Sedum sarmentosum Total Flavonoids Alleviate Schistosomiasis-Induced Liver Fibrosis by Altering TGF-ß1 and Smad7 Expression.

OBJECTIVES: Schistosomiasis is a parasitic disease that affects over 142 million people worldwide. The main causes of death of schistosomiasis include liver granuloma and secondary hepatic cirrhosis resulting from severe fibrosis. Despite intensive research, controlling liver fibrosis associated with schistosomiasis remains challenging. Sedum sarmentosum total flavonoid (SSTF) is a promising agent to reduce liver fibrosis with an unknown mechanism. Thus, the objectives of this study are to validate its effect on the liver fibrosis caused by schistosomiasis and to explore the underlying molecular mechanism. METHODS: Sixty male Sprague-Dawley rats were randomly divided into six groups: one group of normal control and five groups of liver fibrosis induced by schistosomiasis japonica with or without SSTF or colchicine treatment, the latter serving as the positive control. Liver tissues from each animal were harvested to observe the degree and grade of hepatic fibrosis. We also measured the expression of transforming growth factor-beta 1 (TGF-ß1) and Smad7 using RT-qPCR, Western blot, and immunohistochemistry. RESULTS: Compared with the untreated model group, groups treated with SSTF at all three tested doses had significantly reduced hepatic fibrosis (P < 0.05). Each dose of SSTF also significantly reduced TGF-ß1 protein expression and mRNA levels in the liver tissues (P < 0.05). In contrast, the middle and high doses of SSTF significantly increased Smad7 protein expression and mRNA levels (P < 0.05). Immunohistochemistry showed that each dose of SSTF reduced TGF-ß1 protein expression (P < 0.05). CONCLUSION: Our results demonstrated that SSTF alleviated schistosomiasis japonica-induced hepatic fibrosis by inhibiting the TGF-ß1/Smad7 pathway.

Post-Stroke Microglia Induce Sirtuin2 Expression to Suppress the Anti-inflammatory Function of Infiltrating Regulatory T Cells.

Ischemic stroke is among the leading causes of death and disability across the globe. Post-stroke neuroinflammation contributes to the pathophysiology of ischemic stroke in the acute phase through damaging neurons in the penumbra region. Infiltrating regulatory T cells (Treg cells) provide neuronal protection in ischemic brains. In the current study using a mouse-transient middle cerebral artery occlusion (MCAO) model, we characterized the changes of sirtuin expression in infiltrating Treg cells in the acute phase of ischemia. We found that Sirt2 was remarkably upregulated in infiltrating Treg cells at day 3 post-MCAO. In vitro inhibition of Sirt2 activity enhanced the expression of immunosuppression-associated molecules including forkhead box P3 (Foxp3) in Treg cells. Using a lentiviral system to express exogenous Sirt2 in Treg cells, we found that Sirt2 weakened the anti-inflammatory effect of Treg cells on pro-inflammatory macrophages. Additionally, post-MCAO microglia increased Sirt2 expression in Treg cells in a cell-to-cell contact manner. We further found that microglia remarkably induced hypoxia-inducible factor 1-alpha (HIF-1α) expression in Treg cells, and inhibition of HIF-1α abolished microglia-induced Sirt2 upregulation. Collectively, we discovered a novel mechanism by which the immunoregulatory activity of infiltrating Treg cells is modulated after ischemia.