Background IL-17 signaling has been implicated in lung and skin fibrosis. Here we examined the role of IL-17 signaling in the pathogenesis of liver fibrosis. Methods Using cholestatic and hepatotoxic models of liver injury, the development of liver fibrosis in wild type mice was compared to IL-17RA−/− mice, and to bone marrow chimeric mice devoid of IL-17 signaling in immune cells and Kupffer cells (IL-17RA−/−→wt and IL-17A−/− →wt mice), or in liver resident cells (Wt→ IL-17RA−/− mice). Results We determined that IL-17A and its receptor is highly induced in liver injury and has a strong pro-fibrogenic effect on both inflammatory and liver resident cells. IL-17 signaling facilitates production of IL-6, IL-1β, and TNF-α by inflammatory cells, and increases the expression of TGF-β1, the major pro-fibrogenic cytokine. IL-17 directly induces collagen Type I production in hepatic stellate cells (HSCs) via activation of the Stat3 signaling pathway. Mice devoid of Stat3 signaling in HSCs (GFAPStat3−/− mice) are less susceptible to fibrosis. Furthermore, deletion of IL-23 in immune cells results in attenuation of liver fibrosis, while deletion of IL-22 exacerbates fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protects mice from BDL-induced liver fibrosis. Conclusions IL-17 induces liver fibrosis through multiple mechanisms and may serve as an attractive target for anti-fibrotic therapy.

The elevated peripheral Th17 cells were obtained in the patient with chronic active hepatitis B, suggesting its potential role in the immune activation of chronic HBV infection.

Background and aims: Diabetic kidney is more sensitive to ischemia/reperfusion (I/R) injury, which is associated with increased oxidative stress and impaired nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Melatonin, a hormone that is secreted with the rhythm of the light/dark cycle, has antioxidative effects in reducing acute kidney injury (AKI). However, the molecular mechanism of melatonin protection against kidney I/R injury in the state of diabetes is still unknown. In the present study, we hypothesized that melatonin attenuates renal I/R injury in diabetes by activating silent information regulator 2 associated protein 1 (SIRT1) expression and Nrf2/HO-1 signaling. Methods: Control or streptozotocin (STZ)-induced Type 1 diabetic rats were treated with or without melatonin for 4 weeks. Renal I/R injury was achieved by clamping both left and right renal pedicles for 30 min followed by reperfusion for 48 h. Results: Diabetic rats that were treated with melatonin undergoing I/R injury prevented renal injury from I/R, in aspects of the histopathological score, cell apoptosis, and oxidative stress in kidney, accompanied with decreased expressions of SIRT1, Nrf2, and HO-1 as compared with those in control rats. All these alterations were attenuated or prevented by melatonin treatment; but these beneficial effects of melatonin were abolished by selective inhibition of SIRT1 with EX527. Conclusion: These findings suggest melatonin could attenuate renal I/R injury in diabetes, possibly through improving SIRT1/Nrf2/HO-1 signaling.

This study aimed to investigate the protective effect of genistein or puerarin on chronic alcohol-induced liver injury in vivo and to explore the underlying mechanisms of hepatoprotective effects. Mice were administered genistein or puerarin (0.3 mmol kg(-1) body weight) and gastrically infused with 50% alcohol once per day for 5 weeks. Levels of serum transaminases, serum and hepatic lipids, hepatic antioxidant capacities, inflammation, apoptosis, and histopathological sections were analyzed. Results showed that genistein and puerarin exhibited similar effects in ameliorating alcohol-induced liver injury. However, genistein is more effective than puerarin in decreasing levels of malondialdehyde (1.05 ± 0.0947 vs 1.28 ± 0.213 nmol/mg pro, p < 0.05), tumor necrosis factor α (3.12 ± 0.498 vs 3.82 ± 0.277 pg/mg pro, p < 0.05), interleukin-6 (1.46 ± 0.223 vs 1.88 ± 0.309 pg/mg pro, p < 0.05), whereas puerarin is more effective than genistein in ameliorating serum activities or levels of alanine transaminase (35.8 ± 3.95 vs 42.6 ± 6.56 U/L, p < 0.05) and low-density lipoprotein cholesterol (1.12 ± 0.160 vs 1.55 ± 0.150 mmol/L, p < 0.05). In conclusion, both genistein and puerarin effectively alleviate hepatic damage induced by chronic alcohol administration through potential antioxidant, anti-inflammatory, or anti-apoptotic mechanisms.

Background: G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a newly identified liver tumor suppressor in carcinogenesis. This present study was therefore to determine the potential value of serum TGR5 promoter methylation in identifying hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) patients.Methods: The circulating cell-free DNA (cfDNA) was extracted from a retrospective dataset including 160 HCC, 88 CHB and 45 healthy controls (HCs). Methylation status of TGR5 promoter was examined by methylation-specific polymerase chain reaction (MSP).Results: Hypermethylation of the TGR5 promoter occurred significantly more frequent in HCC (77/160, 48.13%) than CHB (12/88, 13.64%; p<0.01) and HCs (2/45, 4.44%; p<0.01). The methylation rate of TGR5 in HCC patients ≥60 years old was significantly higher than those <60 years old (p<0.05). Alpha fetoprotein (AFP) had sensitivity of 58.13%, 30.63% and 24.38% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had sensitivity of 81.25%, 68.13% and 65%. AFP had specificity of 47.73%, 92.05% and 98.86% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had specificity of 38.64%, 78.41% and 85.23%. AFP had Youden index of 0.06, 0.23 and 0.23 at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had Youden index of 0.20, 0.47 and 0.50.Conclusions: Our findings strongly suggested the combination of serum TGR5 promoter methylation and AFP enhanced the diagnostic value of AFP alone in discriminating HCC from CHB patients.