{"title":"基于体内暴露谱和类固醇激素代谢网络，探讨柴胡疏肝散治疗围绝经期综合征的有效物质和作用机制。","authors":"Haiyan Lyu, Ting Li, Yingjie Chen, Yan Xue, Wei Liu, Yue Yuan, Simian Chen, Di Lu, Yixin Ren, Hao Wang, Fengling Cao, Caisheng Wu, Binbin Chen, Xueqin Chen","doi":"10.1016/j.jep.2025.120648","DOIUrl":null,"url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Perimenopause is a transitional period in women marked by hormonal fluctuations, often resulting in symptoms such as hot flashes and mood disturbances. According to traditional Chinese medicine, these symptoms are linked to liver stagnation and kidney deficiency, and ChaiHu ShuGan San (CSS), a classical multi-herbal formulation, has been traditionally used to alleviate mood-related symptoms and modulate endocrine function in women during the perimenopausal transition, but the underlying mechanisms and active compounds remain unclear.</p><p><strong>Aim of the study: </strong>This study aims to explore the active substances and potential mechanisms of CSS in treating PMS through steroid hormone metabolic pathways and in vivo exposure profiles.</p><p><strong>Materials and methods: </strong>A perimenopausal rat model was induced via ovariectomy. LC-MS/MS was employed to establish CSS metabolites profile and the TMAO (trimethylamine-N-oxide) level in rat plasma. High-exposure compounds underwent molecular docking and network pharmacology to explore interactions with steroid metabolism pathways. Biochemical markers HPA axis hormones (in plasma), IL-10 (in plasma) and FMO3 (flavin-containing monooxygenase 3, in rat liver and serum) levels were measured. The Cellular Thermal Shift Assay (CETSA) was used to provide in vitro validation of compounds binding to FMO3.</p><p><strong>Results: </strong>CSS treatment was shown to regulate abnormal hormone levels, reduce triglycerides and cholesterol, and increase IL-10 levels, alleviating PMS symptoms in rats. LC-MS/MS identified liquiritigenin, isosakuranetin, and hesperetin as high-exposure components. Network pharmacology and molecular docking suggest that these three flavonoids interact with the FMO3 enzyme. CETSA results showed that these flavonoids directly bind to the FMO3 protein. CSS decreased the FMO3 level in rat liver and serum.</p><p><strong>Conclusions: </strong>CSS alleviates PMS symptoms in rats and ameliorates the abnormal changes in disease-related biochemical markers. Inhibition of FMO3 pathways is involved in the effects of CSS. This study provides further pharmacological and chemical justifications for the use of CSS in PMS management.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120648"},"PeriodicalIF":5.4000,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exploring the effective substances and mechanisms of action of ChaiHu ShuGan San in treating perimenopausal syndrome based on in vivo exposure profiles and steroid hormone metabolic networks.\",\"authors\":\"Haiyan Lyu, Ting Li, Yingjie Chen, Yan Xue, Wei Liu, Yue Yuan, Simian Chen, Di Lu, Yixin Ren, Hao Wang, Fengling Cao, Caisheng Wu, Binbin Chen, Xueqin Chen\",\"doi\":\"10.1016/j.jep.2025.120648\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Ethnopharmacological relevance: </strong>Perimenopause is a transitional period in women marked by hormonal fluctuations, often resulting in symptoms such as hot flashes and mood disturbances. According to traditional Chinese medicine, these symptoms are linked to liver stagnation and kidney deficiency, and ChaiHu ShuGan San (CSS), a classical multi-herbal formulation, has been traditionally used to alleviate mood-related symptoms and modulate endocrine function in women during the perimenopausal transition, but the underlying mechanisms and active compounds remain unclear.</p><p><strong>Aim of the study: </strong>This study aims to explore the active substances and potential mechanisms of CSS in treating PMS through steroid hormone metabolic pathways and in vivo exposure profiles.</p><p><strong>Materials and methods: </strong>A perimenopausal rat model was induced via ovariectomy. LC-MS/MS was employed to establish CSS metabolites profile and the TMAO (trimethylamine-N-oxide) level in rat plasma. High-exposure compounds underwent molecular docking and network pharmacology to explore interactions with steroid metabolism pathways. Biochemical markers HPA axis hormones (in plasma), IL-10 (in plasma) and FMO3 (flavin-containing monooxygenase 3, in rat liver and serum) levels were measured. The Cellular Thermal Shift Assay (CETSA) was used to provide in vitro validation of compounds binding to FMO3.