Calycosin, Astragali Radix most prominent ingredient, has drawn more attention as a result of its ability to treat atherosclerosis (AS). However, the mechanism of action has not been fully elucidated. We investigated the effects of calycosin on bile acid (BA) metabolism and gut microbiome in ApoE–/– mice fed a high-fat diet (HFD). The data showed that the aorta of ApoE–/– mice treated with HFD showed significant atheromatous plaque formation and lipid accumulation, and the levels of total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) were significantly increased, while the levels of high-density lipoprotein cholesterol (HDL-C) were significantly decreased. Calycosin can substantially regulate lipid levels, thereby alleviating liver lipid deposition induced by atherosclerosis. In addition, 16S rRNA sequencing showed that calycosin treatment has reshaped the gut microbiota disturbed by HFD, in particular, increasing the ratio of Bacteroidetes/Firmicutes, and improving the relative abundance of Bilophila, Desulfovibrio, Bacteroides, Lactobacillus, etc. Meanwhile, targeted metabolomics analysis showed that calycosin treatment significantly modulated glycodeoxycholic acid (CDCA), taurocholic acids (TCA), lithocholic acid (LCA), deoxycholic acid (DCA), taurodeoxycholic acid (TDCA) and BA pool composition, which were associated with atherosclerotic plaque areas. In addition, calycosin treatment also down-regulated farnesoid X receptor (FXR) protein levels and up-regulated cytochrome P450 family 7 subfamily A member 1 (CYP7A1) protein levels in the hepatic. At the same time, calycosin inhibits the ileum FXR/TGR5 signaling pathway, inhibits BA reabsorption, promotes BA excretion, and reduces hepatic cholesterol accumulation by enterohepatic circulation. In addition, we found that calycosin significantly promoted the expression of hepatic ATP-binding cassette transporter A1 (ABCA1) and ABCG1 to mediate cholesterol efflux. Meanwhile, calycosin regulates gut microbiota, and Bacteroides, Alistipes, Desulfovibrio, Lactobacillus, Bilophila and Odoribacter are closely related to specific BAs. This enables us to further understand the relationship between BA metabolism and gut microbiota. Calycosin may reduce high-fat diet-induced hepatic cholesterol accumulation in ApoE–/– mice through gut microbiota and BA metabolism, and play a role in treating AS. Finally, we confirmed that calycosin-altered gut microbiota by fecal microbiota transplantation was sufficient to alleviate atherosclerosis. Taken together, our findings provide important insights into the pharmacological mechanisms underlying the efficacy of calycosin on atherosclerosis.

Resveratrol (Res) has been demonstrated to have beneficial effects on gouty nephropathy (GN). However, the mechanisms of Res on GN remain unclear. This study aimed to investigate the mechanisms of Res on GN. In this study, network pharmacology technology was used to predict the Res targets in the prevention and treatment of GN. Renal metabonomics was used to identify differential metabolites in kidney tissue of GN model rats. Finally, molecular docking technology was used to verify the binding ability of Res to key targets. Metabonomics analysis showed that 24 potentially important metabolites were involved in the prevention and treatment of GN with Res. After exposure to Res, metabolite levels normalized. The network pharmacology analysis showed that 24 key targets were involved in the prevention and treatment of GN disease. According to the metabolite-gene network diagram, we identified two core genes, PTGS1 and PTGS2, and found that both were involved in the arachidonic acid metabolism pathway. Molecular docking further verified the affinity of Res binding to PTGS1 and PTGS2. In conclusion, the mechanism of Res against GN may be the regulation of arachidonic acid metabolism through the regulation of PTGS 1 and PTGS 2.

Introduction: Idiopathic pulmonary fibrosis is a chronic interstitial lung disease characterized by excessive deposition of extracellular matrix. Cannabidiol, a natural component extracted from plant cannabis, has been shown to have therapeutic effects on lung diseases, but its exact mechanism of action is unknown, hindering its therapeutic effectiveness.Methods: To establish a pulmonary fibrosis model, combined with UPLC-Q-TOF/MS metabolomics and 16S rDNA sequencing, to explore cannabidiol’s mechanism in treating pulmonary fibrosis. The rats were randomly divided into the control group, pulmonary fibrosis model group, prednisone treatment group, and cannabidiol low, medium, and high dose groups. The expression levels of HYP, SOD, and MDA in lung tissue and the expression levels of TNF-α, IL-1β, and IL-6 in serum were detected. Intestinal microbiota was detected using UPLC-QTOF/MS analysis of metabolomic properties and 16S rDNA sequencing.Results: Pathological studies and biochemical indexes showed that cannabidiol treatment could significantly alleviate IPF symptoms, significantly reduce the levels of TNF-α, IL-1β, IL-6, MDA, and HYP, and increase the expression level of SOD (p < 0.05). CBD-H can regulate Lachnospiraceae_NK4A136_group, Pseudomonas, Clostridia_UCG-014, Collinsella, Prevotella, [Eubacterium]_coprostanoligenes_group, Fusobacterium, Ruminococcus, and Streptococcus, it can restore intestinal microbiota function and reverse fecal metabolism trend. It also plays the role of fibrosis through the metabolism of linoleic acid, glycerol, linolenic acid, and sphingolipid.Discussion: Cannabidiol reverses intestinal microbiota imbalance and attenuates pulmonary fibrosis in rats through anti-inflammatory, antioxidant, and anti-fibrotic effects. This study lays the foundation for future research on the pathological mechanisms of IPF and the development of new drug candidates.

