Background and Purpose: Recent reports have suggested that salidroside could protect cardiomyocytes from oxidative injury and stimulate glucose uptake in skeletal muscle cells by activating AMP‐activated protein kinase (AMPK). The aim of this study was to evaluate the therapeutic effects of salidroside on diabetic mice and to explore the underlying mechanisms.Experimental Approach: The therapeutic effects of salidroside on type 2 diabetes were investigated. Increasing doses of salidroside (25, 50 and 100 mg·kg⁻¹·day⁻¹) were administered p.o. to db/db mice for 8 weeks. Biochemical analysis and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. Primary cultured mouse hepatocytes were used to further explore the underlying mechanisms in vitro.Key Results: Salidroside dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Hypolipidaemic effects and amelioration of liver steatosis were observed after salidroside administration. In vitro, salidroside dose‐dependently induced an increase in the phosphorylations of AMPK and PI3K/Akt, as well as glycogen synthase kinase 3β (GSK3β) in hepatocytes. Furthermore, salidroside‐stimulated AMPK activation was found to suppress the expression of PEPCK and glucose‐6‐phosphatase. Salidroside‐induced AMPK activation also resulted in phosphorylation of acetyl CoA carboxylase, which can reduce lipid accumulation in peripheral tissues. In isolated mitochondria, salidroside inhibited respiratory chain complex I and disturbed oxidation/phosphorylation coupling and moderately depolarized the mitochondrial membrane potential, resulting in a transient increase in the AMP/ATP ratio.Conclusions and Implications: Salidroside exerts an antidiabetic effect by improving the cellular metabolic flux through the activation of a mitochondria‐related AMPK/PI3K/Akt/GSK3β pathway

Our previous studies suggested that salidroside could alleviate hepatic steatosis in type 2 diabetic C57BLKS/Lepr^db (db/db) mice. The aim of the present study was to evaluate the therapeutic effect of salidroside on high‐fat diet‐ (HFD‐) induced nonalcoholic fatty liver disease (NAFLD) by investigating underlying mechanisms. Mice were fed with HFD or regular diet, randomly divided into two groups, and treated with salidroside or vehicle for 8 weeks. Then, biochemical analyses and histopathological examinations were conducted in vivo and in vitro. Salidroside administration attenuated HFD‐induced obesity, blood glucose variability, and hepatic lipid deposition, markedly increasing insulin sensitivity in HFD mice. In addition, salidroside suppressed oxidative stress, thioredoxin‐interacting protein (TXNIP) expression, and NLRP3 inflammasome activation in the liver. In cultured hepatocytes, salidroside dose dependently regulated lipid accumulation, reactive oxygen species (ROS) generation, and NLRP3 inflammasome activation as well as improved AMP‐activated protein kinase (AMPK) activity and insulin sensitivity. The inhibition of AMPK activation by inhibitor or short interfering RNA (siRNA) resulted in the suppression of the beneficial effects of salidroside in hepatocytes. Our findings demonstrated that salidroside protects against NAFLD by improving hepatic lipid metabolism and NLRP3 inflammasome activation, and these actions are related to the regulation of the oxidative stress and AMPK‐dependent TXNIP/NLRP3 pathways.

Background and Purpose: The retention of plasma low‐density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Whether or not C‐reactive protein (CRP) can directly affect the transcytosis of LDL is not clear. Here we have examined the effect of CRP on transcytosis of LDL across endothelial cells and have explored the underlying mechanisms.Experimental Approach: Effects of CRP on transcytosis of FITC‐labelled LDL were examined with human umbilical vein endothelial cells and venous rings in vitro and, in vivo, ApoE^‐/‐ mice. Laser scanning confocal microscopy, immunohistochemistry and Oil Red O staining were used to assay LDL.Key Results: CRP increased transcytosis of LDL. An NADPH oxidase inhibitor, diphenylene iodonium, and the reducing agent, dithiothreitol partly or completely blocked CRP‐stimulated increase of LDL transcytosis. The PKC inhibitor, bisindolylmaleimide I and the Src kinase inhibitor, PP2, blocked the trafficking of the molecules responsible for transcytosis. Confocal imaging analysis revealed that CRP stimulated LDL uptake by endothelial cells and vessel walls. In ApoE^‐/‐ mice, CRP significantly promoted early changes of atherosclerosis, which were blocked by inhibitors of transcytosis.Conclusions and Implications: CRP promoted atherosclerosis by directly increasing the transcytosis of LDL across endothelial cells and increasing LDL retention in vascular walls. These actions of CRP were associated with generation of reactive oxygen species, activation of PKC and Src, and translocation of caveolar or soluble forms of the N‐ethylmaleimide‐sensitive factor attachment protein.