基于网络药理学及 NLRP3 炎症通路探讨丹参保心茶对冠心病合并 抑郁症小鼠的作用机制.

Objective To explore the mechanism of action of Danshen Baoxin Cha (DBC) on depressed mice with coronary heart disease (CHD) based on network pharmacology and NLRP3 inflammatory pathway. Methods (1) TCMSP and BATMAN-TICAM databases were used to screen the DBC active ingredients and targets. The targets of CHD with depression were screened using the OMIM and Genecards databases. The targets of DBC active ingredients and related targets of CHD with depression were imported into Venny 2.1 online platform to obtain the intersection targets, which was the potential target of DBC in the treatment of CHD with depression. Protein-protein interaction (PPI) analysis was performed on the intersection targets using the STRING platform to screen the key targets. A "drug- active ingredients - disease- targets" network was created to select the main active ingredients and core targets of DBC for the treatment of CHD with depression. Thereafter, the primary targets were examined by GO function and KEGG pathway enrichment using the Metascape database. (2) Kunming mice were split into six groups of eight mice each at random： the control group, the model group, the positive control group (metoprolol tartrate 5.14 mg·kg-1 + sertraline hydrochloride 10.3 mg·kg-1), and the DBC high-, middle-, and low- dose groups (30.8, 15.4 and 7.7 g·kg-1·d-1). Chronic unpredictable mild stimulation (CUMS) and subcutaneous injection of isoprenaline hydrochloride (ISO) were used to induce a mice model of CHD with depression. Mice were treated orally with the corresponding drug once a day for 18 consecutive days. Behavioral experiments involving forced swimming test, tail suspension test, and open-field test were applied to detect depression levels of mice. Histopathological alterations in hippocampus tissues were noted using HE and Nissl staining. qPCR was used to determine the mRNA expression levels of IL-6, TNF-α, NLRP3, IL-1β, IL-10, and Caspase-1 in hippocampus tissues. Results (1) Sixty-five active components in Salvia and seven active components in green tea were screened out. A total of 1 042 potential targets and 2 116 CHD complicated with depression-related targets were obtained. The intersection of the targets of active components and disease- related targets was performed by Venny 2.1.0 platform to obtain 299 potential targets (common targets) of DBC in the treatment of CHD with depression. The core targets including IL-1β, AKT1, TNF-α, IL-6, VEGFA, CASP3 and IL-10 were screened through PPI network analysis of potential targets. Key active ingredients including vitamin B, luteolin, salvianolic acid, tanshinone IIA and catechin, as well as key targets, such as PTGS2、 IL-1β、 IL-6、 TNF- α and IL-10, were obtained by network analysis of “drugs-active ingredients-disease-targets”. The potential targets were correlated with biological processes such as inflammation response, regulation of tumour necrosis factor (TNF), glucocorticoid regulation, regulation of nuclear factor kappa B (NF-κB) transcription factor, as well as major pathways including PI3K-Akt signaling pathway, TNF signaling pathway, apoptosis signaling pathway, and NF-κB signaling pathway. (2) Compared with the control group, mice in the model group showed a significant decrease in the total and center distance of the open field (P＜0.01) and a significant increase in the time of forced swimming and immobility time of tail suspension test (P＜0.01). The mRNA expression of IL-6, TNF- α, NLRP3, IL-1β, and Caspase-1 was significantly up-regulated (P＜0.01) in the hippocampus tissues, but IL-10 mRNA expression was down-regulated (P＜0.05). Compared with the model group, the total and center distance in DBC high-, middle-, and low- dose groups were significantly up-regulated (P＜0.05, P＜0.01), and the time of forced swimming and immobility time of tail suspension test were significantly down-regulated (P＜0.01). The mRNA expression of IL-6, TNF- α, NLRP3, IL-1β and Caspase-1 of the DBC high-, middle-, and low- dose groups were significantly down- regulated (P＜0.01), IL-10 mRNA expression in mice hippocampus tissue of DBC high- and middle- dose groups was up-regulated (P＜0.01). Conclusion The intervention effect of DBC on depressed mice with CHD may be achieved by active ingredients including luteolin, tanshinone, salvianolic acid and catechin acting on the key targets, such as IL-6,TNF-α, IL-1β and IL-10, to regulate the NLRP3 inflammatory signaling pathway. [ABSTRACT FROM AUTHOR]