Modified Zuo Gui Wan Ameliorates Ovariectomy-Induced Osteoporosis in Rats by Regulating the SCFA-GPR41-p38MAPK Signaling Pathway.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-12-27 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S482965

Changheng Song, Qiqi Yan, Yujie Ma, Pei Li, Ying Yang, Yuhan Wang, Wenjie Li, Xinyu Wan, Yubo Li, Ruyuan Zhu, Haixia Liu, Zhiguo Zhang

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Abstract

Objective: Modified Zuo Gui Wan (MZGW) was a combination of Zuo Gui Wan and red yeast rice used for treating osteoporosis (OP), but its mechanism remains unclear. We aimed to validate the anti-OP effect of MZGW and explore its underlying mechanism.

Methods: An ovariectomy (OVX) rat model in vivo and a RANKL-induced osteoclasts (OCs) model in vitro were established. Key active ingredients in MZGW high dose (MZGW-H) group were detected by UPLC-MS/MS. Micro-CT scans and histomorphology analysis were performed in OVX rats. 16S rRNA gene sequencing was performed to investigate the relationship between the anti-OP effect of MZGW-H and intestinal flora. CCK-8 assay was applied to examine the optimal concentration of Modified Zuo Gui Wan drug serum (MZGW-DS) on osteoclasts. The qRT-PCR and Western blotting were utilized to explore the potential anti-OP pathway of MZGW, namely the SCFA-GPR41-p38MAPK signaling pathway. GPR41 was knocked down to further reverse to verify whether the pathway was the key pathway for MZGW-DS to exert its inhibitory effect on osteoclasts.

Results: The three main blood components, Ferulic acid, L-Ascorbic acid and Riboflavin, were examined mainly by UPLC-MS/MS. 16S rRNA gene sequencing showed that MZGW-H changed the metabolism of SCFAs. In vivo studies verified that MZGW-H ameliorated microstructure damage, improved histological changes and reduced TRAP, BALP, and BGP in OVX rats by regulating the SCFA-GPR41-p38MAPK signaling pathway. CCK-8 revealed that 5% MZGW-DS group was the most optimal concentration of MZGW-DS to inhibit osteoclast differentiation. In vitro, MZGW-DS was better than peripheral blood concentration of SCFAs in inhibiting osteoclasts. After the knockout of GPR41, MZGW-DS could not inhibit the expression of osteoclast-related protein (CTSK and NFATc1) via SCFA-GPR41-p38MAPK signaling pathway.

Conclusion: MZGW-H effectively ameliorates OVX-induced osteoporosis partially achieved by increasing SCFAs metabolism and modulating the SCFA-GPR41-p38MAPK signaling pathway.

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左归丸通过调节SCFA-GPR41-p38MAPK信号通路改善大鼠卵巢切除所致骨质疏松症

目的：佐归丸加红曲米治疗骨质疏松症（OP），其作用机制尚不清楚。我们旨在验证MZGW的抗op作用，并探讨其潜在机制。方法：建立卵巢切除（OVX）大鼠体内模型和rankl诱导的破骨细胞（OCs）体外模型。采用UPLC-MS/MS法对MZGW高剂量（MZGW- h）组主要有效成分进行检测。对OVX大鼠进行显微ct扫描和组织形态学分析。通过16S rRNA基因测序研究MZGW-H抗op作用与肠道菌群的关系。采用CCK-8法考察左归丸药血清（MZGW-DS）对破骨细胞的作用。利用qRT-PCR和Western blotting技术探索MZGW潜在的抗op通路，即SCFA-GPR41-p38MAPK信号通路。我们敲低GPR41进一步反向验证该通路是否为MZGW-DS发挥破骨细胞抑制作用的关键通路。结果：阿魏酸、l -抗坏血酸和核黄素3种主要血液成分主要通过UPLC-MS/MS检测。16S rRNA基因测序显示MZGW-H改变了SCFAs的代谢。体内研究证实，MZGW-H通过调节SCFA-GPR41-p38MAPK信号通路，改善OVX大鼠微结构损伤，改善组织学改变，降低TRAP、BALP和BGP。CCK-8结果显示，5% MZGW-DS组是抑制破骨细胞分化的最佳浓度。在体外，MZGW-DS对破骨细胞的抑制作用优于外周血SCFAs浓度。敲除GPR41后，MZGW-DS不能通过SCFA-GPR41-p38MAPK信号通路抑制破骨细胞相关蛋白（CTSK和NFATc1）的表达。结论：MZGW-H通过增加scfa代谢和调节SCFA-GPR41-p38MAPK信号通路，有效改善ovx所致骨质疏松症。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.