Chicoric acid exerts therapeutic effects in DSS-induced ulcerative colitis by targeting the USP9X/IGF2BP2 axis.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Wei Chen, Yunan Shan, Meng Wang, Rui Liang, Ri Sa
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Abstract

Background and purpose: Chicoric acid, a hydroxycinnamic acid, exhibits anti-inflammation activities. However, the specific mechanisms underlying the effects of chicoric acid on dextran sulfate sodium (DSS)-induced colitis remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the protective effects of chicoric acid in DSS-induced colitis.

Experimental approach: Mice with DSS-induced colitis (UC mice) were treated for a week with chicoric acid. Symptoms of colitis, colonic pathology, inflammation-related indicators, and intestinal mucosal barrier function were evaluated. RNA sequencing was performed on colon tissues to obtain differentially expressed genes. The deubiquitinating enzyme USP9X was selected, and the inhibitory and targeting effects of chicoric acid on USP9X were subsequently determined. In vivo and in vitro, DSS-induced colitis was treated with USP9X inhibitors WP1130 and EOAI3402143. Ubiquitination label-free quantitative proteomic analysis was performed to identify protein peptides that may undergo de-ubiquitination by USP9X. Co-immunoprecipitation (Co-IP), immunohistochemistry and western blotting were used to validate in vivo and in vitro results.

Key results: Chicoric acid significantly alleviated clinical activity and histological changes, inhibited pro-inflammatory cytokine production and improved integrity of the intestinal barrier in UC mice. Moreover, chicoric acid suppressed USP9X expression in colonic tissues from UC mice. Furthermore, USP9X contributed to promoting the onset of UC and that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was deubiquitinated by USP9X.

Conclusion and implications: Chicoric acid ameliorated DSS-induced colitis by targeting the USP9X/IGF2BP2 axis, indicating that targeting the USP9X/IGF2BP2 axis presents a promising and innovative therapeutic approach for the treatment of UC.

菊苣酸通过靶向USP9X/IGF2BP2轴对DSS诱导的溃疡性结肠炎产生治疗效果。
背景和目的:菊苣酸是一种羟基肉桂酸,具有抗炎活性。然而,菊苣酸对葡聚糖硫酸钠(DSS)诱导的结肠炎的具体作用机制仍不清楚。在此,我们旨在阐明菊苣酸对右旋糖酐硫酸钠(DSS)诱导的结肠炎具有保护作用的分子机制:实验方法:用菊苣酸治疗 DSS 诱导的结肠炎小鼠(UC 小鼠)一周。实验方法:用菊苣酸对DSS诱导的结肠炎小鼠(UC小鼠)治疗一周,评估结肠炎症状、结肠病理学、炎症相关指标和肠粘膜屏障功能。对结肠组织进行了 RNA 测序,以获得差异表达基因。选择了去泛素化酶 USP9X,随后测定了菊苣酸对 USP9X 的抑制和靶向作用。在体内和体外,用 USP9X 抑制剂 WP1130 和 EOAI3402143 处理 DSS 诱导的结肠炎。进行了无泛素化标记的定量蛋白质组分析,以确定可能被 USP9X 去泛素化的蛋白质肽段。共免疫沉淀(Co-IP)、免疫组织化学和免疫印迹被用来验证体内和体外结果:主要结果:菊苣酸能明显减轻 UC 小鼠的临床活动和组织学变化,抑制促炎细胞因子的产生,改善肠道屏障的完整性。此外,菊苣酸还抑制了 USP9X 在 UC 小鼠结肠组织中的表达。此外,USP9X有助于促进UC的发病,胰岛素样生长因子2 mRNA结合蛋白2(IGF2BP2)被USP9X去泛素化:菊苣酸通过靶向USP9X/IGF2BP2轴改善了DSS诱导的结肠炎,这表明靶向USP9X/IGF2BP2轴是治疗UC的一种前景广阔的创新治疗方法。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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