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吕怡, 蒋鹏飞, 彭俊, 彭清华.基于网络药理学和SIRT1/PGC-1α信号通路探究青光安Ⅱ号方的视神经保护作用[J].湖南中医药大学学报,2024,44(8):1438-1447[点击复制] |
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| 基于网络药理学和SIRT1/PGC-1α信号通路探究青光安Ⅱ号方的视神经保护作用 |
| 吕怡,蒋鹏飞,彭俊,彭清华 |
| (湖南中医药大学, 湖南 长沙 410208;湖南省中医药防治眼耳鼻咽喉疾病与视功能保护工程技术研究中心, 湖南 长沙 410208;湖南中医药大学第一附属医院, 湖南 长沙 410007) |
| 摘要: |
| 目的 基于网络药理学和实验研究探讨青光安Ⅱ号方对青光眼视神经的保护作用机制。方法 通过TCMSP数据库筛选青光安Ⅱ号方成分靶点，在GeneCards、Disgenet、CTD数据库挖掘青光眼相关靶点，进而筛选青光安Ⅱ号方作用于青光眼的靶点；制作蛋白质-蛋白质相互作用（protein-protein interaction, PPI）网络取其交集，并通过GO分析和KEGG富集分析。建立自发性慢性高眼压DBA/2J青光眼小鼠模型，将C57BL/6J小鼠设置为空白组（等体积蒸馏水），DBA/2J小鼠随机分为模型组（等体积蒸馏水）、益脉康组[0.31 g/（kg·d）]、青光安Ⅱ号方低浓度组[0.85 g/（kg·d）]、青光安Ⅱ号方中浓度组[1.7 g/（kg·d）]、青光安Ⅱ号方高浓度组[3.4 g/（kg·d）]，每组8只，每日灌胃1次。干预4周后，触式眼压笔监测小鼠眼压；HE染色观察小鼠视网膜形态结构；Western blot检测沉默信息调节因子-1（silent information regulator type-1, SIRT1）、过氧化物酶体增殖物激活受体γ共激活因子-1α（peroxisome proliferation-activated receptor-γ-coactivator 1α, PGC-1α）的蛋白表达水平；qRT-PCR检测SIRT1、PGC-1α的mRNA表达水平。结果 从青光安Ⅱ号方共筛选得到101个活性成分和245个相关靶点，2 412个青光眼疾病相关基因靶点；药物-活性成分-靶点相互作用最强的5个靶点分别是前列腺素内过氧化物合成酶2、核受体共激活因子2、胃蛋白酶原Ⅱ、前列腺素内过氧化物合成酶1以及过氧化物酶体增殖物激活受体γ（peroxisome proliferative activated receptor gamma, PPARG）；PPI网络显示较强的靶点是SIRT1、PPARG；GO分析和KEGG富集分析得到细胞衰老、IL-17等信号通路。与给药前相比，给药后用药组眼压显著降低（P＜0.01）。给药后，与空白组相比，模型组眼压显著升高（P＜0.01），视网膜中SIRT1、PGC-1α mRNA表达量和蛋白表达量均显著降低（P＜0.01）；与模型组相比，用药组眼压显著降低（P＜0.01），SIRT1、PGC-1α mRNA表达量和蛋白表达量均显著升高（P＜0.01）。与益脉康组和青光安Ⅱ号方低浓度组相比，青光安Ⅱ号方中、高浓度组SIRT1、PGC-1α mRNA表达量和SIRT1蛋白表达量显著升高（P＜0.01）；与青光安Ⅱ号方低浓度组相比，青光安Ⅱ号方高浓度组PGC-1α蛋白表达量均显著上升（P＜0.01）。与青光安Ⅱ号方中浓度组相比，青光安Ⅱ号方高浓度组PGC-1α mRNA表达量和蛋白表达量显著升高（P＜0.01）。结论 青光安Ⅱ号方可有效调控SIRT1/PGC-1α信号通路，抑制RGC的丢失，主要在氧化应激、细胞衰老等方面对青光眼视神经发挥保护作用。 |
| 关键词: 青光眼 青光安Ⅱ号方 细胞衰老 沉默信息调节因子-1 过氧化物酶体增殖物激活受体g共激活因子-1α |
| DOI：10.3969/j.issn.1674-070X.2024.08.013 |
| 投稿时间：2024-04-01 |
| 基金项目:国家自然科学基金面上项目（82274588，81874492）；国家中医药管理局人才支持项目——岐黄学者（国中医药人教函〔2022〕6号）；湖南省中医药科研计划项目（D2022045）；湖南省自然科学基金青年基金项目（2020JJ5436）；湖南中医药大学科研揭榜挂帅项目（2022XJJB003）；中医药防治五官科疾病湖南省重点实验室建设项目（2017TP1018）；国家中医药管理局中医眼科学重点学科建设项目（ZK1801YK015）；湖南中医药大学中医学国内一流建设学科建设项目；中医药防治眼耳鼻咽喉疾病湖南省重点实验室开放基金项目（2018YZD02）。 |
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| Protective effects of Qingguang'an Ⅱ Formula on the optic nerve based on network pharmacology and SIRT1/PGC-1α signaling pathway |
| LV Yi, JIANG Pengfei, PENG Jun, PENG Qinghua |
| (Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;Hunan Engineering Technology Research Center for Prevention & Treatment of Ophthalmology and Otolaryngology Diseases and Visual Function Protection with Chinese Medicine, Changsha, Hunan 410208, China;The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China) |
| Abstract: |
| Objective To explore the mechanism of protective action of Qingguang'an Ⅱ Formula (QGAFⅡ) on optic nerve in glaucoma based on network pharmacology and experimental research. Methods Targets of QGAFⅡ components were screened through the TCMSP database, and glaucoma-related targets were mined from GeneCards, Disgenet, and CTD databases. Then the targets through which QGAFⅡ acts on glaucoma were identified. A protein-protein interaction (PPI) network was constructed using the intersection of these targets, and GO and KEGG pathway