Mechanism of XiJiaQi in the treatment of chronic heart failure: Integrated analysis by pharmacoinformatics, molecular dynamics simulation, and SPR validation.

OBJECTIVE: Chronic heart failure (CHF) is a complicated clinical syndrome with a high mortality rate. XiJiaQi (XJQ) is a traditional Chinese medicine used in the clinical treatment of CHF, but its bioactive components and their modes of action remain unknown. This study was designed to unravel the molecular mechanism of XJQ in the treatment of CHF using multiple computer-assisted and experimental methods. METHODS: Pharmacoinformatics-based methods were used to explore the active components and targets of XJQ in the treatment of CHF. ADMETlab was then utilized to evaluate the pharmacokinetic and toxicological properties of core components. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were to explore the underlying mechanism of XJQ treatment. Molecular docking, surface plasmon resonance (SPR), and molecular dynamics (MD) were employed to evaluate the binding of active components to putative targets. RESULTS: Astragaloside IV, formononetin, kirenol, darutoside, periplocin and periplocymarin were identified as core XJQ-related components, and IL6 and STAT3 were identified as core XJQ targets. ADME/T results indicated that periplocin and periplocymarin may have potential toxicity. GO and KEGG pathway analyses revealed that XJQ mainly intervenes in inflammation, apoptosis, diabetes, and atherosclerosis-related biological pathways. Molecular docking and SPR revealed that formononetin had a high affinity with IL6 and STAT3. Furthermore, MD simulation confirmed that formononetin could firmly bind to the site 2 region of IL6 and the DNA binding domain of STAT3. CONCLUSION: This study provides a mechanistic rationale for the clinical application of XJQ. Modulation of STAT3 and IL-6 by XJQ can impact CHF, further guiding research efforts into the molecular underpinnings of CHF.

Quantitative Metabolomic Profiling of Plasma, Urine, and Liver Extracts by 1H NMR Spectroscopy Characterizes Different Stages of Atherosclerosis in Hamsters.

Atherosclerosis (AS) is a progressive disease that contributes to cardiovascular disease and shows a complex etiology, including genetic and environmental factors. To understand systemic metabolic changes and to identify potential biomarkers correlated with the occurrence and perpetuation of diet-induced AS, we applied 1H NMR-based metabolomics to detect the time-related metabolic profiles of plasma, urine, and liver extracts from male hamsters fed a high fat and high cholesterol (HFHC) diet. Conventional biochemical assays and histopathological examinations as well as protein expression analyses were performed to provide complementary information. We found that diet treatment caused obvious aortic lesions, lipid accumulation, and inflammatory infiltration in hamsters. Downregulation of proteins related to cholesterol metabolism, including hepatic SREBP2, LDL-R, CYP7A1, SR-BI, HMGCR, LCAT, and SOAT1 was detected, which elucidated the perturbation of cholesterol homeostasis during the HFHC diet challenge. Using "targeted analysis", we quantified 40 plasma, 80 urine, and 60 liver hydrophilic extract metabolites. Multivariate analyses of the identified metabolites elucidated sophisticated metabolic disturbances in multiple matrices, including energy homeostasis, intestinal microbiota functions, inflammation, and oxidative stress coupled with the metabolisms of cholesterol, fatty acids, saccharides, choline, amino acids, and nucleotides. For the first time, our results demonstrate a time-dependent metabolic progression of multiple biological matrices in hamsters from physiological status to early AS and further to late-stage AS, demonstrating that 1H NMR-based metabolomics is a reliable tool for early diagnosis and monitoring of the process of AS.

New triterpenoids from the leaves of Cyclocarya paliurus.

Six new triterpenoids including four new secodammarane triterpenoid glycosides (1-4), an epoxydammarane triterpenoid glycoside (5), and a new secodammarane triterpenoid (6) were isolated from the ethanolic extract of the leaves of Cyclocarya paliurus. The structures of these compounds were elucidated by spectroscopic analysis methods. Compounds 1-6 were evaluated for their inhibitory activities against α-glucosidase, lipase, DPP-IV, and aldose reductase.