San-Cao Granule () Ameliorates Hepatic Fibrosis through High Mobility Group Box-1 Protein/Smad Signaling Pathway.

OBJECTIVE: To investigate the possible mechanism of San-Cao Granule (SCG, ) mediating antiliver fibrosis. METHODS: A total of 60 male Sprague-Dawley rats were randomly divided into the normal control group, porcine serum-treated group, ursodesoxycholic acid (UDCA, 60 mg/kg), SCG (3.6 g/kg) group, SCG (1.8 g/kg) group and SCG (0.9 g/kg) group, with 10 rats in each group. Liver fibrosis was induced with porcine serum by intraperitoneal injection for 8 weeks, except for the normal control group. Then, the rats in the three SCG-treated groups and UDCA group were administered SCG and UDCA respectively for 4 weeks. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), albumin (ALB), total bilirubin (TBIL), hyaluronic acid (HA), laminin (LN), and type IV collagen (IVC) were examined using commercial kits and hepatic histopathology was examined with hematoxylin and eosin and Masson staining. Moreover, the protein expression levels of high mobility group box-1 protein (HMGB1), transforming growth factor ß1 (TGF-ß1), phosphorylated mothers against decapentaplegic homolog 3 (p-Smad3), Smad7, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-kappa B (NF-κB) and α-smooth muscle actin (α-SMA) were determined by western blot, immunohistochemistry and real time quantitative-reverse transcription polymerase. RESULTS: Both SCG (3.6 and 1.8 g/kg) and UDCA significantly ameliorated the liver fibrosis induced by porcine serum as indicated by retarding the serum levels increasing of ALT, AST, TBIL, HA, LN and IVC and preventing the serum level reducing of ALB compared with the model group (all P<0.01). Meanwhile, the collagen deposition was attenuated by SCG and UDCA treatment. Furthermore, SCG markedly reduced the expressions of HMGB1, TGF-ß1, p-Smad3, TLR4, MyD88, NF-κB and α-SMA, and enhanced the expression of the Smad7 compared with the model group (all P<0.01). CONCLUSION: SCG ameliorates hepatic fibrosis possibly through inhibiting HMGB1, TLR4/NF-κB and TGF-ß1/Smad signaling pathway.

Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces.

UNLABELLED: Chronic passive hepatic congestion (congestive hepatopathy) leads to hepatic fibrosis; however, the mechanisms involved in this process are not well understood. We developed a murine experimental model of congestive hepatopathy through partial ligation of the inferior vena cava (pIVCL). C57BL/6 and transgenic mice overexpressing tissue factor pathway inhibitor (SM22α-TFPI) were subjected to pIVCL or sham. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, real-time polymerase chain reaction, and western blot assays. Hepatic fibrosis and portal pressure were significantly increased after pIVCL concurrent with hepatic stellate cell (HSC) activation. Liver stiffness, as assessed by magnetic resonance elastography, correlated with portal pressure and preceded fibrosis in our model. Hepatic sinusoidal thrombosis as evidenced by fibrin deposition was demonstrated both in mice after pIVCL as well as in humans with congestive hepatopathy. Warfarin treatment and TFPI overexpression both had a protective effect on fibrosis development and HSC activation after pIVCL. In vitro studies show that congestion stimulates HSC fibronectin (FN) fibril assembly through direct effects of thrombi as well as by virtue of mechanical strain. Pretreatment with either Mab13 or Cytochalasin-D, to inhibit ß-integrin or actin polymerization, respectively, significantly reduced fibrin and stretch-induced FN fibril assembly. CONCLUSION: Chronic hepatic congestion leads to sinusoidal thrombosis and strain, which in turn promote hepatic fibrosis. These studies mechanistically link congestive hepatopathy to hepatic fibrosis.

Combining Oxymatrine or Matrine with Lamivudine Increased Its Antireplication Effect against the Hepatitis B Virus In Vitro.

