Also, Sal B decreased the expressions of α-SMA and TβR-I, inhibited Smad3 nuclear translocation and down-regulated TβR-I kinase activity in vitro. These findings suggested that Sal B could prevent HSCs activation through TGF-β signalling pathway, i.e. inhibiting TGF-β1 expression, activity of TβR-I kinase and Smads phosphorylation. © 2013 by the Society for Experimental Biology and Medicine. Source


Wang Q.-L.,Shanghai University of Traditional Chinese Medicine | Tao Y.-Y.,Shanghai University of Traditional Chinese Medicine | Yuan J.-L.,Shanghai University of Traditional Chinese Medicine | Shen L.,Shanghai University of Traditional Chinese Medicine | And 2 more authors.
BMC Cell Biology | Year: 2010

Background: Salvianolic Acid B (Sal B) is a water-soluble component from Danshen (a traditional Chinese herb widely used for chronic renal diseases) with anti-oxidative and cell protective properties. Sal B also has potential protective effects on renal diseases. Tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT), which plays an important role in the pathogenesis of renal interstitial fibrosis (RIF) and is mainly regulated by TGF-β1/Smads pathway. The aims of the study are to investigate the effect of Sal B on tubular EMT in vivo and in vitro, and to elucidate its underlying mechanism against EMT related to TGF-β1/Smads pathway.Results: For in vivo experiments, RIF was induced in rats by oral administration of HgCl2and prophylaxised with Sal B and vitamin E. The protein expression of E-cadherin was down-regulated, while the expression of α-SMA, TGF-β1, TβR-I, p-Smad2/3 and the activity of matrix metalloproteinase-2 (MMP-2) were up-regulated in kidneys of model rats when compared with those of normal rats. In contrast, Sal B and vitamin E significantly attenuated the expression of α-SMA, TGF-β1, TβR-I, p-Smad2/3, and MMP-2 activity, but increased E-cadherin expression. For in vitro experiments, HK-2 cells were incubated with TGF-β1 to induce EMT, and the cells were co-cultured with 1 and 10 μM Sal B or SB-431542 (a specific inhibitor of TβR-I kinase). TGF-β1 induced a typical EMT in HK-2 cells, while it was blocked by Sal B and SB-431542, as evidenced by blocking morphologic transformation, restoring E-cadherin and CK-18 expression, inhibiting α-SMA expression and F-actin reorganization, and down-regulating MMP-2/9 activities in TGF-β1 mediated HK-2 cells. Furthermore, Sal B and SB-431542 profoundly down-regulated the expressions of TβR-I and p-Smad2/3 but prevented the decreased expression of Smad7 in TGF-β1 stimulated HK-2 cells.Conclusions: Sal B can prevent tubular EMT in the fibrotic kidney induced by HgCl2as well as HK-2 cells triggered by TGF-β1, the mechanism of Sal B is closely related to the regulation of TGF-β1/Smads pathway, manifested as the inhibition of TGF-β1 expression, suppression of TβR-I expression and function, down-regulation of Smad2/3 phosphorylation, and restoration of the down-regulation of Smad7, as well as inhibition of MMP-2 activity. © 2010 Wang et al; licensee BioMed Central Ltd. Source


Peng Y.,Shanghai University of Traditional Chinese Medicine | Chen Q.,Shanghai University of Traditional Chinese Medicine | Chen Q.,Central Laboratory | Yang T.,Shanghai University of Traditional Chinese Medicine | And 6 more authors.
Molecular Biology Reports | Year: 2014

