Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-ß/Smad signaling pathway.

BACKGROUND: Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer. Early liver fibrosis is reversible by intervention. As a member of the transforming growth factor-beta (TGF-ß) superfamily, bone morphogenetic protein 7 (BMP7) has anti-liver fibrosis functions. However, little is known about BMP7 expression changes and its potential regulatory mechanism as well as the relationship between BMP7 and TGF-ß during liver fibrosis. In addition, the mechanism underlying the anti-liver fibrosis function of BMP7 needs to be further explored. AIM: To investigate changes in the dynamic expression of BMP7 during liver fibrosis, interactions between BMP7 and TGF-ß1, and possible mechanisms underlying the anti-liver fibrosis function of BMP7. METHODS: Changes in BMP7 expression during liver fibrosis and the interaction between BMP7 and TGF-ß1 in mice were observed. Exogenous BMP7 was used to treat mouse primary hepatic stellate cells (HSCs) to observe its effect on activation, migration, and proliferation of HSCs and explore the possible mechanism underlying the anti-liver fibrosis function of BMP7. Mice with liver fibrosis received exogenous BMP7 intervention to observe improvement of liver fibrosis by using Masson's trichrome staining and detecting the expression of the HSC activation indicator alpha-smooth muscle actin (α-SMA) and the collagen formation associated protein type I collagen (Col I). Changes in the dynamic expression of BMP7 during liver fibrosis in the human body were further observed. RESULTS: In the process of liver fibrosis induced by carbon tetrachloride (CCl4) in mice, BMP7 protein expression first increased, followed by a decrease; there was a similar trend in the human body. This process was accompanied by a sustained increase in TGF-ß1 protein expression. In vitro experiment results showed that TGF-ß1 inhibited BMP7 expression in a time- and dose-dependent manner. In contrast, high doses of exogenous BMP7 inhibited TGF-ß1-induced activation, migration, and proliferation of HSCs; this inhibitory effect was associated with upregulation of pSmad1/5/8 and downregulation of phosphorylation of Smad3 and p38 by BMP7. In vivo experiment results showed that exogenous BMP7 improved liver fibrosis in mice. CONCLUSION: During liver fibrosis, BMP7 protein expression first increases and then decreases. This changing trend is associated with inhibition of BMP7 expression by sustained upregulation of TGF-ß1 in a time- and dose-dependent manner. Exogenous BMP7 could selectively regulate TGF-ß/Smad pathway-associated factors to inhibit activation, migration, and proliferation of HSCs and exert anti-liver fibrosis functions. Exogenous BMP7 has the potential to be used as an anti-liver fibrosis drug.

[Facial skin lesions in male patients with liver cirrhosis: role of serum sex hormones and correlation with impaired liver function].

OBJECTIVE: To investigate the relationship between serum sex hormone levels, liver function, and pathogenic mechanisms related to cutaneous lesions involving the facial skin in male patients with liver cirrhosis. METHODS: Fifty male cirrhotic patients with facial skin lesions, including spider angiomas, angiotelectasis and special type rash, (mean age: 48.1 +/- 12.2 years) were randomly selected for study and enrolled as the case group. Thirty cirrhotic male patients without facial skin lesions (mean age: 44.5 +/- 11.7 years) were enrolled as the control group. Serum levels of luteinizing hormone (LH), follicular stimulating hormone (FSH), prolactin (PRL), estradiol (E2), progesterone (PRGE), and testosterone (T) were detected and compared between cases and controls by the t-test. All patients were sub-categorized according to severity of cirrhosis (Child-Pugh classification) and comparisons between cases and controls were carried out by single factor analysis of variance. Logistic regression modeling was used to evaluate whether the presence of skin lesions is related to changes in markers of liver impairment, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), serum albumin (Alb), prothrombin time (PT-SEC), creatinine (CREA), platelet count (PLT), and alcoholism. RESULTS: In the cases with spider veins, LH level was significantly elevated (t = 2.01) and T level was significantly decreased (t = -2.20) (both, P less than 0.05 vs. controls). In the cases with telangiectasia, the LH level (t = 3.76, E2 (t = 2.08) and E2/T ratio (t = 2.98) were significantly elevated and T level was significantly decreased (t = -3.77) (all, P less than 0.05 vs. controls). In the cases with special type rash, FSH level was significantly elevated (t = 2.03) and T level was significantly decreased (t = -2.01) (both, P less than 0.05 vs. controls). In the case group, E2 levels decreased as severity of liver damage increased, while in the control group, E2 levels increased as severity of liver damage increased; however, the difference in average E2 values of the two groups did not reach statistical significance (P more than 0.05). In both cases and controls, the T levels were decreased as the severity of liver damage increased (F = 3.70, P less than 0.05). Multivariate logistic regression analysis showed that increased incidence of facial skin lesions is associated with alcoholism (odds ratio (OR) = 4.46, 95% confidence interval (CI) = 1.45-13.7, P less than 0.05) and elevated serum levels of AST (OR = 11.87, 95% CI = 1.24-113.1, P less than 0.05). CONCLUSION: Alcoholism, impaired liver function, and perturbed levels of circulating sex hormones are associated with cirrhosis-related facial lesions and may play important roles in the pathogenesis of cutaneous lesions in patients with cirrhosis.

[Emodin induces apoptosis of cancer cells and inhibits retinoid X receptor transcriptional activity].

The mechanisms by which emodin induces apoptosis and inhibits proliferation of cancer cells remain unclear. In this study, we investigated whether the proapoptotic effect of emodin on human NIH-H460 lung cancer cells and SMMC-7721 liver cancer cells was related to regulating RXR expression and function. MTT assay and DAPI staining were used to detect the anti-proliferative and apoptotic effects of emodin with or without 9-cis-retinoid acid on H460 and SMMC-7721. The reporter assay was used to detect the effect of emodin on RXR homo- and hetero-dimer transactivation. Competitive ligand binding assay was carried out to detect whether emodin could directly bind to RXR. The result showed that emodin could strongly inhibit the proliferation and induce apoptosis of both cancer cell lines, which could be antagonized by 9-cis-RA. The reporter assay showed that emodin could inhibit the transcriptional effect of the homo- and hetero-dimer transactivation of RXRalpha dose-dependently. However, in vitro binding assay did not show that emodin bind to RXRalpha-LBD directly. The findings suggest that exhibition of emodin its anti-cancer activity may be associated with involvement of RXRalpha signal transduction pathways.