Apigenin ameliorates inflamed ulcerative colitis by regulating mast cell degranulation via the PAMP-MRGPRX2 feedback loop

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-03-01 DOI:10.1016/j.phymed.2025.156564

Yihan Huang , Na Wang , Xiaolan Ji , Shiqiong Luo , Ling Gong , Chenrui Zhao , Guodong Zheng , Rui Liu , Tao Zhang

{"title":"Apigenin ameliorates inflamed ulcerative colitis by regulating mast cell degranulation via the PAMP-MRGPRX2 feedback loop","authors":"Yihan Huang , Na Wang , Xiaolan Ji , Shiqiong Luo , Ling Gong , Chenrui Zhao , Guodong Zheng , Rui Liu , Tao Zhang","doi":"10.1016/j.phymed.2025.156564","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><div>The aim of this study was to investigate the therapeutic effect of API on UC via the regulation of PAMP-MRGPRX2-mediated mast cells (MCs) degranulation.</div></div><div><h3>Background</h3><div>The pro-inflammatory positive feedback loop mediated by Mas-related G-protein-coupled receptor X2 (MRGPRX2) and its endogenous ligand, PAMP-12, is associated with ulcerative colitis (UC) progression. However, the therapeutic strategies that target MRGPRX2 in the treatment of UC are less reported. Apigenin (API), a natural flavonoid, can relieve inflammation.</div></div><div><h3>Method</h3><div>A dextran sodium sulfate (DSS)-induced mouse UC model was used to elucidate the therapeutic effects of API. Animal behavior assessment, serological assays, and histological analysis were performed in wild-type (WT) and MC MrgprB2-conditional knockout (CKO) mouse model. mRNA sequencing analysis, PCR, ELISA, and western blotting were performed <em>in vitro</em> and <em>in vivo</em> to elucidate the mechanism underlying the effect of API by a PAMP-12 triggered MC degranulation model.</div></div><div><h3>Results</h3><div>MC degranulation via MrgprB2 was critical for the persistence of inflammation in colitis. API attenuated colonic tissue damage, splenomegaly, and myeloperoxidase (MPO) activity in the colonic tissues. It also ameliorated colonic crypt structure damage and inflammatory cell infiltration. Moreover, API suppressed MCs degranulation, and the level of carboxypeptidases A3 (CPA3), in DSS-induced colitis, thereby blocking the pro-inflammatory positive feedback loop induced by PAMP-MrgprB2. Lastly, API effectively inhibited PAMP-12-triggered mast cell degranulation by regulating Akt1/XBP-1S/CHOP/TXNIP and NF-κB/IL-1β signaling pathways.</div></div><div><h3>Conclusion</h3><div>API alleviates inflammatory symptoms in UC by suppressing PAMP-MRGPRX2/B2 mediated MC sustained degranulation feedback loop.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156564"},"PeriodicalIF":6.7000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0944711325002041","RegionNum":1,"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

Abstract

Purpose

The aim of this study was to investigate the therapeutic effect of API on UC via the regulation of PAMP-MRGPRX2-mediated mast cells (MCs) degranulation.

Background

The pro-inflammatory positive feedback loop mediated by Mas-related G-protein-coupled receptor X2 (MRGPRX2) and its endogenous ligand, PAMP-12, is associated with ulcerative colitis (UC) progression. However, the therapeutic strategies that target MRGPRX2 in the treatment of UC are less reported. Apigenin (API), a natural flavonoid, can relieve inflammation.

Method

A dextran sodium sulfate (DSS)-induced mouse UC model was used to elucidate the therapeutic effects of API. Animal behavior assessment, serological assays, and histological analysis were performed in wild-type (WT) and MC MrgprB2-conditional knockout (CKO) mouse model. mRNA sequencing analysis, PCR, ELISA, and western blotting were performed in vitro and in vivo to elucidate the mechanism underlying the effect of API by a PAMP-12 triggered MC degranulation model.

Results

MC degranulation via MrgprB2 was critical for the persistence of inflammation in colitis. API attenuated colonic tissue damage, splenomegaly, and myeloperoxidase (MPO) activity in the colonic tissues. It also ameliorated colonic crypt structure damage and inflammatory cell infiltration. Moreover, API suppressed MCs degranulation, and the level of carboxypeptidases A3 (CPA3), in DSS-induced colitis, thereby blocking the pro-inflammatory positive feedback loop induced by PAMP-MrgprB2. Lastly, API effectively inhibited PAMP-12-triggered mast cell degranulation by regulating Akt1/XBP-1S/CHOP/TXNIP and NF-κB/IL-1β signaling pathways.

Conclusion

API alleviates inflammatory symptoms in UC by suppressing PAMP-MRGPRX2/B2 mediated MC sustained degranulation feedback loop.

Abstract Image

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.