Effects of XIAP on high fat diet-induced hepatic steatosis: a mechanism involving NLRP3 inflammasome and oxidative stress.

Increasing evidence indicates that prolonged fat-rich diet (HFD) ingestion is a predisposing factor for metabolic disorder-associated system inflammation and oxidative stress injury, which contributes to the occurrence of non-alcoholic fatty liver disease (NAFLD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-mediated inflammatory infiltration was determined to participate in NAFLD. X-linked inhibitor of apoptosis protein (XIAP) was recently confirmed as an essential regulator for apoptosis in cells. However, the role of XIAP in HFD-induced NAFLD is still not understood. Here, XIAP was characterized with respect to HFD-induced NLRP3 inflammasome activation and reactive oxygen species (ROS) generation in vivo and palmitate (PA)-treated cells in vitro. After HFD administration, hepatic injury was confirmed via histological assessment (grading and staging of NAFLD) and biochemical parameters, oxidative stress, and reduced antioxidant activity. Up-regulated hepatic dysfunction were further indicated by elevated dyslipidemia, lipid accumulation, and decreased fatty acid ß-oxidation associated gene expression. Moreover, in the absence of XIAP, NLRP3 signaling activated by HFD-triggered oxidative stress was up-regulated, accompanied by reduction in antioxidants including HO-1, NQO-1, GST, SOD and Nrf2 activity. The detrimental effects of XIAP blocking on hepatic steatosis and related pathologies were also confirmed in PA-treated mouse liver cells. In contrast, overexpression of XIAP by transfection in vitro restrained PA-stimulated hepatic steatosis by suppression of oxidative stress, NLRP3 related inflammatory response, and impairment of Nrf2 activity, further alleviating abnormal metabolic disorder associated NAFLD. Taken together, the present study helped to elucidate how HFD-induced hepatic steatosis was regulated by XIAP, possibly via the inhibition of NLRP3 signaling and oxidative stress injury.

Study on the Effects of Prophylactic Administration of Ramulus mori Polysaccharides on Inflammatory Responses of Renal Ischemia Reperfusion Injury Model Mice and Its Mechanism / 中国药房

OBJECTIVE： To study on the effects of prophylactic administration of Ramulus mori polysaccharides （RMP） on inflammatory response of renal ischemia reperfusion injury （RIRI） model mice and to explore its possible mechanism. METHODS： Totally 60 C57BL/6 mice were randomly divided to sham operation group， model group， atorvastatin group （positive control， 15 mg/kg）， RMP low-dose， medium-dose and high-dose groups （300， 600， 1 200 mg/kg）. Except for sham operation group， RIRI model was induced in other 5 groups. 24 h before surgery， they were given relevant medicine intragastrically， once a day， for consecutive one week. 24 h after reperfusion， the mice were sacrificed. The serum levels of Scr and BUN were detected. The morphological changes of renal tissue were observed under optical microscope. The serum levels of IL-1β， IL-6， IL-10 and TNF-α were determined by ELISA. Western blot assay was used to determine the protein expressions of Toll-like receptor 4 （TLR4）， p38 mitogen-activation protein kinase （p38MAPK） and p-p38MAPK. RESULTS： Compared with sham operation group， the serum levels of Scr and BUN were significantly elevated in model group  （P＜0.01）. RIRI led to typical inflammatory response of renal tissue， widespread renal tubular epithelial cell degeneration and necrosis， and inflammatory cells infiltration. Serum levels of IL-1β， IL-6， IL-10 and TNF-α were increased significantly （P＜0.01）. The protein expressions of TLR4， p38MAPK and p-p38MAPK were increased significantly in renal cortex （P＜0.01）. Compared with model group， serum levels of Scr and BUN were decreased significantly in administration groups （P＜0.05 or P＜0.01）. The pathological damage of renal tissue was improved in varying degrees， especially in the RMP medium-dose and high-dose groups. Serum levels of IL-1β and IL-6 were decreased significantly in administration groups （P＜0.05 or P＜0.01）. Serum levels of IL-10 were further increased in atorvastatin group and RMP high-dose group （P＜0.01）， and serum level of TNF-α was decreased significantly in atorvastatin group and RMP medium-dose and high-dose groups （P＜0.05 or P＜0.01）. The protein expressions of TLR4 and p-p38MAPK in renal cortex were decreased significantly in administration groups （P＜0.05 or P＜0.01）. CONCLUSIONS： RMP prophylactic administration can improve RIRI of mice， the mechanism of which may be associated with relieving the inflammatory response through inhibition of TLR4/p38MAPK signaling pathway.