PMID- 37142141 OWN - NLM STAT- MEDLINE DCOM- 20230522 LR - 20230522 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 313 DP - 2023 Sep 15 TI - Quercetin serves as the major component of Xiang-lian Pill to ameliorate ulcerative colitis via tipping the balance of STAT1/PPARgamma and dictating the alternative activation of macrophage. PG - 116557 LID - S0378-8741(23)00425-7 [pii] LID - 10.1016/j.jep.2023.116557 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese herbal formula, Xiang-lian Pill (XLP), is commonly prescribed for ulcerative colitis (UC) patients to relieve their clinical symptom. Nonetheless, the underlying cellular and molecular mechanisms of XLP's anti-UC effect remain incompletely understood. AIM OF THE STUDY: To evaluate the therapeutic effect and elucidate the possible working mechanisms of XLP in UC treatment. The major active component of XLP was also characterized. MATERIALS AND METHODS: Colitis was induced in C57BL/6 mice with 3% dextran sulfate sodium (DSS) dissolved in drinking water for 7 consecutive days. The UC mice were grouped and treated with XLP (3640 mg/kg) or vehicle orally during the procedure of DSS induction. Mouse body weight, disease activity index (DAI) score and colon length were recorded. Histopathological changes and inflammatory cell infiltration were evaluated by pathological staining and flow cytometric analysis (FACS). Network pharmacology, bioinformatic analysis, widely targeted and targeted metabolomics analysis were performed to screen the potential effective ingredients and key targets. Bone marrow derived macrophages (BMDMs), peripheral blood mononuclear cells (PBMCs), RAW264.7 and THP-1 cells were used to dissect the anti-inflammatory effect of XLP. RESULTS: Oral administration of XLP ameliorated DSS induced mouse colitis, as evidenced by reduced DAI and colonic inflammatory destruction. FACS results demonstrated that XLP treatment effectively restored immune tolerance in colon, inhibited the generation of monocyte derived macrophages and skewed macrophage polarization into M2 phenotype. Network pharmacology analysis suggested that innate effector modules related to macrophage activation comprise the major targets of XLP, and the counter-regulatory STAT1/PPARgamma signaling possibly serves as the critical downstream pathway. Subsequent experiments unveiled an imbalance of STAT1/PPARgamma signaling in monocytes derived from UC patients, and validated that XLP suppressed LPS/IFN-gamma induced macrophage activation (STAT1 mediated) but facilitated IL-4 induced macrophage M2 polarization (PPARgamma dependent). Meanwhile, our data showed that quercetin served as the major component of XLP to recapitulate the regulatory effect on macrophages. CONCLUSION: Our findings revealed that quercetin serves as the major component of XLP that regulates macrophage alternative activation via tipping the balance of STAT1/PPARgamma, which provides a mechanistic explanation for the therapeutic effect of XLP in UC treatment. CI - Copyright (c) 2023. Published by Elsevier B.V. FAU - Zhou, Hai-Feng AU - Zhou HF AD - Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: 309624203@qq.com. FAU - Yang, Chao AU - Yang C AD - Department of Geratology, Hubei Provincial Hospital of Integrated Chinese & Western Medicine, Wuhan, 430015, China. Electronic address: ychbtcm@163.com. FAU - Li, Jun-Yi AU - Li JY AD - Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: lijunyi19901990@163.com. FAU - He, Yu-Yao AU - He YY AD - Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: 1747390551@qq.com. FAU - Huang, Yun AU - Huang Y AD - Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China. Electronic address: 924541899@qq.com. FAU - Qin, Ren-Jie AU - Qin RJ AD - Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: 547045325@qq.com. FAU - Zhou, Qiao-Li AU - Zhou QL AD - Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: 1434942106@qq.com. FAU - Sun, Fei AU - Sun F AD - The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, 430030, China. Electronic address: phil_sunfei@163.com. FAU - Hu, De-Sheng AU - Hu DS AD - Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: desheng.hu@hust.edu.cn. FAU - Yang, Jia AU - Yang J AD - Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: 2017XH0142@hust.edu.cn. LA - eng PT - Journal Article DEP - 20230502 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (PPAR gamma) RN - 9IKM0I5T1E (Quercetin) RN - 9042-14-2 (Dextran Sulfate) RN - 0 (Stat1 protein, mouse) RN - 0 (STAT1 Transcription Factor) SB - IM MH - Animals MH - Mice MH - *Colitis, Ulcerative/chemically induced/drug therapy/metabolism MH - PPAR gamma/metabolism MH - Quercetin/pharmacology/therapeutic use/metabolism MH - Leukocytes, Mononuclear/metabolism MH - Mice, Inbred C57BL MH - Colon MH - *Colitis/drug therapy MH - Macrophages MH - Dextran Sulfate/toxicity MH - Disease Models, Animal MH - STAT1 Transcription Factor/metabolism OTO - NOTNLM OT - Macrophage OT - Quercetin OT - Ulcerative colitis (UC) OT - Xiang-lian pill (XLP) COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/05/05 00:42 MHDA- 2023/05/22 06:42 CRDT- 2023/05/04 19:27 PHST- 2022/11/28 00:00 [received] PHST- 2023/04/21 00:00 [revised] PHST- 2023/04/24 00:00 [accepted] PHST- 2023/05/22 06:42 [medline] PHST- 2023/05/05 00:42 [pubmed] PHST- 2023/05/04 19:27 [entrez] AID - S0378-8741(23)00425-7 [pii] AID - 10.1016/j.jep.2023.116557 [doi] PST - ppublish SO - J Ethnopharmacol. 2023 Sep 15;313:116557. doi: 10.1016/j.jep.2023.116557. Epub 2023 May 2.