摘要
本研究整合组方配伍分析、生物信息学和代谢组学探讨肉桂-熟地黄(Cinnamomi Cortex-Rehmanniae Radix,CR)防治骨质疏松(osteoporosis,OP)的分子作用机制。建立大鼠OP模型,进行Micro-CT指标和病理切片综合评价,结果显示与模型组相比,CR干预后的骨密度、骨体积分数等指标显著回调(P<0.05),骨小梁排列成网状。UHPLC-Q-TOF/MS研究结果主要涉及氨基酸代谢、脂类代谢及雌激素代谢途径。整合生物信息学和代谢组学分析,最终发现:(1)肉桂酸、肉桂酸乙酯抑制TNF、IL-1β、IL-13等炎性因子,进而防治OP;(2)CR多个活性成分靶向作用于ESR2、PPARG、CYP19A1、GABRA1等靶点,调节cAMP的合成、AMPK信号通路及脂类代谢,从而调节雌激素水平来防治OP;(3)油酸、花生四烯酸等作用于AR、VDR等靶点,调控HIF-1、AGE-RAGE信号通路,从而调控成骨、破骨细胞,影响钙磷吸收,维持骨稳态。本研究从炎症因子、雌激素及骨稳态多向调控的角度阐明了CR防治OP的分子机制,为CR的临床应用及复方开发提供理论依据。本实验符合动物实验伦理学标准且得到陕西中医药大学实验动物伦理委员会批准(批号:SUCMDL20210309002)。
In this study,the molecular mechanism of Cinnamomi Cortex-Rehmanniae Radix(CR) in the prevention and treatment of osteoporosis(OP) was investigated by integrating compatibility analysis of compound,bioinformatics and metabolomics.The rat OP models were established,and the Micro-CT indexes and pathological sections were comprehensively evaluated.The results showed that compared with the model group,the indexes such as bone mineral density(BMD) and bone volume/tissue volume(BV/TV) were significantly increased after CR treatment(P < 0.05),and the bone trabeculae were arranged into mesh.The results of UHPLC-Q-TOF/MS mainly involved amino acid metabolism,lipid metabolism and estrogen metabolism pathways.Integrating bioinformatics and metabolomics analysis,it was finally found that:(1) cinnamic acid and ethylcinnamate inhibit inflammatory factors such as TNF,IL-1β,and IL-13,thereby preventing and treating OP;(2) multiple active ingredients of CR target ESR2,PPARG,and CYP19A1,GABRA1 and other targets,regulate cAMP synthesis,AMPK signaling pathway and lipid metabolism,thereby regulating estrogen levels to prevent and treat OP;(3) oleic acid,arachic acid,etc.act on AR,VDR and other targets,and regulate HIF-1 signaling pathway and AGE-RAGE signaling pathway,thereby regulating osteoblasts and osteoclasts,and affecting calcium and phosphorus absorption to maintain bone homeostasis.This study clarified the molecular mechanism of CR in preventing and treating OP from the perspective of multi-directional regulation of inflammatory factors,estrogen and bone homeostasis,and provided theoretical basis for the clinical application of CR and the development of compound.This experiment complied with the ethical standards of animal experiments and was approved by the Animal Ethics Committee of Shaanxi University of Chinese Medicine(No.SUCMDL20210309002).
作者
平凡
朱琳
沈霞
韩奇峰
刘莹
颜永刚
张岗
彭亮
陈艳琰
PING Fan;ZHU Lin;SHEN Xia;HAN Qi-feng;LIU Ying;YAN Yong-gang;ZHANG Gang;PENG Liang;CHEN Yan-yan(College of Pharmacy,Shaanxi University of Chinese Medicine,Xixian New Area 712046,China;Shaanxi Qinling Application Development and Engineering Center of Chinese Herbal Medicine,Xixian New Area 712046,China)
出处
《药学学报》
CAS
CSCD
北大核心
2022年第12期3644-3652,共9页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81973592,81974525)
陕西省自然科学基础研究计划项目(2022JM-538)
陕西中医药大学“秦药”品质评价及资源开发学科创新团队项目(2019-QN01)
陕西高校青年创新团队(2020)。
关键词
肉桂-熟地黄
骨质疏松
中药配伍
代谢组学
骨稳态
Cinnamomi Cortex-Rehmanniae Radix
osteoporosis
Chinese medicine compatibility
metabonomics
bone homeostasis
