CGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1-/- BMDM cells and in Trex1-/- mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases.

Renal fibrosis is an inevitable outcome of various manifestations of progressive chronic kidney diseases (CKD). The need for efficacious treatment regimen against renal fibrosis can therefore not be overemphasized. Here we show a novel protective role of Bacteroides fragilis (B. fragilis) in renal fibrosis in mice. We demonstrate decreased abundance of B. fragilis in the feces of CKD patients and unilateral ureteral obstruction (UUO) mice. Oral administration of live B. fragilis attenuates renal fibrosis in UUO and adenine mice models. Increased lipopolysaccharide (LPS) levels are decreased after B. fragilis administration. Results of metabolomics and proteomics studies show decreased level of 1,5-anhydroglucitol (1,5-AG), a substrate of SGLT2, which increases after B. fragilis administration via enhancement of renal SGLT2 expression. 1,5-AG is an agonist of TGR5 that attenuates renal fibrosis by inhibiting oxidative stress and inflammation. Madecassoside, a natural product found via in vitro screening promotes B. fragilis growth and remarkably ameliorates renal fibrosis. Our findings reveal the ameliorative role of B. fragilis in renal fibrosis via decreasing LPS and increasing 1,5-AG levels.

BACKGROUND AND PURPOSEAnti‐angiogenic agents have recently become one of the major adjuvants for cancer therapy. A cyclopeptide, RA‐V, has been shown to have anti‐tumour activities. Itsin vitroanti‐angiogenic activities were evaluated in the present study, and the underlying mechanisms were also assessed.EXPERIMENTAL APPROACHTwo endothelial cell lines, human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC‐1), were used. The effects of RA‐V on the proliferation, cell cycle phase distribution, migration, tube formation and adhesion were assessed. Western blots and real‐time PCR were employed to examine the protein and mRNA expression of relevant molecules.KEY RESULTSRA‐V inhibited HUVEC and HMEC‐1 proliferation dose‐dependently with IC₅₀values of 1.42 and 4.0 nM respectively. RA‐V inhibited migration and tube formation of endothelial cells as well as adhesion to extracellular matrix proteins. RA‐V treatment down‐regulated the protein and mRNA expression of matrix metalloproteinase‐2. Regarding intracellular signal transduction, RA‐V interfered with the activation of ERK1/2 in both cell lines. Furthermore, RA‐V significantly decreased the phosphorylation of JNK in HUVEC whereas, in HMEC‐1, p38 MAPK was decreased.CONCLUSIONS AND IMPLICATIONSRA‐V exhibited anti‐angiogenic activities in HUVEC and HMEC‐1 cell lines with changes in function of these endothelial cells. The underlying mechanisms of action involved the ERK1/2 signalling pathway. However, RA‐V may regulate different signalling pathways in different endothelial cells. These findings suggest that RA‐V has the potential to be further developed as an anti‐angiogenic agent.