Zexie Tang targeting FKBP38/mTOR/SREBPs pathway improves hyperlipidemia.

ETHNOPHARMACOLOGICAL RELEVANCE: Zexie Tang (ZXT), only two consists with Alismatis Rhizoma (AR) and Atractylodes macrocephala Rhizoma (AM), a classical Chinese medicine formula from Synopsis of the Golden Chamber with a history of 2000 years. Clinical observation in recent years has found that ZXT has excellent lipid-lowering effect. AIM OF THE STUDY: To explore the potential mechanism of ZXT ameliorates hyperlipidemia based on FKBP38/mTOR/SREBPs pathway. MATERIALS AND METHODS: WD-induced hyperlipidemia mice and oleic acid induced cell lipid accumulation model were used to investigate pharmacodynamic. The effect of ZXT on the transcriptional activity of SREBPs was detected by reporter gene assay. Proteins and downstream genes of mTOR/SREBPs pathway were detected in vivo and in vitro. Combined with network pharmacology and HPLC-Q-TOF/MS, the active ingredients were screened and identified. The interaction between active compounds of ZXT and FKBP38 protein were analyzed by docking analysis. RESULTS: ZXT decreased TC, TG and LDL-c levels in blood of WD-induced hyperlipidemia mouse model, and improved insulin resistance in vivo. ZXT also reduced TC, TG and lipid accumulation in cells line, and inhibited SREBPs luciferase activity, protein and its target genes expression such as FASN, HMGCR, etc. Meanwhile, ZXT inhibited protein expression levels of p-mTOR, p-S6K, etc in vitro and in vivo. Combined with network pharmacology and HPLC-Q-TOF/MS, 16 active ingredients were screened and identified. Docking results showed that active compounds of ZXT binding to FKBP38 and formed hydrogen bond. CONCLUSION: Our findings highlighted that ZXT ameliorates hyperlipidemia, in which FKBP/mTOR/SREBPs pathway might be the potential regulatory mechanism.

Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis.

The accumulation of iron-dependent lipid peroxides is one of the important causes of NAFLD. The purpose of this study is to explore the effect of dehydroabietic acid (DA) on ferroptosis in nonalcoholic fatty liver disease (NAFLD) mice and its possible mechanisms. DA improved NAFLD and reduced triglycerides (TG), total cholesterol (TC), and lipid peroxidation level and inhibited ferroptosis in the liver of HFD-induced mice. DA binds with Keap1 to form 3 stable hydrogen bonds at VAL512 and LEU557 and increased nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elemen (ARE) luciferase activity. DA promoted the expression downstream of Nrf2 such as heme oxygenase-1 (HO-1), glutathione (GSH) and its peroxidase 4 (GPX4), so as to eliminate the accumulation of reactive oxygen species (ROS) and reduce lipid peroxides malondialdehyde (MDA) in the liver. DA inhibited ferroptosis and increased the expression of key genes such as ferroptosis suppressor protein 1 (FSP1) in vitro and vivo. In all, DA may bind with Keap1, activate Nrf2-ARE, induce its target gene expression, inhibit ROS accumulation and lipid peroxidation, and reduce HFD-induced NAFLD.

SPE-UHPLC-FLD Method for the Simultaneous Determination of Five Anthraquinones in Human Urine Using Mixed-Mode Bis(tetraoxacalix[2]arene[2]triazine) Modified Silica as Sorbent.

The five anthraquinones compounds (including aloe-emodin, emodin, physcion, chrysophanol, and rhein) are regarded as the main effective ingredients in rhubarb (Dahuang in Chinese, one of the commonly used Chinese herbal medicines). In this work, a simple and effective solid phase extraction (SPE) method based on bis(tetraoxacalix[2]arene[2]triazine) modified silica gel as adsorbent was developed. Coupled with UHPLC-FLD, the developed method was successfully applied for the measuring of main anthraquinones in human urine after oral administration of the extracts of rhubarb. To obtain the highest recoveries of the five anthraquinones in the SPE process, the main parameters which may affect extraction efficiency were optimized. The optimized sorbent amount, sample loading pH, sample loading rate, washing solution, and eluent condition were obtained. The developed method showed good linearity in 0.012-1.800 µg mL-1 for the five anthraquinones with correlation coefficients more than 0.9993. The investigated LOD values ranged from 3.9 to 5.7 ng mL-1, while the LOQs were between 12.0 and 18.2 ng mL-1. The recoveries of the method were also investigated, which were in the range of 94.8-106.6%. The application of the mixed-mode SPE materials in the proposed method was feasible and simple, and suitable for the enrichment of anthraquinones in urine samples.