Untargeted metabolomics reveals the effect of lovastatin on steroid-induced necrosis of the femoral head in rabbits.

PURPOSE: Lovastatin is an important medicine and it shows a significant effect against glucocorticoid-induced necrosis of the femoral head. This study aimed to investigate the effect of lovastatin on preventing necrosis of the femoral head of by serum metabolomics strategy. METHODS: Adult healthy adult Japanese white rabbits were divided into three groups: control group, model group, and drug group. The pathologic changes of femoral head were assessed with magnetic resonance imaging and microscope. Metabolomics based on ultra-high performance liquid chromatography tandem mass spectrometry analysis was used to analyze the collected serum sample. Data were analyzed using principal component analysis, partial least squares-discriminate analysis, and orthogonal partial least squares-discriminant analysis. All potential metabolites were identified by comparing with human metabolome database, Metlin database, lipid maps, and chemspider database. RESULTS: Eleven potential biomarkers were noted and identified as potential biomarkers. The change of biomarkers suggested that lovastatin on preventing necrosis of the femoral head may affect glycerophospholipid metabolism, linoleic acid metabolism, sphingolipid metabolism, alpha-linolenic acid metabolism, pyrimidine metabolism, and arachidonic acid metabolism. CONCLUSION: The study suggested that lovastatin could prevent the glucocorticoid-induced necrosis of the femoral head of rabbits. The possible reasons were closely associated with adjusting the lipid metabolism, inhibiting adipogenesis, and delaying the osteocyte apoptosis.

Tangshen Formula Alleviates Hepatic Steatosis by Inducing Autophagy Through the AMPK/SIRT1 Pathway.

Tangshen formula (TSF), a formula of Chinese herbal medicine, improves lipid metabolism in humans and animals with diabetic kidney disease. However, the effect and mechanism of TSF on nonalcoholic fatty liver disease (NAFLD) remain unclear. The activation of autophagy appears to be a potential mechanism for improving NAFLD. In the present study, we examined the therapeutic effect of TSF on hepatic steatosis and sought to explore whether its effect is related to activating autophagy. Here, we showed that TSF treatment significantly attenuated hepatic steatosis in both high-fat diet (HFD) and methionine choline-deficient diet (MCDD)-fed mice. Meanwhile, TSF reduced lipid accumulation in palmitate (PA)-stimulated HepG2 cells and primary mouse hepatocytes. Furthermore, TSF increased Sirtuin 1 (SIRT1) expression and promoted autophagy activation in vivo. TSF also improved PA-induced suppression of both SIRT1 expression and SIRT1-dependent autophagy, thereby alleviating intracellular lipid accumulation in vitro. In addition, TSF increased SIRT1 expression and induced autophagy in an adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. Moreover, SIRT1 knockdown abolished the autophagy-inducing and lipid-lowering effects of TSF. In conclusion, TSF improved lipid accumulation and hepatic steatosis by inducing the AMPK/SIRT1 pathway-mediated autophagy.

Simultaneous Assay of Oxygen-Dependent Cytotoxicity and Genotoxicity of Anticancer Drugs on an Integrated Microchip.

Oxygen deprivation is a common feature in a variety of cancer tissues and associated with tumor progression, acquisition of antiapoptotic potential, and clinical therapeutic resistance. Thus, great interest has been aroused to develop new platforms or approaches of activity assays to impact on the hypoxic microenvironment and oxygen-dependent drug responses to improve the productivity of new drug discovery. In this study, an integrated microsystem is established to combine the cytotoxic and genotoxic tests together for continuous multiple measurements under mimicking hypoxic tumor microenvironment. We fabricated a double-layer chip device by combining a single-cell-arrayed agarose layer with a microfluidics-based oxygen gradient-generating layer using a PDMS membrane. Using tirapazamine (TPZ) and blemycin (BLM) as model anticancer drugs, we demonstrated its application and performance in single cell loading, cell cultivation, and subsequent drug treatment as well as in situ analysis of oxygen-dependent cytotoxicity and genotoxicity of anticancer drugs. The results demonstrated the opposite oxygen-dependent toxicity of TPZ and BLM, which also indicated that the formation of DNA breaks is related with cell apoptosis. Compared with the traditional assays, this device takes advantage of microfluidic phenomena to generate various oxygen concentrations while exhibiting the combinatorial diversities achieved by the single cell microarray, offering a powerful tool to study single cell behaviors and responses under different oxygen conditions with desired high-content and high-throughput capabilities.