</p><p><strong>Results: </strong>CSS treatment was shown to regulate abnormal hormone levels, reduce triglycerides and cholesterol, and increase IL-10 levels, alleviating PMS symptoms in rats. LC-MS/MS identified liquiritigenin, isosakuranetin, and hesperetin as high-exposure components. Network pharmacology and molecular docking suggest that these three flavonoids interact with the FMO3 enzyme. CETSA results showed that these flavonoids directly bind to the FMO3 protein. CSS decreased the FMO3 level in rat liver and serum.</p><p><strong>Conclusions: </strong>CSS alleviates PMS symptoms in rats and ameliorates the abnormal changes in disease-related biochemical markers. Inhibition of FMO3 pathways is involved in the effects of CSS. This study provides further pharmacological and chemical justifications for the use of CSS in PMS management.</p>\",\"PeriodicalId\":15761,\"journal\":{\"name\":\"Journal of ethnopharmacology\",\"volume\":\" \",\"pages\":\"120648\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-09-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of ethnopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jep.2025.120648\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of ethnopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jep.2025.120648","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
民族药理学相关性：围绝经期是妇女的一个过渡时期，以荷尔蒙波动为特征，通常导致潮热和情绪紊乱等症状。根据中医的说法，这些症状与肝郁和肾虚有关，柴胡疏肝散（CSS）是一种经典的多草药配方，传统上用于缓解围绝经期妇女的情绪相关症状和调节内分泌功能，但其潜在机制和活性成分尚不清楚。研究目的：本研究旨在通过类固醇激素代谢途径和体内暴露谱，探讨CSS治疗经前症候群的活性物质和潜在机制。材料与方法：采用切除卵巢法建立围绝经期大鼠模型。采用LC-MS/MS建立大鼠血浆中CSS代谢物谱和TMAO（三甲胺- n -氧化物）水平。高暴露化合物通过分子对接和网络药理学来探索与类固醇代谢途径的相互作用。测定生化指标HPA轴激素（血浆）、IL-10（血浆）和FMO3（含黄素单加氧酶3，肝脏和血清）水平。细胞热移测定（CETSA）用于提供与FMO3结合的化合物的体外验证。结果：CSS治疗可调节大鼠异常激素水平，降低甘油三酯和胆固醇，提高IL-10水平，减轻经前症候群症状。LC-MS/MS鉴定出高暴露成分为清肾素、异紫花金苷和橙皮素。网络药理学和分子对接表明，这三种黄酮类化合物与FMO3酶相互作用。CETSA结果表明，这些类黄酮直接与FMO3蛋白结合。CSS降低了大鼠肝脏和血清中FMO3的水平。结论：CSS可减轻大鼠经前症候群症状，改善疾病相关生化指标的异常变化。FMO3通路的抑制参与了CSS的作用。本研究为CSS在经前症候群治疗中的应用提供了进一步的药理学和化学依据。
Exploring the effective substances and mechanisms of action of ChaiHu ShuGan San in treating perimenopausal syndrome based on in vivo exposure profiles and steroid hormone metabolic networks.
Ethnopharmacological relevance: Perimenopause is a transitional period in women marked by hormonal fluctuations, often resulting in symptoms such as hot flashes and mood disturbances. According to traditional Chinese medicine, these symptoms are linked to liver stagnation and kidney deficiency, and ChaiHu ShuGan San (CSS), a classical multi-herbal formulation, has been traditionally used to alleviate mood-related symptoms and modulate endocrine function in women during the perimenopausal transition, but the underlying mechanisms and active compounds remain unclear.
Aim of the study: This study aims to explore the active substances and potential mechanisms of CSS in treating PMS through steroid hormone metabolic pathways and in vivo exposure profiles.
Materials and methods: A perimenopausal rat model was induced via ovariectomy. LC-MS/MS was employed to establish CSS metabolites profile and the TMAO (trimethylamine-N-oxide) level in rat plasma. High-exposure compounds underwent molecular docking and network pharmacology to explore interactions with steroid metabolism pathways. Biochemical markers HPA axis hormones (in plasma), IL-10 (in plasma) and FMO3 (flavin-containing monooxygenase 3, in rat liver and serum) levels were measured. The Cellular Thermal Shift Assay (CETSA) was used to provide in vitro validation of compounds binding to FMO3.
Results: CSS treatment was shown to regulate abnormal hormone levels, reduce triglycerides and cholesterol, and increase IL-10 levels, alleviating PMS symptoms in rats. LC-MS/MS identified liquiritigenin, isosakuranetin, and hesperetin as high-exposure components. Network pharmacology and molecular docking suggest that these three flavonoids interact with the FMO3 enzyme. CETSA results showed that these flavonoids directly bind to the FMO3 protein. CSS decreased the FMO3 level in rat liver and serum.
Conclusions: CSS alleviates PMS symptoms in rats and ameliorates the abnormal changes in disease-related biochemical markers. Inhibition of FMO3 pathways is involved in the effects of CSS. This study provides further pharmacological and chemical justifications for the use of CSS in PMS management.
期刊介绍：
The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.
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