网络药理学结合实验验证探讨四逆散“异病同治”抑郁症、焦虑症和乳腺纤维囊性疾病的作用机制

Exploring mechanism of Sini Powder in treatment of depression,anxiety disorder,and breast fibrocystic disease based on network pharmacology and experimental verification

目的探讨四逆散对重度抑郁症、广泛性焦虑症和乳腺纤维囊性疾病“异病同治”的作用机制。方法筛选四逆散活性成分,并与治疗抑郁症、焦虑症和乳腺纤维囊性疾病的药物进行主成分分析判断类药性;利用多个数据库综合分析四逆散和3种疾病的作用靶点,使用DAVID数据库对共有靶点进行基因本体(GO)与京都基因与基因组百科全书(KEGG)通路分析,运用BioGPS数据库对关键靶点进行定位分析。采用皮质酮(CORT)诱导PC12细胞制备抑郁症、焦虑症模型,6.2500、3.1250、1.5625 mg·mL^(-1)四逆散干预处理,MTT检测细胞存活率,实时荧光定量PCR(qRT-PCR)法检测白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)mRNA表达。结果四逆散主要活性成分具有较好的类药性,四逆散“异病同治”共有靶点32个,关键靶点为IL6、肿瘤坏死因子(TNF)、细胞肿瘤抗原p53(TP53)、丝氨酸/苏氨酸激酶1(AKT1)和IL1B等,关键活性成分包括槲皮素、木犀草素和川陈皮素等。四逆散主要通过调控HIF-1、癌症和PI3K-Akt等多条信号通路发挥“异病同治”功能,推测肝、胸腺是药物发挥作用的关键部位。实验结果显示四逆散可逆转CORT对PC12的细胞毒性,影响不同时间点IL-1β、IL-6 mRNA表达。结论四逆散具有“多成分、多靶点、多通路”协同作用的特点,通过调节炎症反应等发挥“异病同治”作用。

Objective To investigate the mechanism of Sini Powder in treatment of major depressive disorder,generalized anxiety disorder,breast fibrocystic disease with the"homotherapy for heteropathy".Methods The active components of Sini Powder were screened and compared the drug-like properties with existing drugs for the treatment of major depressive disorder,generalized anxiety disorder,breast fibrocystic disease using principal component analysis.Multiple databases were used to analyze the targets of Sini Powder and three diseases,DAVID database was used to conduct GO enrichment and KEGG pathway analysis of common targets,BioGPS database was used to locate and analyze the key targets.Corticosterone(CORT)induced PC12 cells was used to prepare models of depression.Sini Powder(6.2500,3.1250,1.5625 mg·mL^(-1))was used for intervention treatment.Cell survival was detected by MTT,IL-1βand IL-6 mRNA expression was tested by qRT-PCR.Results Most of the active components of Sini Powder had good drug-like properties.There were 32 common targets of Sini Powder treating three diseases with"homotherapy for heteropathy".The key targets were IL6,TNF,TP53,AKT1 and IL1B,etc.The key active components were quercetin,luteolin,and nobiletin,etc.Sini Powder mainly played the role of treating different diseases through HIF-1,pathways in cancer and PI3K-Akt signaling pathway.It was speculated that the liver and thymus were the key parts of the drug.The results of cell experiments showed that Sini Powder could reverse the cytotoxicity of CORT on PC12 and affected the mRNA expression of IL-1βand IL-6.Conclusion The treatment of three diseases with Sini Powder reflected the thought of"homotherapy for heteropathy"in Chinese medicine through multiple components,multiple targets,and multiple pathways by regulating inflammatory response and other factors.