Background. Yinchen Wuling powder is often used to treat clinical hyperlipidemia, although its mechanism of action remains unclear. In this study, we aimed to investigate the active ingredients found in Yinchen Wuling powder and find its mechanism of action when treating hyperlipidemia, using a combination of network pharmacology, molecular docking, and molecular dynamics simulation approaches. Methods. The TCMSP database was used to obtain the principle active ingredients found in Yinchen Wuling powder and the NCBI and DisGeNet databases were used to obtain the main target genes involved in hyperlipidemia, and the intersectional targets were obtained by EXCEL. We also used Cytoscape 3.7.2 software to construct a “Traditional Chinese Medicine-Active Ingredient-Target” network and use STRING platform to conduct “protein-protein interactional” (PPI) analyses on the intersection targets. Bioconductor software and RX 64 4.0.0 software were then used to perform GO functional enrichment analysis and KEGG pathway enrichment analysis on the targets. Molecular docking of core protein-ligand interactions was modeled using AutoDock Vina software. A simulation of molecular dynamics was conducted for the optimal core protein-ligand obtained by molecular docking using Amber18 software. Results. A total of 63 active ingredients were found in Yinchen Wuling powder, corresponding to 175 targets, 508 hyperlipidemia targets, and 55 intersection targets in total. Cytoscape 3.7.2 showed that the key active ingredients were quercetin, isorhamnetin, taxifolin, demethoxycapillarisin, and artepillin A. The PPI network showed that the key proteins involved were AKT1, IL6, VEGFA, and PTGS2. GO enrichment analysis found that genes were enriched primarily in response to oxygen levels and nutrient levels of the vesicular lumen and were associated with membrane rafts. These were mainly enriched in AGE-RAGE (advanced glycation end products-receptor for advanced glycation end products) signaling pathway in diabetic complications, fluid shear stress, and atherosclerosis, as well as other pathways. The molecular docking results indicated key binding activity between PTGS2-quercetin, PTGS2-isorhamnetin, and PTGS2-taxifolin. Results from molecular dynamics simulations showed that PTGS2-quercetin, PTGS2-isorhamnetin, and PTGS2-taxifolin bound more stably, and their binding free energies were PTGS2-quercetin -29.5 kcal/mol, PTGS2-isorhamnetin -32 kcal/mol, and PTGS2-taxifolin -32.9 kcal/mol. Conclusion. This study is based on network pharmacology and reveals the potential molecular mechanisms involved in the treatment of hyperlipidemia by Yinchen Wuling powder.

The upregulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) was reported to be involved in regulating the levels of inflammatory markers and apoptosis in macrophages. This study aims to investigate the function and regulation of PCSK9 in myocardial ischaemia. The results of our study showed dramatically increased expression of PCSK9 induced by hypoxia/reoxygenation (H/R) stress rather than by apoptosis in primary murine cardiomyocytes and HL-1 cells. Moreover, PCSK9 promoted H/R-induced pro-inflammatory cytokine release from macrophages, while silencing of PCSK9 inhibited the expression of the pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. Additionally, PCSK9 facilitated the release of pro-inflammatory cytokines from macrophages under H/R conditions, which decreased cardiomyocyte viability and promoted apoptosis of cardiomyocytes. For the underlying mechanisms, we identified PCSK9-induced NF-κB activation as being involved in the cardiomyocyte apoptosis, which was blocked by the NF-κB inhibitor BAY 11-7082. Collectively, this study provides new insights into the therapeutic possibility of regulating PCSK9 in cardiomyocytes for the treatment of ischaemic cardiomyopathy.

Cardiac fibrosis is a key pathological link of various cardiovascular diseases to heart failure. It is of great significance to deeply understand the development process of cardiac fibrosis and the cellular and molecular mechanisms involved. Macrophages play a special role in promoting heart development, maintaining myocardial cell homeostasis and heart function. They are involved in the whole process from inflammatory to cardiac fibrosis. This article summarizes the relationship between inflammation and fibrosis, discusses the bidirectional regulation of cardiac fibrosis by macrophages and analyses the functional heterogeneity of macrophages from different sources. It is believed that CCR2– cardiac resident macrophages can promote cardiac function, but the recruitment and infiltration of CCR2+ cardiac non-resident macrophages aggravate cardiac dysfunction and heart remodeling. After heart injury, damage associated molecular patterns (DAMPs) are released in large quantities, and the inflammatory signal mediated by macrophage chemoattractant protein-1 (MCP-1) promotes the infiltration of CCR2+ monocytes and transforms into macrophages in the heart. These CCR2+ non-resident macrophages not only replace part of the CCR2– resident macrophage subpopulation in the heart, but also cause cardiac homeostasis and hypofunction, and release a large number of mediators that promote fibroblast activation to cause cardiac fibrosis. This article reveals the cell biology mechanism of resident and non-resident macrophages in regulating cardiac fibrosis. It is believed that inhibiting the infiltration of cardiac non-resident macrophages and promoting the proliferation and activation of cardiac resident macrophages are the key to improving cardiac fibrosis and improving cardiac function.

Background The potential role of the gut microbiome (GM) in heart failure (HF) had recently been revealed. However, the underlying mechanisms of the GM and fecal metabolome in HF have not been characterized. The Dahl salt-sensitive rat model of hypertensive heart failure (H-HF) was used to study the clinical symptoms and characteristics. To elucidate the pathogenesis of HF, we combined 16S rRNA gene sequencing and metabolomics to analyze gut microbial compositions and fecal metabolomic profiles of rats with H-HF. Results PCoA of beta diversity shown that the gut microbiome composition profiles among the three groups were separated. Gut microbial composition was significantly altered in H-HF rats, the ratio of Firmicutes to Bacteroidetes(F/B) increased and the abundance of Muribaculaceae, Lachnospiraceae, and Lactobacillaceae decreased. Significantly altered levels of 17 genera and 35 metabolites were identified as the potential biomarker of H-HF. Correlation analysis revealed that specific altered genera were strongly correlated with changed fecal metabolites. The reduction in short-chain fatty acids (SCFA)-producing bacteria and trimethylamine N-oxide (TMAO) might be a notable characteristic for H-HF. Conclusions This is the first study to characterize the fecal microbiome of hypertensive heart failure by integrating 16S rRNA gene sequencing and LC–MS-based metabolomics approaches. Collectively, the results suggesting changes of gut microbiome composition and metabolites are associated with hypertensive heart failure rats.

Follistatin-like 1 (FSTL1) is a key factor in maintaining cardiac growth and development.