ETHNOPHARMACOLOGICAL RELEVANCE:Huangqi Chifeng decoction (HQCF) combined with parsnips is a classic Chinese traditional medicine formula that has certain advantages in the clinical treatment of cardiovascular and cerebrovascular diseases. At present, there is an absence of research on the regulatory effect and mechanism of this formula on atherosclerosis (AS). The synergistic effect of Radix Saposhnikoviae (RS) in HQCF is also unclear.AIM OF THE STUDY:This study was designed to investigate the role of RS, which is designed as a guide drug for HQCF, in improving the lipid metabolism of AS.MATERIALS AND METHODS:In this study, we studied the effect of HQCF on ApoE-/- mice before and after RS compatibility. Hematoxylin and eosin (HE) staining and oil red staining were used to evaluate atherosclerotic lesions and lipid accumulation in the aorta and liver, respectively. The expression of adenosine monophosphate-activated protein kinase (AMPK) and pAMPK in the aorta was measured by immunofluorescence, and AMPK and sterol regulatory element binding protein-1 (SREBP-1),fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) in liver tissue were measured by Western blot analysis. Metabolomics was used to compare the changes in serum and liver metabolites of ApoE-/- mice before and after RS combination.RESULTS:Compared with the control group, the serum lipid levels of ApoE-/- mice increased, the aortic intima thickened with plaque formation, and liver tissue pathological changes and lipid deposition occurred. Both (HQCFT without RS)HQCS and HQCF can improve the pathological condition of tissue and regulate the blood lipid level. It was noted that HQCF could promote the phosphorylation of AMPK to activate it, inhibit the expression of SREBP-1c and FAS, reduce lipid synthesis, and inhibit ACC to promote the oxidative decomposition of fatty acids. Serum and liver metabolome results showed that HQCS and HQCF treated AS mainly by regulating glycerophospholipid metabolism, sphingolipid metabolism and the arachidonic acid metabolism pathway. Importantly, HQCF showed better efficacy in regulating lipid metabolism than the HQCS group.CONCLUSION:HQCF decoction reduces atherosclerotic lesions in the aorta and lipid accumulation in the liver, which may regulate lipid transport and metabolic function by activating the AMPK pathway. These effects can be attributed to the guidance and synergism of RS.

Huangqi Chifeng Decoction (HQCFT), a traditional Chinese medicine preparation, has long been used to treat cardiovascular and cerebrovascular diseases. However, the mechanism of the beneficial effect of HQCFT on atherosclerosis remains to be explored. In this work, to investigate the effects of HQCFT on bile acid (BA) metabolism and the gut microbiome in atherosclerosis, ApoE−/− mice were fed a with high-fat diet for 16 weeks to establish the AS model. HQCFT(1.95 g kg−1 and 3.9 g kg−1 per day) was administered intragastrically for 8 weeks to investigate the regulatory effects of HQCFT on gut microbiota and bile acid metabolism and to inhibit the occurrence and development of AS induced by a high-fat diet. Histopathology, liver function and blood lipids were used to assess whether HQCFT can reduce plaque area, regulate lipid levels and alleviate liver steatosis in AS mice. In addition, 16S rDNA sequencing was used to screen the gut microbiota structure, and ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC‒MS/MS) was used to determine the bile acid profile. The mRNA and protein expression levels of bile acid metabolism were detected by RT‒PCR and WB to find the potential correlation. Results: HQCFT can regulate gut microbiota disorders, which was achieved by increasing gut microbiota diversity and altering Proteobacteria, Desulfobacterota, Deferribacteres, Rodentibacter, Parasutterella, and Mucispirillum interference abundance to improve AS-induced gut microbiota. HQCFT can also adjust the content of bile acids (TCA, LCA, DCA, TDCA, TLCA, UDCA, etc.), regulate bile acid metabolism, relieve liver fat accumulation, and inhibit the process of AS. In addition, HQCFT can restore the abnormal metabolism of bile acid caused by AS by regulating the expression of farnesoid X receptor (FXR), liver X receptor α (LXRα), ABCA1, ABCG1 and CYP7A1. Conclusion: HQCFT may play a part in the prevention of atherosclerosis by inhibiting the FXR/LXRα axis, increasing the expression of CYP7A1 in the liver, and regulating the interaction between the gut microbiota and bile acid metabolism.