| 基于血浆代谢组研究三七皂苷 R1 改善神经炎症的分子作用机制 |
| 投稿时间：2023-12-01 修订日期：2024-04-19 点此下载全文
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| 基金项目:福建省自然科学基金 |
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| 中文摘要:目的：通过血浆代谢组学研究三七皂苷R1（Notoginsenside R1，NGR1）治疗神经炎症的分子作用机制。方法：采用腹腔注射（0.83 mg?kg–1）脂多糖（LPS）构建神经炎症模型，应用（30 mg?kg–1）NGR1进行给药治疗，并采取眼眶静脉丛取血并分离血浆。在使用苏木精-伊红（HE）染色法检测小鼠脑组织损伤情况、采用实时荧光定量聚合酶链式反应（qRT-PCR）技术检测神经炎症相关指标及酶联免疫吸附反应（ELISA）技术分析血清炎症因子变化的基础上，应用液相色谱-质谱法（LC-MS）对各组小鼠血浆样品进行代谢组学分析，通过人类代谢组数据库（HMDB）、京都基因与基因组百科全书（KEGG）数据库进行差异内源代谢物的鉴定，并应用MetaboAnalyst和Metscape数据库进一步分析差异内源代谢物的关键代谢途径，最后通过qRT-PCR检测调控关键代谢途径基因表达水平的变化。结果：实验表明NGR1能够明显改善小鼠脑组织神经损伤，明显降低中枢神经炎症因子离子化钙结合适配分子1（Iba-1）、白细胞介素1β（IL1β）、白细胞介素6（IL-6）的mRNA水平，显著提高转化生长因子β（TGFβ）的mRNA水平，显著降低血清炎症因子IL-6、TNF-α的表达水平。此外，代谢组学发现模型组与给药组之间小鼠血浆中皮质酮、吲哚丙酮酸、泛酸、12S-羟基5Z,8Z,10E,14Z-二十碳四烯酸、PC(18:3(9Z,12Z,15Z)/16:1(9Z))等22个差异内源代谢物发生明显变化，主要涉及甘油磷脂代谢、亚油酸代谢及类固醇激素生物合成等代谢通路。qRT-PCR结果显示，给药后能显著逆转关键代谢途径中2A型磷脂酶A2（PLA2G2A）、1B型磷脂酶A2（PLA2G1B）、12A型磷脂酶A2（PLA2G12A）、醛酮还原酶1D1（AKR1D1）、羟基类固醇11β脱氢酶1（HSD11B1）、羟基类固醇11β脱氢酶2（HSD11B2） mRNA表达水平。结论：该研究表明NGR1对LPS诱导的神经炎症具有治疗作用，并可能通过调控皮质酮等关键代谢物及甘油磷脂代谢、亚油酸代谢及类固醇激素生物合成等关键途径发挥抗神经炎症的作用，将为深入研究NGR1抗神经炎症的作用机制提供参考。 |
| 中文关键词:血浆代谢组 分子机制 三七皂苷R1 神经炎症 |
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| Molecular mechanism of anti-neuroinflammation of notoginsenside R1 based on plasma metabolomic |
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| Abstract:Objective: This study applies metabolomics techniques to systematically analyze the effects of Notoginsenside R1 (NGR1) on plasma metabolism in neuroinflammatory mice, and provides the experimental basis for an in-depth investigation of the mechanism of anti-neuroinflammation of NGR1. Methods: The inflammation-induced depression model was constructed by intraperitoneal injection of (0.83?kg-1) lipopolysaccharide (LPS) and administered with (30 mg?kg-1) NGR1, and blood was collected from the orbital venous plexus of mice in each group. HE staining was employed for assessment of the damage of brain tissue, qRT-PCR and ELISA for the detection of the changes of inflammatory factors. To further explore the metabolic changes linked to LPS stimulation in the plasma of mice, we performed untargeted metabolomics using LC-MS. The compounds' identification was performed on the differential metabolites' base in the HMDB database and KEGG database. Then, Metaboanalyst and Metscape databases were used to further analyze the key metabolic pathways of differential endogenous metabolites. Finally, qRT-PCR was used to detect the changes of gene expression levels of key metabolic pathways. Results: NGR1 pretreatment can significantly alleviate neuro-inflammation, decrease the mRNA levels of IBA-1, IL-1β and IL-6, and increase the mRNA levels of TGFβ, and downregulate the levels of proinflammatory factors TNF-alpha and IL-6. Furthermore, metabolomics results revealed 22 significantly different metabolites between the LPS group and NGR1 group, including corticosterone, indole-3-pyruvic acid, D-(+)-pantothenic acid, 12S-Hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid, PC(18:3(9Z,12Z,15Z)/16:1(9Z)) and so on. They were mainly involved in Glycerophospholipid metabolism, Linoleic acid metabolism and Steroid hormone biosynthesis. The results of qRT-PCR showed that PLA2G2A, PLA2G1B, PLA2G12A, AKR1D1, HSD11B1, HSD11B2 mRNA expression levels in the key metabolic pathways were significantly reversed after administration. Conclusion: This study suggests that NGR1 has a therapeutic effect on LPS-induced neuroinflammation and may act as an anti-inflammatory agent by regulating key metabolites such as corticosterone and key pathways such as Glycerophospholipid metabolism, Linoleic acid metabolism and Steroid hormone biosynthesis, which will provide a basis for in-depth research on the mechanism of anti-neuroinflammation of NGR1. |
| keywords:plasma metabolome molecular mechanism Notoginsenside R1 neuroinflammation |
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