Therapeutic effect of tetrandrine on silicosis rats and its toxic effect on liver and kidney function / 中国职业医学

OBJECTIVE: To explore the therapeutic effect of tetrandrine(TET) on silicosis model rats and its toxic effect on liver and kidney function. METHODS: The specific pathogen free healthy male Wistar rats were randomly divided into the control group, the model group and the TET group, with 14 rats in each group. By un-exposure tracheal injection method, the rats in the model and TET groups were given one-time tracheal infusion of free silicon dioxide suspension with a mass concentration of 50 g/L to establish the rat model of silicosis. Rats in the control group were infused with 1 mL of 0.9% sodium chloride solution with the same method. On the second day after the model was established, the TET group was given 30 mg/kg body mass of TET solution by gavage. The other two groups were given the same amount of 0.9% sodium chloride solution. The treatment was once per day, six times per week. Seven rats in each group were sacrificed on the 28 th and 56 th days after modeling. The morphological change of the lung, liver and kidney tissues of each group was observed. The enzyme-linked immunosorbent assay was used to detect the level of tumor necrosis factor-α(TNF-α), transforming growth factor-β1(TGF-β1), interleukin(IL)-1β and IL-6, in the lung tissues of rats in each group. The activities of aminotransferase(ALT), aspartate aminotransferase(AST) and the levels blood urea nitrogen(BUN), creatinine(CRE) were detected by automatic biochemical analyzer. RESULTS: The lung organ coefficients of rats in the TET group were lower than those of the model group on the 28 th and 56 th days(all P<0.05). The lung organ coefficient of the rats in the TET group on the 56 th day was higher than that in the same group on the 28 th day(P<0.05). The lung tissue structure of the control group was normal. After modeling, the lung tissues of rats in model group showed different degrees of pathological changes such as alveolar structure destruction, inflammatory cell infiltration, and fibrosis on the 28 th and 56 th days. The degree of pathological changes in TET group was less than that of the model group. In the lung tissues of rats in the model group, the levels of TNF-α, TGF-β1, IL-1β and IL-6 were higher than those of the control group(all P<0.01). The levels of TNF-α, TGF-β1, IL-1β and IL-6 in the lung tissues of rats in the TET group were lower than that of the model group(all P<0.01), but there was no statistically significant difference when compared with the control group(all P>0.05). The activities of ALT and AST in the TET group were higher than those in the model group and the control group(all P<0.01). The level of serum BUN in TET group was higher than that in control group(P<0.01), but it showed no statistical difference when compared with the control group(P>0.05). The level of serum CRE in each group showed no significant difference(P>0.05). There were no abnormal pathological changes found in the liver and kidney tissues of rats in each group at different times. CONCLUSION: TET can reduce the inflammatory response in silicosis rats and improve lung tissue fibrosis; however, the therapeutic dose may have certain toxicity to the liver and kidney of the silicosis rats.

Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells

Matrine (MT), the effective component of Sophora flavescens Ait, has been shown to have anti-inflammation, immune-suppressive, anti-tumor, and anti-hepatic fibrosis activities. However, the pharmacological effects of MT still need to be strengthened due to its relatively low efficacy and short half-life. In the present study, we report a more effective thio derivative of MT, MD-1, and its inhibitory effects on the activation of hepatic stellate cells (HSCs) in both cell culture and animal models. Cytological experiments showed that MD-1 can inhibit the proliferation of HSC-T6 cells with a half-maximal inhibitory concentration (IC50) of 62 μmol/L. In addition, MD-1 more strongly inhibits the migration of HSC-T6 cells compared to MT and can more effectively induce G0/G1 arrest and apoptosis. Investigating the biological mechanisms underlying anti-hepatic fibrosis in the presence of MD-1, we found that MD-1 can bind the epidermal growth factor receptor (EGFR) on the surface of HSC-T6 cells, which can further inhibit the phosphorylation of EGFR and its downstream protein kinase B (Akt), resulting in decreased expression of cyclin D1 and eventual inhibition of the activation of HSC-T6 cells. Furthermore, in rats with dimethylnitrosamine (DMN)-induced hepatic fibrosis, MD-1 slowed the development and progression of hepatic fibrosis, protecting hepatic parenchymal cells and improving hepatic functions. Therefore, MD-1 is a potential drug for anti-hepatic fibrosis.

Prognostic value of the model for end-stage liver disease combined with serum sodium levels in patients with decompensated cirrhosis / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the ability of the model for end-stage liver disease (MELD) score combined with serum sodium measurements to effectively evaluate the prognosis of patients with decompensated liver cirrhosis.</p><p><b>METHODS</b>A total of 212 patients with decompensated cirrhosis were retrospectively analyzed. Each patient's MELD scores, and sodium-based MELD scores (MELD-Na, MELDNa, and MESO) were calculated at three-month intervals. The area under the receiver operating characteristic (ROC) curve (AUC) was used to compare the predictive abilities of the four scores for 3-, 6- and 12-month mortality. Kaplan-Meier survival curves were created using the best cut-off values for each score identified by the ROC.</p><p><b>RESULTS</b>Among the 212 patients, 46 died within three months, 56 died within six months, and 87 died within 12 months. The MELD, MELD-Na, MELDNa and MESO scores were significantly different between patients who survived and those who died within three and 12 months (P less than 0.01). The AUCs for the four separate scores were all more than 0.8 at the 3- and 6-month time points; however, the AUCs of MELDNa (3-month: 0.846; 6-month: 0.869) and MESO (0.831; 0.850) were significantly better than those of MELD (0.812; 0.841) (P less than 0.05). At the 12-month time point, the AUCs of MELD, MELD-Na, MELDNa, and MESO were not significantly different (0.774, 0.775, 0.786, and 0.777, respectively). Survival curves showed that all the scores were able to clearly discriminate the patients who survived from those who died within 12 months (P=0.000).</p><p><b>CONCLUSION</b>The MELD score and its sodium-based variants (MELD-Na, MELDNa, and MESO) can precisely predict mortality of patients with decompensated cirrhosis for short and intermediate periods. The MELDNa and MESO scores are superior for predicting 3- and 6-month survival.</p>