Some recent clinical reports have shown that the combination of oxymatrine, a phyto-derived drug, with lamivudine (3TC) could improve its curative effect against hepatitis B virus (HBV) infection. However, the experimental data in support of this combination strategy are lacking. In this study, we investigated the anti-HBV activity of the combination of 3TC and either oxymatrine or matrine on HepG2 2.2.15 in vitro. The activities of the combination and the solo compound, each in different concentrations, were compared on the 3rd, 6th, and 9th experimental days. The cytotoxicity results showed that the nontoxic concentrations of both oxymatrine and matrine to HepG2 2.2.15 cells were 800 µg/mL. We found that the single use of oxymatrine below 100 µg/ml, matrine below 200 µg/ml, and 3TC below 30 µg/ml showed weak inhibitory effects on the secretion of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV-DNA in culture media; the combination of 3TC (30 µg/ml) with oxymatrine (100 µg/ml) or matrine (100 µg/ml) showed significant inhibitory effects that were higher than or equivalent to the single use of 3TC at 100 µg/ml. The results provide a new impetus to develop novel, multicomponent anti-HBV drugs through the combination of natural products with nucleoside analogs to enhance their activity.

The diarrhoeogenic and antidiarrhoeal bidirectional effects of rhubarb and its potential mechanism.

AIM OF THE STUDY: The present study investigated the pharmacological effects of different extracts of rhubarb on intestinal function of mice, further to explore possible reasons for the adverse effects of long-term use of rhubarb as a purgative. MATERIALS AND METHODS: The total extract of rhubarb (TR) was extracted with 60% ethanol and the total anthraquinones extract (TA), total tannins extract (TT) and remaining components extract (RC) of rhubarb were separated from TR using macroporous resin. The pharmacological effects of each extract on the intestinal function of mice were evaluated by defecation test and the antidiarrhoeal activity of rhubarb tannins as well as its mechanism was studied by different animal models and histopathological examination. RESULTS: Both TR and TA produced purgative activities, but the purgative activity of TA was stronger than that of TR. Successive administration of TT produced an antidiarrhoeal activity in a time- and dose-dependent manner. Besides, successive administration of RC showed no significant effect on the intestinal function of mice. The antidiarrhoeal activity of rhubarb tannins was confirmed directly for the first time and its mechanism was probable that rhubarb tannins generated protein-precipitating reaction to the gastrointestinal mucosa due to its protein-precipitating action. CONCLUSIONS: The results confirmed that rhubarb had the diarrhoeogenic and antidiarrhoeal bidirectional effects due to the coexistence of anthraquinones and tannins. The bidirectional effects might be the reason or one of the reasons for the adverse effects of long-term use of rhubarb as a purgative.

[Study on chronical hepatitis B with treatment of integrative traditional Chinese and Western medicine].

OBJECTIVE: To study curative effect of chronical hepatitis B with treatment of integrative traditional Chinese and western medicine. METHOD: 115 cases of HBeAg and/or HBVDNA positive chronical hepatitis B were randomly divided into two groups in control. The first group treated by traditional Chinese medicine (TCM)-Fufang Huangqi granule and the second treated by intergrative traditional Chinese and western medicine (ICWM)-Fufang Huangqi granule and lamivudine for at least 24 weeks. RESULT: The positive rate of HBVDNA at 12, 24 weeks, and the positive rate of HBeAg at 24 weeks in TCM are markedly lower than those of before treatment (P < 0.01). The positive rate of HBeAg and the positive rate of HBVDNA in ICWM are markedly lower than those of before treatment both at 12, 24 weeks (P < 0.01). The average values of HBVDNA are markly lower than before treatment in two groups at both 12,24 weeks (P < 0.01). At 12 weeks, the negative-turning rate of HBVDNA in the ICWM group is 79.17%, which shows significant difference in comparision with 40.00% in the TCM group (P < 0.01). The negative-turning rate of HBeAg in the ICWM group is 26.92%, which shows no significant difference in comparision with 32. 08% in the TCM group. At 24 weeks, the negative-turning rate of HBVDNA in the ICWM group is 85.71%, which shows significant difference in comparision with 50.00% in the TCM group (P < 0.01). The negative-turning rate of HBeAg in the ICWM group is 36.36%, which shows no significant difference in comparision with 28.57% in the TCM group. At 12 weeks,the total effective rate of the ICWM group is 96. 43%, which shows significant difference in comparision with 71.26% in the TCM group (P<0.01). At 24 weeks, the total effective rate of the ICWM group is 88. 00%, which shows significant difference in comparision with 67.61 % in the TCM group (P < 0.01). The average values of ALT and AST are markly improved than those of before treatment in two groups (P < 0.01). The average values of ALB is markly higher than before in TCM groups after 24 weeks treatment (P < 0.01). CONCLUSION: Fufang Huangqi granule integrated with lamivudine possesses a better effect for counteracting the hepatitis B virus and improving the liver functioin than only itself.