Astragaloside IV Mediates the PI3K/Akt/mTOR Pathway to Alleviate Injury and Modulate the Composition of Intestinal Flora in ApoE-/- Atherosclerosis Model Rats.

BACKGROUND: Atherosclerosis (AS) is a chronic inflammatory vascular disease with a complex pathogenesis. Astragaloside IV (AST IV), the primary active component of Astragalus, possesses anti-inflammatory, antioxidant, and immunomodulatory properties. This research aims to investigate the outcome of AST IV on AS and its potential molecular mechanism. METHODS: A high-fat diet (21% fat, 50% carbohydrate, 20% protein, 0.15% cholesterol, and 34% sucrose) was utilized to feed Apolipoprotein E deficient (ApoE-/-) SD rats for 8 weeks, followed by continuous intragastric administration of AST IV for 8 weeks. Biochemical detection was conducted for serum lipid levels and changes in vasoactive substances. After Masson staining, aortic root oil red O staining, and Hematoxylin Eosin (HE) staining, the efficacy of AST IV was verified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The mRNA expression levels of inflammatory factors and endothelial dysfunction-related biomarkers in rat aortic root tissues were appraised. The changes in the composition of intestinal flora in rats after AST IV treatment were appraised using Image J (Multi-point Tool). Western blot was used to evaluate phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway-related protein levels in rat aortic root tissues. RESULTS: AST IV administration alleviated the pathological symptoms of AS rats. AST IV administration reduced serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), endothelin-1 (ET-1) and angiotensin (Ang)-II (Ang-II) levels, and augmented serum high-density lipoprotein cholesterol (HDL-C) and nitric oxide (NO) levels. At the same time, AST IV administration inhibited the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-2 (MMP-2), macrophage inflammatory protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) in the aortic root tissue of AS rats. In addition, the intestinal flora changed significantly after AST IV administration. The number of Bifidobacterium, Lactobacillus, and Bacteroides augmented significantly, and Enterobacter, Enterococcus, Fusobacterium, and Clostridium significantly decreased. Mechanistically, AST IV administration inhibited the phosphorylation of PI3K, Akt, and mTOR in AS rats. When combined with Dactolisib (BEZ235) (a PI3K/Akt/mTOR pathway inhibitor), AST IV could further inhibit phosphorylation and reduce inflammation. CONCLUSION: AST IV has a potential anti-AS effect, which can improve the pathological changes of the aorta in ApoE-/- rats fed with a high-fat diet, reduce the level of inflammatory factors, and modulate the composition of intestinal flora via the PI3K/Akt/mTOR pathway.

Weighted gene co-expression network analysis identifies specific modules and hub genes related to Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. This study aims to screen specific modules and key genes related to PD. METHODS: Gene expression profile data GSE6613 and GSE22491 were downloaded from the Gene Expression Omnibus database. The significantly differentially expressed genes (DEGs) in different datasets were screened, followed by gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The Weighted Gene Co-expression Network Analysis (WGCNA) was used to screen disease-related modules that are significantly stable across datasets. The protein-protein interaction network was constructed using the DEGs in the stable module obtained and preservation modules. Finally, the hub genes directly related to PD were screened. RESULTS: A total of 179 DEGs with the same significant difference direction were screened. The enrichment analysis of GO and KEGG pathways showed that 20 significantly related GO biological processes and 9 KEGG signaling pathways were screened. A total of three highly conservative modules were detected in the WGCNA network. Finally, three significant PD-related KEGG pathways screened from the Comparative Toxicogenomics Database were identified, including neuroactive ligand-receptor interaction (CRHR2, CTSG, GRIN1, GRIN2D, LPAR4 and P2RX3), amyotrophic lateral sclerosis (BCL2, GRIN1 and GRIN2D) and alcoholism (CAMKK2, GRIN1, GRIN2D and SLC18A2). Key genes, such as SLC18A2, GRIN1 and GRIN2D, may be potential candidate genes for PD progression. CONCLUSIONS: Our findings indicate that SLC18A2, GRIN1 and GRIN2D may play an important role in the pathogenesis of PD.