Cultured mycelium Cordyceps sinensis (CMCS) was widely used for a variety of diseases including liver injury, the current study aims to investigate the protective effects of CMCS on liver sinusoidal endothelial cells (LSECs) in acute injury liver and related action mechanisms. The mice were injected intraperitoneally with lipopolysaccharide (LPS) and d-galactosamine (D-GalN). 39 male BABL/c mice were randomly divided into four groups: normal control, model control, CMCS treatment and 1,10-phenanthroline treatment groups. The Serum liver function parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assayed with the commercial kit. The inflammation and scaffold structure in liver were stained with hematoxylin and eosin and silver staining respectively. The LSECs and sub-endothelial basement membrane were observed with the scanning and transmission electronic microscope. The protein expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in liver were analyzed with Western blotting. Expression of von Willebrand factor (vWF) was investigated with immunofluorescence staining. The lipid peroxidation indicators including antisuperoxideanion (ASAFR), hydroxyl free radical (·OH), superoxide dismutase (SOD), malondialdehyde and glutathione S-transferase (GST) were determined with kits, and matrix metalloproteinase-2 and 9 (MMP-2/9) activities in liver were analyzed with gelatin zymography and in situ fluorescent zymography respectively. The model mice had much higher serum levels of ALT and AST than the normal mice. Compared to that in the normal control, more severe liver inflammation and hepatocyte apoptosis, worse hepatic lipid peroxidation demonstrated by the increased ASAFR, ·OH and MDA, but decreased SOD and GST, increased MMP-2/9 activities and VCAM-1, ICAM-1 and vWF expressions, which revealed obvious LSEC injury and scaffold structure broken, were shown in the model control. Compared with the model group, CMCS and 1,10-phenanthroline significantly improved serum ALT/AST, attenuated hepatic inflammation and improved peroxidative injury in liver, decreased MMP-2/9 activities in liver tissue, improved integration of scaffold structure, and decreased protein expression of VCAM-1 and ICAM-1. CMCS could protect LSECs from injury and maintain the microvasculature integration in acute injured liver of mice induced by LPS/D-GalN. Its action mechanism was associated with the down-regulation of MMP-2/9 activities and inhibition of peroxidation in injured liver. © 2014 The Author(s). Source


Tao Y.-Y.,Shanghai University of Traditional Chinese Medicine | Yan X.-C.,Shanghai University of Traditional Chinese Medicine | Zhou T.,Shanghai University of Traditional Chinese Medicine | Shen L.,Shanghai University of Traditional Chinese Medicine | And 4 more authors.
BMC Complementary and Alternative Medicine | Year: 2014

Background: What was the relationship of Fuzheng Huayu recipe (FZHY) inhibiting hepatocyte apoptosis and HSC activation at different stage of liver fibrosis? In order to answer this question, the study was carried out to dynamically observe FZHY's effect on hepatocyte apoptosis and HSC activation and further explored underling mechanism of FZHY against hepatocyte apoptosis. Methods: Mice were randomly divided into four groups: normal, model, FZHY, and N-acetylcystein (NAC) groups. Acute hepatic injury and liver fibrosis in mice were induced by CCl4. Three days before the first CCl4 injection, treatment with FZHY powder or NAC respectively was started. In vitro, primary hepatocytes were pretreated with FZHY medicated serum or Z-VAD-FMK and then incubated with ActD and TNF-α. Primary HSCs were treated with DNA from apoptotic hepatocytes incubated by Act D/TNF-α or FZHY medicated. Liver sections were analyzed for HE staining and immunohistochemical evaluation of apoptosis. Serum ALT and AST, Alb content and TNF-α expression in liver tissue were detected. Hyp content was assayed and collagen deposition was visualized. Expressions of α-SMA and type I collagen were analyzed by immunofluorescence and immunoblotting. Flow cytometry, immunofluorescence, and DNA ladder for hepatocyte apoptosis and immunoblotting for TNF-R1, Bcl-2 and Bax were also analyzed. Results: Mice showed characteristic features of massive hepatocytes apoptosis in early stage of liver injury and developed severe hepatic fibrosis in later phase. FZHY treatment significantly alleviated acute liver injury and hepatocyte apoptosis, and inhibited liver fibrosis by decreasing α-SMA expression and hepatic Hyp content. In vitro, primary hepatocytes were induced by TNF-α and Act D. The anti-apoptotic effect of FZHY was generated by reducing TNFR1 expression and balancing the expressions of Bcl-2 and Bax. Meanwhile, the nuclear DNA from apoptotic hepatocytes stimulated HSC activation in a dose dependent manner, and the DNA from apoptotic hepatocytes treated with FZHY or Z-VAD-FMK reduced HSC activation and type I collagen expression. Conclusion: These findings suggested that FZHY suppressed hepatocyte apoptosis through regulating mediators in death receptor and mitochondrial pathways, and the effect of FZHY on hepatocyte apoptosis might play an important role in inhibiting liver fibrosis. © 2014 Tao et al. Source

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