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Outline
To explore the protective effect and underlying mechanisms of Jiawei Zexie Decoction（加味泽泻汤, JWZXD）on endothelial injury in hyperlipidemia through the phosphatidylinositol-3-kinase/protein kinase B/nuclear factor-κB（PI3K/AKT/NF-κB）pathway.
Thirty 4-week-old male SD rats were randomly divided into a normal group（n = 6）and a modeling group（n = 24）. The modeling group was fed a high-fat diet for 20 weeks to establish a hyperlipidemia model. The 24 successfully modeled rats were then randomly divided into four groups：the model group, the JWZXD standard dose group, the JWZXD high-dose group, and the atorvastatin calcium group. After 4 weeks of drug intervention, the body weight, four blood lipid parameters［total cholesterol（TC）, triglyceride（TG）, high-density lipoprotein cholesterol（HDL-C）, low-density lipoprotein cholesterol（LDL-C）］and endothelial function-related indicators［endothelin-1（ET-1）, nitric oxide（NO）］were detected, and the aortic tissue was stained with hematoxylin and eosin（HE）to evaluate the therapeutic effect of JWZXD on endothelial injury in hyperlipidemia. Subsequently, the network pharmacology analysis was conducted to further explore the pharmacological mechanisms at play. The active components and targets of JWZXD were predicted using the TCMSP, Swiss Target Prediction, HERB, ETCM and BATMAN databases. The targets related to hyperlipidemia and endothelial dysfunction were retrieved from the GeneCards, OMIM, DisGeNET and TTD databases. Venn diagrams, protein-protein interaction（PPI）networks and enrichment analysis were employed to identify mechanism pathways. Real-time fluorescent quantitative PCR（RT-qPCR）was used to detect the mRNA expressions of PI3K, AKT1, NF-κB, IL-6 and TNF in each group and Western blot analysis was conducted to measure the expression levels of endothelial injury pathway-related proteins p-PI3K, PI3K, p-AKT, AKT and NF-κB.
Compared with the normal group, the model group showed increased levels of TC, TG, LDL-C and ET-1（P < 0.01）, and decreased levels of HDL-C and NO（P < 0.05, P < 0.01）. Network pharmacology analysis identified 29 active ingredients in JWZXD, including 24-acetyl alismol A, kaempferol, alismol A, alismol B, alismol C and atractylenolide I. After PPI network and topological analysis, 62 core targets such as IL-6, AKT1, TNF, IL-1B and STAT3 were identified. Enrichment analysis using the DAVID platform mainly identified 156 signaling pathways, including the PI3K-AKT signaling pathway, lipids and atherosclerosis, HIF-1 signaling pathway, TNF signaling pathway and EGFR tyrosine kinase inhibitor resistance. Animal experiment results showed that compared with the model group, JWZXD down-regulated the mRNA expression levels of PI3K, AKT1, NF-κB, IL-6, TNF, etc., and up-regulated the protein expression levels of endothelial p-PI3K, PI3K, p-AKT and AKT（P < 0.05, P < 0.01）while down-regulated the protein expression of NF-κB（P < 0.05, P < 0.01）.
JWZXD has a good effect on lowering blood lipids, inhibiting the expression of inflammatory factors and protecting vascular endothelial function. Its mechanism may be achieved through the activation of the PI3K/AKT/NF-κB signaling pathway.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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