Lei TAO , Renjie DOU , Xueming CHEN , Yu CAO , Zhen DAI , Ziyan HU , Zhi MA , Xiaoming GE , Ling ZHANG , Xiaoping WANG
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In this study, we investigated the molecular mechanisms by which oroxyloside mitigates dextran sulfate sodium (DSS)-induced colitis. We examined the effects of oroxyloside on ROS-mediated ER stress in colitis, including the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, and CHOP, which are associated with ER stress. The beneficial impact of oroxyloside was reversed by the PPARγ antagonist GW9662 (1 mg·kg<sup>−1</sup>, i.v.) <em>in vivo</em>. Furthermore, oroxyloside decreased pro-inflammatory cytokines and ROS production in both bone marrow-derived macrophages (BMDM) and the mouse macrophage cell line RAW 264.7. However, PPARγ siRNA transfection blocked the anti-inflammatory effect of oroxyloside and even abolished ROS generation and ER stress activation inhibited by oroxyloside <em>in vitro</em>. In conclusion, our study demonstrates that oroxyloside ameliorates DSS-induced colitis by inhibiting ER stress <em>via</em> PPARγ activation, suggesting that oroxyloside might be a promising effective agent for IBD.</p></div>","PeriodicalId":10002,"journal":{"name":"Chinese Journal of Natural Medicines","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Oroxyloside protects against dextran sulfate sodium-induced colitis by inhibiting ER stress via PPARγ activation\",\"authors\":\"Lei TAO , Renjie DOU , Xueming CHEN , Yu CAO , Zhen DAI , Ziyan HU , Zhi MA , Xiaoming GE , Ling ZHANG , Xiaoping WANG\",\"doi\":\"10.1016/S1875-5364(24)60615-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), may result from immune system dysfunction, leading to the sustained overproduction of reactive oxygen species (ROS) and subsequent cellular oxidative stress damage. Recent studies have identified both peroxisome proliferator-activated receptor-γ (PPARγ) and endoplasmic reticulum (ER) stress as critical targets for the treatment of IBD. Oroxyloside (C<sub>22</sub>H<sub>20</sub>O<sub>11</sub>), derived from the root of <em>Scutellaria</em> <em>baicalensis</em> Georgi, has traditionally been used in treating inflammatory diseases. In this study, we investigated the molecular mechanisms by which oroxyloside mitigates dextran sulfate sodium (DSS)-induced colitis. We examined the effects of oroxyloside on ROS-mediated ER stress in colitis, including the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, and CHOP, which are associated with ER stress. The beneficial impact of oroxyloside was reversed by the PPARγ antagonist GW9662 (1 mg·kg<sup>−1</sup>, i.v.) <em>in vivo</em>. Furthermore, oroxyloside decreased pro-inflammatory cytokines and ROS production in both bone marrow-derived macrophages (BMDM) and the mouse macrophage cell line RAW 264.7. 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引用次数: 0
摘要
溃疡性结肠炎(UC)是炎症性肠病(IBD)的一种常见形式,可能是由于免疫系统功能紊乱导致活性氧(ROS)持续过量产生,进而引起细胞氧化应激损伤。最近的研究发现,过氧化物酶体增殖激活受体-γ(PPARγ)和内质网(ER)应激是治疗 IBD 的关键靶点。从黄芩(Scutellaria baicalensis Georgi)根中提取的木犀草苷(Oroxyloside,C22H20O11)历来被用于治疗炎症性疾病。在这项研究中,我们探讨了木犀草苷缓解右旋糖酐硫酸钠(DSS)诱导的结肠炎的分子机制。我们研究了氧氟沙星苷对 ROS 介导的结肠炎 ER 应激的影响,包括与 ER 应激相关的 GRP78、p-PERK、p-eIF2α、ATF4 和 CHOP 的蛋白表达。在体内,PPARγ拮抗剂GW9662(1 mg-kg-1, i.v.)逆转了氧代木糖苷的有益影响。此外,氧代木糖苷还能减少骨髓源性巨噬细胞(BMDM)和小鼠巨噬细胞系 RAW 264.7 中的促炎细胞因子和 ROS 的产生。然而,PPARγ siRNA 转染阻断了氧氟沙星苷的抗炎作用,甚至取消了氧氟沙星苷在体外抑制 ROS 生成和 ER 应激活化的作用。总之,我们的研究表明,氧代木糖苷可通过 PPARγ 激活抑制 ER 应激,从而改善 DSS 诱导的结肠炎,这表明氧代木糖苷可能是一种治疗 IBD 的有效药物。
Oroxyloside protects against dextran sulfate sodium-induced colitis by inhibiting ER stress via PPARγ activation
Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), may result from immune system dysfunction, leading to the sustained overproduction of reactive oxygen species (ROS) and subsequent cellular oxidative stress damage. Recent studies have identified both peroxisome proliferator-activated receptor-γ (PPARγ) and endoplasmic reticulum (ER) stress as critical targets for the treatment of IBD. Oroxyloside (C22H20O11), derived from the root of Scutellariabaicalensis Georgi, has traditionally been used in treating inflammatory diseases. In this study, we investigated the molecular mechanisms by which oroxyloside mitigates dextran sulfate sodium (DSS)-induced colitis. We examined the effects of oroxyloside on ROS-mediated ER stress in colitis, including the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, and CHOP, which are associated with ER stress. The beneficial impact of oroxyloside was reversed by the PPARγ antagonist GW9662 (1 mg·kg−1, i.v.) in vivo. Furthermore, oroxyloside decreased pro-inflammatory cytokines and ROS production in both bone marrow-derived macrophages (BMDM) and the mouse macrophage cell line RAW 264.7. However, PPARγ siRNA transfection blocked the anti-inflammatory effect of oroxyloside and even abolished ROS generation and ER stress activation inhibited by oroxyloside in vitro. In conclusion, our study demonstrates that oroxyloside ameliorates DSS-induced colitis by inhibiting ER stress via PPARγ activation, suggesting that oroxyloside might be a promising effective agent for IBD.
期刊介绍:
The Chinese Journal of Natural Medicines (CJNM), founded and sponsored in May 2003 by China Pharmaceutical University and the Chinese Pharmaceutical Association, is devoted to communication among pharmaceutical and medical scientists interested in the advancement of Traditional Chinese Medicines (TCM). CJNM publishes articles relating to a broad spectrum of bioactive natural products, leading compounds and medicines derived from Traditional Chinese Medicines (TCM).
Topics covered by the journal are: Resources of Traditional Chinese Medicines; Interaction and complexity of prescription; Natural Products Chemistry (including structure modification, semi-and total synthesis, bio-transformation); Pharmacology of natural products and prescription (including pharmacokinetics and toxicology); Pharmaceutics and Analytical Methods of natural products.