analyses were performed on them. A spontaneous chronic high intraocular pressure (IOP) DBA/2J glaucoma mouse model was established. C57BL/6J mice were set as the blank group (an equal volume of distilled water), and DBA/2J mice were randomize into the model group (an equal volume of distilled water), Yimaikang (YMK) group [0.31 g/(kg·d)], and low- [0.85 g/(kg·d)], medium- [1.7 g/(kg·d)], and high-concentration [3.4 g/(kg·d)] QGAFⅡ groups. Each group consisted of eight mice, and they were administered by gavage once daily. After 4 weeks of intervention, the IOP of mice was monitored by a contact tonometer; HE staining was used to observe the morphological structure of the mouse retina; Western blot was used to examine the protein expression levels of silent information regulator type-1 (SIRT1) and peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α); qRT-PCR was used to check the mRNA expression levels of SIRT1 and PGC-1α. Results A total of 101 active ingredients and 245 related targets were screened from QGAFⅡ. Additionally, 2,412 disease-related gene targets for glaucoma were identified. The five targets with the strongest drug-active ingredient-target interactions were prostaglandin-endoperoxide synthase 2, nuclear receptor coactivator 2, pepsinogen Ⅱ, prostaglandin-endoperoxide synthase 1, and peroxisome proliferator activated receptor gamma (PPARG). The PPI network showed that the stronger targets were SIRT1 and PPARG. Signaling pathways such as oxidative stress, cellular senescence, and IL-17 were obtained by GO and KEGG enrichment analyses. Compared with before administration, the IOP of the treatment groups significantly decreased after administration (P＜0.01). After administration, compared with the blank group, the model group showed a significant increase in IOP (P＜0.01), and the mRNA and protein expression levels of SIRT1 and PGC-1α in the retina were significantly reduced (P＜0.01). Compared with the model group, the IOP in the treatment groups showed a significant decrease (P＜0.01), while the mRNA and protein expression levels of SIRT1 and PGC-1α significantly increased (P＜0.01). Compared with the YMK group and the low-concentration QGAFⅡ group, the mRNA expression levels of SIRT1 and PGC-1α and the protein expression level of SIRT1 significantly increased in the medium- and high-concentration QGAFⅡ groups (P＜0.01); compared with the low-concentration QGAFⅡ group, the protein expression level of PGC-1α in the high-concentration QGAFⅡ group significantly increased (P＜0.01); compared with the medium-concentration QGAFⅡ group, the mRNA and protein expression levels of PGC-1α significantly increased in the high-concentration QGAFⅡ group (P＜0.01). Conclusion QGAFⅡ can effectively regulate the SIRT1/PGC-1α signaling pathway, and inhibit the loss of retinal ganglion cells (RGCs). It mainly exerts protective effects on the optic nerve in glaucoma by targeting oxidative stress and cellular senescence. |
| Key words: glaucoma Qinguang'an Ⅱ Formula cellular senescence silent information regulator type-1 peroxisome proliferation-activated receptor-γ-coactivator 1α |
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