C1q/tumor necrosis factor-related protein-3 acts as a target treating hepatic fibrosis.

OBJECTIVE: C1q/tumor necrosis factor-related protein-3 (CTRP3) is demonstrated as a crucial factor that participated in various fibrotic diseases. Activation of hepatic stellate cell in liver takes a critical effect on the pathogenesis of hepatic fibrosis. However, the role of CTRP3 in hepatic fibrosis remains elusive. Our present study aimed to explore the molecular mechanism of CTRP3 in fibroblast activation and the development of hepatic fibrosis. MATERIALS AND METHODS: We carried out overexpression (OE) of CTRP3 or knockout (KO) of CTRP3 in hepatic stellate cells (HSCs), respectively. Then, transforming growth factor-beta (TGF-ß) was used to stimulate HSCs activation. Adult male C57BL/6J mice were treated tetrachloromethane by intraperitoneal injection and mice injected saline were served as control. Recombinant CTRP3 (RC-CTRP3) was employed to treat CCl4-induced liver fibrosis. Then, the expression of fibrotic biomarkers, Notch signaling pathway-associated factors, liver histology and liver function were investigated in vivo, respectively. RESULTS: Our results showed that CTRP3 decreased in fibrotic liver and TGF-ß treated HSCs. In vitro, CTRP3 inhibited the activation of HSCs and impeded extracellular matrix (ECM) including collagen I and fibronectin via inhibiting Notch-1/Jagged-1 signaling pathway. In vivo, the indexes of fibrogenesis in liver fibrotic mice received RC-CTRP3 were mitigated via regulation of Notch-1/Jagged-1 signaling pathway. Moreover, liver histology and liver function were improved through the increase of CTRP3 level. CONCLUSIONS: The results proved that CTRP3 as a distinguished anti-fibrotic target inhibited HSCs activation by TGF-ß inducement and protected the liver tissue in the process of liver fibrosis.

Moderate swimming suppressed the growth and metastasis of the transplanted liver cancer in mice model: with reference to nervous system.

Physical activity has been shown to suppress tumor initiation and progression. The neurotransmitter dopamine (DA) is closely related to movement and exhibits antitumor properties. However, whether the suppressive effects of physical activity on tumors was mediated by the nervous system via increased DA level remains unknowns. Here we show that regular moderate swimming (8 min/day, 9 weeks) raised DA levels in the prefrontal cortex, serum and tumor tissue, suppressed growth, reduced lung metastasis of transplanted liver cancer, and prolonged survival in a C57BL/6 mouse model, while overload swimming (16 and 32 min/day, 9 weeks) had the opposite effect. In nude mice that were orthotopically implanted with human liver cancer cell lines, DA treatment significantly suppressed growth and lung metastasis by acting on the D2 receptor (DR2). Furthermore, DR2 blockade attenuated the suppressive effect of moderate swimming on liver cancer. Both moderate swimming and DA treatment suppressed the transforming growth factor-beta (TGF-ß1)-induced epithelial-mesenchymal transition of transplanted liver cancer cells. At the molecular level, DR2 signaling inhibited extracellular signal-regulated kinase phosphorylation and expression of TGF-ß1 in vitro. Together, these findings demonstrated a novel mechanism by which the moderate exercise suppressed liver cancer through boosting DR2 activity, while overload exercise had the opposite effect, highlighting the possible importance of the dopaminergic system in tumor growth and metastasis of liver cancer.